Edwin H Kolodny, M.D.

Biosensors for Brain Trauma and Dual Laser Doppler Flowmetry: Enoxaparin Simultaneously Reduces Stroke-Induced Dopamine and Blood Flow while Enhancing Serotonin and Blood Flow in Motor Neurons of Brain, In Vivo
Broderick, Patricia A.; Kolodny, Edwin H.
2011 JAN ;11(1):138-161, Sensors (Basel, Switzerland)
Neuromolecular Imaging (NMI) based on adsorptive electrochemistry, combined with Dual Laser Doppler Flowmetry (LDF) is presented herein to investigate the brain neurochemistry affected by enoxaparin (Lovenox (R)), an antiplatelet/antithrombotic medication for stroke victims. NMI with miniature biosensors enables neurotransmitter and neuropeptide (NT) imaging; each NT is imaged with a response time in milliseconds. A semiderivative electronic reduction circuit images several NT's selectively and separately within a response time of minutes. Spatial resolution of NMI biosensors is in the range of nanomicrons and electrochemically-induced current ranges are in pico- and nano-amperes. Simultaneously with NMI, the LDF technology presented herein operates on line by illuminating the living brain, in this example, in dorso-striatal neuroanatomic substrates via a laser sensor with low power laser light containing optical fiber light guides. NMI biotechnology with BRODERICK PROBE (R) biosensors has a distinct advantage over conventional electrochemical methodologies both in novelty of biosensor formulations and on-line imaging capabilities in the biosensor field. NMI with unique biocompatible biosensors precisely images NT in the body, blood and brain of animals and humans using characteristic experimentally derived half-wave potentials driven by oxidative electron transfer. Enoxaparin is a first line clinical treatment prescribed to halt the progression of acute ischemic stroke (AIS). In the present studies, BRODERICK PROBE (R) laurate biosensors and LDF laser sensors are placed in dorsal striatum (DStr) dopaminergic motor neurons in basal ganglia of brain in living animals; basal ganglia influence movement disorders such as those correlated with AIS. The purpose of these studies is to understand what is happening in brain neurochemistry and cerebral blood perfusion after causal AIS by middle cerebral artery occlusion in vivo as well as to understand consequent enoxaparin and reperfusion effects actually while enoxaparin is inhibiting blood clots to alleviate AIS symptomatology. This research is directly correlated with the medical and clinical needs of stroke victims. The data are clinically relevant, not only to movement dysfunction but also to the depressive mood that stroke patients often endure. These are the first studies to image brain neurotransmitters while any stroke medications, such as anti-platelet/anti-thrombotic and/or anti-glycoprotein are working in organ systems to alleviate the debilitating consequences of brain trauma and stroke/brain attacks
— id: 124111, year: 2011, vol: 11, page: 138, stat: Journal Article,

An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay-Sachs or Sandhoff variants)
Clarke, Joe T R; Mahuran, Don J; Sathe, Swati; Kolodny, Edwin H; Rigat, Brigitte A; Raiman, Julian A; Tropak, Michael B
2011 Jan;102(1):6-12, Molecular genetics & metabolism
Late-onset GM2 gangliosidosis is an autosomal recessive, neurodegenerative, lysosomal storage disease, caused by deficiency of ss-hexosaminidase A (Hex A), resulting from mutations in the HEXA (Tay-Sachs variant) or the HEXB (Sandhoff variant) genes. The enzyme deficiency in many patients with juvenile or adult onset forms of the disease results from the production of an unstable protein, which becomes targeted for premature degradation by the quality control system of the smooth endoplasmic reticulum and is not transported to lysosomes. In vitro studies have shown that many mutations in either the alpha or beta subunit of Hex A can be partially rescued, i.e. enhanced levels of both enzyme protein and activity in lysosomes, following the growth of patient cells in the presence of the drug, pyrimethamine. The objectives of the present clinical trial were to establish the tolerability and efficacy of the treatment of late-onset GM2 gangliosidosis patients with escalating doses of pyrimethamine, to a maximum of 100 mg per day, administered orally in a single daily dose, over a 16-week period . The primary objective, tolerability, was assessed by regular clinical examinations, along with a panel of hematologic and biochemical studies. Although clinical efficacy could not be assessed in this short trial, treatment efficacy was evaluated by repeated measurements of leukocyte Hex A activity, expressed relative to the activity of lysosomal ss-glucuronidase. A total of 11 patients were enrolled, 8 males and 3 females, aged 23 to 50 years. One subject failed the initial screen, another was omitted from analysis because of the large number of protocol violations, and a third was withdrawn very early as a result of adverse events which were not drug-related. For the remaining 8 subjects, up to a 4-fold enhancement of Hex A activity at doses of 50 mg per day or less was observed. Additionally marked individual variations in the pharmacokinetics of the drug among the patients were noted. However, the study also found that significant side effects were experienced by most patients at or above 75 mg pyrimethamine per day. We concluded that pyrimethamine treatment enhances leukocyte Hex A activity in patients with late-onset GM2 gangliosidosis at doses lower than those associated with unacceptable side effects. Further plans are underway to extend these trials and to develop methods to assess clinical efficacy
— id: 126499, year: 2011, vol: 102, page: 6, stat: Journal Article,

Hippocampal atrophy as a surrogate of neuronal involvement in Fabry disease
Fellgiebel A; Wolf DO; Kolodny E; Muller MJ
2011 Sep 20;:?-? #, Journal of inherited metabolic disease
Cerebral micro- and macro-vasculopathy have been described in Fabry disease (FD). Neuronal globotriaosylceramide accumulation in selective cortical and brain stem areas including the hippocampus has been reported by autopsy studies in FD, but clinical surrogates as well as the clinical relevance of these findings have not been investigated so far. We measured the hippocampus volumes in a group of clinically affected patients with FD and correlated the findings with the cognitive performance of the patients. Hippocampal volumes were determined manually on T1-weighted MR-images of 25 FD patients (age 36.5 +/- 11.0 years) and 20 age-matched controls. Additionally, individual white matter (WM) and gray matter (GM) volumes were measured using brain segmentation analyses. After controlling for age, white matter lesion (WML) volume, and WM/GM-volumes hippocampal volumes were significantly decreased in FD. These findings were substantially more pronounced in a subgroup of men with FD. WM and WM/GM volumes, and memory function did not significantly differ between patients and controls. In patients with FD hippocampal volumes were neither significantly correlated to WML volume nor to WM or WM/GM volumes. Hippocampus atrophy was not driven by the WML or other brain tissue atrophy and seems to correlate with the neuronal involvement in FD. In this young to middle-aged Fabry cohort the hippocampus degeneration was functionally compensated without memory impairment. Longitudinal studies are needed to determine whether this degenerative component in FD will progress and, in concert with the individual WML-load, predict subsequent cognitive decline
— id: 141328, year: 2011, vol: , page: ?, stat: Journal Article,

Metronomic breathing shows altered parasympathetic baroreflex function in untreated Fabry patients and baroreflex improvement after enzyme replacement therapy
Hilz, Max J; Koehn, Julia; Kolodny, Edwin H; Brys, Miroslaw; Moeller, Sebastian; Stemper, Brigitte
2011 Dec;29(12):2387-2394, Journal of hypertension
OBJECTIVE: In untreated Fabry patients without overt autonomic dysfunction and normal baroreflex sensitivity (BRS) at rest, BRS is impaired during orthostatic, sympathetic challenge but normalizes after enzyme-replacement therapy (ERT) (Hilz et al., J Hypertens 2010; 28:1438-1448). This study evaluated BRS during parasympathetic challenge with six cycles per minute metronomic deep breathing (MDB) in Fabry patients before and after ERT. METHODS: In 22 Fabry patients (28 +/- 8years), we monitored RR-intervals (RRIs), SBP, and respiratory frequency during spontaneous breathing (spont_breath) and MDB, before and after 18 (11 patients) or 23 months (11 patients) of biweekly ERT (1.0 mg/kg agalsidase beta). We determined spectral powers of mainly sympathetic low-frequency (0.04-0.15 Hz) RRI fluctuations, parasympathetic high-frequency (0.15-0.5 Hz) RRI fluctuations, sympathetically mediated low-frequency powers of SBP and high-frequency powers of SBP. We calculated BRS (ms/mmHg) during spont_breath and MDB as low-frequency-high-frequency alpha index (coherence >0.5). We compared parameters during spont_breath and MDB within and between patients before and after ERT and 15 age-matched (27 +/- 5years) healthy men (RANOVA and posthoc analysis; significance: P < 0.05). RESULTS: During spont_breath and MDB, parameters were similar between groups. Within the three groups, RRIs were lower, whereas RRI low-frequency powers and SBP low-frequency powers were higher during MDB than during spont_breath. BRS was similar during MBD and spont_breath in untreated patients (P > 0.05), but increased significantly with MDB in patients after ERT (P = 0.048) and in controls (P = 0.035). CONCLUSION: In untreated Fabry patients, MDB uncovers impaired BRS. After 18 or 23 months of ERT, MDB-induced BRS increase is similar in Fabry patients and controls, demonstrating that ERT not only restores sympathetic but also parasympathetic baroreflex activation
— id: 141327, year: 2011, vol: 29, page: 2387, stat: Journal Article,

The enigma of the E326K mutation in acid beta-glucocerebrosidase
Horowitz, Mia; Pasmanik-Chor, Metsada; Ron, Idit; Kolodny, Edwin H
2011 Sep-Oct;104(1-2):35-38, Molecular genetics & metabolism
A large number of mutations, and several polymorphisms, have been characterized in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase, the activity of which is impaired in Gaucher disease. In this communication we summarize published and new data concerning biochemical characterization of the E326K amino acid change (1093G>A in the GBA1 cDNA) in tissue culture and its association with Parkinson disease, suggesting it is a disease causing mutation and not merely a polymorphism in the GBA gene
— id: 137970, year: 2011, vol: 104, page: 35, stat: Journal Article,

Pathology of GM2 gangliosidosis in Jacob sheep
Porter, B F; Lewis, B C; Edwards, J F; Alroy, J; Zeng, B J; Torres, P A; Bretzlaff, K N; Kolodny, E H
2011 Jul;48(4):807-813, Veterinary pathology
The G(M2) gangliosidoses are a group of lysosomal storage diseases caused by defects in the genes coding for the enzyme hexosaminidase or the G(M2) activator protein. Four Jacob sheep from the same farm were examined over a 3-year period for a progressive neurologic disease. Two lambs were 6-month-old intact males and 2 were 8-month-old females. Clinical findings included ataxia in all 4 limbs, proprioceptive deficits, and cortical blindness. At necropsy, the nervous system appeared grossly normal. Histologically, most neurons within the brain, spinal cord, and peripheral ganglia were enlarged, and the cytoplasm was distended by foamy to granular material that stained positively with Luxol fast blue and Sudan black B stains. Other neuropathologic findings included widespread astrocytosis, microgliosis, and scattered spheroids. Electron microscopy revealed membranous cytoplasmic bodies within the cytoplasm of neurons. Biochemical and molecular genetic studies confirmed the diagnosis of G(M2) gangliosidosis. This form of G(M2) gangliosidosis in Jacob sheep is very similar to human Tay-Sachs disease and is potentially a useful animal model
— id: 141329, year: 2011, vol: 48, page: 807, stat: Journal Article,

The incidence of Parkinsonism in patients with type 1 Gaucher disease: data from the ICGG Gaucher Registry
Rosenbloom, Barry; Balwani, Manisha; Bronstein, Jeff M; Kolodny, Edwin; Sathe, Swati; Gwosdow, Andrea R; Taylor, John S; Cole, J Alexander; Zimran, Ari; Weinreb, Neal J
2011 Jan 15;46(1):95-102, Blood cells, molecules, & diseases
PURPOSE: Investigate the incidence of Parkinsonism among patients with Gaucher disease type 1 (GD1) and describe demographics, genotypes, and Gaucher disease (GD)-related characteristics for affected and non-affected patients. METHODS: Study type: Cohort study with age- and gender-matched nested case-control analysis. Calculation of event incidence, standardized morbidity ratio, and event-free survival (Kaplan-Meier). Data source: The International Collaborative Gaucher Group (ICGG) Gaucher Registry data as of June 2010. Study cohort: GD1 patients with any report of Parkinsonism. Pre-matching control group: All GD1 patients with no report of Parkinsonism. RESULTS: The matched study cohort comprised of 68 patients with reports of Parkinsonism and 649 patients without Parkinsonism. Demographic and clinical characteristics suggest a milder GD phenotype in patients with Parkinsonism compared to the control group. The most prevalent GD1 genotype was N370S/N370S (39% for controls; 46% for patients with Parkinsonism). Patients with Parkinsonism were diagnosed with GD1 at a mean age of 37 years compared to 31 years in control patients. The standardized morbidity ratio for the development of Parkinsonism among all GD1 patients indicated an approximately 6 to 17 fold increase over that of 2 reference populations. The mean age of reported Parkinsonism onset was 57 years compared to 60 years in the general population (Lees, Hardy, and Revesz, 2009 [1]). The probability that a patient with GD1 will develop Parkinsonism before age 70 years is 5 to 7% and 9 to 12% before age 80 years. CONCLUSIONS: The incidence of Parkinsonism among GD1 patients is significantly increased compared to two reference populations. GD1 patients with Parkinsonism have a later median age at GD diagnosis, later age at the start of treatment, and later age at death than patients with GD1 alone. The Gaucher-related clinical profile of GD1 patients with Parkinsonism is similar to or milder than the GD1 alone group. Therefore, severity of the common GD1 clinical manifestations does not appear to be predictive for the onset of Parkinsonism
— id: 133195, year: 2011, vol: 46, page: 95, stat: Journal Article,

A mutation in SCARB2 is a modifier in gaucher disease
Velayati, Arash; Depaolo, John; Gupta, Nidhi; Choi, Jae H; Moaven, Nima; Westbroek, Wendy; Goker-Alpan, Ozlem; Goldin, Ehud; Stubblefield, Barbara K; Kolodny, Edwin; Tayebi, Nahid; Sidransky, Ellen
2011 Nov;32(11):1232-1238, Human mutation
Lysosomal integral membrane protein type 2 (LIMP-2) is responsible for proper sorting and lysosomal targeting of glucocerebrosidase, the enzyme deficient in Gaucher disease (GD). Mutations in the gene for LIMP-2, SCARB2, are implicated in inherited forms of myoclonic epilepsy, and myoclonic epilepsy is part of the phenotypic spectrum associated with GD. We investigated whether SCARB2 mutations impact the Gaucher phenotype focusing on patients with myoclonic epilepsy, including a pair of siblings with GD who were discordant for myoclonic seizures. Sequencing of SCARB2 genomic and cDNA identified a heterozygous, maternally inherited novel mutation, c.1412A>G (p.Glu471Gly), in the brother with GD and myoclonic epilepsy, absent from his sibling and controls. Glucocerebrosidase activity, Western blots, real-time PCR, and immunofluorescence studies demonstrated markedly decreased LIMP-2 and glucocerebrosidase in cells from the sibling with (p.Glu471Gly) LIMP-2, and diminished glucocerebrosidase in lysosomes. The cells secreted highly glycosylated enzyme and showed mistrafficking of glucocerebrosidase. Sequencing of SCARB2 in 13 other subjects with GD and myoclonic epilepsy and 40 controls failed to identify additional mutations. The study provides further evidence for the association of LIMP-2 and myoclonic epilepsy, explains the drastically different phenotypes encountered in the siblings, and demonstrates that LIMP-2 can serve as a modifier in GD. Hum Mutat 32:1232-1238, 2011. (c)2011 Wiley Periodicals, Inc
— id: 141323, year: 2011, vol: 32, page: 1232, stat: Journal Article,

Open-label Phase I/II clinical trial of pyrimethamine for the treatment of chronic GM2 gangliosidosis
Clarke, J; Kolodny, E; Mahuran, D; Fuller, M; Tropak, M; Keimel, J; Sathe, S; Pesotchinsky, S; Rigat, B
2010 FEB ;99(2):S14-S14, Molecular genetics & metabolism
— id: 109682, year: 2010, vol: 99, page: S14, stat: Journal Article,

Vitamin B12-responsive severe leukoencephalopathy and autonomic dysfunction in a patient with "normal" serum B12 levels
Graber, J J; Sherman, F T; Kaufmann, H; Kolodny, E H; Sathe, S
2010 Dec;81(12):1369-1371, Journal of neurology neurosurgery & psychiatry
Leukoencephalopathy and autonomic dysfunction have been described in individuals with very low serum B(12) levels (<200 pg/ml), in addition to psychiatric changes, neuropathy, dementia and subacute combined degeneration. Elevated homocysteine and methylmalonic acid levels are considered more sensitive and specific for evaluating truly functional B(12) deficiency. A previously healthy 62-year-old woman developed depression and cognitive deficits with autonomic dysfunction that progressed over the course of 5 years. The patient had progressive, severe leukoencephalopathy on multiple MRI scans over 5 years. Serum B(12) levels ranged from 267 to 447 pg/ml. Homocysteine and methylmalonic acid levels were normal. Testing for antibody to intrinsic factor was positive, consistent with pernicious anaemia. After treatment with intramuscular B(12) injections (1000 mug daily for 1 week, weekly for 6 weeks, then monthly), she made a remarkable clinical recovery but remained amnesic for major events of the last 5 years. Repeat MRI showed partial resolution of white matter changes. Serum B(12), homocysteine and methylmalonic acid levels are unreliable predictors of B(12)-responsive neurologic disorders, and should be thoroughly investigated and presumptively treated in patients with unexplained leukoencephalopathy because even long-standing deficits may be reversible
— id: 141324, year: 2010, vol: 81, page: 1369, stat: Journal Article,

Enzyme replacement therapy improves cardiovascular responses to orthostatic challenge in Fabry patients
Hilz, Max J; Marthol, Harald; Schwab, Stefan; Kolodny, Edwin H; Brys, Miroslaw; Stemper, Brigitte
2010 Jul;28(7):1438-1448, Journal of hypertension
OBJECTIVE: Fabry patients have autonomic dysfunction but usually do not present clinically overt signs of orthostatic dysregulation. This study evaluated orthostatic regulation and baroreflex sensitivity (BRS) in untreated Fabry patients and possible baroreflex improvement with enzyme replacement therapy (ERT). METHODS: In 22 Fabry patients (aged 28W8 years), we assessed electrocardiographic RR intervals (RRIs), SBP, DBP and respiratory frequency, in supine and standing position, before and after 18 (11 patients) or 23 months (11 patients) of biweekly alpha-galactosidase A infusions (1.0 mg/kg agalsidase beta). We determined spectral powers of mainly sympathetically mediated low-frequency (0.04-0.15 Hz) and parasympathetically mediated high-frequency (0.15-0.5 Hz) RRI fluctuations, and sympathetic low-frequency powers of blood pressure fluctuations. We normalized RRI powers by relating low-frequency and high-frequency powers to total powers (low-frequency + high-frequency powers), assessed the RRI low-frequency/high-frequency ratio reflecting sympathicovagal balance. As a measure of BRS, we used the alpha-index, obtained as square root of the ratio between powers of simultaneous spectral analyses of spontaneous low-frequency variabilities in RRIs and SBP (coherence>0.5). We compared parameters in supine and standing position of untreated and treated patients with those of 15 healthy age-matched (27+/-5 years) men (repeated-measure analysis of variance, significance at P<0.05). RESULTS: Supine biosignals were similar in all groups. Upon standing, RRIs were lower in controls and patients after ERT than in patients before ERT (P<0.05); normalized RRI high-frequency powers as well as BRS decreased, whereas DBP, low-frequency/high-frequency ratios and sympathetic low-frequency powers of SBP increased in controls and treated patients only (P<0.05). CONCLUSION: Reduced increase in heart rate, blood pressure and sympathetic activation, and limited cardiovagal withdrawal and BRS adjustment seen in untreated Fabry patients upon standing normalized after 18 and 23 months of ERT demonstrating improved baroreflex function, which, in turn, is an established parameter of improved disease prognosis
— id: 138172, year: 2010, vol: 28, page: 1438, stat: Journal Article,

Vulnerability of brain white matter in lysosomal storage diseases
Kolodny, E
2010 APR 1 ;48(4):S29-S30, International journal of clinical pharmacology & therapeutics
— id: 108781, year: 2010, vol: 48, page: S29, stat: Journal Article,

Head trauma can initiate the onset of adreno-leukodystrophy
Raymond, Gerald V; Seidman, Roberta; Monteith, Teshamae S; Kolodny, Edwin; Sathe, Swati; Mahmood, Asif; Powers, James M
2010 Mar 15;290(1-2):70-74, Journal of the neurological sciences
X-linked adreno-leukodystrophy and its adult variant, adrenomyeloneuropathy, are caused by mutations in ABCD1 that encodes a peroxisomal membrane protein of unknown physiological significance. In spite of identical mutations, they can have markedly divergent neurological and neuropathologic characteristics. Adreno-leukodystrophy classically presents in normal boys with mild neuropsychiatric features, which progress to frank neurological signs, the vegetative state and death in approximately three years. Adrenomyeloneuropathy typically affects young men with spastic paraparesis and sensory ataxia that can progress over decades. The neuropathologic correlate for adreno-leukodystrophy is severe inflammatory demyelination of posterior cerebral white matter, while a chronic distal axonopathy of spinal cord and peripheral nerve occurs in adrenomyeloneuropathy. Consequently, both modifier genes and environmental factors have been implicated in their pathogeneses. We report five cases of adreno-leukodystrophy whose onsets were initiated by moderate to severe head trauma, two of whom were conversions from adrenomyeloneuropathy. Their clinical courses were rapidly incapacitating, short (i.e., weeks to a few years) and fatal due to marked cerebral inflammatory demyelination. These cases, in concert with several previous reports, indicate that head trauma is one environmental factor that can have a profoundly deleterious effect on those genetically at risk for, or with milder clinical phenotypes of, this disease. Avoidance of potential head trauma and a rapid response to episodes of moderate to severe head trauma in this patient population seem prudent
— id: 141325, year: 2010, vol: 290, page: 70, stat: Journal Article,

Tay-Sachs disease in Jacob sheep
Torres, Paola A; Zeng, Bai Jin; Porter, Brian F; Alroy, Joseph; Horak, Fred; Horak, Joan; Kolodny, Edwin H
2010 Dec;101(4):357-363, Molecular genetics & metabolism
Autopsy studies of four Jacob sheep dying within their first 6-8months of a progressive neurodegenerative disorder suggested the presence of a neuronal storage disease. Lysosomal enzyme studies of brain and liver from an affected animal revealed diminished activity of hexosaminidase A (Hex A) measured with an artificial substrate specific for this component of beta-hexosaminidase. Absence of Hex A activity was confirmed by cellulose acetate electrophoresis. Brain lipid analyses demonstrated the presence of increased concentrations of G(M2)-ganglioside and asialo-G(M2)-ganglioside. The hexa cDNA of Jacob sheep was cloned and sequenced revealing an identical number of nucleotides and exons as in human HexA and 86% homology in nucleotide sequence. A missense mutation was found in the hexa cDNA of the affected sheep caused by a single nucleotide change at the end of exon 11 resulting in skipping of exon 11. Transfection of normal sheep hexa cDNA into COS1 cells and human Hex A-deficient cells led to expression of Hex S but no increase in Hex A indicating absence of cross-species dimerization of sheep Hex alpha-subunit with human Hex beta-subunits. Using restriction site analysis, the heterozygote frequency of this mutation in Jacob sheep was determined in three geographically separate flocks to average 14%. This large naturally occurring animal model of Tay-Sachs disease is the first to offer promise as a means for trials of gene therapy applicable to human infants
— id: 114819, year: 2010, vol: 101, page: 357, stat: Journal Article,

Neuronopathic Gaucher disease: demographic and clinical features of 131 patients enrolled in the International Collaborative Gaucher Group Neurological Outcomes Subregistry
Tylki-Szymanska, Anna; Vellodi, Ashok; El-Beshlawy, Amal; Cole, J Alexander; Kolodny, Edwin
2010 Aug;33(4):339-346, Journal of inherited metabolic disease
OBJECTIVE: To describe demographic, genetic, and clinical characteristics of patients with neuronopathic Gaucher disease (NGD). METHODS: All patients enrolled in the Neurological Outcomes Subregistry of the International Collaborative Gaucher Group (ICGG) Gaucher Registry as of June 2007 were identified. RESULTS: The study cohort comprised 131 patients from 17 countries who were enrolled in the Neurological Outcomes Subregistry. The onset of neurological manifestations had occurred before 2 years of age in 47% (61 out of 131 patients), 2 years of age or older in 41% (54 out of 131), and could not be ascertained in the remaining 12% (16 out of 131). The most common manifestations were inability to look to the extreme up or down (45%, 55 out of 123), abnormally slow object tracking (43%, 53 out of 123), convergent squint (36%, 44 out of 121), and ataxia (15 to 20%, 18-27 out of 117). Seizures were reported in 19 out of 122 patients (16%), and myoclonic seizures were reported in 3 out of 121 patients (2%). The most common genotypes were L444P/L444P (76 out of 108, 70%), L444P/D409H (9 out of 108, 8%), D409H/D409H (8 out of 108, 7%), and L444P/rare allele (6 out of 108, 6%); full sequencing was not performed in all patients. CONCLUSIONS: Neurological manifestations of GD often begin to appear before the age of 2 years. The most common neurological signs and manifestations are brainstem abnormalities and fine motor dysfunction. The most common genotype is L444P/L444P
— id: 133787, year: 2010, vol: 33, page: 339, stat: Journal Article,

INTRA-OPERATIVE NEUROMOLECULAR IMAGING (NMI) IN NEOCORTEX OF EPILEPSY PATIENTS: COMPARISON WITH RESECTED EPILEPTOGENIC TISSUE
Broderick, PA; Doyle, WK; Pacia, SV; Kuzniecky, RI; Devinsky, O; Kolodny, EH
2009 NOV ;50(1):47-48, Epilepsia
— id: 106071, year: 2009, vol: 50, page: 47, stat: Journal Article,

Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I
Clarke, Lorne A; Wraith, J Edmond; Beck, Michael; Kolodny, Edwin H; Pastores, Gregory M; Muenzer, Joseph; Rapoport, David M; Berger, Kenneth I; Sidman, Marisa; Kakkis, Emil D; Cox, Gerald F
2009 Jan;123(1):229-240, Pediatrics
OBJECTIVE: Our goal was to evaluate the long-term safety and efficacy of recombinant human alpha-l-iduronidase (laronidase) in patients with mucopolysaccharidosis I. PATIENTS AND METHODS: All 45 patients who completed a 26-week, double-blind, placebo-controlled trial of laronidase were enrolled in a 3.5-year open-label extension study. Mean patient age at baseline was 16 (range: 6-43) years. All patients had attenuated disease (84% Hurler-Scheie, 16% Scheie phenotypes). Clinical, biochemical, and health outcomes measures were evaluated through the extension phase. Changes are presented as the mean +/- SEM. RESULTS: All 40 patients (89%) who completed the trial received at least 80% of scheduled infusions. As shown in earlier trials, urinary glycosaminoglycan levels decreased within the first 12 weeks and liver volume decreased within the first year. Percent predicted forced vital capacity remained stable, with a linear slope of -0.78 percentage points per year. The 6-minute walk distance increased 31.7 +/- 10.2 m in the first 2 years, with a final gain of 17.1 +/- 16.8 m. Improvements in the apnea/hypopnea index (decrease of 7.6 +/- 4.5 events per hour among the patients with significant baseline sleep apnea) and shoulder flexion (increase of 17.4 degrees +/- 3.6 degrees) were most rapid during the first 2 years. Improvements in the Child Health Assessment Questionnaire/Health Assessment Questionnaire disability index (decrease of 0.31 +/- 0.11, signifying a clinically meaningful improvement in activities of daily living) were gradual and sustained over the treatment period. Laronidase infusions were generally well tolerated except in 1 patient who experienced an anaphylactic reaction. Infusion-associated reactions, which occurred in 53% of the patients, were mostly mild, easily managed, and decreased markedly after 6 months. One patient died as a result of an upper respiratory infection unrelated to treatment. Antibodies to laronidase developed in 93% of the patients; 29% of the patients were seronegative at their last assessment. CONCLUSIONS: This trial demonstrates the long-term clinical benefit and safety of laronidase in attenuated patients with mucopolysaccharidosis I and highlights the magnitude and chronology of treatment effects. Prompt diagnosis and early treatment will maximize treatment outcomes
— id: 94365, year: 2009, vol: 123, page: 229, stat: Journal Article,

Newborn screening for Krabbe disease: the New York State model
Duffner, Patricia K; Caggana, Michele; Orsini, Joseph J; Wenger, David A; Patterson, Marc C; Crosley, Carl J; Kurtzberg, Joanne; Arnold, Georgianne L; Escolar, Maria L; Adams, Darius J; Andriola, Mary R; Aron, Alan M; Ciafaloni, Emma; Djukic, Alexandra; Erbe, Richard W; Galvin-Parton, Patricia; Helton, Laura E; Kolodny, Edwin H; Kosofsky, Barry E; Kronn, David F; Kwon, Jennifer M; Levy, Paul A; Miller-Horn, Jill; Naidich, Thomas P; Pellegrino, Joan E; Provenzale, James M; Rothman, Stanley J; Wasserstein, Melissa P
2009 Apr;40(4):245-252, Pediatric neurology
Krabbe disease is a rare inherited neurologic disorder affecting the central and peripheral nervous systems. The disease has four phenotypes: early infantile, later onset, adolescent, and adult. The only known treatment is hematopoietic stem cell transplantation, which is, in the early infantile form of the disease, most beneficial if performed before onset of clinical symptoms. In August 2006, New York State began screening all newborns for Krabbe disease. A rapid and accurate technique for assessing galactocerebrosidase activity and performing DNA mutation analysis had been developed. Interpreting these results was limited, however, because neither enzyme activity nor genetic mutation reliably predicts phenotype. A series of initiatives were therefore developed by a multidisciplinary group of neurologists, geneticists, metabolic pediatricians, neurodevelopmental pediatricians, and transplant physicians (the Krabbe Consortium of New York State) to enhance the effectiveness of the newborn screening program. A standardized clinical evaluation protocol was designed based on the available literature, criteria for transplantation for the early infantile phenotype were formulated, a clinical database and registry was developed, and a study of developmental and functional outcomes was instituted. This multidisciplinary standardized approach to evaluating infants who have positive results on newborn screening may serve as a model for other states as they begin the process of screening for Krabbe disease and other lysosomal storage disorders
— id: 126508, year: 2009, vol: 40, page: 245, stat: Journal Article,

Variable Expression of a Novel PLP1 Mutation in Members of a Family With Pelizaeus-Merzbacher Disease
Fattal-Valevski, Aviva; DiMaio, Miriam S; Hisama, Fuki M; Hobson, Grace M; Davis-Williams, Angelique; Garbern, James Y; Mahoney, Maurice J; Kolodny, Edwin H; Pastores, Gregory M
2009 May;24(5):618-624, Journal of child neurology
Pelizaeus-Merzbacher disease is a rare X-linked disorder caused by mutations of the proteolipid protein 1 gene that encodes a structural component of myelin. It is characterized by progressive psychomotor delay, nystagmus, spastic quadriplegia, and cerebellar ataxia. Variable clinical expression was seen in 5 members of a family bearing a novel missense mutation in proteolipid protein 1, c.619T>C. Symptomatic patients included a 6-year-old girl, her younger brother, and their maternal uncle, a 29-year-old college graduate initially diagnosed with cerebral palsy; their brain magnetic resonance imaging studies showed diffuse dysmyelination. The mother had a history of delayed walking, achieved independently by age 3; she and the maternal grandmother were asymptomatic on presentation. Review of clinical information and family history led to consideration of Pelizaeus-Merzbacher disease. Subsequent identification of the causal mutation enabled preimplantation genetic diagnosis and the birth of an unaffected child
— id: 95738, year: 2009, vol: 24, page: 618, stat: Journal Article,

ENZYME REPLACEMENT THERAPY DECREASED FOREARM AND HAND COMPLIANCE IN FABRY DISEASE
Hilz, MJ; Kolodny, EH; Marthol, H
2009 JUL ;14(9):65-65, Journal of the peripheral nervous system
— id: 102290, year: 2009, vol: 14, page: 65, stat: Journal Article,

Acute Confusional Migraine May Be a Presenting Feature of CADASIL
Sathe, Swati; DePeralta, Edgar; Pastores, Gregory; Kolodny, Edwin H
2009 Apr;49(4):590-596, Headache
Objective.- Characterize the phenomenon of acute confusional migraine (ACM) among Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients and emphasize the possibility of CADASIL in adults with ACM. Background.- ACM, well described in children, has rarely been reported in adults. Although 30-60% of CADASIL patients have migraine, acute confusional state during migraine has not been described. We describe 7 patients with ACM that complicated up to 50% of the migraine episodes. Design/Methods.- Detailed neurologic evaluation was performed in 20 CADASIL patients; International Classification of Headache Disorders 2nd edition criteria were used to diagnose migraine. Results.- The mean age was 51 years. Fourteen patients reported headache and 11 met the criteria for migraine (mean age of onset 25). Seven patients experienced concomitant confusion, within 3 years of migraine onset. Confusion occurred either abruptly or insidiously, at the onset of aura or headache, lasting for 2-48 hours, and ending abruptly. These episodes were stereotypic, characterized by disorientation with agitation, and retrograde amnesia for the episodes. Patients reported disorientation to time and place, inability to recognize friends and relatives, difficulty with finding directions home, fear of getting lost, inability to analyze traffic lights or tell time. Patients reliably predicted the episodes and felt the need to seek a safe place for protection. Severity of the episodes progressed, but a striking improvement occurred after the first stroke. Conclusion.- ACM may be a presenting feature and important clue, enabling CADASIL to be recognized up to a decade or earlier than at present. Therefore, a brain MRI and/or testing for Notch3 mutations should be considered in adult patients with ACM
— id: 95736, year: 2009, vol: 49, page: 590, stat: Journal Article,

Re: Neurocognitive testing in late-onset Tay-Sachs disease: A pilot study
Shapiro, Barbara E; Kolodny, Edwin H; Pastores, Gregory M; Luzy, Cecile
2009 Apr;32(2):310-311, Journal of inherited metabolic disease
— id: 95737, year: 2009, vol: 32, page: 310, stat: Journal Article,

Miglustat in late-onset Tay-Sachs disease: a 12-month, randomized, controlled clinical study with 24 months of extended treatment
Shapiro, Barbara E; Pastores, Gregory M; Gianutsos, John; Luzy, Cecile; Kolodny, Edwin H
2009 Jun;11(6):425-433, Genetics in medicine
PURPOSE: To evaluate the safety and efficacy of miglustat in patients with GM2 gangliosidosis. METHODS: A randomized, multicenter, open-label, 12-month study involving patients aged 18 years or older, randomized 2:1 to miglustat (200 mg TID) or 'no miglustat treatment.' This study was followed by 24 months of extended treatment during which all patients received miglustat. Primary efficacy endpoints were change in eight measures of isometric muscle strength in the limbs and isometric grip strength, evaluated at baseline, and months 12 and 36. Secondary efficacy endpoints included gait, balance, disability, and other neurological assessments. Safety evaluations included adverse event reporting. RESULTS: Thirty patients (67% male, age range 18-56 years) with late-onset Tay-Sachs disease were enrolled; 20 were randomized to miglustat and 10 to 'no miglustat treatment.' Muscle and grip strength generally decreased over the study period. No differences were observed between the two groups in any efficacy measure, either during the 12-month randomized phase or the full 36 months. The most common treatment-related adverse events were decrease in weight and diarrhea. CONCLUSION: Miglustat treatment was not shown to lead to measurable benefits in this cohort of patients with late-onset Tay-Sachs disease. The observed safety profile was consistent with that of the approved dose (100 mg TID) in type 1 Gaucher disease
— id: 109088, year: 2009, vol: 11, page: 425, stat: Journal Article,

Neuronopathic Gaucher Disease: Demographics, Clinical Features in 131 Patients Enrolled in the ICGG Neurological Outcomes Subregistry
Tylki-Szymanska, A; Vellodi, A; El-Beshlawy, A; Cole, JA; Kolodny, E
2009 AUG ;18(8):S224-S225, Pharmacoepidemiology & drug safety
— id: 101936, year: 2009, vol: 18, page: S224, stat: Journal Article,

Management of neuronopathic Gaucher disease: revised recommendations
Vellodi, A; Tylki-Szymanska, A; Davies, E H; Kolodny, E; Bembi, B; Collin-Histed, T; Mengel, E; Erikson, A; Schiffmann, R
2009 Oct;32(5):660-664, Journal of inherited metabolic disease
The original guidelines drawn up for the management of the neuronopathic forms of Gaucher disease were felt to be in need of revision; in particular, the role of high-dose enzyme replacement therapy (120 IU/kg of body weight every 2 weeks) in stabilizing neurological disease. The existing published evidence was analysed; it was concluded that it did not support the role of high-dose ERT, although this might be required to treat severe visceral disease
— id: 141326, year: 2009, vol: 32, page: 660, stat: Journal Article,

Enzyme replacement therapy improves skin blood flow control in Fabry patients
Hilz, MJ; Kolodny, EH; Marthol, H
2008 AUG ;15(3):49-49, European journal of neurology
— id: 98134, year: 2008, vol: 15, page: 49, stat: Journal Article,

Enzyme replacement therapy lowers forearm and hand compliance in Fabry patients
Hilz, MJ; Kolodny, EH; Marthol, H
2008 AUG ;15(3):48-49, European journal of neurology
— id: 98133, year: 2008, vol: 15, page: 48, stat: Journal Article,

GMI-gangliosidosis in an American Black Bear
Kolodny, E; Frankel, B; Torres, P; Alroy, J; Raghavan, S
2008 FEB ;93(2):S28-S28, Molecular genetics & metabolism
— id: 87126, year: 2008, vol: 93, page: S28, stat: Journal Article,

A novel GM2-activator deficiency mutation as a cause of AB variant GM2-gangliosidosis
Kolodny, E; Sathe, S; Zeng, BJ; Torres, P; Alroy, J; Pastores, G
2008 FEB ;93(2):S27-S28, Molecular genetics & metabolism
— id: 87125, year: 2008, vol: 93, page: S27, stat: Journal Article,

Clinical and demographic characteristics of 131 patients with neuronopathic Gaucher disease enrolled in the Neurological Outcomes Sub-Registry of the ICGG Gaucher Registry
Kolodny, E; Vellodi, A; El Beshlawy, A; Cole, JA; Tylki-Szymanski, A
2008 FEB ;93(2):S27-S27, Molecular genetics & metabolism
— id: 87124, year: 2008, vol: 93, page: S27, stat: Journal Article,

p.[G576S; E689K]: pathogenic combination or polymorphism in Pompe disease ?
Kroos, Marian A; Mullaart, Reinier A; Van Vliet, Laura; Pomponio, Robert J; Amartino, Hernan; Kolodny, Edwin H; Pastores, Gregory M; Wevers, Ron A; Van der Ploeg, Ans T; Halley, Dicky J J; Reuser, Arnold J J
2008 Aug;16(8):875-879, European journal of human genetics
We discuss four cases of acid alpha-glucosidase deficiency (EC, 3.2.1.3/20) without evident symptoms of Pompe disease (OMIM No 232300) in individuals of Asian descent. In three cases, the deficiency was associated with homozygosity for the sequence variant c.[1726G>A; 2065G>A] in the acid alpha-glucosidase gene (GAA) translating into p.[G576S; E689K]. One of these cases was a patient with profound muscular atrophy, another had cardio-myopathy and the third had no symptoms. The fourth case, the mother of a child with Pompe disease, was compound heterozygote for the GAA sequence variants c.[1726G>A; 2065G>A]/c.2338G>A (p.W746X) and had no symptoms either. Further investigations revealed that c.[1726A; 2065A] is a common GAA allele in the Japanese and Chinese populations. Our limited study predicts that approximately 4% of individuals in these populations are homozygote c.[1726A; 2065A]. The height of this figure in contrast to the rarity of Pompe disease in Asian populations and the clinical history of the cases described in this paper virtually exclude that homozygosity for c.[1726A; 2065A] causes Pompe disease. As c.[1726A; 2065A] homozygotes have been observed with similarly low acid alpha-glucosidase activity as some patients with Pompe disease, we caution they may present as false positives in newborn screening programs especially in Asian populations.European Journal of Human Genetics advance online publication, 27 February 2008; doi:10.1038/ejhg.2008.34
— id: 77799, year: 2008, vol: 16, page: 875, stat: Journal Article,

Juvenile-onset g(m2)-gangliosidosis in an african-american child with nystagmus
Paciorkowski, Alex R; Sathe, Swati; Zeng, Bei-Jin; Torres, Paola; Rosengren, Sally S; Kolodny, Edwin
2008 Apr;38(4):284-286, Pediatric neurology
G(M2)-gangliosidosis is a neurodegenerative lysosomal disease with several clinical variants. We describe a 2-year-old black child with juvenile-onset disease, who presented with abnormal eye movements and cherry-red spots of the maculae. Mutation analysis of the HEXA gene revealed the patient to be a compound heterozygote (M1V/Y37N). The M1V mutation was previously described in an African-American child with acute infantile G(M2)-gangliosidosis. The Y37N mutation is novel. This combination of mutations is consistent with juvenile-onset disease, and provides further evidence for the association of the M1V mutation with individuals of black ancestry. The presence of oculomotor abnormalities is an unusual finding in this form of G(M2)-gangliosidosis, and adds to the phenotypic spectrum
— id: 77798, year: 2008, vol: 38, page: 284, stat: Journal Article,

Novel mutations in juvenile Sandhoff disease presenting as motor neuron disease
Pierson, TM; Zeng, BJ; Torres, P; Pastores, G; Finkel, R; Mahuran, D; Kolodny, E; Tennekoon, G
2008 FEB ;93(2):S33-S33, Molecular genetics & metabolism
— id: 87128, year: 2008, vol: 93, page: S33, stat: Journal Article,

Homozygosity for a tandem mutation (D409H and H255Q) leads to acute neuronopathic Gaucher disease
Sathe, S; Basturk, O; Miller, D; Greco, MA; Potaznik, D; Pastores, G; Kolodny, E
2008 FEB ;93(2):S34-S35, Molecular genetics & metabolism
— id: 87129, year: 2008, vol: 93, page: S34, stat: Journal Article,

Acute Confusional Migraine may be the Presenting Feature of CADASIL
Sathe, S; Deperalta, E; Kolodny, EH
2008 DEC ;64(6):S161-S162, Annals of neurology
— id: 91498, year: 2008, vol: 64, page: S161, stat: Journal Article,

Late-onset Tay-Sachs disease: the spectrum of peripheral neuropathy in 30 affected patients
Shapiro, Barbara E; Logigian, Eric L; Kolodny, Edwin H; Pastores, Gregory M
2008 Aug;38(2):1012-1015, Muscle & nerve
Late-onset Tay-Sachs (LOTS) disease is a chronic, progressive, lysosomal storage disorder caused by a partial deficiency of beta-hexosaminidase A (HEXA) activity. Deficient levels of HEXA result in the intracellular accumulation of GM2-ganglioside, resulting in toxicity to nerve cells. Clinical manifestations primarily involve the central nervous system (CNS) and lower motor neurons, and include ataxia, weakness, spasticity, dysarthria, dysphagia, dystonia, seizures, psychosis, mania, depression, and cognitive decline. The prevalence of peripheral nervous system (PNS) involvement in LOTS has not been well documented, but it has traditionally been thought to be very low. We examined a cohort of 30 patients with LOTS who underwent clinical and electrophysiologic examination, and found evidence of a predominantly axon loss polyneuropathy affecting distal nerve segments in the lower and upper extremities in eight patients (27%)
— id: 95739, year: 2008, vol: 38, page: 1012, stat: Journal Article,

CLINICAL AND DEMOGRAPHIC CHARACTERISTICS OF 131 PATIENTS WITH NEURONOPATHIC GAUCHER DISEASE ENROLLED IN THE NEUROLOGICAL OUTCOMES SUBREGISTRY OF THE INTERNATIONAL COLLABORATIVE GAUCHER GROUP GAUCHER REGISTRY
Tylki-Szymanska, A; Vellodi, A; El-Beshlawy, A; Cole, JA; Kolodny, E
2008 OCT ;30(10):S96-S97, Clinical therapeutics
— id: 90779, year: 2008, vol: 30, page: S96, stat: Journal Article,

Spontaneous appearance of Tay-Sachs disease in an animal model
Zeng, B J; Torres, P A; Viner, T C; Wang, Z H; Raghavan, S S; Alroy, J; Pastores, G M; Kolodny, E H
2008 Sep-Oct;95(1-2):59-65, Molecular genetics & metabolism
Tay-Sachs disease (TSD) is a progressive neurodegenerative disorder due to an autosomal recessively inherited deficiency of beta-hexosaminidase A (Hex A). Deficiency of Hex A in TSD is caused by a defect of the alpha-subunit resulting from mutations of the HEXA gene. To date, there is no effective treatment for TSD. Animal models of genetic diseases, similar to those known to exist in humans, are valuable and essential research tools for the study of potentially effective therapies. However, there is no ideal animal model of TSD available for use in therapeutic trials. In the present study, we report an animal model (American flamingo; Phoenicopterus ruber) of TSD with Hex A deficiency occurring spontaneously in nature, with accumulation of G(M2)-ganglioside, deficiency of Hex A enzymatic activity, and a homozygous P469L mutation in exon 12 of the hexa gene. In addition, we have isolated the full-length cDNA sequence of the flamingo, which consists of 1581 nucleotides encoding a protein of 527 amino acids. Its coding sequence indicates approximately 71% identity at the nucleotide level and about 72.5% identity at the amino acid level with the encoding region of the human HEXA gene. This animal model, with many of the same features as TSD in humans, could represent a valuable resource for investigating therapy of TSD
— id: 93349, year: 2008, vol: 95, page: 59, stat: Journal Article,

A phase III extension study of Aldurazyme (R) (Laronidase) in mucopolysaccharidosis I
Clarke, LA; Wraith, JE; Beck, M; Kolodny, EH; Pastores, GM; Muenzers, J
2007 DEC ;29(6):S111-S111, Clinical therapeutics
— id: 98159, year: 2007, vol: 29, page: S111, stat: Journal Article,

Neuropathology of LSDs
Kolodny, Edwin
2007 Apr;96(455):25-25, Acta paediatrica. Supplement
— id: 72966, year: 2007, vol: 96, page: 25, stat: Journal Article,

Phenotypic characterization of parkinsonism in patients with Gaucher Disease
Sathe S; Pastores GM; Kolodny E; DiRocco A
2007 ;13(Suppl 2):S64-S64 A1.216, Parkinsonism & related disorders
— id: 75296, year: 2007, vol: 13, page: S64, stat: Journal Article,

Very long chain acyl-CoA dehydrogenase deficiency in a pair of mildly affected monozygotic twin sister in their late fifties
Zia, A; Kolodny, E H; Pastores, G M
2007 Oct;30(5):817-817, Journal of inherited metabolic disease
Very long-chain acyl-CoA dehydrogenase (VLCAD) catalyses the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons. Deficiency of VLCAD activity has been associated with a range of phenotypes, including a severe lethal form presenting in the infantile period and a milder variant with onset in childhood. Varying rates of residual enzyme activity partly explain the heterogeneity in presentations. Here we report the course of disease in a pair of monozygotic twin sisters who were diagnosed in their late forties during an evaluation for rhabdomyolysis and fatigue. Interestingly, the patients' complaints were most severe during puberty and declined significantly after the menopause. The basis for this observation is uncertain, but may be related to hormonally-mediated changes in lipid metabolism that may occur at these times. As metabolic decompensation can be associated with significant morbidity, timely diagnosis of VLCAD deficiency is important. The introduction of appropriate dietary measures (i.e. avoidance of fasting, long-chain fat restriction and supplementation with medium-chain triglycerides) greatly reduces the likelihood of complications
— id: 75013, year: 2007, vol: 30, page: 817, stat: Journal Article,

A phase 3 extension study of Aldurazyme (R) (laronidase) in mucopolysaccharidosis I (MPS I)
Clarke, LA; Wraith, JE; Beck, M; Kolodny, EH; Pastores, GM; Muenzer, J
2006 AUG ;29(5):28-28, Journal of inherited metabolic disease
— id: 74922, year: 2006, vol: 29, page: 28, stat: Journal Article,

Splice-site contribution in alternative splicing of PLP1 and DM20: molecular studies in oligodendrocytes
Hobson, Grace M; Huang, Zhong; Sperle, Karen; Sistermans, Erik; Rogan, Peter K; Garbern, James Y; Kolodny, Edwin; Naidu, Sakkubai; Cambi, Franca
2006 Jan;27(1):69-77, Human mutation
Mutations in the proteolipid protein 1 (PLP1) gene cause the X-linked dysmyelinating diseases Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia 2 (SPG2). We examined the severity of the following mutations that were suspected of affecting levels of PLP1 and DM20 RNA, the alternatively spliced products of PLP1: c.453G>A, c.453G>T, c.453G>C, c.453+2T>C, c.453+4A>G, c.347C>A, and c.453+28_+46del (the old nomenclature did not include the methionine codon: G450A, G450T, G450C, IVS3+2T>C, IVS3+4A>G, C344A, and IVS3+28-+46del). These mutations were evaluated by information theory-based analysis and compared with mRNA expression of the alternatively spliced products. The results are discussed relative to the clinical severity of disease. We conclude that the observed PLP1 and DM20 splicing patterns correlated well with predictions of information theory-based analysis, and that the relative strength of the PLP1 and DM20 donor splice sites plays an important role in PLP1 alternative splicing
— id: 62685, year: 2006, vol: 27, page: 69, stat: Journal Article,

Mild-onset presentation of Canavan's disease associated with novel G212A point mutation in aspartoacylase gene
Janson, Christopher G; Kolodny, Edwin H; Zeng, Bai-Jin; Raghavan, Srinivasa; Pastores, Gregory; Torres, Paola; Assadi, Mitra; McPhee, Scott; Goldfarb, Olga; Saslow, Beth; Freese, Andrew; Wang, D J; Bilaniuk, Larissa; Shera, David; Leone, Paola
2006 Feb;59(2):428-431, Annals of neurology
We describe two sisters with a mild-onset variant of Canavan's disease who presented at age 50 and 19 months with developmental delay but without macrocephaly, hypotonia, spasticity, or seizures. Remarkably, both patients had age-appropriate head control, gross motor development, and muscle tone. There were very mild deficits in fine motor skills, coordination, and gait. Both sisters had a history of strabismus, but otherwise vision was normal. The older child showed evidence of mild cognitive and social impairment, whereas language and behavior were normal for age in the infant. Both patients were found to be compound heterozygotes for C914A (A305E) and G212A (R71H) mutations in ASPA. Like all other known ASPA mutations, this previously unknown G212A mutation appears to have low absolute enzyme activity. Nevertheless, it is associated in these patients with an extremely benign phenotype that is highly atypical of Canavan's disease. Biochemical and clinical data were evaluated using a generalized linear mixed model generated from 25 other subjects with Canavan's disease. There were statistically significant differences in brain chemistry and clinical evaluations, supporting a distinct variant of Canavan's disease. Future studies of ASPA enzyme structure and gene regulation in these subjects could lead to a better understanding of Canavan's pathophysiology and improvements in ASPA gene therapy Ann Neurol 2006;59:428-431
— id: 62683, year: 2006, vol: 59, page: 428, stat: Journal Article,

CNS pathology and vascular/circulatory abnormalities in Fabry disease
Kolodny, Edwin H; Pastores, Gregory M
2006 Apr;95(451):55-56, Acta paediatrica. Supplement
— id: 69022, year: 2006, vol: 95, page: 55, stat: Journal Article,

Spontaneous appearance of Tay-Sachs disease in American flamingos
Kolodny, EH; Zeng, BJ; Viner, T; Torres, PA; Wang, ZH; Raghavan, SS
2006 MAR 14 ;66(5):274-274, Neurology
— id: 74924, year: 2006, vol: 66, page: 274, stat: Journal Article,

Leukodystrophies: clinical and genetic aspects
Lyon, Gilles; Fattal-Valevski, Aviva; Kolodny, Edwin H
2006 Aug;17(4):219-242, Topics in magnetic resonance imaging
The leukodystrophies comprise an ever-expanding group of rare central nervous system disorders with defined clinical, pathological, and genetic characteristics. The broader term, leukoencephalopathy, is applied to all brain white matter diseases, whether their molecular cause is known. Magnetic resonance imaging has helped to elucidate new forms of leukodystrophy as well as to permit longitudinal studies of disease progression. The white matter abnormality may appear similar in different forms of leukodystrophy so that in most cases, further studies such as magnetic resonance spectroscopy, tissue biopsies, enzyme studies, and molecular DNA analyses are needed to pinpoint the specific diagnosis. The primary inherited leukoencephalopathies include dysmyelinating, hypomyelinative, and vacuolating forms. Metabolic and vascular causes account for most of the secondary forms, but other inherited syndromes are recognized that have their onset in childhood or adult life and are characterized by distinctive clinical and neuropathologic features. This review discusses some of the mechanisms that have been proposed to explain deficiencies of myelin and the molecular genetic bases underlying these disorders
— id: 74921, year: 2006, vol: 17, page: 219, stat: Journal Article,

Neurology of hereditary metabolic diseases of children
Lyon, Gilles; Kolodny, Edwin H; Pastores, Gregory M
New York : McGraw-Hill, 2006,
— id: 1362, year: 2006, vol: , page: , stat: ,

T118M PMP22 mutation causes partial loss of function and HNPP-like neuropathy
Shy, Michael E; Scavina, Mena T; Clark, Alisa; Krajewski, Karen M; Li, Jun; Kamholz, John; Kolodny, Edwin; Szigeti, Kinga; Fischer, Richard A; Saifi, Gulam Mustafa; Scherer, Steven S; Lupski, James R
2006 Feb;59(2):358-364, Annals of neurology
OBJECTIVE: To determine the clinical consequences of the PMP22 point mutation, T118M, which has been previously considered to either cause an autosomal recessive form of Charcot-Marie-Tooth (CMT) disease or be a benign polymorphism. METHODS: We analyzed patients from five separate kindreds and characterized their peripheral nerve function by clinical and electrophysiological methods. RESULTS: All heterozygous patients had clinical and/or electrophysiological features of a neuropathy similar to hereditary neuropathy with liability to pressure palsies (HNPPs). The homozygous patient had a severe axonal neuropathy without features of demyelination. INTERPRETATION: These findings suggest that T118M PMP22 retains some normal PMP22 activity, allowing the formation of compact myelin and normal nerve conduction velocities in the homozygous state. Taken together, these findings suggest that T118M is a pathogenic mutation causing a dominantly inherited form of CMT by a partial loss of PMP22 function. Ann Neurol 2006;59:358-364
— id: 62684, year: 2006, vol: 59, page: 358, stat: Journal Article,

Mucopolysaccharidosis type VII (Sly syndrome) in a Thai boy: First reported case
Wasant, P; Kolodny, EH
2006 AUG ;29(5):156-156, Journal of inherited metabolic disease
— id: 74923, year: 2006, vol: 29, page: 156, stat: Journal Article,

Rapid detection of three large novel deletions of the aspartoacylase gene in non-Jewish patients with Canavan disease
Zeng, B J; Wang, Z H; Torres, P A; Pastores, G M; Leone, P; Raghavan, S S; Kolodny, E H
2006 Sep-Oct;89(1-2):156-163, Molecular genetics & metabolism
Canavan disease (CD), an autosomal recessive neurodegenerative disorder, is caused by mutations in the aspartoacylase (ASPA) gene. In the present study, the ASPA gene was analyzed in 24 non-Jewish patients with CD from 23 unrelated families. Within this cohort, we found three large novel deletions of approximate 92, 56, and 12.13 kb in length, using both self-ligation of restriction endonuclease-digested DNA fragments with long-distance inverse PCR and multiplex dosage quantitative PCR analysis of genomic DNA. The 92 kb large deletion results in complete absence of the ASPA gene in one homozygous and one compound heterozygous patient, respectively. The 56 kb large deletion causes absence of the majority of the ASPA gene except for exon 1 alone in a compound heterozygous patient. The 12.13 kb deletion involves deletion of the ASPA gene from intron 3 to intron 5 including exons 4 and 5 (I3 to E4E5I5) in a compound heterozygous patient. Patients with the three large deletions clinically manifested severe symptoms at birth, including seizures. Our study showed that the combined use of long-distance inverse PCR and multiplex dosage quantitative PCR analysis of genomic DNA is a helpful and rapid technique to search for large deletions, particularly for detection of large deletions in compound heterozygous patients
— id: 69024, year: 2006, vol: 89, page: 156, stat: Journal Article,

Mutation analysis of the aspartoacylase gene in non-Jewish patients with Canavan disease
Zeng, Bai-Jin; Pastores, Gregory M; Leone, Paola; Raghavan, Srinivasa; Wang, Zhao-Hui; Ribeiro, Lucilene A; Torres, Paola; Ong, Elton; Kolodny, Edwin H
2006 ;576:165-173, Advances in experimental medicine & biology
— id: 67534, year: 2006, vol: 576, page: 165, stat: Journal Article,

Bioimaging in neurodegeneration
Broderick, Patricia A; Rahni, David N; Kolodny, Edwin H
Totowa NJ : Humana Press, 2005,
— id: 1361, year: 2005, vol: , page: , stat: ,

MR imaging and proton spectroscopy of neuronal injury in late-onset GM2 gangliosidosis
Inglese, Matilde; Nusbaum, Annette O; Pastores, Gregory M; Gianutsos, John; Kolodny, Edwin H; Gonen, Oded
2005 Sep;26(8):2037-2042, AJNR. American journal of neuroradiology
BACKGROUND AND PURPOSE: Despite the ubiquity of G(M2) gangliosides accumulation in patients with late-onset G(M2) gangliosidosis (G(M2)G), the only clinical MR imaging-apparent brain abnormality is profound cerebellar atrophy. The goal of this study was to detect the presence and assess the extent of neuroaxonal injury in the normal-appearing gray and white matter (NAGM and NAWM) of these patients. METHODS: During a single imaging session, 9 patients with late-onset G(M2)G and 8 age-matched normal volunteers underwent the following protocol: (1) T1- and T2-weighted and fluid-attenuated inversion recovery MR images, as well as (2) multivoxel proton MR spectroscopy (1H-MR spectroscopy) to quantify the distribution of the n-acetylaspartate (NAA), creatine (Cr), and choline (Cho), were obtained. RESULTS: The patients' NAA levels in the thalamus (6.5 +/- 1.9 mmol/L) and NAWM (5.8 +/- 2.1 mmol/L) were approximately 40% lower than the controls' (P = .003 and P = .005), whereas the Cr and Cho reductions ( approximately 30% and approximately 26%) did not reach significance (P values of .06-.1). All cerebellar metabolites, especially NAA and Cr, were much (30%-90%) lower in the patients, which reflects the atrophy. CONCLUSION: In late-onset G(M2)G, NAA decreases are detectable in NAGM and NAWM even absent morphologic (MR imaging) abnormalities. Because the accumulation of G(M2) gangliosides can be reduced pharmacologically, 1H-MR spectroscopy might be a sensitive and specific for detecting and quantifying neuroaxonal injury and monitoring response to emerging treatments
— id: 61242, year: 2005, vol: 26, page: 2037, stat: Journal Article,

Overview of the leukoencephalopathies : an MRI point of view
Kolodny, Edwin
Bioimaging in neurodegeneration Totowa NJ : Humana Press, 2005,
— id: 4619, year: 2005, vol: , page: ?, stat: Chapter,

Late-onset Tay-Sachs disease: Phenotypic characterization and genotypic correlations in 21 affected patients
Neudorfer, Orit; Pastores, Gregory M; Zeng, Bai J; Gianutsos, John; Zaroff, Charles M; Kolodny, Edwin H
2005 Feb;7(2):119-123, Genetics in medicine
PURPOSE:: The purpose of this study was to describe the phenotype (and corresponding genotype) of adult patients with late-onset Tay-Sachs disease, a clinical variant of the GM2-gangliosidoses. METHODS:: A comprehensive physical examination, including neurological assessments, was performed to establish the current disease pattern and severity. In addition, the patients' past medical histories were reviewed. The patients' alpha-subunit mutations (beta-Hexosaminidase A genotype) were determined and correlated with their corresponding clinical findings and disease course. RESULTS:: Twenty-one patients (current mean age: 27.0 years; range: 14-47 years) were identified. The pedigree revealed a relative with the 'classic' infantile or late-onset form of Tay-Sachs disease in four (out of 18) unrelated families. The patients were predominantly male (15/21 individuals) and of Ashkenazi Jewish ancestry (15/18 families). Mean age at onset was 18.1 years; balance problems and difficulty climbing stairs were the most frequent presenting complaints. In several cases, the diagnosis was delayed (mean age at diagnosis: 27.0 years). Analysis of the beta-hex A gene revealed the G269S mutation as the most common disease allele; found in homozygosity (N = 1) or heterozygosity (N = 18; including 2 sib pairs). Disease onset (age 36 years) was delayed and progression relatively slower in the homozygous G269S patient. Two siblings (ages 28 and 31 years), of non-Jewish ancestry, were compound heterozygotes (TATC1278/W474C); their clinical course is dominated by psychiatric problems. Brain imaging studies revealed marked cerebellar atrophy in all patients (N = 18) tested, regardless of disease stage. CONCLUSIONS:: Late-onset Tay-Sachs disease is an infrequent disorder and the diagnosis is often missed or delayed (by approximately 8 years). Early on, the majority of patients develop signs of either cerebellar or anterior motor neuron involvement. Affected individuals may also develop psychotic episodes. In most cases, the later-onset of expression results from the presence of at least one allele (usually the G269S mutation), associated with residual enzyme (beta-hexosaminidase A) activity. A positive family history is a valuable clue, enabling early diagnosis. Nonspecific cerebellar atrophy on brain imaging is another important finding. This entity should be considered among patients presenting with speech, gait, and balance problems, and those with psychiatric disorders even when focal neurologic deficits may be initially absent. Accurate diagnosis will permit appropriate genetic counseling regarding disease prognosis and reproductive risks
— id: 48748, year: 2005, vol: 7, page: 119, stat: Journal Article,

An open-label, noncomparative study of miglustat in type I Gaucher disease: Efficacy and tolerability over 24 months of treatment
Pastores, Gregory M; Barnett, Natalie L; Kolodny, Edwin H
2005 Aug;27(8):1215-1227, Clinical therapeutics
Abstract BACKGROUND:: The substrate synthesis inhibitor miglustat (N-butyldeoxynojirimycin) is the first oral agent to receive regulatory approval for the treatment of type I Gaucher disease (GD). OBJECTIVES:: The aims of this study were to further assess previous observations of the effects of miglustat in adult patients with mild to moderate type I GD and to evaluate the tolerability and safety profile of this drug. METHODS:: This was a noncomparative, open-label study in adult patients with type I GD (confirmed by genotyping and glucocerebrosidase assay) who were unwilling or unable to receive enzyme replacement therapy (ERT) or who had discontinued ERT for at least 3 months. Patients received miglustat 100 mg TID for 12 months, with the option of continuing treatment for a further 12 months. The primary end point was the percentage change in liver volume. Secondary end points included the percentage change in spleen volume and changes in hematologic parameters (hemoglobin, platelets), chitotriosidase activity (a surrogate marker of disease burden), and bone assessments (dual-energy X-ray absorptiometry, magnetic resonance imaging, and radiography). Clinical safety was monitored, including assessment of neurologic status at baseline and throughout the study using a comprehensive battery of standardized neurologic tests (eg, Purdue Pegboard Test, Mini-Mental State Examination, nerve conduction studies) and neuropsychological tests. RESULTS:: Of the 10 patients (7 men, 3 women) who received at least 1 dose of miglustat, 7 completed 24 months of treatment. Patients were aged between 32 and 62 years (mean, 46.3 years) and weighed between 55 and 88 kg (mean, 72.4 kg). All patients had at least 1 manifestation of GD, including 10 with splenomegaly (mean size, 8.1 times normal; range, 3.9-15.9 times normal), 9 with thrombocytopenia, and 8 with hepatomegaly (mean size, 1.5 times normal; range, 1.0-2.0 times normal). At baseline, hemoglobin concentrations ranged from 11.5 to 15.1 g/dL (mean, 13.2 g/dL), platelet counts from 55 to 161 x 10(9)/L (mean, 83.8 x 10(9)/L), and chitotriosidase activity from 526 to 29636 nmol/mL . h (mean, 8143.7 nmol/mL . h). In the 8 patients comprising the efficacy set, significant mean percentage changes from baseline in liver volume were seen at 6 months (-8.4%; P = 0.036; 95% CI, -16.1 to -0.7) and 18 months (-15.1%; P = 0.022; 95% CI, -27.1 to -3.0). Although not statistically significant, the 95% CIs for the percentage changes in liver volume at 12 months (-9.4%; 95% CI, -19.5 to 0.6) and 24 months (-5.6%; 95% CI, -12.1 to 1.0) were similar to those at 6 and 18 months, supporting a consistent clinical effect. Significant mean percentage reductions in spleen volume were observed at 6 months (-19.0%; P = 0.006; 95% CI, -30.4 to -7.6) and 18 months (-24.3%; P = 0.001; 95% CI, -33.6 to -15.1). Mean hemoglobin concentrations, which were normal at baseline, remained stable over the course of the study. There were no significant changes in bone status. There was a significant mean increase in absolute platelet count at 12 months (by 13.9 x 10(9)/L; P = 0.030; 95% CI, 1.8 to 26.0); at 24 months, the mean percentage increase from baseline (23.0%) was not statistically significant. The mean percentage reduction from baseline in chitotriosidase activity at 24 months was 25.3%. Treatment was well tolerated, and the incidence of most adverse events decreased with time. Gastrointestinal and central nervous system adverse events reported during 3-month periods at the beginning (0-3 months) and end (>21-24 months) of the study were flatulence (10 and 2 patients, respectively), diarrhea (9 and 0), abdominal pain (7 and 1), tremor (4 and 1), paresthesia (3 and 0), headache (2 and 3), and abdominal distention (2 and 0). No evidence of clinically significant adverse effects on neurologic or neuropsychological function was found during the study. CONCLUSIONS:: In this small study in symptomatic adult patients with type I GD, miglustat treatment resulted in a significant decrease in liver and spleen volume at 6 and 18 months, with clinical improvement noted over 24 months. Bone involvement and platelet and hemoglobin values remained stable, with no significant changes noted during the observation period. The effects of treatment were consistent with those of earlier studies of miglustat in type I GD
— id: 62686, year: 2005, vol: 27, page: 1215, stat: Journal Article,

Globoid cell leukodystrophy (Krabbe disease): normal umbilical cord blood galactocerebrosidase activity and polymorphic mutations
Raghavan, S; Zeng, B; Torres, P A; Pastores, G M; Kolodny, E H; Kurtzberg, J; Krivit, W
2005 ;28(6):1005-1009, Journal of inherited metabolic disease
Globoid cell leukodystrophy is an inherited metabolic disorder of the central nervous system caused by deficiency of the lysosomal enzyme galactocerebrosidase. Haematopoietic stem cell transplantation is the only available effective treatment. The engraftment from normal donors provides competent cells able to correct the metabolic defect. Umbilical cord blood cells have proved to significantly decrease complications and improve engraftment rate compared to adult marrow cells in haematopoietic stem cell transplantation. Umbilical cord blood cells must be of sufficient activity to provide central nervous system recovery after engraftment is obtained. Galactocerebrosidase activity is known to be affected by two polymorphic alleles found at nucleotides 502 and 1637 of the cDNA for this gene. This enzyme activity and the polymorphic alleles noted above were analysed in 83 random samples of umbilical cord blood. The activity, assayed with the fluorogenic substrate 6-hexadecanoylamino-4-methylumbelliferyl-beta-galactopyranoside, in those with neither polymorphic allele was 4.6 +/- 1.7 units (nmol/h per mg protein). This optimal choice of cord blood was found in only 24% of specimens. Homozygotes for 1637T > C with activity of only 1.5 +/- 0.4 units represented 16% of the samples. Those heterozygous for 1637T > C with slightly better activity (2.3 +/- 0.7 units) represented 52% of the samples. Choice of umbilical cord blood for haematopoietic stem cell transplantation, therefore, requires consideration not only of cell quantity and HLA compatibility but also selection for normal alleles to obtain maximal enzymatic activity for central nervous system correction
— id: 64662, year: 2005, vol: 28, page: 1005, stat: Journal Article,

ALDURAZYME (LARONIDASE) ENZYME REPLACEMENT THERAPY FOR MPS I: 96-WEEK EXTENSION DATA
Wraith, JE; Muenzer, J; Kolodny, EH; Pastores, GM; Beck, M; Clarke, LA
2005 JUL ;28(6):182-182, Journal of inherited metabolic disease
— id: 100634, year: 2005, vol: 28, page: 182, stat: Journal Article,

Enzyme replacement therapy and monitoring for children with type 1 Gaucher disease: consensus recommendations
Charrow, Joel; Andersson, Hans C; Kaplan, Paige; Kolodny, Edwin H; Mistry, Pramod; Pastores, Gregory; Prakash-Cheng, Ainu; Rosenbloom, Barry E; Scott, C Ronald; Wappner, Rebecca S; Weinreb, Neal J
2004 Jan;144(1):112-120, Journal of pediatrics
— id: 62688, year: 2004, vol: 144, page: 112, stat: Journal Article,

Aldurazyme (laronidase) enzyme replacement therapy for MPS I: 72-week extension data
Clarke, LA; Wraith, JE; Beck, M; Kolodny, EH; Pastores, GM; Muenzer, J
2004 MAR ;81(3):169-169, Molecular genetics & metabolism
— id: 74925, year: 2004, vol: 81, page: 169, stat: Journal Article,

Reduced cerebral blood flow velocity and impaired cerebral autoregulation in patients with Fabry disease
Hilz, Max Josef; Kolodny, Edwin H; Brys, Miroslaw; Stemper, Brigitte; Haendl, Thomas; Marthol, Harald
2004 Jun;251(5):564-570, Journal of neurology
In Fabry disease, there is glycosphingolipid storage in vascular endothelial and smooth muscle cells and neurons of the autonomic nervous system. Vascular or autonomic dysfunction is likely to compromise cerebral blood flow velocities and cerebral autoregulation. This study was performed to evaluate cerebral blood flow velocities and cerebral autoregulation in Fabry patients. In 22 Fabry patients and 24 controls, we monitored resting respiratory frequency, electrocardiographic RR-intervals, blood pressure, and cerebral blood flow velocities (CBFV) in the middle cerebral artery using transcranial Doppler sonography. We assessed the Resistance Index, Pulsatility Index, Cerebrovascular Resistance, and spectral powers of oscillations in RR-intervals, mean blood pressure and mean CBFV in the high (0.15-0.5 Hz) and sympathetically mediated low frequency (0.04-0.15 Hz) ranges using autoregressive analysis. Cerebral autoregulation was determined from the transfer function gain between the low frequency oscillations in mean blood pressure and mean CBFV. Mean CBFV (P < 0.05) and the powers of mean blood pressure (P < 0.01) and mean CBFV oscillations (P < 0.05) in the low frequency range were lower,while RR-intervals, Resistance Index (P < 0.01), Pulsatility Index, Cerebrovascular Resistance (P < 0.05), and the transfer function gain between low frequency oscillations in mean blood pressure and mean CBFV (P < 0.01) were higher in patients than in controls. Mean blood pressure, respiratory frequency and spectral powers of RR-intervals did not differ between the two groups (P > 0.05). The decrease of CBFV might result from downstream stenoses of resistance vessels and dilatation of the insonated segment of the middle cerebral artery due to reduced sympathetic tone and vessel wall pathology with decreased elasticity. The augmented gain between blood pressure and CBFV oscillations indicates inability to dampen blood pressure fluctuations by cerebral autoregulation. Both, reduced CBFV and impaired cerebral autoregulation, are likely to be involved in the increased risk of stroke in patients with Fabry disease
— id: 46144, year: 2004, vol: 251, page: 564, stat: Journal Article,

Enzyme replacement therapy (ERT) for infantile onset Pompe disease: long term follow-up results
Kishnani, P; Nicolino, M; Voit, T; Tsai, C; Herman, G; Waterson, J; Rogers, R; Levine, J; Amalfitano, A; Charrow, J; Tiller, G; Schaefer, B; Kolodny, E; Corzo, D; Chen, YT
2004 JUL-AUG ;6(4):268-268, Genetics in medicine
— id: 48692, year: 2004, vol: 6, page: 268, stat: Journal Article,

Enzyme replacement therapy for infantile onset Pompe disease: long term follow-up results
Kishnani, P; Nicolino, M; Voit, T; Tsai, CH; Herman, G; Waterson, J; Rogers, RC; Levine, J; Amalfitano, A; Charrow, J; Tiller, G; Schaefer, B; Kolodny, E; Corzo, D; Chen, YT
2004 MAR ;81(3):169-169, Molecular genetics & metabolism
— id: 42476, year: 2004, vol: 81, page: 169, stat: Journal Article,

Late-onset Tay-Sachs disease: natural history and treatment with OGT 918 (Zavesca (TM))
Kolodny, EH; Neudorfer, O; Gianutsos, J; Zaroff, C; Barnett, N; Zeng, B; Raghavan, S; Torres, P; Pastores, G
2004 AUG ;90(5):54-54, Journal of neurochemistry
— id: 46902, year: 2004, vol: 90, page: 54, stat: Journal Article,

Late-onset Tay-Sachs disease
Neudorfer, Orit; Kolodny, Edwin H
2004 Feb;6(2):107-111, Israel Medical Association journal
— id: 42582, year: 2004, vol: 6, page: 107, stat: Journal Article,

Gaucher disease type 1: revised recommendations on evaluations and monitoring for adult patients
Weinreb, Neal J; Aggio, Mario C; Andersson, Hans C; Andria, Generoso; Charrow, Joel; Clarke, Joe T R; Erikson, Anders; Giraldo, Pilar; Goldblatt, Jack; Hollak, Carla; Ida, Hiroyuki; Kaplan, Paige; Kolodny, Edwin H; Mistry, Pramod; Pastores, Gregory M; Pires, Ricardo; Prakash-Cheng, Ainu; Rosenbloom, Barry E; Scott, C Ronald; Sobreira, Elisa; Tylki-Szymanska, Anna; Vellodi, Ashok; vom Dahl, Stephan; Wappner, Rebecca S; Zimran, Ari
2004 Oct;41(4 Suppl 5):15-22, Seminars in hematology
For patients with type 1 Gaucher disease, challenges to patient care posed by clinical heterogeneity, variable progression rates, and potential permanent disability that can result from untreated or suboptimally treated hematologic, skeletal, and visceral organ involvement dictate a need for comprehensive, serial monitoring. An updated consensus on minimum recommendations for effective monitoring of all adult patients with type 1 Gaucher disease has been developed by the International Collaborative Gaucher Group (ICGG) Registry coordinators. These recommendations provide a schedule for comprehensive and reproducible evaluation and monitoring of all clinically relevant aspects of this disease. The initial assessment should include confirmation of deficiency of beta-glucocerebrosidase, genotyping, and a complete family medical history. Other assessments to be performed initially and at regular intervals include a complete physical examination, patient-reported quality of life using the SF-36 survey, and assessment of hematologic (hemoglobin and platelet count), visceral, and skeletal involvement, and biomarkers. Specific radiologic imaging techniques are recommended for evaluating visceral and skeletal pathology. All patients should undergo comprehensive regular assessment, the frequency of which depends on treatment status and whether therapeutic goals have been achieved. Additionally, reassessment should be performed whenever enzyme therapy dose is altered, or in case of significant clinical complication
— id: 62687, year: 2004, vol: 41, page: 15, stat: Journal Article,

Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase)
Wraith, James E; Clarke, Lorne A; Beck, Michael; Kolodny, Edwin H; Pastores, Gregory M; Muenzer, Joseph; Rapoport, David M; Berger, Kenneth I; Swiedler, Stuart J; Kakkis, Emil D; Braakman, Tanja; Chadbourne, Elenie; Walton-Bowen, Karen; Cox, Gerald F
2004 May;144(5):581-588, Journal of pediatrics
OBJECTIVE: To confirm the efficacy and safety of recombinant human alpha-L-iduronidase (laronidase) in patients with mucopolysaccharidosis I (MPS I). STUDY DESIGN: This was a randomized, double-blinded, multinational study of 45 patients with MPS I administered 100 U/kg (0.58 mg/kg) laronidase, or placebo intravenously weekly for 26 weeks. The coprimary efficacy end points compared the median change from baseline to week 26 between groups in percentage of predicted normal forced vital capacity (FVC) and in 6-minute walk test (6MWT) distance through the use of the Wilcoxon rank sum test. RESULTS: The laronidase (n=22) and placebo (n=23) groups had similar baseline characteristics. After 26 weeks, patients receiving laronidase compared with placebo showed mean improvements of 5.6 percentage points in percent of predicted normal FVC (median, 3.0; P=.009) and 38.1 meters in 6MWT distance (median, 38.5; P=.066; P=.039, analysis of covariance). Laronidase also significantly reduced hepatomegaly and urinary glycosaminoglycans, and, in more severely affected patients, improved sleep apnea/hypopnea and shoulder flexion. Laronidase was well-tolerated. Nearly all patients receiving enzyme had development of IgG antibodies, without apparent clinical effects. CONCLUSIONS: In patients with MPS I, laronidase significantly improves respiratory function and physical capacity, reduces glycosaminoglycan storage, and has a favorable safety profile
— id: 43226, year: 2004, vol: 144, page: 581, stat: Journal Article,

Neuropsychological assessment of patients with late onset GM2 gangliosidosis
Zaroff, C M; Neudorfer, O; Morrison, C; Pastores, G M; Rubin, H; Kolodny, E H
2004 Jun 22;62(12):2283-2286, Neurology
OBJECTIVE: To characterize cognitive status in a sample of individuals with late-onset GM2 gangliosidosis (commonly referred to as late-onset Tay-Sachs disease). METHODS: Seventeen subjects (13 men, 4 women) diagnosed with GM2 gangliosidosis were evaluated. Subjects ranged in age from 18 to 56 years and were in various stages of disease progression. Subjects underwent comprehensive neuropsychological assessment. Impairment was defined as performance more than 1.6 SD below the normative mean. RESULTS: Group mean performance was within the denoted normal range on all measures except on a task assessing visual sequencing and set shifting. Approximately one-half of the sample scored in the impaired range on measures of processing speed, visual sequencing, and set shifting. One-third of the sample also scored in the impaired range on measures of delayed verbal recall. Impairment tended to be restricted to a subset of the sample, as 5 of the 14 subjects able to undergo formal testing accounted for 70% of the total number of impaired scores. If the three subjects unable to participate in formal testing are also considered impaired, 47% of the current sample exhibited significant cognitive impairment in at least one cognitive domain. CONCLUSION: In late-onset GM2 gangliosidosis, there is a risk of impairment in executive functioning and memory as well as cerebellar dysfunction. Dementia was not present in any subjects in the current sample
— id: 47856, year: 2004, vol: 62, page: 2283, stat: Journal Article,

Effects of Aldurazyme (R) (laronidase) on joint mobility in MPS I
Bajbouj, M; Beck, M; Wraith, JE; Clarke, LA; Kolodny, EH; Pastores, GM; Muenzer, J
2003 NOV ;73(5):621-621, American journal of human genetics
— id: 74928, year: 2003, vol: 73, page: 621, stat: Journal Article,

Aldurazyme (R) (laronidase) enzyme replacement therapy for MPS I: 48-week extension data
Clarke, LA; Wraith, JE; Beck, M; Kolodny, EH; Pastores, GM
2003 NOV ;73(5):623-623, American journal of human genetics
— id: 74929, year: 2003, vol: 73, page: 623, stat: Journal Article,

Demography of untreated Type 1 Gaucher disease (GD1) in children
Kaplan, P; Andersson, HC; Charrow, J; Prakash-Cheng, A; Kolodny, EH; Mistry, P; Pastores, GM; Rosenbloom, B; Scott, CR; Wappner, RS; Weinreb, N
2003 NOV ;73(5):456-456, American journal of human genetics
— id: 74927, year: 2003, vol: 73, page: 456, stat: Journal Article,

Glycosphingolipid reduction in fibroblasts of Tay-Sachs disease patients treated with n-butyldeoxynojirimycin
Ong, E; Raghavan, S; Pastores, G; Kolodny, EH
2003 MAY ;85(9):68-68, Journal of neurochemistry
— id: 38572, year: 2003, vol: 85, page: 68, stat: Journal Article,

A neurological symptom survey of patients with type I Gaucher disease
Pastores, G M; Barnett, N L; Bathan, P; Kolodny, E H
2003 ;26(7):641-645, Journal of inherited metabolic disease
Gaucher disease is an inborn error of glycosphingolipid metabolism resulting from deficiency of the lysosomal enzyme glucocerebrosidase. The majority of the patients (with type I disease) do not have primary central nervous system involvement. However, several studies have noted that secondary neurological complications may develop as a consequence of nerve root or spinal cord compression following vertebral body collapse or, for those with coagulation disorders, bleeding within confined compartments. An epidemiological survey was conducted to ascertain the incidence of neurological symptoms in patients with Gaucher disease type I (GD I). The survey included a review of the patients' medical history, an estimate of Gaucher disease severity according to a modified Symptom Severity Index (SSI), and completion of a questionnaire regarding their neurological status and Quality of Life (QoL) according to the SF-36 Health Survey. Seventy-three per cent of respondents were found to have experienced at least one neurological complaint in the preceding 3 months. Adult patients with Gaucher disease often have other medical problems unrelated to their primary diagnosis. Thus, the high incidence of neurological complaints in these patients may be attributable to concurrent medical problems and/or side-effects from concomitant medications. These issues may influence patients' assessment of their disease severity and/or response to treatment
— id: 46030, year: 2003, vol: 26, page: 641, stat: Journal Article,

The clinical benefit of Aldurazyme (R) (laronidase) for the treatment of MPS I
Pastores, GM; Wraith, JE; Clarke, LA; Beck, M; Kolodny, EH; Muenzer, J; Cox, FG; Skrinar, AM
2003 NOV ;73(5):624-624, American journal of human genetics
— id: 74930, year: 2003, vol: 73, page: 624, stat: Journal Article,

Incidence of malignancies among adult patients with type I Gaucher disease: Data from a single referral clinic and from the International Gaucher Registry (ICGG)
Zimran, A; Rosenbloom, B; Andersson, HC; Charrow, J; Kaplan, P; Kolodny, EH; Mistry, P; Prakash-Cheng, A; Scott, CR; Wappner, RS; Weinreb, NJ; Elstein, D
2003 NOV 16 ;102(11):43B-43B, Blood
— id: 74926, year: 2003, vol: 102, page: 43B, stat: Journal Article,

RhIDU enzyme replacement therapy for MPS 1: 24-week extension study
Clarke, LA; Muenzer, J; Kolodny, EH; Pastores, GM; Beck, M; Wraith, JE
2002 OCT ;71(4):581-581, American journal of human genetics
— id: 74932, year: 2002, vol: 71, page: 581, stat: Journal Article,

Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain
Janson, Christopher; McPhee, Scott; Bilaniuk, Larissa; Haselgrove, John; Testaiuti, Mark; Freese, Andrew; Wang, Dah-Jyuu; Shera, David; Hurh, Peter; Rupin, Joan; Saslow, Elizabeth; Goldfarb, Olga; Goldberg, Michael; Larijani, Ghassem; Sharrar, William; Liouterman, Larisa; Camp, Angelique; Kolodny, Edwin; Samulski, Jude; Leone, Paola
2002 Jul 20;13(11):1391-1412, Human gene therapy
This clinical protocol describes virus-based gene transfer for Canavan disease, a childhood leukodystrophy. Canavan disease, also known as Van Bogaert-Bertrand disease, is a monogeneic, autosomal recessive disease in which the gene coding for the enzyme aspartoacylase (ASPA) is defective. The lack of functional enzyme leads to an increase in the central nervous system of the substrate molecule, N-acetyl-aspartate (NAA), which impairs normal myelination and results in spongiform degeneration of the brain. No effective treatment currently exists; however, virus-based gene transfer has the potential to arrest or reverse the course of this otherwise fatal condition. This procedure involves neurosurgical administration of approximately 900 billion genomic particles (approximately 10 billion infectious particles) of recombinant adeno-associated virus (AAV) containing the aspartoacylase gene (ASPA) directly to affected regions of the brain in each of 21 patients with Canavan disease. Pre- and post-delivery assessments include a battery of noninvasive biochemical, radiological, and neurological tests. This gene transfer study represents the first clinical use of AAV in the human brain and the first instance of viral gene transfer for a neurodegenerative disease
— id: 62689, year: 2002, vol: 13, page: 1391, stat: Journal Article,

Anderson-Fabry disease: extrarenal, neurologic manifestations
Kolodny, Edwin H; Pastores, Gregory M
2002 Jun;13 Suppl 2(3):S150-S153, Journal of the American Society of Nephrology
— id: 39626, year: 2002, vol: 13 Suppl 2, page: S150, stat: Journal Article,

Therapeutic effects of astrocytes expressing both tyrosine hydroxylase and brain-derived neurotrophic factor on a rat model of Parkinson's disease
Wang, Z H; Ji, Y; Shan, W; Zeng, B; Raksadawan, N; Pastores, G M; Wisniewski, T; Kolodny, E H
2002 ;113(3):629-640, Neuroscience
Tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF), expressed in normal astrocytes, were used in combination for the treatment of Parkinson's disease (PD) symptoms in a rat model. Normal neonatal rat astrocytes were co-transfected with a vector expressing BDNF (AAVBDNF) and a retroviral vector expressing TH (termed TH-BDNF-DA(+) cells), and then implanted into the striatum of PD rats induced by 6-hydroxydopamine. TH-BDNF-DA(+) cells compensated for a severe insufficiency of endogenous dopaminergic neurons in the PD rats, resulting in a significant improvement of PD symptoms. The decrease in the rotational rate of PD rats implanted with TH-BDNF-DA(+) cells was more marked than that in PD rats implanted with normal astrocytes expressing either TH or BDNF alone (termed TH(+) and BDNF(+) cells, P<0.01 and 0.001, respectively), and suggested a synergistic effect between TH and BDNF. In contrast, the rotational rate was not altered from the baseline in PD rats without treatment or implanted with parental rat astrocytes alone (P>0.05). BDNF protected the dopaminergic neurons from apoptosis induced by 6-hydroxydopamine, and significantly increased the long-term survival of TH-positive cells in the striatum.Our data indicate that the combined use of TH and BDNF has a synergistic therapeutic effect, and is more efficient for the treatment of PD than a single gene therapy using either TH or BDNF alone
— id: 39612, year: 2002, vol: 113, page: 629, stat: Journal Article,

Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry
Weinreb, Neal J; Charrow, Joel; Andersson, Hans C; Kaplan, Paige; Kolodny, Edwin H; Mistry, Pramod; Pastores, Gregory; Rosenbloom, Barry E; Scott, C Ronald; Wappner, Rebecca S; Zimran, Ari
2002 Aug 1;113(2):112-119, American journal of medicine
PURPOSE: Gaucher disease is the first lysosomal storage disorder to be treated with macrophage-targeted enzyme replacement therapy. Previous studies in relatively small numbers of patients demonstrated short-term efficacy of this treatment. This study describes the effects of 2 to 5 years of treatment on specific manifestations of type 1 Gaucher disease. SUBJECTS AND METHODS: Physicians reported data from 1028 patients to the Gaucher Registry. Assessment of response included serial measurements of hemoglobin concentration, platelet count, liver and spleen volumes, and the occurrence of bone pain and bone crises. RESULTS: Among anemic patients, hemoglobin concentration increased to normal or near normal within 6 to 12 months, with a sustained response through 5 years. In thrombocytopenic patients with intact spleens, the most rapid response occurred during the first 2 years, with slower improvement thereafter. The likelihood of achieving a normal platelet count decreased with increasing severity of baseline thrombocytopenia. In patients who had undergone splenectomy, platelet counts returned to normal within 6 to 12 months. Hepatomegaly decreased by 30% to 40% during follow-up; splenomegaly decreased 50% to 60%, but rarely to volumes below five times normal size. In patients with pretreatment bone pain or bone crises, 52% (67/128) were pain free after 2 years and 94% (48/51) reported no additional crises. CONCLUSION: Enzyme replacement therapy prevents progressive manifestations of Gaucher disease, and ameliorates Gaucher disease-associated anemia, thrombocytopenia, organomegaly, bone pain, and bone crises
— id: 62690, year: 2002, vol: 113, page: 112, stat: Journal Article,

Massive and partially refractory splenomegaly significantly influences the platelet (PLT) response to enzyme replacement therapy (ERT) in thrombocytopenic patients with Gaucher disease (GD): Report from the Gaucher Registry
Weinreb, NJ; Andersson, H; Charrow, J; Kaplan, P; Kolodny, EH; Mistry, PK; Pastores, G; Prakash-Cheng, A; Rosenbloom, BE; Scott, CR; Wappner, RS
2002 NOV 16 ;100(11):485A-485A, Blood
— id: 74931, year: 2002, vol: 100, page: 485A, stat: Journal Article,

Identification and characterization of novel mutations of the aspartoacylase gene in non-Jewish patients with Canavan disease
Zeng, B J; Wang, Z H; Ribeiro, L A; Leone, P; De Gasperi, R; Kim, S J; Raghavan, S; Ong, E; Pastores, G M; Kolodny, E H
2002 Nov;25(7):557-570, Journal of inherited metabolic disease
Canavan disease, an inherited leukodystrophy, is caused by mutations in the aspartoacylase (ASPA) gene. It is most common among children of Ashkenazi Jewish descent but has been diagnosed in many diverse ethnic groups. Two mutations comprise the majority of mutant alleles in Jewish patients, while mutations in the ASPA gene among non-Jewish patients are different and more diverse. In the present study, the ASPA gene was analysed in 22 unrelated non-Jewish patients with Canavan disease, and 24 different mutations were found. Of these, 14 are novel, including five missense mutations (E24G, D68A, D249V, C152W, H244R), two nonsense mutations (Q184X, E214X), three deletions (923delT, 33del13, 244delA), one insertion mutation (698insC), two sequence variations in one allele ([10T>G; 11insG]), an elimination of the stop codon (941A>G, TAG-->TGG, X314W), and one splice acceptor site mutation (IVS1 - 2A>T). The E24G mutation resulted in substitution of an invariable amino acid residue (Glu) in the first esterase catalytic domain consensus sequence. The IVS1 - 2A>T mutation caused the retention of 40 nucleotides of intron 1 upstream of exon 2. The results of transient expression of the mutant ASPA cDNA containing these mutations in COS-7 cells and assays for ASPA activity of patient fibroblasts indicated that these mutations were responsible for the enzyme deficiency. In addition, patients with the novel D249V mutation manifested clinically at birth and died early. Also, patients with certain other novel mutations, including C152W, E214X, X314W, and frame shift mutations in both alleles, developed clinical manifestations at an earlier age than in classical Canavan disease
— id: 39272, year: 2002, vol: 25, page: 557, stat: Journal Article,

Growth improvement in response to enzyme replacement therapy (ERT) among children with Gaucher disease: The Gaucher Registry
Kaplan, P; Andersson, HC; Charrow, J; Kolodny, EH; Mistry, P; Pastores, GM; Rosenbloom, BE; Scott, CR; Wappner, RS; Weinreb, NJ
2001 OCT ;69(4):674-674, American journal of human genetics
— id: 74935, year: 2001, vol: 69, page: 674, stat: Journal Article,

Molecular genetics of the beta-hexosaminidase isoenzymes: an introduction
Kolodny EH
2001 ;44(3):101-126, Advances in genetics
— id: 39475, year: 2001, vol: 44, page: 101, stat: Journal Article,

Rapid detection of the two common mutations in Ashkenazi Jewish patients with mucolipidosis type IV
Wang ZH; Zeng B; Pastores GM; Raksadawan N; Ong E; Kolodny EH
2001 Summer;5(2):87-92, Genetic testing
Among Ashkenazi Jewish individuals with mucolipidosis IV (ML IV), two mutations in the ML IV gene, IVS3-1A --> G and delEX1-EX7, account for more than 95% of disease alleles. The reported method of genotyping for the delEX1-EX7 mutation involves a cumbersome multistep procedure. In the present study, a new simplified one-step procedure is described that detects this mutation in both patients and carriers. An improved procedure is also described for detection of the IVS3-1A --> G mutation. Using these improved procedures, we have characterized the ML IV mutant alleles in 27 patients and 95 of their relatives from 22 families, and in 123 unrelated and unaffected Ashkenazi Jewish controls. Of the 27 ML IV patients, 16 patients (59.3%) were found to be homozygous for the IVS3-1A --> G mutation and 1 patient (3.7%) homozygous for the delEX1-EX7 mutation. Additionally, 9 patients (33.3%) were compound heterozygotes for IVS3-1A --> G/delEX1-EX7. Among the 123 Ashkenazi Jewish controls, two individuals were identified as heteroallelic with one IVS3-1A --> G mutation (carrier frequency: approximately 1 in 61); none showed the delEX1-EX7 mutation. The modifications described here provide a more facile means of genotyping patients and carriers and expand the possibilities for screening at-risk populations
— id: 39483, year: 2001, vol: 5, page: 87, stat: Journal Article,

The major mutation in mucolipidosis IV among Ashkenazi Jewish individuals requires further clarification. (vol 5, pg 87, 2001)
Wang, ZH; Zeng, B; Pastores, GM; Raksadawan, N; Ong, E; Kolodny, EH
2001 ;5(3):273-273 FAL, Genetic testing
— id: 74933, year: 2001, vol: 5, page: 273, stat: Journal Article,

Clinical factors influencing the achievement of a complete response (CR) after 24 months of enzyme replacement therapy (ERT) in patients with Gaucher disease (GD): The Gaucher Registry
Weinreb, NJ; Andersson, HC; Charrow, J; Kaplan, P; Kolodny, EH; Mistry, P; Pastores, G; Rosenbloom, BE; Scott, CR; Wappner, RS
2001 NOV 16 ;98(11):20A-20A, Blood
— id: 74934, year: 2001, vol: 98, page: 20A, stat: Journal Article,

The Gaucher Registry: Demographics and disease characteristics and response to enzyme replacement therapy (ERT) for 78 pediatric patients (pts)
Andersson, H; Charrow, J; Kaplan, P; Kolodny, EH; Mistry, P; Pastores, G; Rosenbloom, BE; Wappner, RS
2000 NOV 16 ;96(11):8A-8A, Blood
— id: 74936, year: 2000, vol: 96, page: 8A, stat: Journal Article,

Polyglucosan body myopathy
Carniciu, S; Kiprovski, K; Levine, DN; ZagZag, D; Bronfin, L; Kolodny, EH
2000 SEP ;48(3):440-440, Annals of neurology
— id: 74939, year: 2000, vol: 48, page: 440, stat: Journal Article,

The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease
Charrow, J; Andersson, H C; Kaplan, P; Kolodny, E H; Mistry, P; Pastores, G; Rosenbloom, B E; Scott, C R; Wappner, R S; Weinreb, N J; Zimran, A
2000 Oct 9;160(18):2835-2843, Archives of internal medicine
BACKGROUND: The Gaucher Registry, the largest database of patients with Gaucher disease (GD) worldwide, was initiated to better delineate the progressive nature of the disorder and determine optimal therapy. This report describes the demographic and clinical characteristics of 1698 patients with GD before they received enzyme replacement therapy. METHODS: Physicians worldwide who treat patients with GD were invited to submit prospective and retrospective data for an ongoing registry, using standardized data collection forms, for central processing and review. RESULTS: Most patients were from the United States (45%) and Israel (17%), but patients are from 38 countries. Most (94%) had type 1 GD, fewer than 1% had type 2, and 5% had type 3. Mutant allele frequency data, available for 45% of patients, showed the most common alleles to be N370S (53%), L444P (18%), 84GG (7%), and IVS2+1 (2%). Twenty-five percent of L444P homozygotes (13 of 52 patients) had type 1 GD phenotype. Mean age at diagnosis in patients with the N370S/N370S genotype was 27.2 years (SD, 19.7 years); in L444P/L444P patients, 2. 3 years (SD, 3.2 years). Histories of bone pain and radiological bone disease were reported by 63% and 94% of patients, respectively; both were more likely in asplenic patients than in patients with spleens. Mean spleen and liver volumes were 19.8 and 2.0 multiples of normal, respectively. Anemia and thrombocytopenia were present in 64% and 56%, respectively. Thrombocytopenia was present in 13% of asplenic patients. CONCLUSIONS: The Gaucher Registry permits a comprehensive understanding of the clinical spectrum of GD because of the uniquely large sample size. The Registry will be useful in evaluating the effects of specific therapies in GD and the possible influences of environment, ethnicity, and genotype on the natural history of the disorder
— id: 75015, year: 2000, vol: 160, page: 2835, stat: Journal Article,

Measurements from normal umbilical cord blood of four lysosomal enzymatic activities: alpha-L-iduronidase (Hurler), galactocerebrosidase (globoid cell leukodystrophy), arylsulfatase A (metachromatic leukodystrophy), arylsulfatase B (Maroteaux-Lamy)
deGasperi R; Raghavan SS; Sosa MG; Kolodny EH; Carrier C; Rubenstein P; Peters C; Wagner J; Kurtzberg J; Krivit W
2000 Mar;25(5):541-544, Bone marrow transplantation
Umbilical cord blood (UCB) has received increasing attention as a source of unrelated hematopoietic stem cells for transplantation. Lysosomal diseases have been effectively treated and normal enzymatic activity has occurred subsequent to engraftment using UCB. The use of donor cells with normal amounts of enzyme, rather than those from carriers whose level may be 50% or less, is an obvious goal. The frequency of such heterozygotes varies from 1:10 to 1:140 or lower depending upon the disease at issue. We assayed the levels of lysosomal enzymes in normal UCB in random samples as well as those used for transplantation. We measured the following enzymatic activities: alpha-l-iduronidase (Hurler), galactocerebrosidase (globoid cell leuko- dystrophy) and arylsulfatase A (metachromatic leukodystrophy). For the latter, levels of activity in UCB are comparable to those found in adult blood. In the case of arylsulfatase B (Maroteaux-Lamy) a level lower than adult level was found. An informed choice by the transplanting physician based on the activity of the relevant enzyme in the UCB donor will provide a better opportunity for an improved prognosis for more complete correction of the recipient's primary disease. Bone Marrow Transplantation (2000) 25, 541-544
— id: 11805, year: 2000, vol: 25, page: 541, stat: Journal Article,

Lower limb cold exposure induces pain and prolonged small fiber dysfunction in Fabry patients
Hilz MJ; Stemper B; Kolodny EH
2000 Feb;84(2-3):361-365, Pain
In Fabry disease, an X-linked alpha-galactosidase A deficiency, painful crises and limb paresthesias are possibly linked to thermal exposure. Small nerve fiber function has not yet been tested after cold challenge. In two Fabry patients (15 and 17 years old), their heterozygote mother, their healthy sister, and eight controls, we determined warm and cold perception thresholds at the dorsal foot and the lower medial calf (method of limits, Somedic-Thermotest), before and 1, 5, 10 and 15 min after 30 s immersion of one leg into 5 degrees C water. Discomfort was rated from 0 to 10. At baseline, thermal thresholds of all participants were normal. In contrast to controls, the patients tolerated 30 s cold stimulation only with interruptions. The mother aborted stimulation after 6 s because of pain. The patients and their mother reported intense burning pain and numbness during and after stimulation. After cold exposure, thermal sensation was highly abnormal for 20 min in one and 80 min in the other brother. In controls, thermal thresholds were somewhat elevated after stimulation but normalized within 10.0+/-4.6 min. Discomfort during cold exposure was rated 8-10 by the patients and their mother, but 3-5 by the healthy persons.We assume that glycolipid accumulation in cutaneous and vasa nervorum vessels as well as small nerve axons accounts for skin and small fiber malperfusion during cold induced vasoconstriction. Transitory ischemia initiated burning pain and prolonged small fiber dysfunction
— id: 37038, year: 2000, vol: 84, page: 361, stat: Journal Article,

Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease
Hobson, G M; Davis, A P; Stowell, N C; Kolodny, E H; Sistermans, E A; de Coo, I F; Funanage, V L; Marks, H G
2000 Oct 24;55(8):1089-1096, Neurology
BACKGROUND: Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive dysmyelinating disorder of the CNS. Duplications or point mutations in exons of the proteolipid protein (PLP) gene are found in most patients. OBJECTIVE: To describe five patients with PMD who have mutations in noncoding regions of the PLP gene. METHODS: Quantitative multiplex PCR and Southern blot analyses were used to detect duplication of the PLP gene, and DNA sequence analysis, including exon-intron borders, was used to detect mutation of the PLP gene. RESULTS: Duplication of the PLP gene was ruled out, and mutations were identified in noncoding regions of five patients in four families with PMD. In two brothers with a severe form of PMD, a G to T transversion at IVS6+3 was detected. This mutation resulted in skipping of exon 6 in the PLP mRNA of cultured fibroblasts. A patient who developed nystagmus at 16 months and progressive spastic ataxia at 18 months was found to have a 19-base pair (bp) deletion of a G-rich region near the 5' end of intron 3 of the PLP gene. A patient with a T to C transition at IVS3+2 and a patient with an A to G transition at IVS3+4 have the classic form of PMD. These, like the 19-bp deletion, are in intron 3, which is involved in PLP/DM20 alternative splice site selection. CONCLUSIONS: Mutations in introns of the PLP gene, even at positions that are not 100% conserved at splice sites, are an important cause of PMD
— id: 75014, year: 2000, vol: 55, page: 1089, stat: Journal Article,

Analysis of splice site mutations of the proteolipid protein (PLP) gene in Pelizaeus-Merzbacher disease
Hobson, GM; Sistermans, EA; de Coo, IFM; Stabley, D; Kolodny, EH; Funanage, VL; Garbern, JY; Marks, HG
2000 OCT ;67(4):374-374, American journal of human genetics
— id: 54433, year: 2000, vol: 67, page: 374, stat: Journal Article,

Results of a phase I clinical trial of allogeneic mesenchymal stem cell (MSC) transplantation in patients with Hurler disease and metachromatic leukodystrophy (MLD)
Koc, ON; Day, J; Brown, D; Andrews, P; Peters, C; Nieder, M; Gerson, SL; Lazarus, HM; Caplan, AI; Laughlin, MJ; Raghavan, S; Kolodny, EH; Krivit, W
2000 NOV 16 ;96(11):170A-170A, Blood
— id: 74938, year: 2000, vol: 96, page: 170A, stat: Journal Article,

Niemann-Pick disease
Kolodny EH
2000 Jan;7(1):48-52, Current opinion in hematology
Niemann-Pick disease, originally defined in terms of its histology as a reticuloendotheliosis, is now subdivided on the basis of biochemical and molecular criteria into two separate classes. This categorization has been aided by the discovery of the genes for acid sphingomyelinase, deficient in types A and B, and for the NPC-1 protein, deficient in types C and D, and the finding of mutations in each. Animal models of type A and type C disease are known or have been developed. These models have been utilized in therapeutic trials of bone marrow transplantation and gene transfection of stem cells and in studies of disease pathogenesis. Lysosphingomyelin has been implicated in the nervous system involvement associated with type A disease in humans and accumulations of the NPC-1 protein and apolipoprotein D have been found in murine NP-C brain. Cells from both human and murine Niemann-Pick disease type A have been studied to assess the role of acid sphingomyelinase in signal transduction pathways involving cell proliferation, differentiation, and apoptosis
— id: 11894, year: 2000, vol: 7, page: 48, stat: Journal Article,

Researching Neurometabolic Diseases: The Work of Dr.Roscoe O. Brady
Rowland, Lewis P; Kolodny, Edwin
[S.l.] : NIH, 2000,
— id: 1433, year: 2000, vol: , page: , stat: ,

Researching neurometabolic diseases : the work of Dr. Roscoe O. Brady
Rowland, Lewis P; Kolodny, Edwin H; Brady, Roscoe O
[Bethesda MD : National Institutes of Health], 2000,
— id: 1662, year: 2000, vol: , page: , stat: ,

Isolation and characterization of the normal canine beta-galactosidase gene and its mutation in a dog model of GM1-gangliosidosis
Wang ZH; Zeng B; Shibuya H; Johnson GS; Alroy J; Pastores GM; Raghavan S; Kolodny EH
2000 Sep;23(6):593-606, Journal of inherited metabolic disease
The acid beta-galactosidase cDNA of Portuguese Water dogs was isolated and sequenced. The entire coding region of the gene consists of 2004 nucleotides encoding a protein of 668 amino acids. Its encoding sequence indicates approximately 86.5% identity at the nucleotide level and about 81% identity at the amino acid level with the encoding region of the human acid beta-galactosidase gene. The deduced amino acid sequence contains a 24-amino-acid putative signal sequence, six possible glycosylation sites, and seven cysteine residues. A homozygous recessive mutation, causing canine GM1-gangliosidosis, was identified at nucleotide G200-->A in exon 2 resulting in an Arg60-->His (mutation R60H) amino acid substitution. The mutation creates a new restriction enzyme site for Pml1. Genotyping 115 dog samples for this acid beta-galactosidase gene alteration readily distinguished affected homozygous recessives (n=5), heterozygous carriers (n=50) and normal homozygotes (n=60). DNA mutation analysis provided a method more specific than enzyme assay of beta-galactosidase for determination of carriers
— id: 39537, year: 2000, vol: 23, page: 593, stat: Journal Article,

The Gaucher Registry: Severe bone disease among patients with Gaucher disease in the absence of significant hematologic abnormalities
Weinreb, NJ; Andersson, H; Charrow, J; Kaplan, P; Kolodny, EH; Mistry, P; Pastores, G; Rosenbloom, BE; Scott, CR; Wappner, RS
2000 NOV 16 ;96(11):8A-8A, Blood
— id: 74937, year: 2000, vol: 96, page: 8A, stat: Journal Article,

Gaucher disease - In reply
Charrow, J; Esplin, JA; Kaplan, P; Kolodny, EH; Pastores, GM; Scott, CR; Wappner, RS; Weinreb, NJ; Wisch, JS
1999 APR 26 ;159(8):881-882, Archives of internal medicine
— id: 74943, year: 1999, vol: 159, page: 881, stat: Journal Article,

Recommendations for diagnosis, evaluation, and monitoring of patients with Gaucher disease - In reply
Charrow, J; Esplin, JA; Kaplan, P; Kolodny, EH; Pastores, GM; Scott, CR; Wappner, RS; Weinreb, NJ; Wisch, JS
1999 JUN 14 ;159(11):1255-1255, Archives of internal medicine
— id: 74941, year: 1999, vol: 159, page: 1255, stat: Journal Article,

Molecular basis of late-life globoid cell leukodystrophy
De Gasperi R; Gama Sosa MA; Sartorato E; Battistini S; Raghavan S; Kolodny EH
1999 ;14(3):256-262, Human mutation
Globoid cell leukodystrophy is an autosomal recessive inherited disease caused by deficiency of the lysosomal enzyme galactocerebrosidase (GALC). Although the severe, rapidly progressing infantile form is the most common, late-onset forms have been described. We investigated the molecular basis of GALC deficiency in a patient with a late-life mild form of globoid cell leukodystrophy who survived into the eighth decade. Since material suitable for mutation analysis was no longer available from the proband, her GALC genotype was reconstructed by analyzing this gene in her six obligate carrier offspring. One allele contained the mutation 809G>A (G270D) in the 1637C background, while the other allele contained three sequence variants: 1609G>A (G537R), 1873G>A (A625T), and 1650T>A (V550V) in the 1637T background. These mutations were confirmed in the proband's genomic DNA isolated from a sural nerve biopsy. Expression studies indicated that the G537R is a disease-causing mutation, as it resulted in no GALC activity, either alone or together with the A625T. This A625T sequence variant did not affect the enzyme activity, at least when expressed in the 1637T background. The mild clinical phenotype was likely to be associated with the 809G>A, since residual GALC activity, about 17% of the control activity, was detected in the expression studies of this mutation. This mutation has been found in several other patients with late-onset GLD.
— id: 9849, year: 1999, vol: 14, page: 256, stat: Journal Article,

Glycolipid-like molecular mimicry of a human protein
Gama, Sosa M A; DeGasperi, R; Kolodny, E H
1999 Oct 23-28;25(1-2):998-998, Abstracts (Society for Neuroscience)
— id: 15851, year: 1999, vol: 25, page: 998, stat: Journal Article,

Sympathetic skin response following thermal, electrical, acoustic, and inspiratory gasp stimulation in familial dysautonomia patients and healthy persons
Hilz MJ; Azelrod FB; Schweibold G; Kolodny EH
1999 Aug;9(4):165-177, Clinical autonomic research
To determine whether sympathetic skin response (SSR) testing evaluates afferent small or efferent sympathetic nerve fiber dysfunction, we studied SSR in patients with familial dysautonomia (FD) in whom both afferent small and efferent sympathetic fibers are largely reduced. We analyzed whether the response pattern to a combination of stimuli specific for large or small fiber activation allows differentiation between afferent and efferent small fiber dysfunction. In 52 volunteers and 13 FD patients, SSR was studied at palms and soles after warm, cold and heat as well as electrical, acoustic, and inspiratory gasp stimulation. In addition, thermal thresholds were assessed at four body sites using a Thermotest device (Somedic; Stockholm, Sweden). In volunteers, any stimulus induced reproducible SSRs. Only cold failed to evoke SSR in two volunteers. In all FD patients, electrical SSR was present, but amplitudes were reduced. Five patients had no acoustic SSR, four had no inspiratory SSR. Thermal SSR was absent in 10 patients with abnormal thermal perception and present in one patient with preserved thermal sensation. In two patients, thermal SSR was present only when skin areas with preserved temperature perception were stimulated. In patients with FD, preserved electrical SSR demonstrated the overall integrity of the SSR reflex but amplitude reduction suggested impaired sudomotor activation. SSR responses were dependent on the perception of the stimulus. In the presence of preserved electrical SSR, absent thermal SSR reflects afferent small fiber dysfunction. A combination of SSR stimulus types allows differentiation between afferent small or efferent sympathetic nerve fiber dysfunction
— id: 56486, year: 1999, vol: 9, page: 165, stat: Journal Article,

Quantitative thermal perception testing in adults
Hilz MJ; Stemper B; Axelrod FB; Kolodny EH; Neundorfer B
1999 Sep;16(5):462-471, Journal of clinical neurophysiology
In 225 adults aged 18 to 80 years, normative warm and cold perception thresholds were assessed at the volar distal forearm, thenar eminence, lower medial calf, and lateral dorsal foot using the method of limits and a Thermotest (Somedic, Stockholm, Sweden). A 1.5-cm x 2.5-cm thermode, a 1 degrees C/s stimulus change rate, and a 32 degrees C baseline temperature were applied. Thresholds of five consecutive stimuli were averaged. At the thenar eminence a 3 degrees C/s stimulation was applied in addition to the 1 degree C/s stimulation. Effects of spatial summation were studied at the calf and forearm by additional testing with a 2.5-cm x 5.0-cm thermode. To evaluate the influence of skin temperature, thresholds were correlated with the pretest skin temperature at the tested sites. Reproducibility of stimulus perception was determined by comparing the lowest to the highest response to five consecutive stimuli. Results showed sufficient accuracy of thermal perception thresholds. Thresholds were higher with the 3 degrees C/s stimulation than with the 1 degree C/s stimulation. Thresholds were lower with the large than with the small probe. Skin temperature had only minimal influence on thresholds. The use of a 32 degrees C baseline temperature and a 1 degree C/s stimulus change rate is recommended. The large probe should be used at body sites where the entire thermode surface adjusts planely to the skin. Warming up the tested skin area is not necessary before thermotesting
— id: 37039, year: 1999, vol: 16, page: 462, stat: Journal Article,

Mutations in noncoding regions of the proteolipid protein gene in patients with pelizaeus Merzbacher disease (PMD) and PMD-like disorders
Hobson, GM; Davis, A; Stowell, N; Funanage, VL; Kolodny, EH; Marks, HG
1999 SEP ;46(3):530-530, Annals of neurology
— id: 74940, year: 1999, vol: 46, page: 530, stat: Journal Article,

Mutations in non-coding regions of the proteolipid protein (PLP) gene in patients with Pelizaeus Merzbacher disease (PMD) and PMD-like disorders
Hobson, GM; Davis, A; Stowell, N; Kolodny, EH; Funanage, VL; Marks, HG
1999 OCT ;65(4):A301-A301, American journal of human genetics
— id: 53827, year: 1999, vol: 65, page: A301, stat: Journal Article,

Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases
Koc, O N; Peters, C; Aubourg, P; Raghavan, S; Dyhouse, S; DeGasperi, R; Kolodny, E H; Yoseph, Y B; Gerson, S L; Lazarus, H M; Caplan, A I; Watkins, P A; Krivit, W
1999 Nov;27(11):1675-1681, Experimental hematology
Human bone marrow contains mesenchymal stem cells (MSCs) that can differentiate into various cells of mesenchymal origin. We developed an efficient method of isolating and culture expanding a homogenous population of MSCs from bone marrow and determined that MSCs express alpha-L-iduronidase, arylsulfatase-A and B, glucocerebrosidase, and adrenoleukodystrophy protein. These findings raised the possibility that MSCs may be useful in the treatment of storage disorders. To determine if donor derived MSCs are transferred to the recipients with lysosomal or peroxisomal storage diseases by allogeneic hematopoietic stem cell (HSC) transplantation, we investigated bone marrow derived MSCs of 13 patients 1-14 years after allogeneic transplantation. Highly purified MSCs were genotyped either by fluorescence in situ hybridization using probes for X and Y-chromosomes in gender mis-matched recipients or by radiolabeled PCR amplification of polymorphic simple sequence repeats. Phenotype was determined by the measurement of disease specific protein/enzyme activity in purified MSCs. We found that MSCs isolated from recipients of allogeneic HSC transplantation are not of donor genotype and have persistent phenotypic defects despite successful donor type hematopoietic engraftment. Whether culture expanded normal MSCs can be successfully transplanted into patients with storage diseases and provide therapeutic benefit needs to be determined
— id: 75016, year: 1999, vol: 27, page: 1675, stat: Journal Article,

A gene involved in mucolipidosis type IV is located on chromosome 1
Kolodny, EH; Gordon, D; Brown, DM; De Gasperi, R; Ott, J; Sosa, MAG
1999 APR ;52(6):A316-A316, Neurology
— id: 74942, year: 1999, vol: 52, page: A316, stat: Journal Article,

G(M2)-ganglioside metabolism in situ in mucolipidosis IV fibroblasts
Raghavan S; Leshinsky E; Kolodny EH
1999 Apr;24(4):475-479, Neurochemical research
Mucolipidosis IV (ML IV) is an inherited lysosomal disorder for which the primary biochemical defect has not been identified. In order to detect any defect in glycosphingolipid metabolism, we have examined the metabolism of sphingosine-labeled (3H)G(M2) in situ in fibroblasts from patients diagnosed with ML IV. Fibroblasts were exposed for 10 days in medium containing (3H)G(M2) (15 uM; Sp. Act. 35000 cpm/nmole), washed, harvested and analyzed for radioactivity in extracted lipids. Control cells metabolized about half of the internalized ganglioside, mostly to ceramide. In ML IV fibroblasts, 70-80% of the cellular radioactivity was present as G(M2) indicating reduced degradation. This is not as severe as in G(M2) gangliosidosis as a small amount of G(M2) was metabolized in ML IV cells to ceramide. Since there is no defect in the lysosomal enzyme profile in these cells, it is possible that an abnormality in the translocation of membrane constituents to the lysosomes may explain the slower ganglioside metabolism
— id: 6109, year: 1999, vol: 24, page: 475, stat: Journal Article,

In vivo and in vitro glioma cell killing induced by an adenovirus expressing both cytosine deaminase and thymidine kinase and its association with interferon-alpha
Wang ZH; Zagzag D; Zeng B; Kolodny EH
1999 Aug;58(8):847-858, Journal of neuropathology & experimental neurology
An adenovirus, AdCDTK, expressing both bacterial cytosine deaminase (CD) and herpes simplex virus thymidine kinase (HSVTK) was constructed and introduced into glioma cells. AdCDTK selectively rendered glioma cells sensitive to both 5-fluorocytosine (5-FCyt) and ganciclovir (GCV) (termed AdCDTK/5-FCyt-GCV). AdCDTK/5-FCyt-GCV not only potently mediated apoptosis and the arrest of glioma cell growth in vitro, but also significantly increased the survival time of glioma-bearing rats as compared with controls. The 90-day survival time was observed in 50% of rats. Interferon-alpha (IFN-alpha) further enhanced the tumor cell killing of AdCDTK/5-FCyt-GCV. In the group of AdCDTK/5-FCyt-GCV/IFN-alpha, the average survival time was significantly increased, and the average tumor size was smaller than that in the group of AdCDTK/5-FCyt-GCV. Ninety-day survival increased from 50% in the group of AdCDTK/5-FCyt-GCV to 75% in the group of AdCDTK/5-FCyt-GCV/IFN-alpha. Complete tumor regression was observed in 50% of rats in the group of AdCDTK/5-FCyt-GCV/IFN-alpha. The data indicate that AdCDTK/5-FCyt-GCV induces glioma cell killing greater than that induced by either CD/5-FCyt or HSVTK/GCV alone. IFN-alpha synergistically enhances this effect by increasing apoptosis
— id: 57538, year: 1999, vol: 58, page: 847, stat: Journal Article,

Gaucher disease: recommendations on diagnosis, evaluation, and monitoring
Charrow, J; Esplin, J A; Gribble, T J; Kaplan, P; Kolodny, E H; Pastores, G M; Scott, C R; Wappner, R S; Weinreb, N J; Wisch, J S
1998 Sep 14;158(16):1754-1760, Archives of internal medicine
BACKGROUND: Timely diagnosis and continued monitoring of patients with type I Gaucher disease is critical because skeletal involvement can permanently disable patients and visceral organ involvement can lead to abdominal pain and secondary hematologic and biochemical complications. OBJECTIVE: To seek clinical consensus for minimum recommendations for effective diagnosis and monitoring of patients with type I Gaucher disease. PARTICIPANTS, EVIDENCE, AND CONSENSUS PROCESS: Contributing authors collaborated in quarterly meetings over a 2-year period to synthesize recommendations from peer-reviewed publications and their own medical experiences. These physicians care for most patients with Gaucher disease in the United States and serve as the US Regional Coordinators for the International Collaborative Gaucher Group Registry, the world's largest database for this disorder. CONCLUSIONS: The definitive method of diagnosis is enzyme assay of beta-glucocerebrosidase activity. Schedules differ for monitoring complications of type I Gaucher disease, depending on symptoms and whether enzyme replacement therapy is used. Hematologic and biochemical involvement should be assessed by complete blood cell count, including platelets, acid phosphatase, and liver enzymes, at baseline and every 12 months in untreated patients and every 3 months and at enzyme replacement therapy changes in treated patients. Visceral involvement should be assessed at diagnosis using magnetic resonance imaging or computed tomographic scans. Skeletal involvement should be assessed at diagnosis using T1- and T2-weighted magnetic resonance imaging of the entire femora and plain radiography of the femora, spine, and symptomatic sites. Follow-up skeletal and visceral assessments are recommended every 12 to 24 months in untreated patients, and every 12 months and at enzyme replacement therapy changes in treated patients
— id: 75017, year: 1998, vol: 158, page: 1754, stat: Journal Article,

Highly abnormal thermotests in familial dysautonomia suggest increased cardiac autonomic risk
Hilz MJ; Kolodny EH; Neuner I; Stemper B; Axelrod FB
1998 Sep;65(3):338-343, Journal of neurology neurosurgery & psychiatry
OBJECTIVE: Patients with familial dysautonomia have an increased risk of sudden death. In some patients with familial dysautonomia, sympathetic cardiac dysfunction is indicated by prolongation of corrected QT (QTc) interval, especially during stress tests. As many patients do not tolerate physical stress, additional indices are needed to predict autonomic risk. In familial dysautonomia there is a reduction of both sympathetic neurons and peripheral small nerve fibres which mediate temperature perception. Consequently, quantitative thermal perception test results might correlate with QTc values. If this assumption is correct, quantitative thermotesting could contribute to predicting increased autonomic risk. METHODS: To test this hypothesis, QTc intervals were determined in 12 male and eight female patients with familial dysautonomia, aged 10 to 41 years (mean 21.7 (SD 10.1) years), in supine and erect positions and postexercise and correlated with warm and cold perception thresholds assessed at six body sites using a Thermotest. RESULTS: Due to orthostatic presyncope, six patients were unable to undergo erect and postexercise QTc interval assessment. The QTc interval was prolonged (>440 ms) in two patients when supine and in two additional patients when erect and postexercise. Supine QTc intervals correlated significantly with thermal threshold values at the six body sites and with the number of sites with abnormal thermal perception (Spearman's rank correlation p<0.05). Abnormal Thermotest results were more frequent in the four patients with QTc prolongation and the six patients with intolerance to stress tests. CONCLUSION: The results suggest that impaired thermal perception correlates with cardiac sympathetic dysfunction in patients with familial dysautonomia. Thus thermotesting may provide an alternative, albeit indirect, means of assessing sympathetic dysfunction in autonomic disorders
— id: 7601, year: 1998, vol: 65, page: 338, stat: Journal Article,

Quantitative thermal perception testing in 225 children and juveniles
Hilz MJ; Stemper B; Schweibold G; Neuner I; Grahmann F; Kolodny EH
1998 Nov;15(6):529-534, Journal of clinical neurophysiology
Quantitative Thermotesting evaluates peripheral small nerve fiber function. The method of limits is a widely used algorithm of perception threshold determination. Normative data are needed to apply the method of limits in children and juveniles. In 225 healthy boys and girls, aged 7 to 17.9 years, warm and cold perception thresholds were established with the method of limits at the volar distal forearm, the thenar eminence, the lower medial calf, the lateral dorsal foot, and the cheek. A 1 degree C/s stimulus velocity, a 32 degrees C thermode baseline, and a 1.5-cm x 2.5-cm Thermotest stimulator were used. Accuracy of stimulus perception was studied by comparing the lowest to the highest response of five consecutive stimuli. The influence of different stimulator sizes on thresholds was tested at the lower calf and distal forearm with an additional 2.5-cm x 5.0-cm thermode. To determine the impact of the pretest skin temperature on thresholds, skin temperature was correlated with thresholds. Results showed good intratrial reproducibility of thresholds. The large thermode yielded lower thresholds than the small probe. Skin temperature had only minor influence on thresholds. The large probe should be used at body sites where it adjusts planely
— id: 6043, year: 1998, vol: 15, page: 529, stat: Journal Article,

[Mucolipidosis: clinical and genetic aspects]
Kolodny, E H
1998 Aug;27(156):337-341, Revista de neurologia
INTRODUCTION: The concept of the mucolipidoses developed as the result of encounters with patients whose clinical appearance suggested a mucopolysaccharidosis, i.e. coarse facies, short stature, skeletal dysplasia, joint contractures and lysosomal accumulations but did not have an excess of mucopolysaccharides in their urine. DEVELOPMENT: This clinical phenotype embraces the early onset forms of sialidosis (mucolipidosis I), as well as I-cell disease (mucolipidosis II) and pseudoHurler polydystrophy (mucolipidosis III). Two disorders that were later added to the mucolipidoses, the Cherry-red Spot Myoclonus Epilepsy Syndrome (sialidosis type I) and mucolipidosis IV differ in that the facial appearance is normal and they do no have skeletal dysmorphism. Enzyme deficiencies have been identified in mucolipidosis I, II and III. The basic molecular cause of mucolipidosis IV is not known but linkage analysis is underway to identify the chromosomal map position of the defective gene. Precise diagnosis of these autosomal recessively inherited diseases depends upon radiographic studies for skeletal dysplasias, analyses of urine for sialyloligosaccharides, morphologic studies of bone marrow and skin biopsy specimens and enzymatic determinations of sialidase and UDP-N-acetylglucosamine: lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. CONCLUSIONS: Case descriptions from the author's experience are presented to illustrate the use of a decision tree employing these diagnostic modalities. The existence of naturally-occurring animal models for sialidase deficiency (SM/J mouse) and the phosphotransferase deficiency (mucolipidosis III cat) provide opportunities to develop new therapeutic approaches
— id: 75018, year: 1998, vol: 27, page: 337, stat: Journal Article,

Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy
Krivit W; Shapiro EG; Peters C; Wagner JE; Cornu G; Kurtzberg J; Wenger DA; Kolodny EH; Vanier MT; Loes DJ; Dusenbery K; Lockman LA
1998 Apr 16;338(16):1119-1126, New England journal of medicine
BACKGROUND: Globoid-cell leukodystrophy is caused by a deficiency of galactocerebrosidase, which results in progressive central nervous system deterioration. We investigated whether allogeneic hematopoietic stem-cell transplantation can provide a source of leukocyte galactocerebrosidase and thereby prevent the decline of central nervous system function in patients with the disease. METHODS: Five children with globoid-cell leukodystrophy (one with the infantile type and four with late-onset disease) were treated with allogeneic hematopoietic stem-cell transplantation. Measurement of leukocyte galactocerebrosidase levels, neurologic examinations, neuropsychological tests, magnetic resonance imaging of the central nervous system, cerebrospinal fluid protein assays, and neurophysiologic measurements were performed before and after transplantation, with follow-up ranging from one to nine years. RESULTS: Engraftment of donor-derived hematopoietic cells occurred in all patients and was followed by restoration of normal leukocyte galactocerebrosidase levels. In the four patients with late-onset disease, the central nervous system deterioration was reversed, and in the patient with the infantile form of the disease, signs and symptoms have not appeared. Magnetic resonance imaging showed a decrease in signal intensity in the three patients with late-onset disease who were assessed both before and after transplantation. Abnormalities in cerebrospinal fluid total protein levels were corrected in three patients with late-onset disease and substantially reduced in the patient with the infantile form. CONCLUSIONS:Central nervous system manifestations of globoid-cell leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation
— id: 57184, year: 1998, vol: 338, page: 1119, stat: Journal Article,

Phenotypic genotypic correlation in patients with proteolipid protein gene abnormalities
Marks, HG; Kolodny, EH; Kobayashi, H; Hoffman, E; Graf, WD; Roe, E; Hobson, G
1998 SEP ;44(3):545-545, Annals of neurology
— id: 74944, year: 1998, vol: 44, page: 545, stat: Journal Article,

Clinical heterogeneity of familial spastic paraplegia linked to chromosome 2p21
Nance, M A; Raabe, W A; Midani, H; Kolodny, E H; David, W S; Megna, L; Pericak-Vance, M A; Haines, J L
1998 May-Jun;48(3):169-178, Human heredity
The clinical features of four families with autosomal dominant spastic paraparesis (FSP) are described, along with the results of linkage analysis to markers from the regions of chromosomes 2, 14, and 15 which are known to contain spastic paraplegia genes. All families had 'pure' spastic paraparesis (FSP), but the severity of symptoms varied widely among families, and other mild neurologic signs were observed in some subjects. Although no family individually yielded a lod score >3.0, all families yielded positive lod scores with chromosome 2 markers, and a maximal lod score of 5.7 was obtained for the families combined using marker D2S352. There was no evidence of linkage to chromosome 14 or 15 in any of the families
— id: 75019, year: 1998, vol: 48, page: 169, stat: Journal Article,

Cognitive functioning after pallidotomy for refractory Parkinson's disease [see comments]
Perrine K; Dogali M; Fazzini E; Sterio D; Kolodny E; Eidelberg D; Devinsky O; Beric A
1998 Aug;65(2):150-154, Journal of neurology neurosurgery & psychiatry
BACKGROUND: Earlier approaches to pallidotomy for refractory Parkinson's disease had significant complication rates. More recent approaches show fewer complications, but the effect of pallidotomy on cognition is unclear. The current study was conducted to examine the neuropsychological effects of unilateral pallidotomy. METHODS: Neuropsychological testing was performed on patients with medically refractory, predominantly unilateral Parkinson's disease at baseline and after unilateral ventral pallidotomy (n=28) or after an equivalent period without surgery in control patients (n=10). RESULTS: Pallidotomy patients showed no significant changes from baseline to retesting relative to the control group for any measure. Across all of the tests administered, only five of the surgery patients showed a significant decline, and of these five none declined on more than one test. Depression did not relate to preoperative or postoperative cognition. The pallidotomy group showed a significant improvement in motor functioning and activities of daily living whereas the control group did not. These measures were not associated with the neuropsychological test scores at baseline or retest. CONCLUSIONS: Stereotactic unilateral ventral pallidotomy does not seem to produce dramatic cognitive declines in most patients
— id: 7740, year: 1998, vol: 65, page: 150, stat: Journal Article,

5-Fluorocytosine-mediated apoptosis and DNA damage in glioma cells engineered to express cytosine deaminase and their enhancement with interferon
Wang ZH; Samuels S; Gama Sosa MA; Kolodny EH
1998 Feb;36(3):219-229, Journal of neuro-oncology
To explore the antitumor mechanism of bacterial cytosine deaminase plus 5-fluorocytosine (CD/5-FCyt) in combination with interferons (IFNs), glioma cells were transduced with recombinant retroviruses expressing CD. The transduced glioma cells become sensitive to the nontoxic prodrug 5-FCyt. Apoptosis, DNA damage, bystander effect, and inhibition of thymidylate synthase (TS) and DNA synthesis are associated with CD/5-FCyt-mediated glioma cell killing. Furthermore, IFNs enhance this effect by increasing DNA damage and further inhibiting TS activity. The bystander effect is mediated by the release of cytotoxic metabolites of 5-FCyt into the extracellular milieu triggering apoptosis and DNA damage. Our data indicate that the use of CD/5-FCyt in combination with IFNs may provide a more effective approach for the treatment of brain tumors
— id: 9850, year: 1998, vol: 36, page: 219, stat: Journal Article,

Adult-onset Krabbe's disease in siblings with novel mutations in the galactocerebrosidase gene
Bernardini GL; Herrera DG; Carson D; DeGasperi R; Gama Sosa MA; Kolodny EH; Trifiletti R
1997 Jan;41(1):111-114, Annals of neurology
Krabbe's disease or globoid cell leukodystrophy is a rare demyelinating disorder of the central and peripheral nervous systems, the diagnosis of which is based on clinical findings and the determination of low to absent functional activity of the enzyme beta-galactocerebrosidase. We report the presentation of late-onset Krabbe's disease in 2 siblings, a 17-year-old boy and his 16-year-old sister, both with marked deficiency of the enzyme beta-galactocerebrosidase. Only the older sibling manifested clinical signs and symptoms of the disease, while the younger sister remained asymptomatic to date. Molecular analyses disclosed the presence in this family of two novel single point mutations within the gene for galactocerebrosidase
— id: 9852, year: 1997, vol: 41, page: 111, stat: Journal Article,

Tetrahydrobiopterin (BH4): Cofactor for dopamine beta hydroxylase (D beta H)
Dashman, T; Samuels, S; Leshinsky-Silver, E; Kolodny, E; Axelrod, F
1997 JUL 31 ;11(9):A1311-A1311, FASEB journal
— id: 53458, year: 1997, vol: 11, page: A1311, stat: Journal Article,

An alteration in the alpha-chain propeptide is associated with beta-hexosaminidase A pseudodeficiency
De Gasperi, R; Sosa, MAG; Horowitz, M; Mitchell, DA; Lehrerfeld, T; Kolodny, EH
1997 OCT ;61(4):A250-A250, American journal of human genetics
— id: 53607, year: 1997, vol: 61, page: A250, stat: Journal Article,

Hereditary spastic paraplegia: LOD-score considerations for confirmation of linkage in a heterogeneous trait
Dube MP; Mlodzienski MA; Kibar Z; Farlow MR; Ebers G; Harper P; Kolodny EH; Rouleau GA; Figlewicz DA
1997 Mar;60(3):625-629, American journal of human genetics
Hereditary spastic paraplegia (HSP) is a degenerative disorder of the motor system, defined by progressive weakness and spasticity of the lower limbs. HSP may be inherited as an autosomal dominant (AD), autosomal recessive, or an X-linked trait. AD HSP is genetically heterogeneous, and three loci have been identified so far: SPG3 maps to chromosome 14q, SPG4 to 2p, and SPG4a to 15q. We have undertaken linkage analysis with 21 uncomplicated AD families to the three AD HSP loci. We report significant linkage for three of our families to the SPG4 locus and exclude several families by multipoint linkage. We used linkage information from several different research teams to evaluate the statistical probability of linkage to the SPG4 locus for uncomplicated AD HSP families and established the critical LOD-score value necessary for confirmation of linkage to the SPG4 locus from Bayesian statistics. In addition, we calculated the empirical P-values for the LOD scores obtained with all families with computer simulation methods. Power to detect significant linkage, as well as type I error probabilities, were evaluated. This combined analytical approach permitted conclusive linkage analyses on small to medium-size families, under the restrictions of genetic heterogeneity
— id: 18396, year: 1997, vol: 60, page: 625, stat: Journal Article,

Antisulfatide IgG antibodies recognize HIV proteins
Gama Sosa MA; De Gasperi R; Patarca R; Fletcher MA; Kolodny EH
1997 May 1;15(1):83-84, Journal of acquired immune deficiency syndromes & human retrovirology
— id: 8408, year: 1997, vol: 15, page: 83, stat: Journal Article,

Multiple mutations in the galactocerebrosidase gene are associated with a very mild late-onset form of globoid cell leukodystrophy
Kolodny, EH; Sosa, MAG; Battistini, S; Sartorato, E; Raghavan, S; DeGasperi, R
1997 SEP ;42(3):T197-T197, Annals of neurology
— id: 74945, year: 1997, vol: 42, page: T197, stat: Journal Article,

N-acetyl aspartoglutamate metabolism in brain: Application to Canavan disease
Leshinsky, E; Ribeiro, L; Gage, DA; Kolodny, EH
1997 SEP ;69(3):S192-S192, Journal of neurochemistry
— id: 74947, year: 1997, vol: 69, page: S192, stat: Journal Article,

Krabbe's disease presenting as a peripheral neuropathy
Marks, H G; Scavina, M T; Kolodny, E H; Palmieri, M; Childs, J
1997 Aug;20(8):1024-1028, Muscle & nerve
A 13-year-old female initially presented with scoliosis and pes cavus. Initial examination revealed distal lower extremity weakness and sensory loss, as well as greater auricular nerve hypertrophy. There was a Babinski sign on the right. Nerve conduction velocities were consistent with a demyelinating neuropathy. Four years after initial presentation she developed lower extremity spasticity and bilateral Babinski signs. Magnetic resonance imaging of the brain showed diffuse white matter disease. Laboratory evaluation revealed an abnormally low galactocerebroside beta-galactosidase level. Nerve biopsy demonstrated inclusions consisting of globoid clusters and evidence of demyelination. DNA analysis was used to identify mutations consistent with Krabbe's disease. Patients presenting with an atypical peripheral neuropathy should be evaluated for Krabbe's disease
— id: 75020, year: 1997, vol: 20, page: 1024, stat: Journal Article,

A human cell surface protein recognized by a anti-galactosylceramide monoclonal antibody
Sosa, MAG; DeGasperi, R; Battistini, S; Gorman, MP; Kolodny, R; Kolodny, EH
1997 SEP ;69(3):S5-S5, Journal of neurochemistry
— id: 74946, year: 1997, vol: 69, page: S5, stat: Journal Article,

Use of amphotropic recombinant SL3-3 retroviruses in the stable reversion of the Tay-Sachs phenotype in human brain cells
Sosa, MAG; DeGasperi, R; Sugandhi, NS; Lehrerfeld, TJ; Undevia, S; Kolodny, EH
1997 OCT ;61(4):A413-A413, American journal of human genetics
— id: 53618, year: 1997, vol: 61, page: A413, stat: Journal Article,

Correlation of glioma cell regression with inhibition of insulin-like growth factor 1 and insulin-like growth factor-binding protein-2 expression
Wang ZH; Ma J; Zeng BJ; Catanese VM; Samuels S; Gama Sosa MA; Kolodny EH
1997 Sep;66(3):203-211, Neuroendocrinology
To explore the antitumor effect of insulin-like growth factor 1 (IGF-I) antisense RNA and the interaction of IGF-I with insulin-like growth factor-binding proteins (IGFBPs) in glioma cells, a recombinant retrovirus expressing IGF-I antisense RNA was constructed and introduced into C6 glioma cells. IGF-I antisense RNA reverses the transformed phenotype in glioma cells and inhibits glioma cell growth by blocking overexpression of endogenous IGF-I. Expression of IGFBP-2 is increased in glioma cells as compared with normal adult glial cells. IGF-I antisense RNA also inhibits expression of IGFBP-2 in glioma cells, but does not influence expression of the other IGFBPs. Although IGFBP-2 in conditioned medium from wild-type C6 cell cultures itself does not directly influence glioma cell growth, it synergistically enhances exogenous IGF-I-mediated DNA synthesis in IGF-I-negative C6 cells. These findings indicate the inhibitory effect of IGF-I antisense RNA on growth and development of glioma cells. IGF-I-dependent glioma cell growth may, in some circumstances, require IGFBP-2 as a cofactor. The antitumor effect of IGF-I antisense RNA is also associated with inhibition of IGFBP-2 expression
— id: 9851, year: 1997, vol: 66, page: 203, stat: Journal Article,

Characteristics of pallidal neuronal discharges in Parkinson's disease patients
Beric A; Sterio D; Dogali M; Fazzini E; Eidelberg D; Kolodny E
1996 ;69:123-128, Advances in neurology
— id: 12696, year: 1996, vol: 69, page: 123, stat: Journal Article,

Late-onset Krabbe disease in galactosylceramide beta-galactosidase compound heterozygotes
Bernardini, GL; Herrera, DG; Carson, D; DeGasperi, R; Sosa, MAG; Kolodny, EH; Trifiletti, RR
1996 AUG ;40(2):56-56, Annals of neurology
— id: 74948, year: 1996, vol: 40, page: 56, stat: Journal Article,

Intrathecal synthesis of anti-sulfatide IgG is associated with peripheral nerve disease in acquired immunodeficiency syndrome
De Gasperi R; Angel M; Sosa G; Patarca R; Battistini S; Lamoreux MR; Raghavan S; Kowall NW; Smith KH; Fletcher MA; Kolodny EH
1996 Feb 10;12(3):205-211, AIDS research & human retroviruses
Peripheral nervous system involvement in the acquired immunodeficiency syndrome (AIDS) can take the form of an acute or chronic inflammatory demyelinating polyneuropathy, polyradiculopathy, mononeuropathy multiplex, or autonomic neuropathy. There is no widely held consensus on the etiology of PNS or other neurological complications associated with HIV infection. We report here that PNS disease in HIV-infected individuals is associated with intrathecal synthesis of an antibody directed against sulfatide, a major component of myelin. The anti-sulfatide antibody is also present nonspecifically in serum. The antibody requires the presence of the 3-O-sulfogalactosyl residue for binding and recognizes preferentially the hydroxy fatty acid-containing form of sulfatide. Anti-sulfatide antibodies are therefore one of the humoral factors responsible for demyelinating diseases in AIDS patients
— id: 6899, year: 1996, vol: 12, page: 205, stat: Journal Article,

Late-onset GM2 gangliosidosis: Ashkenazi Jewish family with an exon 5 mutation (Tyr180-->His) in the Hex A alpha-chain gene
De Gasperi R; Gama Sosa MA; Battistini S; Yeretsian J; Raghavan S; Zelnik N; Leshinsky E; Kolodny EH
1996 Aug;47(2):547-552, Neurology
Late-onset GM2 gangliosidosis is a variant form of Tay-Sachs disease characterized by onset of symptoms and signs in adolescence or in early adult life. The deficiency of beta-hexosaminidase A (Hex A) in this form of GM2 gangliosidosis has been invariably associated with the presence of the Gly269-->Ser substitution in the alpha-chain. We found two siblings of Ashkenazi Jewish descent diagnosed with late-onset GM2 gangliosidosis who were negative for the Gly269-->Ser mutation. Analysis of the HEXA gene showed that they were compound heterozygotes for the functionally silent 4-bp insertion in exon 11, typical of the infantile form of the disease and for a novel mutation, T538-->C, resulting in the missense Tyr180-->His. Expression studies in COS-7 cells suggested that the effect of this mutation was to decrease the stability of the alpha-chain at physiologic temperatures and therefore to indirectly affect the formation of mature Hex A
— id: 9854, year: 1996, vol: 47, page: 547, stat: Journal Article,

Molecular heterogeneity of late-onset forms of globoid-cell leukodystrophy [published erratum appears in Am J Hum Genet 1997 May;60(5):1264]
De Gasperi R; Gama Sosa MA; Sartorato EL; Battistini S; MacFarlane H; Gusella JF; Krivit W; Kolodny EH
1996 Dec;59(6):1233-1242, American journal of human genetics
Globoid-cell leukodystrophy (GLD) is an autosomal recessive inherited disorder caused by the deficiency of galactocerebrosidase, the lysosomal enzyme responsible for the degradation of the myelin glycolipid galactocerebroside. Although the most common form of the disease is the classical infantile form (Krabbe disease), later-onset forms also have been described. We have analyzed the galactocerebrosidase gene in 17 patients (nine families) with late-onset GLD and in 1 patient with classical Krabbe disease. Half of the patients were heterozygous for the large gene deletion associated with the 502C-->T polymorphism, the most common mutation in infantile patients. Several novel mutations that result in deficient galactocerebrosidase activity were also identified in these patients. They include the missense mutations R63H, G95S, M101L, G268S, Y298C, and I234T; the nonsense mutation S7X; a one-base deletion (805delG); a mutation that interferes with the splicing of intron 1; and a 34-nt insertion in the RNA, caused by the aberrant splicing of intron 6. All of these genetic defects are clustered in the first 10 exons of the galactocerebrosidase gene and therefore affect the 50-kD subunit of the mature enzyme. Studies on the distribution and enzymatic activity of the polymorphic alleles 1637T/C (I546/T546) provided support for previous data that had indicated the existence of two galactocerebrosidase forms with different catalytic activities in the general population. Our data also indicate that the mutations occur preferentially in the 'low activity' 1637C allele
— id: 9853, year: 1996, vol: 59, page: 1233, stat: Journal Article,

Effects of posteroventral pallidotomy on Parkinson's disease
Dogali M; Sterio D; Fazzini E; Kolodny E; Eidelberg D; Beric A
1996 ;69(4):585-590, Advances in neurology
— id: 18386, year: 1996, vol: 69, page: 585, stat: Journal Article,

Correction of the galactocerebrosidase deficiency in globoid cell leukodystrophy-cultured cells by SL3-3 retroviral-mediated gene transfer
Gama Sosa MA; de Gasperi R; Undevia S; Yeretsian J; Rouse SC 2nd; Lyerla TA; Kolodny EH
1996 Jan 26;218(3):766-771, Biochemical & biophysical research communications
Globoid cell leukodystrophy (GCL) or Krabbe disease is an autosomal recessive inherited disease caused by the deficiency of galactocerebrosidase, the lysosomal enzyme responsible for the degradation of galactocerebroside, a major component of myelin. An animal model homologue of GCL is the twitcher mouse. In the present work, using novel recombinant retroviruses harboring the SL3-3 LTR, we have been able to stably correct the galactocerebrosidase deficiency in twitcher mouse TM-2 cells and in primary human fibroblasts from a patient with globoid cell leukodystrophy. These results show the possibility of retroviral-mediated gene therapy for the treatment of GCL
— id: 8043, year: 1996, vol: 218, page: 766, stat: Journal Article,

The application of laser microprobe mass analysis to the study of biological material
Iancu, T C; Perl, D P; Sternlieb, I; Lerner, A; Leshinsky, E; Kolodny, E H; Hsu, A; Good, P F
1996 Jan;9(1):57-65, Biometals
Laser microprobe mass analysis (LAMMA) is an investigational method which is a powerful tool for the identification and quantitation of various elements present in small volumes of tissue. LAMMA is highly sensitive and capable of rapidly detecting concentrations of 1-3 p.p.m. of most metallic elements, in precisely localized cellular compartments. In order to further assess its value, cultured skin fibroblasts and biopsy tissues from human subjects and experimental animals were probed by LAMMA, and the results were correlated with ultrastructural findings. Biopsy samples were obtained from patients suffering from Gaucher disease, and from patients and animals with pathologic iron or copper metabolism. No significant abnormalities were detected in the cultured fibroblasts from patients with Gaucher disease, in contrast to the iron content of tissue biopsy Gaucher cells, which was markedly increased, apparently as a consequence of erythrophagocytosis. Particularly intense iron-related peaks were found in liver cytosiderosis due to neonatal or genetic haemochromatosis, thalassaemia major and in animal models of iron overload. An additional finding was the presence of aluminium accumulation in siderosomes of different cells. In liver biopsy samples from human Wilson's disease and from rats with an inherited disorder causing copper toxicosis, copper-containing compounds were identified and localized, and their relative concentration was estimated by LAMMA. The present study showed that LAMMA is a valuable technique for the localization and estimation of relative abundance of trace elements in various tissues containing excessive amounts of metals
— id: 75021, year: 1996, vol: 9, page: 57, stat: Journal Article,

Amyloid beta peptides in cerebellar preamyloid and cortical neuritic plaques of Down's syndrome patients
Lalowski, M.; Golabek, A.; Lemere, C. A.; Selkoe, D. J.; Kolodny, E.; Frangione, B.; Wisniewski, T.
1996 ;22(1-3):1208-145, Abstracts (Society for Neuroscience)
— id: 97641, year: 1996, vol: 22, page: 1208, stat: Journal Article,

Neurology of hereditary metabolic diseases of children
Lyon, Gilles; Adams, Raymond D.; Kolodny, Edwin H
New York : McGraw-Hill, Health Professions Division, c1996,
— id: 528, year: 1996, vol: , page: , stat: ,

Heller syndrome in a pre-school boy. Proposed medical evaluation and hypothesized pathogenesis
Russo, M; Ferry, R; Kolodny, E; Gillberg, C
1996 SEP ;5(3):172-177, European journal of child & adolescent psychiatry
The case of a 6-year-old boy who developed childhood disintegrative disorder (Heller syndrome) at the age of 4 years is presented, and specifics of the neurologic evaluation are detailed. A table is provided suggesting the complete neurologic work-up with the potential findings for children presenting with signs and symptoms of deterioration. A hypothesis for the aetiology of Heller syndrome proposes that predisposing genetic factors when combined with an environmental stress result in the deposition of amyloid and the disruption of synaptic transmission during the deterioration period. Speculation that the deterioration may be self-limited by activation of an immune response is based upon earlier findings that interleukin 1 has been shown to be involved in the breakdown of amyloid precursor protein in humans
— id: 52752, year: 1996, vol: 5, page: 172, stat: Journal Article,

A human kidney cDNA which induces a cell surface protein epitope recognized by a monoclonal antibody against galactosylceramide
Sosa MA; De Gasperi R; Battistini S; Gorman MP; Kolodny R; Kolodny EH
1996 Oct 14;227(2):636-641, Biochemical & biophysical research communications
Antibodies against the myelin glycolipid galactosylceramide are widely used to study the distribution and function of this molecule. However, anti-galactosylceramide antibodies are not monospecific and have been shown to recognize epitopes carried not only by other glycolipids, but also by proteins. Using expression cloning we have identified a human kidney cDNA which induces a cell-surface protein recognized by the anti-galactosylceramide monoclonal antibody R-mab. These findings further support the idea that cross-reactive proteins may mediate some of the biological effects of the anti galactosylceramide antibodies
— id: 12515, year: 1996, vol: 227, page: 636, stat: Journal Article,

Mitochondrial encephalomyopathies presenting with features of autonomic and visceral dysfunction
Zelnik N; Axelrod FB; Leshinsky E; Griebel ML; Kolodny EH
1996 Apr;14(3):251-254, Pediatric neurology
Three children are reported with mitochondrial encephalomyopathy who presented with autonomic dysfunction. Autonomic dysfunction included gastrointestinal dysmotility, apnea, cardiac arrhythmias, decreased lacrimation, supersensitivity to metacholine, altered sweating, and postural hypotension. These patients illustrate that in some mitochondrial encephalomyopathies autonomic features may be prominent and can mimic the clinical features associated with hereditary sensory and autonomic neuropathies
— id: 12624, year: 1996, vol: 14, page: 251, stat: Journal Article,

Congenital pontocerebellar atrophy in three patients: clinical, radiologic and etiologic considerations
Zelnik N; Dobyns WB; Forem SL; Kolodny EH
1996 Oct;38(7):684-687, Neuroradiology
We report three patients with severe pontocerebellar atrophy (PCA) associated with a variable degree of cerebral atrophy. The clinical features consisted of progressive microcephaly, central hypotonia, visual impairment, abnormal eye movements and delayed psychomotor development. These are similar but not identical to the features of pontocerebellar hypoplasia type 2 described by Barth. The picture also differs from the classical form of autosomal dominant olivopontocerebellar atrophy. While in two patients the disease seemed to be genetic with highly suspicious autosomal recessive inheritance, the etiology in the third patient was probably nongenetic. We suggest that PCA is a morphologic entity with distinct radiologic features but variable clinical, pathophysiologic and etiologic backgrounds
— id: 12525, year: 1996, vol: 38, page: 684, stat: Journal Article,

Substitution of alanine543 with a threonine residue at the carboxy terminal end of the beta-chain is associated with thermolabile hexosaminidase B in a Jewish family of Oriental ancestry
De Gasperi R; Gama Sosa MA; Grebner EE; Mansfield D; Battistini S; Sartorato EL; Raghavan SS; Davis JG; Kolodny EH
1995 Oct;56(1):31-36, Biochemical & molecular medicine
Thermolabile forms of the lysosomal enzyme beta-hexosaminidase B (Hex B), likely to result from different genetic defects, have been described. Ten individuals in five generations of a family of Oriental Jewish ancestry were identified biochemically as carriers of a thermolabile Hex B form. The beta-chain thermolability was found to be associated with the presence of a G --> A transition at nucleotide 1627 of the HEX B gene causing the substitution of Ala543 with a threonine. Oriental Jew whose Hex B was heat labile. Since thermolabile Hex B has been shown to occur more frequently among Jews of Oriental origin, the Ala543 --> Thr mutation may be the common mutation associated with beta-chain thermolability in this ethnic group
— id: 9855, year: 1995, vol: 56, page: 31, stat: Journal Article,

LATE-ONSET G(M2)-GANGLIOSIDOSIS IN 2 SIBLINGS OF ASHKENAZI JEWISH ANCESTRY RESULTS FROM A MUTATION IN THE HEXA GENE CAUSING ABNORMAL THERMOLABILITY OF HEXOSAMINIDASE-A
DEGASPERI, R; SOSA, MAG; BATTISTINI, S; YERETSIAN, J; KOLODNY, EH
1995 OCT ;57(4):1375-1375, American journal of human genetics
— id: 74951, year: 1995, vol: 57, page: 1375, stat: Journal Article,

Anatomic and physiological considerations in pallidotomy for Parkinson's disease
Dogali M; Beric A; Sterio D; Eidelberg D; Fazzini E; Takikawa S; Samelson DR; Devinsky O; Kolodny EH
1995 ;64:9-12, Acta neurochirurgica. Supplementum
Our ongoing study of ventral pallidotomy for the control of Parkinson's disease in selected patients has provided the opportunity to explore the topographical and somatotopic organization of the human globus pallidus. Utilizing microelectrode techniques we have obtained recordings which were correlated with data from MPTP-parkinsonian primates. In addition, we performed pre- and post-operative FDG/PET scans in these patients. Our studies reveal similarities between the MPTP-parkinsonian primate model and human Parkinson's disease in terms of physiologic recordings and responses. However, we have encountered significant differences between dominant and non-dominant hemisphere representations, particularly for the hand, in the human. In addition, our PET studies confirmed, as in previous parkinsonian primate models, glucose hypermetabolism in the lenticular area of Parkinson's disease patients. This hypermetabolism is dramatically altered by creation of a lesion in the globus pallidus medialis. This is demonstrated by follow-up PET scans which reveal not only a decrease in metabolism of the operated lenticular region, but also in the frontal cortical projections. These combined observations of the cellular activity in the globus pallidus and the observed changes in PET metabolism support the selection of the pallidum for lesioning and control of Parkinson's disease, and offer insight into the underlying physiology of this disorder. The above physiological and PET data will be clinically correlated with our ongoing series of 35+ patients
— id: 12822, year: 1995, vol: 64, page: 9, stat: Journal Article,

Stereotactic ventral pallidotomy for Parkinson's disease
Dogali M; Fazzini E; Kolodny E; Eidelberg D; Sterio D; Devinsky O; Beric A
1995 Apr;45(4):753-761, Neurology
Eighteen patients with medically intractable Parkinson's disease that was characterized by bradykinesia, rigidity, and marked 'on-off' fluctuations underwent stereotactic ventral pallidotomy under local anesthesia. Targeting was aided by anatomic coordinates derived from the MRI, intraoperative cell recordings, and electrical stimulation prior to lesioning. A nonsurgically treated group of seven similarly affected individuals was also followed. Assessment of motor function was made at baseline and at 3-month intervals for 1 year. Following the lesioning, patients improved in bradykinesia, rigidity, resting tremor, and balance with resolution of medication-induced contralateral dyskinesia. When compared with preoperative baseline, all quantifiable test scores after surgery improved significantly with the patients off medications for 12 hours: UPDRS by 65%, and CAPIT subtest scores on the contralateral limb by 38.2% and the ipsilateral limb by 24.2%. Walk scores improved by 45%. Medication requirements were unchanged, but the patients who had had surgery were able to tolerate larger doses because of reduced dyskinesia. Ventral pallidotomy produces statistically significant reduction in parkinsonism and contralateral 'on' dyskinesia without morbidity or mortality and with a short hospitalization in Parkinson's disease patients for whom medical therapy has failed
— id: 12789, year: 1995, vol: 45, page: 753, stat: Journal Article,

AUTOSOMAL-DOMINANT HEREDITARY SPASTIC PARAPLEGIA - LINKAGE ANALYSIS OF A HETEROGENEOUS TRAIT
DUBE, MP; ROULEAU, GA; KIBAR, Z; FARLOW, MR; EBERS, G; HARPER, P; KOLODNY, EH; BAUMBACH, L; FIGLEWICZ, DA
1995 OCT ;57(4):1093-1093, American journal of human genetics
— id: 74949, year: 1995, vol: 57, page: 1093, stat: Journal Article,

Mucolipidosis IV: morphology and histochemistry of an autopsy case
Folkerth, R D; Alroy, J; Lomakina, I; Skutelsky, E; Raghavan, S S; Kolodny, E H
1995 Mar;54(2):154-164, Journal of neuropathology & experimental neurology
Mucolipidosis Type IV is a rare, autosomal recessive disorder characterized by corneal opacification, mental retardation, and delayed motor milestones. Whereas lysosomal storage material has been demonstrated in biopsied tissues and leukocytes, the complete autopsy pathology, including neuropathology, is unknown. The metabolic defect remains speculative. We report the general and neuropathologic findings of the only known autopsy. In the central nervous system, neuronal loss in the cerebral cortex, basal ganglia, deep cerebellar nuclei, and brainstem nuclei was marked by astrocytosis; the cytoplasm of residual neurons had brown granules. These granules were positive with periodic acid-Schiff, Concanavalia ensiformis, and Sudan black, but not with Luxol-fast blue. Ultrastructurally, neurons contained lysosomes laden with osmiophilic, amorphous and granular material, and few lamellated membrane structures. Hepatocytes, epithelia, endothelia, chondrocytes, and tissue macrophages also stained positively with Datura stramonium and Ricinus communis-I agglutinins, with renal glomeruli also staining with peanut agglutinin; most non-neural cells contained osmiophilic granules on toluidine blue-stained, plastic embedded sections, corresponding to lamellated membrane structures. These findings complement the previously reported ocular morphology and brain and liver biochemistry performed in the same patient, and suggest that the storage material in neurons differs from that in non-neural cells. Furthermore, the underlying defect is not likely to be a deficiency of a single enzyme (i.e. a lysosomal hydrolase)
— id: 75022, year: 1995, vol: 54, page: 154, stat: Journal Article,

SYMPATHETIC SKIN-RESPONSE DIFFERENTIATES HEREDITARY SENSORY AND AUTONOMIC NEUROPATHIES TYPE-IV FROM TYPE-III
HILZ, MJ; STEMPER, B; BAER, R; KOLODNY, EH; AXELROD, FB
1995 AUG ;38(2):335-336, Annals of neurology
— id: 74954, year: 1995, vol: 38, page: 335, stat: Journal Article,

ANTISULFATIDE IMMUNOGLOBULIN-G IS ELEVATED IN THE SERUM OF MULTIPLE-SCLEROSIS PATIENTS
KOLODNY, EH; DEGASPERI, R; SOSA, MAG; WEINREB, HJ; HERBERT, J
1995 AUG ;38(2):340-340, Annals of neurology
— id: 74955, year: 1995, vol: 38, page: 340, stat: Journal Article,

MOLECULAR-GENETICS OF LATE-ONSET FORMS OF KRABBES DISEASE
KOLODNY, EH; SOSA, MAG; BATTISTINI, S; DEGASPERI, R
1995 AUG ;38(2):292-293, Annals of neurology
— id: 74953, year: 1995, vol: 38, page: 292, stat: Journal Article,

MOLECULAR-GENETICS OF LATE-ONSET KRABBE DISEASE
KOLODNY, EH; SOSA, MAG; BATTISTINI, S; SARTORATO, EL; YERETSIAN, J; MACFARLANE, H; GUSELLA, J; DEGASPERI, R
1995 OCT ;57(4):1250-1250, American journal of human genetics
— id: 74950, year: 1995, vol: 57, page: 1250, stat: Journal Article,

SUBSTITUTION OF ALANINE(531) WITH A THREONINE RESIDUE AT THE CARBOXY-TERMINAL END OF THE BETA-CHAIN IS ASSOCIATED WITH THERMOLABILE HEXOSAMINIDASE-B IN A JEWISH FAMILY OF ORIENTAL ANCESTRY
SOSA, MAG; DEGASPERI, R; GREBNER, EE; MANSFIELD, D; BATTISTINI, S; SARTORATO, EL; RAGHAVAN, SS; DAVIS, JG; KOLODNY, EH
1995 OCT ;57(4):1386-1386, American journal of human genetics
— id: 74952, year: 1995, vol: 57, page: 1386, stat: Journal Article,

Lysosomal storage disorders in Thailand: the Siriraj experience
Wasant, P; Wattanaweeradej, S; Raksadawan, N; Kolodny, E H
1995 ;26 Suppl 1:54-58, Southeast Asian journal of tropical medicine & public health
Lysosomal storage disorders are a heterogeneous group of biochemical genetic disorders; currently 40-50 are known. The clinical phenotype is determined by the tissue distribution of the storage material and degree of enzyme deficiency. The genetic transmission is mostly autosomal recessive. Lysosomal storage disorders can be divided into three groups according to the major organ system pathology: (1) Primary involvement of the central nervous system without significant somatic or skeletal pathology. Disorders of grey matter, eg gangliosidosis and disorders of white matter eg the leucodystrophy are the most common; (2) Primary involvement of the reticuloendothelial system with or without associated neuropathology, eg Niemann-Pick disease and Gaucher disease; (3) Multisystem involvement in which skeletal manifestations are prominent features. The mucopolysaccharidosis and mucolipidoses are the two major forms with this clinical phenotype. Lysosomal storage disorders identified at Siriraj Hospital are neuronal ceroid lipofuscinosis, GMI gangliosidosis, mucolipidosis II, Maroteaux-Lamy, sialidosis, Sly syndrome, Hunter syndrome, Morquio syndrome, Gaucher disease, Niemann-Pick, Sandhoff disease, Pompe's disease and many more. Most patients came from the provinces where consanguinity is common. Confirmation usually is done by enzyme assays using skin fibroblast culture or leucocytes. Genetic counseling is extremely important and prenatal diagnosis is recommended to high-risk couple
— id: 75024, year: 1995, vol: 26 Suppl 1, page: 54, stat: Journal Article,

Familial spastic paraparesis. Is it a mitochondrial disorder?
Zelnik, N; Leshinsky, E; Kolodny, E H
1995 ;23(4):225-226, Pediatric neurosurgery
— id: 75023, year: 1995, vol: 23, page: 225, stat: Journal Article,

Anatomic and physiological considerations in pallidotomy for Parkinson's disease
Dogali M; Beric A; Sterio D; Eidelberg D; Fazzini E; Takikawa S; Samelson DR; Devinsky O; Kolodny EH
1994 ;62(1-4):53-60, Stereotactic & functional neurosurgery
Our ongoing study of central pallidotomy for the control of Parkison's disease in selected patients has provided the opportunity to explore the topographical and somatotopic organization of the human globus pallidus. Utilizing microelectrode techniques we have obtained recordings which were correlated with data from MPTP-parkinsonian primates. In addition, we performed pre- and postoperative FDG/PET scans in these patients. Our studies reveal similarities between the MPTP-parkisonian primate model and human Parkinson's disease in terms of physiological recordings and responses. However, we have encountered significant differences between dominant and nondominant hemisphere representations, particularly for the hand, in the human. In addition, our PET studies confirmed, as in previous parkinsonian primate models, glucose hypermetabolism in the lenticular area of Parkinson's disease patients. This hypermetabolism is dramatically altered by creation of a lesion in the globus pallidus medialis. This is demonstrated by follow-up PET scans which reveal not only a decrease in metabolism of the operated lenticular region, but also in the frontal cortical projections. These combined observations of the cellular activity in globus pallidus and the observed changes in PET metabolism support the selection of the pallidum for lesioning and control of Parkinson's disease, and offer insight into the underlying physiology of this disorder. The above physiological and PET data will be clinically correlated with our ongoing series of 35+ patients
— id: 13043, year: 1994, vol: 62, page: 53, stat: Journal Article,

CANAVAN-DISEASE IN COMPOUND HETEROZYGOTE WITH NOVEL MUTATION (C-914-]A) IN ASPARTOACYLASE GENE (VOL 11, PG 145, 1994)
KOLODNY, EH; SOSA, MAG; LESHINSKY, E; DWYER, D; BATTISTINI, S; DEGASPERI, R
1994 NOV ;11(4):349-349, Pediatric neurology
Canavan disease (CD) is an autosomal-recessive leukodystrophy characterized by macrocephaly, hypotonia, and psychomotor retardation with death usually occurring in the first decade of life. It is caused by the deficiency of N-acetylaspartoacylase (ASP) which hydrolyses N-acetyl-L-aspartic acid and is most prevalent among Ashkenazim. Recently, a common mutation (A(854) --> C) in the ASP coding region has been found in 85% of Ashkenazic Jewish patients [Nature Genet 1993;5:118]. In this study we present an 18-year-old male of Creek and Ashkenazic Jewish origin with CD whose clinical features and low levels of aspartoacylase activity in fibroblasts suggested a variant form of the disease. He has had progressive spastic quadriparesis, loss of visual function, and marked volumetric reduction of cerebral and cerebellar cortex and white matter by cranial CT and MRI. Molecular analysis showed the proband as a compound heterozygote carrying in the maternal allele the A(854) --> C Ashkenazic mutation and a new mutation in the paternal allele. DNA sequencing and allele-specific oligonucleotide (ASO) analyses revealed a novel mutation, C-914 --> A, resulting in the missense Ala(305) --> Glu in the paternal Greek allele. This novel mutation may be responsible for the less severe involvement and slower progression of the disease in this patient than in classical CD
— id: 74956, year: 1994, vol: 11, page: 349, stat: Journal Article,

Prevalence of nine mutations among Jewish and non-Jewish Gaucher disease patients
Horowitz, M; Tzuri, G; Eyal, N; Berebi, A; Kolodny, E H; Brady, R O; Barton, N W; Abrahamov, A; Zimran, A
1993 Oct;53(4):921-930, American journal of human genetics
The frequency of nine different mutated alleles known to occur in the glucocerebrosidase gene was determined in 247 Gaucher patients, of whom 176 were of Jewish extraction, 2 were Jewish with one converted parent, and 69 were of non-Jewish origin. DNA was prepared from peripheral blood, active glucocerebrosidase sequences were amplified by using the PCR technique, and the mutations were identified by using the allele-specific oligonucleotide hybridization method. The N37OS mutation appeared in 69.77% of the mutated alleles in Jewish patients and in 22.86% of the mutated alleles in non-Jews. The 84GG mutation, which has not been found so far among non-Jewish patients, existed in 10.17% of the disease alleles among Jewish patients. The IVS + 1 mutation constituted 2.26% of the disease alleles among Jewish patients and 1.43% among the non-Jewish patients. RecTL, a complex allele containing four single-base-pair changes, occurred in 2.26% of the alleles in Jewish patients and was found in two (1.43%) of the patients of non-Jewish extraction. Another complex allele, designated 'RecNciI' and containing three single-point mutations, appeared in 7.8% of alleles of non-Jewish patients and in only two (0.56%) of the Jewish families. The prevalence of the L444P mutation among non-Jewish Gaucher patients was 31.43%, while its prevalence among Jewish patients was only 4.24%. The prevalence of two other point mutations--D409H and R463C--was 5.00% and 3.57%, respectively, among non-Jewish patients and was not found among the Jewish Gaucher patient population. The prevalence of the R496H mutation, found so far only among Jewish patients, was 1.13%. The results presented demonstrate that seven mutations identify 90.40% of the mutations among Jewish patients and that these seven mutations allow diagnosis of only 73.52% of the non-Jewish patients. Identification of additional mutant alleles will enhance the accuracy of carrier detection
— id: 75025, year: 1993, vol: 53, page: 921, stat: Journal Article,

Dysmyelinating and demyelinating conditions in infancy
Kolodny EH
1993 Jun;6(3):379-386, Current opinion in neurology & neurosurgery
The myelin membrane is essential for rapid conduction of nerve impulses through the central nervous system. Failure of myelination--dysmyelination--may arise through several mechanisms. The synthesis of a particular myelin protein can be defective, as occurs for proteolipid protein in Pelizaeus-Merzbacher disease and for myelin basic protein in the 18q- syndrome. Delay in myelination with a more generalized diminution in white matter is characteristic of many inherited metabolic diseases, including galactosemia, pyridoxine-dependent seizure disorder, glutaric aciduria type 1, and infantile Refsum disease. Demyelination or breakdown in myelin is characteristic of metachromatic leukodystrophy, Krabbe disease, mitochondrial disorders, adrenoleukodystrophy, Canavan disease, Alexander disease, and orthochromatic leukodystrophy. A fourth category is reserved for malformation syndromes. These include Cockayne, Fukuyama, Walker-Warburg, and Angelman syndromes. Demyelination also occurs in HIV-infected individuals with central nervous system findings and in multiple sclerosis. Much of the evidence for leukodystrophy in these disorders comes from neuroimaging. Some of these disorders are treatable
— id: 13140, year: 1993, vol: 6, page: 379, stat: Journal Article,

ANTISULFATIDE IGG AS A MARKER FOR POTENTIAL NEURODEGENERATION IN HIV-SEROPOSITIVE INDIVIDUALS
KOLODNY, EH; DEGASPERI, R; GAMA, MA; RAGHAVAN, S
1993 APR ;43(4):A187-A187, Neurology
— id: 74957, year: 1993, vol: 43, page: A187, stat: Journal Article,

Fabry disease: immunocytochemical characterization of neuronal involvement
deVeber, G A; Schwarting, G A; Kolodny, E H; Kowall, N W
1992 Apr;31(4):409-415, Annals of neurology
Fabry disease is an X-linked glycosphingolipid storage disease caused by deficiency of alpha-galactosidase. Storage of globotriaosylceramide, also known as ceramide trihexoside, is maximal in blood vessels but also occurs in neurons. We performed neuropathological histochemical studies on the brains and spinal cords of 2 patients with confirmed Fabry disease. Luxol fast blue-positive deposits were found in blood vessels throughout the central and peripheral nervous system and within selected neurons in spinal cord and ganglia, brainstem, amygdala, hypothalamus, and entorhinal cortex. Regions adjacent to involved neuronal groups, including nucleus basalis, striatum, globus pallidus, and thalamus, were spared. Electron microscopy showed lamellar cytoplasmic neuronal inclusion bodies. Using a monoclonal antibody reactive with ceramide trihexoside, we found more extensive neuronal deposition than evident by Luxol-fast blue staining and new areas of neuronal storage in the spinal cord and cerebral cortex. Blood vessels throughout the nervous system were strongly immunoreactive. The highly selective pattern of neuronal involvement we found suggests that glycosphingolipid exposure, uptake, or catabolism varies greatly with respect to neuronal morphology and distribution. The degree of toxicity to neurons and the clinical significance of this neuronal storage remains to be defined
— id: 75027, year: 1992, vol: 31, page: 409, stat: Journal Article,

Possible use of CSF glycosphingolipids for the diagnosis and therapeutic monitoring of lysosomal storage diseases
Kaye, E M; Ullman, M D; Kolodny, E H; Krivit, W; Rischert, J C
1992 Dec;42(12):2290-2294, Neurology
We used a high-performance liquid chromatography method to measure CSF gangliosides, neutral glycolipids, and sulfatides in patients with lysosomal storage disorders. These measurements could be done on less than 1 milliliter of CSF. In patients with GM1 gangliosidosis, GM1 ganglioside was increased, and in GM2 gangliosidosis patients, GM2 ganglioside was increased in CSF. Sulfatides were variably increased in CSF early in the course of the disease and appeared to be a means of monitoring patients, following bone marrow transplantation. Fabry's disease patients showed an increase in globotriaosylceramide, but Krabbe's disease patients did not demonstrate an increase in galactosylceramide. This study suggests that CSF glycosphingolipid measurements may prove helpful in the diagnosis and monitoring of lysosomal storage diseases
— id: 75026, year: 1992, vol: 42, page: 2290, stat: Journal Article,

Electroconvulsive therapy treatment of depression in a patient with adult GM2 gangliosidosis
Renshaw, P F; Stern, T A; Welch, C; Schouten, R; Kolodny, E H
1992 Mar;31(3):342-344, Annals of neurology
Adult GM2 gangliosidosis is a rare disorder that often presents with both neurological and psychiatric syndromes. Effective treatment of the psychotic and affective symptoms associated with this disorder has been complicated by poor treatment response and the concern that many psychotropic agents may worsen the underlying gangliosidosis. We report the successful use of electroconvulsive therapy for treatment of severe depression in a young man with adult GM2 gangliosidosis
— id: 75028, year: 1992, vol: 31, page: 342, stat: Journal Article,

Three unique base pair changes in a family with Gaucher disease
Eyal, N; Firon, N; Wilder, S; Kolodny, E H; Horowitz, M
1991 Jul;87(3):328-332, Human genetics
Single-stranded cDNA was prepared from RNA obtained from a patient with type 1 Gaucher disease. The cDNA was amplified in vitro and analyzed by sequencing. Three base-pair changes were identified which included a G to C transversion at nucleotide 3119 of the active gene (Asp140----His), an A to C transversion at nucleotide 3170 (Lys157----Gln) and a G to A change at nucleotide 5309 (Glu326----Lys). To study the mode of inheritance of the three different base-pair changes, genomic DNA was prepared from blood or skin fibroblasts of several family members. Genomic glucocerebrosidase DNA sequences were amplified and subjected to hybridization with allele-specific oligonucleotides (ASOs). The hybridization profiles demonstrated that two of the base-pair changes originated from the mother and were transmitted to her two affected sons and to a grandchild, while the third base-pair change, originating from the father, was transmitted to his two affected sons, a carrier daughter and a second grandchild. Tests of other patients with Gaucher disease failed to disclose the presence of the three base-changes. This is a unique family with three base-pair changes tightly linked to Gaucher disease
— id: 75030, year: 1991, vol: 87, page: 328, stat: Journal Article,

Late-onset Krabbe disease (globoid cell leukodystrophy): clinical and biochemical features of 15 cases
Kolodny, E H; Raghavan, S; Krivit, W
1991 ;13(4-5):232-239, Developmental neuroscience
The diagnosis of late-onset variants of Krabbe disease (globoid cell leukodystrophy) has been facilitated by the recognition of galactocerebrosidase deficiency as its biochemical hallmark. Fifteen patients, ages 4-73, are presented. Signs included pes cavus, optic disc pallor, progressive spastic tetraparesis, a sensorimotor demyelinating neuropathy and hypodense lesions in the parieto-occipital periventricular white matter. Although intellect was preserved in more than half the cases, significant intrafamilial variability in mental functioning was encountered in 3 families. Bone marrow transplantation was successful in 1 13-year-old girl, but caused the death of 2 teenage twin sisters
— id: 75032, year: 1991, vol: 13, page: 232, stat: Journal Article,

Dietary management reverses grooving and abnormal polarization of hair shafts in argininosuccinase deficiency
Kvedar, J C; Baden, H P; Baden, L A; Shih, V E; Kolodny, E H
1991 Aug 1;40(2):211-213, American journal of medical genetics
We have observed that the fragile hair of two untreated patients with argininosuccinic aciduria showed abnormal alternating zones of bright and dark banding by polarizing microscopy. Scanning electron microscopy documented discontinuous grooves with a 50 to 100 microns periodicity. Results of amino acid analysis of the hair were essentially normal. After the patients were treated with a low-protein, arginine-supplemented diet, the hair assumed a normal appearance. Five patients already treated with diet showed no hair abnormalities. The pathogenesis of the hair changes in unknown, but our findings suggest that products generated in the disease can adversely affect metabolically active tissue such as hair
— id: 75029, year: 1991, vol: 40, page: 211, stat: Journal Article,

Molecular aspects of Gaucher disease
Levy, H; Or, A; Eyal, N; Wilder, S; Widgerson, M; Kolodny, E H; Zimran, A; Horowitz, M
1991 ;13(4-5):352-362, Developmental neuroscience
Gaucher disease is the most common sphingolipid storage disorder. Due to its high prevalence it may appear with a nonrelated neurological disease and be misinterpreted as Gaucher type 3. A family is described in which 2 Gaucher brothers presented different clinical signs. Molecular analysis has shown that both carried two mutated alleles. One allele had a G to C transversion at nucleotide 3119 of the active gene (Asp140-His) while the other presented two base pair changes, an A to C transversion at nucleotide number 3170 (Lys157-Gly), and a G-A transition at nucleotide number 5309 (Glu324-Lys). Therefore, both presented the same type of Gaucher disease which was accompanied with a nonrelated neurological disease in one of them. Molecular diagnosis of 161 patients has provided a relative abundance of different mutations among Jewish and non-Jewish patients and allowed some genotype-phenotype correlation. Differential expression of the murine glucocerebrosidase activator gene (the prosaposine) has been demonstrated using Northern technique and in situ hybridization. High expression levels were observed in the brain and testes. In the testes the prosaposine expression was confined to the supporting cells. In the female gonad prosaposine expression has also been shown, in the corpus luteum. In a 12 1/2-day-old embryo, prosaposine gene expression was detected mainly in brain stem, in dorsal ganglia and in the genital ridge
— id: 75031, year: 1991, vol: 13, page: 352, stat: Journal Article,

Genotype assignment in Gaucher disease by selective amplification of the active glucocerebrosidase gene
Firon, N; Eyal, N; Kolodny, E H; Horowitz, M
1990 Mar;46(3):527-532, American journal of human genetics
Genomic DNA prepared from human cells in culture was amplified by the polymerase chain-reaction technique using two primers specific for the active human glucocerebrosidase gene. The 1,036-bp amplified fragment derived from the active gene was tested for the existence of three mutations--designated '370,' 'NciI,' and 'HhaI'--by allele-specific oligonucleotide hybridization. The results obtained from the cell lines examined permitted a clear distinction between homozygous affected, heterozygous, and normal genotypes. However, 28% of the possible affected loci were normal with respect to the three mutations, indicating the presence of additional mutations that remain to be elucidated. While the NciI mutation could be found in both Ashkenazi Jewish and non-Jewish type 1 patients, the only homozygotes with this mutation had the neurological (type 2 or type 3) form of the disease. The 370 mutation, on the other hand, was only present in type 1 patients and was not identified among any of the patients with neurologic forms of the disease
— id: 75036, year: 1990, vol: 46, page: 527, stat: Journal Article,

Mutation analysis of an Ashkenazi Jewish family with Gaucher disease in three successive generations
Kolodny, E H; Firon, N; Eyal, N; Horowitz, M
1990 Aug;36(4):467-472, American journal of medical genetics
Seven members of an Ashkenazi Jewish family with Gaucher disease in 3 successive generations were tested for the presence of the 2 common mutations known to occur in the glucocerebrosidase gene. Genomic DNA from blood or skin fibroblasts of relatives was amplified by using the PCR technique and individual mutations identified by oligonucleotides specific to the mutated sequences. Four individuals were homozygous for a mutation at amino acid 370 (370 mutation) known to occur only in type 1 disease. The other 3 affected relatives were compound heterozygotes for this mutation and for a mutation at amino acid 444 (NciI mutation) which, in the homozygous state, is associated with neurological disease. Clinical severity was more marked in the compound heterozygotes than in the homozygotes. Since the mutation is present in Ashkenazim, molecular diagnosis in families which carry the NciI mutation should prove useful in assessing their risk of the neurologic forms of Gaucher disease
— id: 75033, year: 1990, vol: 36, page: 467, stat: Journal Article,

Ashkenazi-Jewish and non-Jewish adult GM2 gangliosidosis patients share a common genetic defect
Navon, R; Kolodny, E H; Mitsumoto, H; Thomas, G H; Proia, R L
1990 Apr;46(4):817-821, American journal of human genetics
The adult form of Tay-Sachs disease, adult GM2 gangliosidosis, is an autosomal recessive neurological disorder caused by a partial deficiency of beta-hexosaminidase A. We had previously identified, in Ashkenazi-Jewish adult GM2 gangliosidosis patients, a Gly269----Ser mutation in the beta-hexosaminidase alpha-subunit. All of the Ashkenazi patients were found to be compound heterozygotes with an allele containing the Gly269----Ser mutation together with one of the Ashkenazi infantile Tay-Sachs alleles. We have now found the same Gly269----Ser mutation in six adult GM2 gangliosidosis patients from four different non-Jewish families. Genomic DNA from three of the patients, two of whom were brothers, exhibited a hybridization pattern consistent with homozygosity for the Gly269----Ser mutation. The remaining non-Jewish patients were compound heterozygotes of the Gly269----Ser mutation together with an unidentified alpha-subunit mutation. The results demonstrate that individuals homozygous for the Gly269----Ser change can be clinically affected. The same Gly269----Ser mutation in both the Ashkenazi and non-Jewish patients may be the result of a common ancestor, given that the ancestry of these non-Jewish patients, like the Ashkenazim, can be traced to eastern Europe
— id: 75035, year: 1990, vol: 46, page: 817, stat: Journal Article,

Corneal surface irregularities and episodic pain in a patient with mucolipidosis IV
Newman, N J; Starck, T; Kenyon, K R; Lessell, S; Fish, I; Kolodny, E H
1990 Feb;108(2):251-254, Archives of ophthalmology
Mucolipidosis IV is a lysosomal storage disease characterized by prominent involvement of the corneal epithelium. A 5-year-old boy with mucolipidosis IV experienced recurrent episodes of severe ocular pain, tearing, and ipsilateral facial flushing. This was suggestive of reflex sympathetic dystrophy, a syndrome of pain and sympathetic hyperactivity. The examination revealed marked corneal surface irregularities, corresponding to massive accumulations of intracytoplasmic storage material in the epithelium. Episodic pain in patients with mucolipidosis IV is an important symptom, presumably reflecting the distinctive corneal ultrastructural abnormality in this disease
— id: 75037, year: 1990, vol: 108, page: 251, stat: Journal Article,

HEXOSAMINIDASE PSEUDODEFICIENCY - REPLY
PROIA, RL; KOLODNY, EH; NAVON, R
1990 NOV ;47(5):881-882, American journal of human genetics
— id: 74958, year: 1990, vol: 47, page: 881, stat: Journal Article,

GM2-gangliosidosis B1 variant: analysis of beta-hexosaminidase alpha gene abnormalities in seven patients
Tanaka, A; Ohno, K; Sandhoff, K; Maire, I; Kolodny, E H; Brown, A; Suzuki, K
1990 Feb;46(2):329-339, American journal of human genetics
A single nucleotide transition within exon 5 of the beta-hexosaminidase alpha chain gene was identified in a Puerto Rican patient with GM2-gangliosidosis B1 variant as the mutation responsible for the unusual enzymological characteristics of this variant (G533----A; Arg178----His) (the DN-allele). A total of seven patients with enzymological characteristics of B1 variant have since been studied. They were Puerto Rican (DN), Italian, French, Spanish, two patients of mixed ethnic origin (English/Italian/Hungarian and English/French/Azores), and a Czechoslovakian. In confirmation of our earlier finding based on screening with allele-specific probes, all patients except the one from Czechoslovakia carried the same DN-allele. A new point mutation found in this patient changed the same codon affected in the DN-allele (C532----T; Arg178----Cys). An asymptomatic Japanese individual included as a control also carried one allele with the DN-mutation. Site-directed mutagenesis and expression studies in COS I cells demonstrated that either of the two point mutations abolishes the catalytic activity of the alpha subunit. The Spanish patient was homozygous for the DN-allele, but others were all compound heterozygotes. The Puerto Rican patient was a compound heterozygote with the DN-mutation in one allele and with the four-base insertion in exon 11, one of the two mutations found in the classical Ashkenazi Jewish Tay-Sachs disease, in the other allele. Abnormalities of the other allele were not identified in all other compound heterozygous patients. In these patients, the level of mRNA derived from the other allele was variable, ranging from being undetectable to being much lower than normal. This series of studies uncovered a new B1 variant mutation, confirmed our preliminary finding that the DN-allele has a surprisingly wide geographic and ethnic distribution, and pointed out the highly complex nature of the molecular genetics of this rare disorder. They also support our working hypothesis that mutations responsible for the unique enzymological characteristics of the B1 variant should be located in or near exon 5 of the gene and that this region of the enzyme protein is critical for its catalytic function
— id: 75038, year: 1990, vol: 46, page: 329, stat: Journal Article,

Screening for carriers of Tay-Sachs disease among Ashkenazi Jews. A comparison of DNA-based and enzyme-based tests
Triggs-Raine, B L; Feigenbaum, A S; Natowicz, M; Skomorowski, M A; Schuster, S M; Clarke, J T; Mahuran, D J; Kolodny, E H; Gravel, R A
1990 Jul 5;323(1):6-12, New England journal of medicine
BACKGROUND AND METHODS. The prevention of Tay-Sachs disease (GM2 gangliosidosis, type 1) depends on the identification of carriers of the gene for this autosomal recessive disorder. We compared the enzyme-based test widely used in screening for Tay-Sachs disease with a test based on analysis of DNA. We developed methods to detect the three mutations in the HEXA gene that occur with high frequency among Ashkenazi Jews: two mutations cause infantile Tay-Sachs disease, and the third causes the adult-onset form of the disease. DNA segments containing these mutation sites were amplified with the polymerase chain reaction and analyzed for the presence of the mutations. RESULTS. Among 62 Ashkenazi obligate carriers of Tay-Sachs disease, the three specific mutations accounted for all but one of the mutant alleles (98 percent). In 216 Ashkenazi carriers identified by the enzyme test, DNA analysis showed that 177 (82 percent) had one of the identified mutations. Of the 177, 79 percent had the exon 11 insertion mutation, 18 percent had the intron 12 splice-junction mutation, and 3 percent had the less severe exon 7 mutation associated with adult-onset disease. The results of the enzyme tests in the 39 subjects (18 percent) who were defined as carriers but in whom DNA analysis did not identify a mutant allele were probably false positive (although there remains some possibility of unidentified mutations). In addition, of 152 persons defined as noncarriers by the enzyme-based test, 1 was identified as a carrier by DNA analysis (i.e., a false negative enzyme-test result). CONCLUSIONS. The increased specificity and predictive value of the DNA-based test make it a useful adjunct to the diagnostic tests currently used to screen for carriers of Tay-Sachs disease. Although some false positive results may be desirable on an enzyme-based test that is used in screening, the DNA test allows precise definition of the carrier state for the known mutations
— id: 75034, year: 1990, vol: 323, page: 6, stat: Journal Article,

Animal models for lysosomal storage diseases: their past and future contribution
Alroy, J; Warren, C D; Raghavan, S S; Kolodny, E H
1989 Sep;20(9):823-826, Human pathology
— id: 75039, year: 1989, vol: 20, page: 823, stat: Journal Article,

Early cerebellar degeneration in twins with infantile neuroaxonal dystrophy
Barlow, J K; Sims, K B; Kolodny, E H
1989 Apr;25(4):413-415, Annals of neurology
Dizygotic twin girls with typical infantile neuroaxonal dystrophy (INAD) were studied at age 19 months with computed tomography and magnetic resonance imaging (MRI). Both methods showed distinct atrophy confined to the cerebellum and MRI revealed diffuse signal abnormality of the cerebellar parenchyma. This neuro-imaging evidence for selective early involvement of the cerebellum is consistent with both the typical presenting symptoms and the gross pathological findings in the disorder. Neuroimaging may aid in differentiation of INAD from other neurodegenerative disorders with onset in late infancy, providing impetus for diagnostic biopsy and early genetic counseling
— id: 75041, year: 1989, vol: 25, page: 413, stat: Journal Article,

Neurological progress. The neuronal ceroid lipofuscinoses: a review
Boustany, R M; Kolodny, E H
1989 ;145(2):105-110, Revue neurologique
Neuronal ceroid lipofuscinosis is a common cause of neurodegenerative disease in children. The disease is characterized by visual failure, seizures and dementia. The presence of cortical atrophy by computerized axial tomography and distinctive ultrastructural findings by skin biopsy, together with a suggestive clinical course and neurophysiologic abnormalities, lead to a diagnosis. Presently four subtypes and rare atypical forms are recognized: the infantile, late infantile, juvenile and adult or Kufs variants and atypical early juvenile and protracted juvenile types. The inheritance pattern is autosomal recessive in all subtypes with some of the adult cases representing autosomal dominant inheritance. The biochemical characterization of this disorder is just beginning. There is some evidence to implicate overglycosylation of proteins as playing a role in pathogenesis. Further biochemical description coupled with linkage analysis techniques using DNA probes are needed to develop a better understanding of this group of disorders
— id: 75043, year: 1989, vol: 145, page: 105, stat: Journal Article,

Agenesis of the corpus callosum: a marker for inherited metabolic disease?
Kolodny, E H
1989 Jun;39(6):847-848, Neurology
— id: 75040, year: 1989, vol: 39, page: 847, stat: Journal Article,

Familial spastic paraplegia: clinical observations and genetic studies
Kolodny, E H; Boustany, R M; Rouleau, G A; Growden, J H; Martin, J B
1989 ;306:205-211, Progress in clinical & biological research
— id: 75042, year: 1989, vol: 306, page: 205, stat: Journal Article,

NEURONAL CEROID LIPOFUSCINOSIS - CLINICAL AND PATHOLOGICAL CHARACTERISTICS IN A REVIEW OF 262 CASES
PATXOT, OF; WISNIEWSKI, KE; KITAGUCHI, T; DYKEN, P; PHILIPPART, M; KOLODNY, EH
1989 SEP ;26(3):467-468, Annals of neurology
— id: 74959, year: 1989, vol: 26, page: 467, stat: Journal Article,

Clinical classification of neuronal ceroid-lipofuscinosis subtypes
Boustany, R M; Alroy, J; Kolodny, E H
1988 ;5:47-58, American journal of medical genetics. Supplement
Neuronal ceroid-lipofuscinosis is the most common class of neurodegenerative disease in children. After decades of study, the biochemical basis for this group of diseases continues to elude scientists. One obstacle has been the difficulty in establishing specific criteria for diagnosis. This paper reviews case material from 65 patients referred to the Shriver Center for study from January, 1984 to December, 1986. The late-infantile type was the most commonly encountered (35%) with a mean age-of-onset of 3.1 +/- 0.5 yr. The juvenile type was slightly less frequent (32%) with a mean age-of-onset of 7.8 +/- 4 yr. The infantile type ranked third (23%); age-of-onset 11 +/- 4 months) and the adult form of the disease was the least common (10%; age-of-onset 25 +/- 4 yr). Consistent clinical findings were a progressive decline in mental faculties and seizures, predominantly of the myoclonic type. Neuroradiological changes of cerebral and cerebellar cortical atrophy were common when studies were obtained more than a year after clinical onset. Ataxia was a frequent manifestation in the late-infantile and juvenile types whereas dystonia was unique to the latter. There was a diversity of ultrastructural findings in skin biopsies between and within types. The absence of findings in a few familial cases necessitated sampling a second tissue such as muscle, particularly when the history was suggestive and urine dolichols were high. Elevated urine dolichol levels was a nonspecific but helpful finding
— id: 75047, year: 1988, vol: 5, page: 47, stat: Journal Article,

GEOGRAPHIC-DISTRIBUTION AND ETHNIC-BACKGROUND OF PERSONS WITH NEURONAL CEROID LIPOFUSCINOSIS IN THE UNITED-STATES
BOUSTANY, RMN; MECSAS, S; KOLODNY, EH
1988 AUG ;24(2):307-308, Annals of neurology
— id: 74960, year: 1988, vol: 24, page: 307, stat: Journal Article,

Nervous system involvement in Fabry's disease: clinicopathological and biochemical correlation
Kaye, E M; Kolodny, E H; Logigian, E L; Ullman, M D
1988 May;23(5):505-509, Annals of neurology
A detailed neuropathological and biochemical study was performed to evaluate the accumulation of ceramide trihexoside within the central and peripheral nervous systems of 2 patients with Fabry's disease. Luxol fast blue-staining lipid was noted in the leptomeninges and in the choroidal stroma; biochemical studies showed increased quantities of ceramide trihexoside in the cerebrospinal fluid. The permeable blood-brain barrier regions of the central and peripheral nervous systems contained increased quantities of ceramide trihexoside. Some central nervous system nuclei associated with autonomic function were also noted to store lipid. Other areas of increased ceramide trihexoside accumulation included specific cortical and brainstem structures. Possible sources for this selective accumulation of ceramide trihexoside within the central and peripheral nervous system include transport of glycolipid from the systemic vascular network and retrograde transsynaptic glycolipid transport
— id: 75045, year: 1988, vol: 23, page: 505, stat: Journal Article,

Infantile sialic acid storage disease associated with renal disease
Pueschel, S M; O'Shea, P A; Alroy, J; Ambler, M W; Dangond, F; Daniel, P F; Kolodny, E H
1988 Jul-Aug;4(4):207-212, Pediatric neurology
A child with infantile sialic acid storage disease is reported. Ultrasonography demonstrated fetal ascites. At birth, the infant appeared hydropic and presented with numerous dysmorphic features, including sparse white hair, coarse facies, hypertelorism, epicanthal folds, anteverted nostrils, and a long philtrum. In addition, he had visceromegaly, bilateral inguinal hernias, and a slight gibbus deformity. Lymphocytes were vacuolated and bone marrow contained large numbers of foam cells. There were generalized vacuolations of both reticuloendothelial and parenchymal cells in the examined tissues. Neuropathologic studies revealed wide-spread neuronal storage, myelin loss, axonal spheroids, and gliosis. Neurons, endothelial cells, and Kupffer cells stained with wheat germ agglutinin indicated an accumulation of sialic acid. Free sialic acid was significantly increased in urine and serum, as well as in liver, heart, and brain tissues. The alpha-neuraminidase activity was normal. It is assumed that the basic defect of infantile sialic acid storage disease lies in impaired transport of sialic acid across the lysosomal membrane
— id: 75044, year: 1988, vol: 4, page: 207, stat: Journal Article,

Characterization of alpha-mannosidase in feline mannosidosis
Raghavan, S; Stuer, G; Riviere, L; Alroy, J; Kolodny, E H
1988 ;11(1):3-16, Journal of inherited metabolic disease
Acidic alpha-mannosidase deficiency has been identified in a family of Blue Persian cats. Characterization of the residual activity revealed that the Km for the substrate, 4-methylumbelliferyl-alpha-D-mannoside, increased approximately three-fold with a severe deficiency in Vmax (1-2%) in homogenates of liver and brain of affected cats compared with controls. The residual activity at pH 4.0 in liver homogenates from affected cats is very thermolabile at 51 degrees C while the control activity is stable at this temperature for 1 h. Subcellular fractionation of liver was performed from a control and diseased cat in order to compare the properties of the different alpha-mannosidases localized in these fractions. The residual activity present in the lysosomal fraction from diseased cat liver showed altered pH optimum, two-fold increase in Km with a severely reduced Vmax and increased thermolability compared with the activity in the lysosomal fraction from control liver. The thermal inactivation pattern and Km of the residual activity in the lysosomal fraction is different from the non-lysosomal alpha-mannosidase in the liver of the affected cat. This suggests that the residual activity in the lysosomal fraction of the liver from the affected cat is not due to contamination of non-lysosomal alpha-mannosidase in this fraction. Whether this residual activity represents the properties of the mutant enzyme or yet another minor normal component of lysosomes different from the major inactive mutant or absent lysosomal enzyme remains to be elucidated
— id: 75048, year: 1988, vol: 11, page: 3, stat: Journal Article,

Gaucher-like changes in human blood-derived macrophages induced by beta-glucocerebrosidase inhibition
Yatziv, S; Newburg, D S; Livni, N; Barfi, G; Kolodny, E H
1988 Apr;111(4):416-420, Journal of laboratory & clinical medicine
Human blood-derived macrophages were cultured in the presence of conduritol-B-epoxide, a specific inhibitor of beta-glucosidase, to induce changes resembling those occurring in the cells of patients with Gaucher's disease. After 24 hours of incubation, only 5% of the original beta-glucosidase activity remained; on removal of the inhibitor, the enzyme activity recovered almost fully to control levels after 5 days. After 30 days of incubation with conduritol-B-epoxide, the macrophages contained almost 10 times as much glucocerebroside as the untreated controls, and the cells displayed morphologic changes reminiscent of Gaucher's cells. This in vitro system may enable detailed studies on the pathogenetic mechanisms associated with glucocerebroside accumulation in human macrophages as well as on the turnover of the accumulated substrate and reversal of the morphologic abnormalities on removal of the inhibitor
— id: 75046, year: 1988, vol: 111, page: 416, stat: Journal Article,

Biochemical, ultrastructural and histochemical studies of cat placentae deficient in activity of lysosomal alpha-mannosidase
Alroy, J; Warren, C D; Raghavan, S S; Daniel, P F; Schunk, K L; Kolodny, E H
1987 Sep-Oct;8(5):545-553, Placenta
Lysosomal alpha-mannosidase activity, oligosaccharide profiles, light and electron microscopy and lectin histochemistry studies were performed on full-term placentae obtained from five litters of cats. They resulted from breeding related cats who are obligate heterozygotes for lysosomal alpha-mannosidase deficiency. alpha-Mannosidase activity in placentae from affected kittens was less than 10 per cent of control, while in placentae from presumptive heterozygotes the activity was less than 50 per cent of control. High-pressure liquid chromatographic analysis of oligosaccharides revealed massive accumulation of undegraded oligosaccharides in placentae of affected kittens. A small elevation was found in placentae from presumptive heterozygous kittens, and none was detected in placentae of normal kittens. Light and electron microscopic examinations revealed vacuolization of fetal endothelial and mesenchymal cells only in placentae of affected kittens. Succinylated wheat germ agglutinin and concanavalin A stained the fetal fibroblasts only in placentae of affected kittens
— id: 75049, year: 1987, vol: 8, page: 545, stat: Journal Article,

COMPUTED TOMOGRAPHIC AND MAGNETIC IMAGING IN TWINS WITH NEUROAXONAL DYSTROPHY
BARLOW, JK; SIMS, KB; KOLODNY, EH
1987 SEP ;22(3):444-445, Annals of neurology
— id: 74962, year: 1987, vol: 22, page: 444, stat: Journal Article,

The autosomal dominant form of "pure" familial spastic paraplegia: clinical findings and linkage analysis of a large pedigree
Boustany, R M; Fleischnick, E; Alper, C A; Marazita, M L; Spence, M A; Martin, J B; Kolodny, E H
1987 Jun;37(6):910-915, Neurology
We studied 33 affected members in a family with autosomal dominant 'pure' familial spastic paraplegia (FSP). Symptoms began in the fourth or fifth decade, expression varied, and progression was slow. We excluded close linkage to the HLA locus (distal end of short arm of chromosome 6); C8 alpha-gamma locus (proximal end of short arm of chromosome 1); PGM1 (middle region of short arm of chromosome 1); and P blood group (location unknown). Although there was no statistically significant linkage between FSP and any of the other markers, lod scores were positive with loci for GC (vitamin D binding globulin) located on chromosome 4 (4q11-q13) and Rh located on chromosome 1 (1p34-p36)
— id: 75050, year: 1987, vol: 37, page: 910, stat: Journal Article,

ADULT-ONSET KRABBES DISEASE - CLINICAL AND BIOCHEMICAL FEATURES OF AN UNUSUAL CASE
BOUSTANY, RM; RISKIND, P; RAGHAVAN, S; KOLODNY, EH
1987 JUL ;22(1):167-168, Annals of neurology
— id: 74963, year: 1987, vol: 22, page: 167, stat: Journal Article,

DETERMINATION BY HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY OF CEREBROSPINAL-FLUID GANGLIOSIDES IN GM1 AND GM2 GANGLIOSIDOSES
KAYE, EM; KOLODNY, EH; ULLMAN, MD
1987 SEP ;22(3):444-444, Annals of neurology
— id: 74961, year: 1987, vol: 22, page: 444, stat: Journal Article,

The adrenoleukodystrophy-adrenomyeloneuropathy complex: is it treatable?
Kolodny, E H
1987 Mar;21(3):230-231, Annals of neurology
— id: 75052, year: 1987, vol: 21, page: 230, stat: Journal Article,

PSYCHIATRIC MANIFESTATIONS OF ADULT-ONSET STORAGE DISEASES
KOLODNY, EH
1987 MAY-JUN ;32(1-2):624-624, International journal of neuroscience
— id: 74964, year: 1987, vol: 32, page: 624, stat: Journal Article,

Metabolic activities in human skin fibroblasts preloaded with labeled GM2-ganglioside
Raghavan, S; Lyerla, T A; Krusell, A; Kolodny, E H
1987 Jan 13;917(1):42-47, Biochimica & biophysica acta
Confluent cultures of human skin fibroblasts were maintained for 10 days with sphingosine labeled [3H]GM2. Labeled medium was then replaced with normal medium and the cells maintained for 42 days with weekly medium changes. Cells were harvested at regular intervals and cells, medium, and trypsin digest supernatant analyzed for [3H]GM2 and its metabolic products. The ganglioside can be membrane associated and removed by trypsin, or membrane incorporated and trypsin insensitive. The membrane incorporated material is apparently transported to the lysosomes slowly by membrane flow, where 80% of the cellular GM2 can be metabolized by day 42. [3H]GM2 as well as its metabolic products in control cells is continuously released into the medium, during which it can also become associated with the cell surface membrane. There is no detectable metabolism of the [3H]GM2 in GM2 gangliosidosis cell lines over the extended post-labeling period, indicating that there is no residual enzyme activity in these cells. Undegraded GM2 is continuously released into the medium and remains associated with the cell surface membrane as well
— id: 75053, year: 1987, vol: 917, page: 42, stat: Journal Article,

Niemann-Pick variant lipodosis presenting as "neonatal hepatitis"
Semeraro, L A; Riely, C A; Kolodny, E H; Dickerson, G R; Gryboski, J D
1987 May-Jun;6(3):480-481, Journal of pediatric gastroenterology & nutrition
— id: 75051, year: 1987, vol: 6, page: 480, stat: Journal Article,

Pathologic findings in fetal GM1 gangliosidosis
Bieber, F R; Mortimer, G; Kolodny, E H; Driscoll, S G
1986 Jul;43(7):736-738, Archives of neurology
A 24-week fetus with GM1 gangliosidosis (type 1) was studied using biochemical and histopathologic methods. Foam cells in viscera and placenta demonstrated widespread accumulation of a lipidlike material. By microscopy, central nervous system storage appeared confined to the retina and dorsal root ganglia, but the brain ganglioside content was measurably elevated compared with that of age-matched controls. These data, along with those of others, imply that, if the observed pathologic findings are irreversible, any attempts at intrauterine therapy must commence prior to the middle of the second trimester
— id: 75055, year: 1986, vol: 43, page: 736, stat: Journal Article,

COMPARISON OF MAGNETIC-RESONANCE-IMAGING AND CT SCAN FINDINGS IN 2 SISTERS WITH JUVENILE NEURONAL CEROID LIPOFUSCINOSIS
BOUSTANY, RMN; FILIPEK, PA; CAVINESS, VS; KOLODNY, EH
1986 SEP ;20(3):441-441, Annals of neurology
— id: 74965, year: 1986, vol: 20, page: 441, stat: Journal Article,

STORAGE DISEASES OF ADULT ONSET ARE COMMON AMONG BIOCHEMICALLY DIAGNOSED NEUROGENETIC DISORDERS (3-YEAR EXPERIENCE OF A LYSOSOMAL STORAGE DISEASE LABORATORY)
BOUSTANY, RMN; KOLODNY, EH
1986 APR ;36(4):78-78, Neurology
— id: 74966, year: 1986, vol: 36, page: 78, stat: Journal Article,

Lysosomal enzymes in chorionic villi, cultured amniocytes, and cultured skin fibroblasts
Evans MI; Moore C; Kolodny EH; Casassa M; Schulman JD; Landsberger EJ; Karson EM; Dorfmann AD; Larsen JW Jr; Barranger JA
1986 May 30;157(1):109-113, Clinica chimica acta
— id: 23053, year: 1986, vol: 157, page: 109, stat: Journal Article,

Two abnormalities of hexosaminidase A in clinically normal individuals
Grebner, E E; Mansfield, D A; Raghavan, S S; Kolodny, E H; d'Azzo, A; Neufeld, E F; Jackson, L G
1986 Apr;38(4):505-514, American journal of human genetics
Two abnormalities of beta-hexosaminidase A (HEX A) activity are described. One, found in two unrelated Jewish children, was characterized by the complete absence of HEX A activity in serum, but low levels of activity in leukocytes and fibroblasts using artificial substrate. The other, found in a non-Jewish man, was characterized by uniformly low levels of HEX A activity in leukocytes, fibroblasts, and serum against artificial substrate. In all cases, the pH optimum of HEX A was normal, there was no increased lability at 37 degrees C, and no inhibitor was detected to account for the deficiency of activity. Cultured fibroblasts of these individuals were capable of synthesizing and processing alpha- and beta-subunits of HEX A and capable of cleaving GM2 ganglioside. The patients, ranging in age from 6 to 30 years, are clinically normal. They are probably genetic compounds carrying the classical Tay-Sachs gene and a differently mutated allele that imparts the anomalous phenotypic features observed
— id: 75058, year: 1986, vol: 38, page: 505, stat: Journal Article,

Early detection of lysosomal storage diseases
Kolodny, E H
1986 ;477:312-320, Annals of the New York Academy of Sciences
— id: 75060, year: 1986, vol: 477, page: 312, stat: Journal Article,

Myoclonus epilepsy in two brothers. Clinical features and neuropathology of a unique syndrome
Logigian, E L; Kolodny, E H; Griffith, J F; Filipek, P A; Richardson, E P Jr
1986 Jun;109 ( Pt 3):411-429, Brain
We report 2 brothers with progressive ataxia, seizures, myoclonus, supranuclear ophthalmoplegia, progressive visual loss and embolic strokes. The epilepsy and myoclonus came on many years after the onset of the ataxia. In the more severely affected brother the myoclonus was often unilateral and focal but ultimately involved both sides of the body. His sibling had only unilateral myoclonus after a contralateral middle cerebral artery stroke. When focal, persistent and unilateral, the myoclonus in both brothers was clinically similar to epilepsia partialis continua except that muscles of the trunk and proximal limbs were the most affected. It was exacerbated by movement of the affected part but was otherwise not stimulus sensitive. The more severely affected brother had a pigmentary retinopathy and a cardiac fibromyxoid valvulopathy. In his sibling, visual loss was not fully investigated and the heart was not examined at autopsy though he had a longstanding heart murmur. Neuropathological studies showed pancerebellar cortical atrophy, cell loss in the inferior olivary nuclei and old right middle cerebral artery infarctions in both brothers. Biochemical assays for known metabolic diseases were negative. We suggest that this syndrome represents a unique autosomal recessive form of progressive myoclonus epilepsy of unclear aetiology. It is distinguished from other familial myoclonus epilepsies by the presence of early onset cerebellar ataxia, supranuclear ophthalmoplegia, pigmentary retinopathy and possibly cardiac valvulopathy with subsequent cerebral emboli
— id: 75056, year: 1986, vol: 109 ( Pt 3), page: 411, stat: Journal Article,

Macular halos associated with Niemann-Pick type B disease
Matthews, J D; Weiter, J J; Kolodny, E H
1986 Jul;93(7):933-937, Ophthalmology
Macular halos describe a striking clinical finding of bilaterally elevated, doughnut-shaped, white rings around th fovea. This paper presents the third well-documented report of the association of macular halos with Niemann-Pick type B disease, demonstrated by color photographs and subtle fluorescein angiographic findings. The systemic association with Niemann-Pick type B disease was confirmed by bone marrow biopsy and enzyme assay. Of 13 family members examined, only the proposita had macular halos; 10 were found to be carriers by sphingomyelinase assay. Recognition of this pathognomonic eye finding warrants more widespread awareness as a presenting sign of Niemann-Pick type B disease
— id: 75054, year: 1986, vol: 93, page: 933, stat: Journal Article,

Niemann-Pick variant lipidosis presenting as "neonatal hepatitis"
Semeraro, L A; Riely, C A; Kolodny, E H; Dickerson, G R; Gryboski, J D
1986 May-Jun;5(3):492-500, Journal of pediatric gastroenterology & nutrition
Neonatal hepatitis is a nonspecific term that may include a variety of disease entities. Two patients are presented who developed jaundice in the neonatal period and progressive hepatosplenomegaly. The infants were initially felt to have 'neonatal hepatitis' but were subsequently found to have Niemann-Pick disease. Biochemical investigation revealed normal levels of sphingomyelinase activity in leukocytes and liver but diminished levels in cultured skin fibroblasts, compatible with Niemann-Pick type C
— id: 75057, year: 1986, vol: 5, page: 492, stat: Journal Article,

Oligosaccharides from placenta: early diagnosis of feline mannosidosis
Warren, C D; Alroy, J; Bugge, B; Daniel, P F; Raghavan, S S; Kolodny, E H; Lamar, J J; Jeanloz, R W
1986 Jan 20;195(1-2):247-252, FEBS letters
High-pressure liquid chromatography analysis of oligosaccharides from placentas allowed the diagnosis of alpha-mannosidosis in three litters of kittens. The chromatography also afforded a detailed comparison of the oligosaccharide pattern and levels in placenta, liver, brain, urine and ocular fluid of the affected animals. In all cases, two series of compounds were observed, with one or two residues of N-acetylglucosamine at the reducing terminus, respectively, and between two and nine mannose residues. This pattern is unlike that of human mannosidosis, and resembles that of ruminants, except that the major oligosaccharide contains three mannose residues instead of two
— id: 75059, year: 1986, vol: 195, page: 247, stat: Journal Article,

Neurovisceral and skeletal GM1-gangliosidosis in dogs with beta-galactosidase deficiency
Alroy, J; Orgad, U; Ucci, A A; Schelling, S H; Schunk, K L; Warren, C D; Raghavan, S S; Kolodny, E H
1985 Aug 2;229(4712):470-472, Science
Beta-galactosidase-deficient siblings in two litters of English springer spaniel puppies showed a progressive neurological impairment, dwarfism, orbital hypertelorism, and dysostosis multiplex. An excess of GM1-ganglioside was found in the brain. Three abnormal oligosaccharides were present in samples of urine, brain, liver, and cartilage. Light microscopy of selected tissue specimens revealed cytoplasmic vacuoles in neurons, circulating blood cells, macrophages, and chondrocytes. Ultrastructural studies demonstrated that these membrane-bound vacuoles were of two types--one containing lamellated membranes and the other, finely granular material. These clinical and pathological findings are similar to those observed in human patients affected by the infantile form of GM1-gangliosidosis
— id: 75062, year: 1985, vol: 229, page: 470, stat: Journal Article,

LECTIN HISTOCHEMISTRY OF GLYCOLIPID STORAGE DISEASES ON FROZEN AND PARAFFIN SECTIONS
ALROY, J; UCCI, AA; RAGHAVAN, SS; KOLODNY, EH
1985 NOV ;44(3):351-351, Journal of neuropathology & experimental neurology
— id: 74969, year: 1985, vol: 44, page: 351, stat: Journal Article,

Peroxisomes in fibroblasts from skin of Refsum's disease patients
Beard, M E; Sapirstein, V; Kolodny, E H; Holtzman, E
1985 May;33(5):480-484, Journal of histochemistry & cytochemistry
Skin fibroblasts were cultured from young adult patients with Refsum's disease, an inherited metabolic disorder characterized by a deficiency in oxidation of phytanic acid and by increased serum and tissue concentrations of this fatty acid. These cultures were compared to cultures of normal fibroblasts in terms of the number and distribution of peroxisomes demonstrable cytochemically in preparations incubated for catalase activity. Refsum's fibroblasts were found to contain 1-10 peroxisome profiles per 100 micron 2 of cytoplasm; the controls contained 1-2 profiles per 100 micron 2. The peroxisomes in normal fibroblasts were found in all regions of the cytoplasm. In the Refsum's material they were relatively scarce in the perinuclear region, where many of the cells showed numerous large inclusions containing lipid-like material and myelin figures. Our findings indicate that in the adult form of Refsum's disease, which is the more thoroughly studied variety, peroxisomes in fibroblasts are not diminished in number. This contrasts with a recent report concerning a case of what is thought to be an infantile form of the disorder, in which no peroxisomes were detected in a liver biopsy. If phytanic acid accumulations in the adult form are a consequence of peroxisomal defects, the defects presumably are at the level of specific enzymatic deficiencies and do not involve a generalized absence of peroxisomes
— id: 75063, year: 1985, vol: 33, page: 480, stat: Journal Article,

Laboratory approaches for inherited neurometabolic diseases
Kolodny, E H; Yatziv, S
1985 Apr;27(2):252-257, Developmental medicine & child neurology
— id: 75065, year: 1985, vol: 27, page: 252, stat: Journal Article,

LINKAGE RELATIONS OF PLG (PLASMINOGEN)
MARAZITA, ML; SPENCE, MA; BOUSTANY, RM; FLEISHNICK, E; MARTIN, JB; KOLODNY, EH
1985 NOV ;40(1-4):689-689, Cytogenetics & cell genetics
— id: 74967, year: 1985, vol: 40, page: 689, stat: Journal Article,

GM2-ganglioside metabolism in hexosaminidase A deficiency states: determination in situ using labeled GM2 added to fibroblast cultures
Raghavan, S S; Krusell, A; Krusell, J; Lyerla, T A; Kolodny, E H
1985 Nov;37(6):1071-1082, American journal of human genetics
To clarify the relationship between hexosaminidase A (HEX A) activity and GM2-ganglioside hydrolysis in atypical clinical situations of HEX A deficiency, we have developed a simple method to assess GM2-ganglioside metabolism in cultured fibroblasts utilizing GM2 labeled with tritium in the sphingosine portion of the molecule. The radioactive lipid is added to the media of cultured skin fibroblasts, and after 10 days the cells are thoroughly washed, then harvested, and their lipid composition analyzed by HPLC. The degree of hydrolysis of the ingested GM2 is determined by comparing the amount of radioactive counts recovered in undegraded substrate with total cellular radioactivity. A deficiency in GM2-ganglioside hydrolysis was demonstrated in seven HEX A-deficient adults with neurological signs and in two healthy-appearing adolescents with older affected siblings. In each case, an analysis of endogenous monosialoganglioside composition revealed an increase in GM2-ganglioside, confirming the presence of a block in the metabolism of GM2. No defect in GM2-catabolism was found in four other healthy individuals with HEX A deficiency. This method of assay is especially helpful in the evaluation of atypical cases of HEX A deficiency for the definitive diagnosis of GM2-gangliosidosis
— id: 75061, year: 1985, vol: 37, page: 1071, stat: Journal Article,

GM2-ganglioside metabolism in cultured human skin fibroblasts: unambiguous diagnosis of GM2-gangliosidosis
Raghavan, S; Krusell, A; Lyerla, T A; Bremer, E G; Kolodny, E H
1985 Apr 25;834(2):238-248, Biochimica & biophysica acta
The metabolism of GM2-ganglioside was studied in situ using cultured skin fibroblasts from normal individuals and patients with different forms of GM2-gangliosidosis. [3H]Sphingosine-labeled GM2 was provided in the culture medium to confluent cells in 6-cm petri dishes. After 10 days, the cells were washed free of radioactivity and harvested by trypsinization. The cellular lipids were extracted and analyzed for radioactivity in GM2 and its metabolic products. In fibroblasts from healthy subjects, 50-60% of the total cellular radioactivity was found in the neutral glycosphingolipids, ceramide, sphingomyelin and fatty acids. Degradation of the labeled GM2 progressed rapidly via GM3, ceramide dihexoside and ceramide monohexoside with a build-up of radioactivity mainly in the ceramide pool of the cell. The labeled ceramide is also reutilized for the synthesis of ceramide trihexoside, globoside and sphingomyelin or is converted to fatty acid and incorporated in ester linkages. In contrast, cells from patients with GM2-gangliosidosis representing Tay-Sachs, Sandhoff and AB variant forms of the disease did not metabolize the ingested labeled GM2-like controls. Nearly all of the radioactivity was present in the ganglioside fraction in the lipid extracts from these cells and consisted of unhydrolyzed GM2. High-performance liquid chromatographic analysis of monosialogangliosides from cells grown without added labeled GM2 in the medium indicated accumulation of endogenously synthesized GM2 in cell lines from all patients with GM2 gangliosidosis compared to healthy controls. This approach provides a reliable tool for pre- and post-natal diagnosis of all forms of GM2-gangliosidosis without ambiguity
— id: 75064, year: 1985, vol: 834, page: 238, stat: Journal Article,

Ocular abnormalities in mucolipidosis IV
Riedel, K G; Zwaan, J; Kenyon, K R; Kolodny, E H; Hanninen, L; Albert, D M
1985 Feb 15;99(2):125-136, American journal of ophthalmology
Systemic findings in a 23-year-old white man with mucolipidosis type IV included early delayed psychomotor development, mental retardation, and mild facial dysplasia. There was urinary excretion of chondroitin sulfate. Ophthalmologic examination showed corneal haze, pigmentary retinopathy, and severe optic atrophy. Light microscopy showed massively engorged superficial and intermediate epithelial cells of both the cornea and the conjunctiva. By transmission electron microscopy these contained fine granular material consistent with acid mucopolysaccharide and concentric lamellar bodies presumably representing phospholipids. This storage phenomenon was also found in macrophages, plasma cells, ciliary epithelial cells, Schwann cells, retinal ganglion cells, and vascular endothelial cells. Light microscopy also disclosed early cataract formation, marked outer retinal degeneration, and optic atrophy
— id: 75066, year: 1985, vol: 99, page: 125, stat: Journal Article,

NEUROVISCERAL AND SKELETAL GM1-GANGLIOSIDOSIS
SCHELLING, SH; ORGAD, U; GARVIS, VE; UCCI, AA; SCHUNK, K; CASASSA, MMK; RAGHAVAN, S; WARREN, C; KOLODNY, EH; ALROY, J
1985 NOV ;52(1):A59-A59, Laboratory investigation
— id: 74970, year: 1985, vol: 52, page: A59, stat: Journal Article,

LECTIN HISTOCHEMISTRY OF GLOBOID-CELLS IN HUMAN AND ANIMALS WITH GLOBOID LEUKODYSTROPHY
UCCI, AA; ALROY, J; RAGHAVAN, SS; KOLODNY, EH
1985 NOV ;44(3):351-351, Journal of neuropathology & experimental neurology
— id: 74968, year: 1985, vol: 44, page: 351, stat: Journal Article,

Diagnosis of pseudo-arylsulfatase A deficiency with electrophoretic techniques
Chang, P L; Rosa, N E; Varey, P A; Kihara, H; Kolodny, E H; Davidson, R G
1984 Oct;18(10):1042-1045, Pediatric research
Deficient arylsulfatase A activity in man has long been associated with the neurodegenerative disease, metachromatic leukodystrophy. However, similar deficiency has been noted in clinically normal individuals, and is referred to as the pseudoarylsulfatase A deficiency condition. Although direct quantitative analysis of arylsulfatase A activity failed to differentiate between these two conditions, analysis of residual arylsulfatase A activity with either Cellogel electrophoresis or isoelectric focusing in polyacrylamide gels now has been shown to distinguish between them unequivocally. With both techniques, cultured fibroblasts from patients with pseudo-arylsulfatase A deficiency showed faint but clear bands of arylsulfatase A activity. Under identical conditions, fibroblasts from patients with metachromatic leukodystrophy showed no trace of activity. These methods can be adapted easily for general laboratory analysis in cases when results from quantitative arylsulfatase A assays are noninformative
— id: 75067, year: 1984, vol: 18, page: 1042, stat: Journal Article,

Faulty association of alpha- and beta-subunits in some forms of beta-hexosaminidase A deficiency
d'Azzo, A; Proia, R L; Kolodny, E H; Kaback, M M; Neufeld, E F
1984 Sep 10;259(17):11070-11074, Journal of biological chemistry
We have previously described the kinetics of association of the alpha- and beta-subunits of beta-hexosaminidase A in intact cultured human fibroblasts, using biosynthetic labeling and immunoprecipitation with antisera that distinguish between monomeric and associated alpha-chains (Proia, R. L., d'Azzo, A., and Neufeld, E. F. (1984) J. Biol. Chem. 259, 3350-3354). We now show lack of alpha-beta association in fibroblasts of several individuals deficient in beta-hexosaminidase A (5 patients with nonclassic forms of Tay-Sachs disease and 2 asymptomatic siblings). Defective association was accompanied by markedly reduced (less than one-tenth of normal) conversion of the alpha-chain precursor of Mr = 67,000 to the mature lysosomal form of Mr = 54,000. Analysis by hybridization with fibroblasts lacking the alpha- or beta-chain showed that the association defect resided in the alpha-chain. Most of the cell strains studied also had decreased synthesis of the alpha-chain, suggesting compound heterozygosity with the Ashkenazi Tay-Sachs (no synthesis) allele. An unusual feature of the association defect is the variability in the resulting clinical manifestations, even within families, implying that other factors determine the adequacy of the residual associated beta-hexosaminidase A in vivo
— id: 75068, year: 1984, vol: 259, page: 11070, stat: Journal Article,

A 47-YEAR-OLD MAN WITH CORONARY-ARTERY DISEASE AND VARIABLE NEUROLOGIC ABNORMALITIES - FABRYS-DISEASE (ALPHA-GALACTOSIDASE-A DEFICIENCY), WITH INVOLVEMENT OF NERVOUS-SYSTEM AND BLOOD-VESSELS, WITH CEREBRAL, MYOCARDIAL, AND RENAL INFARCTS
DAWSON, DM; MILLER, DC; ADAMS, RD; MARK, EJ; KUTER, DJ; KOLODNY, EH; HALPERIN, JJ
1984 NOV ;310(2):106-114, New England journal of medicine
— id: 74973, year: 1984, vol: 310, page: 106, stat: Journal Article,

Jejunal diverticulosis with perforation as a complication of Fabry's disease
Friedman, L S; Kirkham, S E; Thistlethwaite, J R; Platika, D; Kolodny, E H; Schuffler, M D
1984 Mar;86(3):558-563, Gastroenterology
This study presents the case of a patient who had jejunal diverticulosis with perforation and abscess formation as a complication of Fabry's disease. Light microscopy disclosed glycolipid deposition in the neurons and nerve fibers of the intestinal nerve plexuses and smooth muscle. Silver stains of the myenteric plexus in the involved segment of the bowel showed enlarged, granular argyrophobic neurons and a marked decrease in the number of argyrophilic neurons, with those remaining being enlarged and distorted by the cytoplasmic glycolipid accumulation. These abnormalities of the myenteric plexus suggest that jejunal diverticulosis may be the result of a variety of disorders of the smooth muscle or myenteric plexus, or both. We propose that jejunal diverticulosis in our patient was a consequence of uncoordinated smooth muscle activity resulting from Fabry's involvement of myenteric plexus neurons, with mucosal protrusion through the smooth muscle
— id: 75070, year: 1984, vol: 86, page: 558, stat: Journal Article,

Communicating hydrocephalus and lysosomal inclusions in mannosidosis
Halperin JJ; Landis DM; Weinstein LA; Lott IT; Kolodny EH
1984 Jul;41(7):777-779, Archives of neurology
A 32-year-old man with mannosidosis had a gait disorder develop that was associated with communicating hydrocephalus. The gait disorder improved with ventriculoperitoneal shunting, but proximal muscle weakness remained. Biopsy specimens of muscle and nerve disclosed typical lysosomal inclusions in both tissues, as well as selective loss of unmyelinated axons
— id: 65106, year: 1984, vol: 41, page: 777, stat: Journal Article,

Biomedical genetics of the inherited metabolic diseases: the GM2-gangliosidoses
Kolodny, E H
1984 Mar;88(5):582-589, American journal mental dificiency
Many of the known gene defects result in inborn errors of metabolism that produce irreversible damage to the central nervous system. A variety of new clinical, morphologic, biochemical, and genetic techniques are being used to characterize these disorders more precisely. At the Shriver Center, the different genotypes of GM2-gangliosidosis are distinguished according to the ability of cells in culture to metabolize radioactively-labeled GM2-ganglioside. Large-scale screening for carriers of the trait for Tay-Sachs disease, the most common of the GM2-gangliosidoses, has dramatically reduced the incidence of this disease. Current efforts to isolate the genes for the alpha and beta chains of hexosaminidase A will lay the groundwork for better understanding of the molecular defects in these diseases and offers hope for a possible treatment
— id: 75069, year: 1984, vol: 88, page: 582, stat: Journal Article,

THE EUNICE-KENNEDY-SHRIVER-CENTER
KOLODNY, EH
1984 NOV ;88(5):580-581, American journal mental dificiency
— id: 74972, year: 1984, vol: 88, page: 580, stat: Journal Article,

HYDROPS FETALIS IN GAUCHERS-DISEASE
RICE, GE; MOSTOUFIZADEH, M; KOLODNY, EH; DRISCOLL, SG
1984 NOV ;29(2):A53-A54, Teratology
— id: 74971, year: 1984, vol: 29, page: A53, stat: Journal Article,

BIOSYNTHESIS, ASSEMBLY AND MATURATION OF BETA-HEXOSAMINIDASE IN VARIANTS OF TAY-SACHS DISEASE
DAZZO, A; PROIA, RL; KOLODNY, EH; KABACK, MM; NEUFELD, EF
1983 NOV ;35(6):A40-A40, American journal of human genetics
— id: 74974, year: 1983, vol: 35, page: A40, stat: Journal Article,

NEURONAL CEROID LIPOFUSCINOSIS - A DIAGNOSTIC-APPROACH
FINKEL, RS; BRESNAN, MJ; KOLODNY, EH; SOTREL, A; FULTON, AB
1983 NOV ;14(3):366-366, Annals of neurology
— id: 74977, year: 1983, vol: 14, page: 366, stat: Journal Article,

Impaired cerebroside sulfate hydrolysis in fibroblasts of sibs with "pseudo" arylsulfatase A deficiency without metachromatic leukodystrophy
Hreidarsson, S J; Thomas, G H; Kihara, H; Fluharty, A L; Kolodny, E H; Moser, H W; Reynolds, L W
1983 Sep;17(9):701-704, Pediatric research
Low arylsulfatase A levels are reported in two siblings, one with a neurologic disability not typical for metachromatic leukodystrophy, the other a healthy 18-year-old female with a normal developmental history. In both individuals, arylsulfatase A levels in white blood cells were 7-8% of control values. Cultured fibroblasts gave low values (8-10% of normal) for both cerebroside sulfatase and arylsulfatase A activities. Other family members had enzyme levels consistent with heterozygote or normal status. Cerebroside sulfate loading tests of cultured fibroblasts in 199-CO2 media were normal for all family members who were tested. In MEM-HEPES media, however, cells from the two arylsulfatase A deficient siblings showed attenuated sulfolipid catabolism. Additional clinical and laboratory studies on these individuals failed to demonstrate any features suggestive of metachromatic leukodystrophy, i.e., normal nerve conduction velocities, normal sural nerve biopsy results, and normal urinary sulfatide excretion. It is concluded that the neurologic abnormalities in the one sibling are not the result of the low enzyme activity and that both individuals represent examples of pseudo arylsulfatase A deficiency (arylsulfatase A deficiency without metachromatic leukodystrophy). These results thus call into question the ability of the high-sensitivity cerebroside sulfate loading test as carried out in MEM-HEPES media to differentiate pathologically significant defects i.e., metachromatic leukodystrophy from benign 'pseudo-deficiencies.'
— id: 75071, year: 1983, vol: 17, page: 701, stat: Journal Article,

GM2-GANGLIOSIDOSIS - HEXOSAMINIDASE MUTATIONS NOT OF THE TAY-SACHS TYPE PRODUCE UNUSUAL CLINICAL VARIANTS
KOLODNY, EH; RAGHAVAN, SS
1983 NOV ;6(1):16-20, Trends in neurosciences
— id: 74978, year: 1983, vol: 6, page: 16, stat: Journal Article,

MIS-DIAGNOSIS IN A FETUS WITH AN UNSTABLE HEXOSAMINIDASE A CATALYTICALLY IN-ACTIVE TOWARD GM2-GANGLIOSIDE
KOLODNY, EH; RAGHAVAN, SS; LYERLA, TA; PROIA, RL; NEUFELD, EF; GREBNER, EE
1983 NOV ;35(6):A47-A47, American journal of human genetics
— id: 74975, year: 1983, vol: 35, page: A47, stat: Journal Article,

A 41-YEAR-OLD WOMAN WITH SPASTIC TETRAPARESIS AND SHORT STATURE - MUCOPOLYSACCHARIDOSIS, TYPE-VI, MILD FORM (MAROTEAUX-LAMY SYNDROME)
POSER, CM; SOBEL, RA; HALPERIN, JJ; OOT, RF; SCULLY, RE; DELONG, GR; OJEMANN, RG; KOLODNY, EH
1983 NOV ;309(18):1109-1117, New England journal of medicine
— id: 74976, year: 1983, vol: 309, page: 1109, stat: Journal Article,

Fabry disease: significance of ultrastructural localization of lipid inclusions in dermal nerves
Cable, W J; Dvorak, A M; Osage, J E; Kolodny, E H
1982 Apr;32(4):347-353, Neurology
An ultrastructural examination of intradermal nerve fibers in Fabry disease revealed signs of lipid accumulation and small unmyelinated nerve fiber degeneration. Many axons were swollen, and their internal organelles were lost. In several damaged axons, dense inclusions, probably lipid, were observed. No lipid inclusions were found in Schwann cells, which may indicate that they utilize different metabolic processes or are impervious to ceramide trihexoside. It is hypothesized that Schwann cells and myelin sheaths act as a metabolic barrier protecting the larger myelinated fibers. Lacking this barrier, the smaller unmyelinated fibers are more susceptible to lipid infiltration. This view may explain the small fiber neuropathy in Fabry disease
— id: 75075, year: 1982, vol: 32, page: 347, stat: Journal Article,

Fabry disease: impaired autonomic function
Cable, W J; Kolodny, E H; Adams, R D
1982 May;32(5):498-502, Neurology
Previous reports of extensive lipid accumulation within neurons of the autonomic nervous system in Fabry disease suggest an anatomicopathologic basis for the peculiar pain, diminished sweating, and gastrointestinal symptoms experienced in this disorder. To further assess autonomic function in Fabry disease, noninvasive clinical tests were performed on 10 patients. Diminished sweating was found in each; the loss was approximately uniform proximally and distally, suggesting sweat gland dysfunction rather than autonomic neuropathy. Impaired pupillary constriction with pilocarpine, and reduced saliva and tear formation were found in half the patients. Disordered intestinal mobility was demonstrated in the oldest patients. In all cases, the cutaneous flare response to scratch and intradermal histamine was diminished, and pruritus was not experienced. Signs of autonomic dysfunction are present in Fabry disease and correlate with the known lipid deposition in autonomic neurons
— id: 75074, year: 1982, vol: 32, page: 498, stat: Journal Article,

Fabry disease: detection of heterozygotes by examination of glycolipids in urinary sediment
Cable, W J; McCluer, R H; Kolodny, E H; Ullman, M D
1982 Oct;32(10):1139-1145, Neurology
Fabry disease is an X-linked sphingolipid disorder that is manifest clinically as a disease of nerves, kidneys, and blood vessels. Precise identification of Fabry heterozygotes is essential for genetic counseling. Heterozygote detection by enzyme assay does not consistently distinguish them from unaffected females. We describe a method for Fabry heterozygote detection, based on quantitation of urinary sediment glycolipids by high-performance liquid chromatography. In specimens from 12 Fabry heterozygotes, the total glycolipid fraction was increased (10 to 100-fold) and trihexosyl ceramide (CTH) was 2- to 70-fold times normal. Digalactosyl ceramide (Digal-Cer), which is normally present in trace amounts in urine, was also increased. The ratio of CTH and Digal-Cer to hydroxy fatty acid glucosyl ceramide was increased and seemed to be characteristic of Fabry disease. This method provides rapid and accurate detection of Fabry heterozygotes
— id: 75072, year: 1982, vol: 32, page: 1139, stat: Journal Article,

AUTONOMIC DYSFUNCTION IN ADRENOMYELONEUROPATHY
CABLE, WJ; KOLODNY, EH
1982 NOV ;32(4):A216-A216, Neurology
— id: 74981, year: 1982, vol: 32, page: A216, stat: Journal Article,

A micromethod for the detection of arylsulfatases A and B in cultured fibroblasts and amniocytes
Gravel, R A; Leung, A; Tsui, F; Kolodny, E H
1982 Jan 15;119(2):360-364, Analytical biochemistry
— id: 75078, year: 1982, vol: 119, page: 360, stat: Journal Article,

Microcephaly vera, progressive motor neuron disease, and nigral degeneration
Halperin JJ; Williams RS; Kolodny EH
1982 Mar;32(3):317-320, Neurology
A patient is described who was microcephalic at birth. After attaining early motor milestones, she developed progressive lower motor neuron dysfunction of the limb and bulbar musculature, combined with dystonia and an action tremor. The pathology and possible pathogenesis are discussed
— id: 65111, year: 1982, vol: 32, page: 317, stat: Journal Article,

CEREBROSPINAL-FLUID GLYCOLIPIDS IN KRABBE DISEASE
KAYE, EM; KOLODNY, EH; ULLMAN, MD
1982 NOV ;32(4):A122-A122, Neurology
— id: 74980, year: 1982, vol: 32, page: A122, stat: Journal Article,

Inborn errors of metabolism
Kolodny, E H; Cable, W J
1982 Mar;11(3):221-232, Annals of neurology
Inborn errors of metabolism often cause neurological dysfunction. These disorders are most common in childhood, but adult-onset forms with a different clinical presentation are encountered, examples being Pompe disease, Tay-Sachs disease, metachromatic leukodystrophy, Gaucher disease, and Maroteaux-Lamy disease. In the evaluation of a patient with a possible inborn error of metabolism, simple screening tests may aid in the diagnosis and provide direction for more comprehensive laboratory analysis. In most cases, diagnosis can be established without a brain biopsy through biochemical and ultrastructural analysis of peripheral tissues, blood, and urine. New clinical, genetic, and biochemical variants of inherited metabolic disorders are being recognized through wider application of screening tests, improved specificity of laboratory analysis, cell complementation experiments, and the identification of enzyme activator factors. Accurate diagnosis is important for medical management, determining prognosis, and genetic counseling
— id: 75077, year: 1982, vol: 11, page: 221, stat: Journal Article,

Phenotypic manifestations of Gaucher disease: clinical features in 48 biochemically verified type 1 patients and comment on type 2 patients
Kolodny, E H; Ullman, M D; Mankin, H J; Raghavan, S S; Topol, J; Sullivan, J L
1982 ;95:33-65, Progress in clinical & biological research
— id: 75079, year: 1982, vol: 95, page: 33, stat: Journal Article,

SIGNIFICANCE OF HEXOSAMINIDASE-A DEFICIENCY IN ADULTS
KOLODNY, EH; LYERLA, T; RAGHAVAN, SS; SEASHORE, G; FOGELSON, H; POPE, HG
1982 NOV ;32(4):A81-A82, Neurology
— id: 74979, year: 1982, vol: 32, page: A81, stat: Journal Article,

The early laboratory diagnosis of mucopolysaccharidoses
Lorincz, A E; Hurst, R E; Kolodny, E H
1982 Jul-Aug;12(4):258-266, Annals of clinical & laboratory science
— id: 75073, year: 1982, vol: 12, page: 258, stat: Journal Article,

Nonuniform deficiency of hexosaminidase A in tissues and fluids of two unrelated individuals
Thomas, G H; Raghavan, S; Kolodny, E H; Frisch, A; Neufeld, E F; O'Brien, J S; Reynolds, L W; Miller, C S; Shapiro, J; Kazazian, H H Jr; Heller, R H
1982 Mar;16(3):232-237, Pediatric research
Serum samples from two unrelated, clinically normal individuals lacked detectable hexosaminidase A by heat inactivation and electrophoretic analysis. In contrast, 15 and 17% of the hexosaminidase in their leukocytes and 23 and 26% of the hexosaminidase of their cultured fibroblasts had the heat stability and electrophoretic properties of the A form of this enzyme. An in vitro measurement of fibroblasts GM2 ganglioside-beta-galactosaminidase was in the range expected for Tay-Sachs disease (TSD) heterozygotes (2.5 and 3.1 versus a normal mean of 3.7). In contrast, fibroblasts from a patient with TSD, analyzed in an identical fashion, contained no detectable activity. Ten days after addition of labeled GM2 ganglioside to the medium of the cultured fibroblasts, 43 and 59% of the radioactivity taken up by the cells of these patients remained as unhydrolyzed ganglioside as compared with 94% in TSD fibroblasts and 42% in control cells. An analysis of sphingolipid composition by high performance liquid chromatography although the endogenous level of GM2 was elevated in TSD fibroblasts (0.39 nmoles/mg protein) there was no increase in the cells of these patients (0 and 0.12 versus control of 0.17 nmoles/mg protein). Finally, the synthesis of hexosaminidase was examined by an electrophoretic analysis of immunoprecipitates of the enzyme precursors that had been radiolabeled by culturing fibroblasts in medium containing [3H]-leucine. These studies revealed a normal pattern of biosynthesis, processing and secretion of the alpha and beta chains. The ratio of the alpha chain to the beta chain, however, was in the range expected for TSD heterozygotes
— id: 75076, year: 1982, vol: 16, page: 232, stat: Journal Article,

FAMILIAL DYSAUTONOMIA VARIANT IN A MIDDLE-AGED MALE OF JEWISH ANCESTRY
CABLE, WJL; KOLODNY, EH; GROWDON, JH; ADAMS, RD
1981 NOV ;31(4):98-99, Neurology
— id: 74986, year: 1981, vol: 31, page: 98, stat: Journal Article,

HPLC ANALYSIS OF URINARY SEDIMENT GLYCOLIPIDS IN OBLIGATE CARRIERS OF FABRY DISEASE
CABLE, WJL; KOLODNY, EH; MCCLUER, RH; ULLMAN, MD
1981 NOV ;31(4):86-86, Neurology
— id: 74985, year: 1981, vol: 31, page: 86, stat: Journal Article,

Diagnostic electron microscopy. II. Fabry's disease: use of biopsies from uninvolved skin. Acute and chronic changes involving the microvasculature and small unmyelinated nerves
Dvorak, A M; Cable, W J; Osage, J E; Kolodny, E H
1981 ;16 Pt 1:139-158, Pathology annual
— id: 75081, year: 1981, vol: 16 Pt 1, page: 139, stat: Journal Article,

PROPOSED REGISTRY FOR LYSOSOMAL STORAGE DISEASES
KOLODNY, EH
1981 NOV ;33(6):A8-A8, American journal of human genetics
— id: 74982, year: 1981, vol: 33, page: A8, stat: Journal Article,

LOW SULFATIDASE ACTIVITY AND DEMYELINATING DISEASE
KOLODNY, EH; RAGHAVAN, SS; LOTT, IT; SERGAY, SM
1981 NOV ;31(4):86-86, Neurology
— id: 74984, year: 1981, vol: 31, page: 86, stat: Journal Article,

Leukocyte sulfatidase for the reliable diagnosis of metachromatic leukodystrophy
Raghavan, S S; Gajewski, A; Kolodny, E H
1981 Feb;36(2):724-731, Journal of neurochemistry
A simple assay technique for the determination of sulfatidase activity in leukocytes has been developed for the reliable diagnosis of metachromatic leukodystrophy (MLD). Sulfatide is tritiated in sphingosine and fatty acid by reduction with [3H]sodium borohydride in alkali in the presence of palladium chloride. This labeled natural substrate for aryl sulfatase A (AsA) is hydrolyzed by normal human leukocytes in 25 mM-acetate buffer, pH 5.0, in the presence of 0.3% sodium taurodeoxycholate. The enzyme activity is greatly improved after dialysis, exhibiting better linearity with protein concentration. It is stimulated maximally by 5 mM-MnCl2 with an apparent Km of 0.17 mM for the substrate. Patients with MLD exhibited virtually no detectable sulfatidase activity although they had residual AsA activity that was measured with the synthetic substrate, p-nitrocatechol sulfate (NCS). Potential heterozygotes could be identified by the sulfatidase assay in instances where the NCS assay for AsA was inconclusive. Several individuals with levels of AsA activity characteristic of MLD, including a few healthy carriers and certain patients with unknown neurological diseases, were shown not to have MLD by the presence of measurable levels of sulfatidase in their leukocytes
— id: 75080, year: 1981, vol: 36, page: 724, stat: Journal Article,

RETINAL-PIGMENT EPITHELIAL DEGENERATION AND ARYLSULFATASE-A DEFICIENCY - REPLY
WEITER, JJ; KOLODNY, EH; FEINGOLD, M; RAGHAVEN, SS
1981 NOV ;92(1):137-138, American journal of ophthalmology
— id: 74983, year: 1981, vol: 92, page: 137, stat: Journal Article,

Incorporation of glucosamine by activated human neutrophils. A myeloperoxidase-mediated process
Bearman, S I; Schwarting, G A; Kolodny, E H; Babior, B M
1980 Nov;96(5):893-902, Journal of laboratory & clinical medicine
Zymosan-activated neutrophils were found to incorporate large amounts of [3H]glucosamine into TCA-precipitable material as compared with resting cells. The burst of glucosamine incorporation began 2 min after zymosan exposure and lasted 3 to 5 min, after which the incorporation rate returned to that of resting cells. Studies with cells from patients with chronic granulomatous disease and hereditary myeloperoxidase deficiency as well as experiments with inhibitors indicated that glucosamine incorporation required both the respiratory burst and the myeloperoxidase system. SDS-polyacrylamide gel electrophoresis of [3H]glucosamine-containing TCA precipitates from zymosan-activated cells revealed radioactivity migrating throughout the length of the gel. The radioactivity in precipitates from resting cells or cells activated in the presence of a small amount of a myeloperoxidase inhibitor was found in a peak migrating close to the tracking dye. These results indicate that zymosan-activated neutrophils are able to incorporate glucosamine into protein by a process dependent on H2O2 and myeloperoxidase. The biosynthetic significance of this phenomenon is not certain, but it most likely represents the reaction of amino sugar with macromolecular degradation products formed by the action of the myeloperoxidase system on cellular and particulate constituents
— id: 75083, year: 1980, vol: 96, page: 893, stat: Journal Article,

FABRY DISEASE - A CLINICAL DEMONSTRATION OF IMPAIRED AUTONOMIC FUNCTION
CABLE, WJL; KOLODNY, EH; ADAMS, RD
1980 NOV ;30(4):352-352, Neurology
— id: 74992, year: 1980, vol: 30, page: 352, stat: Journal Article,

FABRY DISEASE - SIGNIFICANCE OF ULTRASTRUCTURAL-LOCALIZATION OF LIPID INCLUSIONS IN DERMAL NERVES
CABLE, WJL; KOLODNY, EH; DVORAK, AM
1980 NOV ;30(4):352-353, Neurology
— id: 74993, year: 1980, vol: 30, page: 352, stat: Journal Article,

A light and electron microscopic study of mannosidosis
Dickersin, G R; Lott, I T; Kolodny, E H; Dvorak, A M
1980 May;11(3):245-256, Human pathology
The present work investigated the light and electron microscopic changes in hypertrophied gingiva in a patient with mannosidosis. The biopsy specimens studied covered a period of 20 months; biopsy specimens were taken before and after a therapeutic trial with oral and local zinc sulfate. The intensity of the disease was progressive, in spite of the zinc, and was characterized by marked hyperplasia of the epithelium and severe inflammation of the stroma. Many of the cells in the inflammatory infiltrate, as well as cells indigenous to the gingiva, showed a striking vacuolation of their cytoplasm. Histiocytes were most numerous and also were most heavily vacuolated, but fibroblasts, endothelial cells, plasma cells, and epithelial cells also manifested the vacuolar change. In the histiocytes, the vacuoles occupied most of the cytoplasm, ranged widely in size, and were contiguous, molded, and intercommunicating. The vacuoles were bound by a single membrane and were filled predominantly by a finely granular material of medium density but also by varying amounts of coarser, darker granules, fragmented membranes, myelin-like figures, lipid droplets, and small vesicles. The vacuoles were interpreted as being consistent with secondary lysosomes that contained excessively stored substrate, similar to what has been observed in the mucopolysaccharidoses, in which the vacuoles have also been demonstrated histochemically and cytochemically to contain acid phosphatase, a known lysosomal marker
— id: 75087, year: 1980, vol: 11, page: 245, stat: Journal Article,

CONGENITAL MICROCEPHALY WITH PROGRESSIVE MOTOR NEURON DISEASE AND NIGRAL DEGENERATION
HALPERIN, JJ; WILLIAMS, RS; KOLODNY, EH
1980 NOV ;30(4):353-353, Neurology
— id: 74994, year: 1980, vol: 30, page: 353, stat: Journal Article,

LATE-ONSET GLOBOID-CELL LEUKODYSTROPHY
KOLODNY, EH; ADAMS, RD; HALLER, JS; JOSEPH, J; CRUMRINE, PK; RAGHAVAN, SS
1980 NOV ;8(2):219-219, Annals of neurology
— id: 74989, year: 1980, vol: 8, page: 219, stat: Journal Article,

AB VARIANT OF GM2 GANGLIOSIDOSIS - DIAGNOSIS BY INVIVO ASSAY OF GM2 CLEAVING ACTIVITY IN CULTURED SKIN FIBROBLASTS
KOLODNY, EH; RAGHAVAN, SS; ELLISON, PH; LYERLA, TA; BREMER, EG
1980 NOV ;8(2):215-215, Annals of neurology
— id: 74987, year: 1980, vol: 8, page: 215, stat: Journal Article,

FUCOSIDOSIS PRESENTING AS A LEUKODYSTROPHY
KOLODNY, EH; SOTREL, A; CABLE, W; LACSON, A; BRESNAN, MJ; DANIEL, P; WILLIAMS, R; EVANS, J; CROCKER, AC
1980 NOV ;8(1):114-114, Annals of neurology
— id: 74990, year: 1980, vol: 8, page: 114, stat: Journal Article,

Carbonic anhydrase and 2',3' cyclic nucleotide 3'-phosphohydrolase activity in normal human brain and in demyelinating diseases
Lees, M B; Sapirstein, V S; Reiss, D S; Kolodny, E H
1980 Jul;30(7 Pt 1):719-725, Neurology
The activities of carbonic anhydrase and 2',3' cyclic nucleotide 3'-phosphohydrolase (CNPase) were measured in gray and white matter and in myelin from human brains obtained at autopsy. Carbonic anhydrase activity increased with age, and at all ages a major part of the activity was associated with membrane fractions. The percentage of membrane-bound carbonic anhydrase was lower than normal in white matter from Krabbe disease and adrenoleukodystrophy; isolated myelin had a low specific activity in these diseases. CNPase activity was decreased in both white matter and myelin, but was somewhat higher than normal in gray matter. Although the yield of myelin from a case of metachromatic leukodystrophy was markedly reduced, changes in the enzymes activities were minimal
— id: 75086, year: 1980, vol: 30, page: 719, stat: Journal Article,

Leukocyte beta-glucosidase in homozygotes and heterozygotes for Gaucher disease
Raghavan, S S; Topol, J; Kolodny, E H
1980 Mar;32(2):158-173, American journal of human genetics
Human leukocytes contain at least two isozymes of 4-methylumbelliferyl-beta-glucosidase acting optimally at pH 4.0 and 4.8; in Gaucher disease, only the former is deficient. Brief exposure of the leukocyte homogenate to pH 4.0 at room temperature results in irreversible inactivation of the pH 4.8 activity, while the activity at pH 4.0 remains unaffected. The more acidic isozyme is stimulated four- to fivefold by 0.2% sodium taurodeoxycholate (TDC) with a shift in the pH optimum to 5.0. The less acidic isozyme is completely suppressed in the presence of this detergent. Both leukocyte isozymes appear to be membrane-bound since gel filtration of Sephadex G-200 produces only one peak of activity located at the void volume, unlike in liver and kidney where a second peak also can be demonstrated. Heat inactivation analysis indicated that in controls, assayed in the absence of detergent, pH 4.0 activity is more thermostable than pH 4.8 activity. However, in Gaucher disease, the residual beta-glucosidase at pH 4.0 is just as thermolabile as the unaffected pH 4.8 activity. Heat inactivation of the enzyme in the presence of TDC resulted in rapid loss of activity, suggesting a direct effect of the bile salt on the configuration of the enzyme decreasing its thermal stability. In the absence of detergent, acid beta-glucosidase shows two K(m)'s, one at 3.2 mM and another at 0.9 mM. In the presence of detergent, only the higher K(m) at 3.3 mM is obtained. In patients with Gaucher disease and in obligate carriers, the K(m) remains essentially unaffected while the V(max) shows the expected deficiency.A reliable and reproducible selective assay technique has been developed for the diagnosis of Gaucher disease homozygotes and obligate heterozygotes and for the carrier screening of individuals at risk for this inherited disorder. The efficacy of this technique has been demonstrated by studying the activity in 42 controls, 26 patients, 32 obligate heterozygotes, and 23 healthy relatives of patients with Gaucher disease
— id: 75089, year: 1980, vol: 32, page: 158, stat: Journal Article,

SIMILARITY OF ACID BETA-XYLOSIDASE TO ACID BETA-GLUCOSIDASE-DEFICIENCY IN GAUCHER DISEASE
RAGHAVAN, SS; TOPOL, J; KOLODNY, EH
1980 NOV ;39(6):2185-2185, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 74991, year: 1980, vol: 39, page: 2185, stat: Journal Article,

Carbohydrate metabolism in phenylketonuria
Stewart, R M; Hemli, S; Kolodny, E H; Miller, A L; Pallotta, J A
1980 Jul;14(7):849-853, Pediatric research
Carbohydrate metabolism was studied in 6 adult patients with phenylketonuria both on a low phenylalanine and an unrestricted institutional diet. Tolerance tests included PO glucose, PO phenylalanine, and combined glucose phenylalanine loading. Glucose, insulin, pyruvate, lactate, and phenylalanine were sampled at 0, 1/2, 1, 2, 3, and 4 hr. Fasting glucose levels were normal as were mean glucose values after challenge. Basal insulin secretion, as well as insulin response, to glucose challenge and to combined phenylalanine and glucose loading appeared normal. Insulin response to phenylalanine alone, however, was lower than expected in the phenylketonuria patients. Both off and on low phenylalanine diet, blood pyruvate and lactate were also normal. Thus, our data from blood did not show evidence of the abnormalities in glucose and pyruvate metabolism which have been proposed to occur in phenylketonuric patients but did not suggest that the potency of phenylalanine as an insulin secretagogue is diminished by chronic hyperphenylalaninemia
— id: 75085, year: 1980, vol: 14, page: 849, stat: Journal Article,

Application of "high-performance" liquid chromatography to the study of sphingolipidoses
Ullman, M D; Pyeritz, R E; Moser, H W; Wenger, D A; Kolodny, E H
1980 Sep;26(10):1499-1503, Clinical chemistry
Quantitative high-performance liquid chromatographic analysis of perbenzoylated sphingolipids has been used to study the correlations of body chemistry to clinical phenomena. Plasma sphingolipids were isolated from 32 Gaucher (beta-glucosidase deficiency) and six Fabry (alpha-galactosidase deficiency) patients by solvent partition and chromatographic separation on silicic acid columns. Plasma sphingolipids from a patient undergoing plasma-exchange were separated from interfering lipids with reversed-phase columns. Liquid-chromatographic analysis of sphingolipids provides useful supportive information for diagnoses because affected individuals are shown to possess increased circulating concentrations of the pathognomonic sphingolipid. We also used this technique to monitor sphingolipid concentrations in plasma and urine sediment during plasma exchange of a p atient with Fabry's disease. Regular plasma exchanges produced and maintained decreased concentrations of sphingolipids in plasma, but near pre-exchange concentrations were observed within days after the therapy was terminated
— id: 75084, year: 1980, vol: 26, page: 1499, stat: Journal Article,

Retinal pigment epithelial degeneration associated with leukocytic arylsulfatase A deficiency
Weiter, J J; Feingold, M; Kolodny, E H; Raghaven, S S
1980 Dec;90(6):768-772, American journal of ophthalmology
A family exhibiting a leukocytic arylsulfatase A deficiency, probably inherited in an autosomal recessive manner, differed from patients with typical metachromatic leukodystrophy in that sulfatiduria was absent and there was readily detectable cerebroside sulfatase activity. To our knowledge, this family was unique in that there were no known members with metachromatic leukodystrophy and the only neurologic abnormality was progressive retinal pigment degeneration in the proband
— id: 75082, year: 1980, vol: 90, page: 768, stat: Journal Article,

Reverse phase high-performance liquid chromatography of cerebrosides,sulfatides, and ceramides: microanalysis of homolog composition without hydrolysis and application to cerebroside analysis in peripheral nerves of adrenoleukodystrophy pateints
Yahara, S; Moser, H W; Kolodny, E H; Kishimoto, Y
1980 Mar;34(3):694-699, Journal of neurochemistry
— id: 75088, year: 1980, vol: 34, page: 694, stat: Journal Article,

SELECTIVE NEURONAL VULNERABILITY IN THE LYSOSOMAL STORAGE DISEASES
YOUNG, RSK; WILLIAMS, RT; NORMAN, MG; ZALNERAITIS, EL; KOLODNY, EH
1980 NOV ;8(2):218-218, Annals of neurology
— id: 74988, year: 1980, vol: 8, page: 218, stat: Journal Article,

34-YEAR-OLD MAN WITH A CEREBRAL DISORDER, NEUROPATHY AND HYPER-PIGMENTATION - ADRENOLEUKODYSTROPHY, WITH PERIPHERAL NEUROPATHY
BRESNAN, MJ; DAVIS, KR; KLIMAN, B; COHEN, ME; DICKERSIN, GR; KOLODNY, EH; VICKERY, AL
1979 NOV ;300(18):1037-1045, New England journal of medicine
— id: 74997, year: 1979, vol: 300, page: 1037, stat: Journal Article,

LIGHT AND ELECTRON-MICROSCOPIC STUDY OF MANNOSIDOSIS
DICKERSIN, GR; LOTT, IT; KOLODNY, EH; DVORAK, AM
1979 NOV ;40(2):251-252, Laboratory investigation
— id: 74999, year: 1979, vol: 40, page: 251, stat: Journal Article,

GENETIC-HETEROGENEITY IN ARYL SULFATASE-A (ASA) DEFICIENCY
KOLODNY, EH; RAGHAVAN, S; SPIELVOGEL, C; GAJEWSKI, A; LACSON, AC; JUNGALWALA, FB; LOTT, IT; DULANEY, JT; HOEFNAGEL, D
1979 NOV ;29(4):576-576, Neurology
— id: 74998, year: 1979, vol: 29, page: 576, stat: Journal Article,

CARBOHYDRATE-METABOLISM IN PHENYLKETONURIA
STEWART, RM; HEMLI, S; KOLODNY, EH; MILLER, AL; PALLOTTA, JA
1979 NOV ;13(4):482-482, Pediatric research
— id: 74996, year: 1979, vol: 13, page: 482, stat: Journal Article,

COMPRESSIVE MYELOPATHY IN MAROTEAUX-LAMY SYNDROME - PATHOLOGICAL FINDINGS
YOUNG, RSK; ZALNERAITIS, EL; KLEINMAN, GM; KOLODNY, EH; OJEMANN, RG
1979 NOV ;6(2):185-185, Annals of neurology
— id: 74995, year: 1979, vol: 6, page: 185, stat: Journal Article,

Occurrence of novel branched-chain fatty acids in Refsum's disease
Dulaney, J T; Williams, M; Evans, J E; Costello, C E; Kolodny, E H
1978 Apr 28;529(1):1-12, Biochimica & biophysica acta
Two novel branched-chain fatty acids, which appear to be unsaturated analogs of phytanic acid, have been observed in sera and urine of patients with Refsum's disease. They occur in both phospholipids and neutral lipids, and have been isolated and characterized
— id: 75092, year: 1978, vol: 529, page: 1, stat: Journal Article,

Improved thin-layer chromatographic method in the diagnosis of mannosidosis
Friedman, R B; Williams, M A; Moser, H W; Kolodny, E H
1978 Sep;24(9):1576-1577, Clinical chemistry
An improved thin-layer chromatographic method is described for the facile separation of neutral oligosaccharides excreted in the urine of patients with mannosidosis. The urine sample is treated with mixed-bed ion-exchange resin to remove charged species. The eluate is then chromatographed on silica gel thin-layer plates with n-propanol water as the developer. Eleven unique orcinol-positive components can thus be resolved. The advantages of this method over previously described techniques are the ease and rapidity of assay, better resolution of components, and clarity of resolution. It should be applicable to other disease states in which distinctive neutral carbohydrate products are produced
— id: 75090, year: 1978, vol: 24, page: 1576, stat: Journal Article,

Normality of erythrocyte phospholipids in Duchenne muscular dystrophy
Koski, C L; Jungalwala, F B; Kolodny, E H
1978 May 2;85(3):295-298, Clinica chimica acta
— id: 75091, year: 1978, vol: 85, page: 295, stat: Journal Article,

ZINC THERAPY IN MANNOSIDOSIS
LOTT, IT; DICKERSIN, R; DVORAK, AB; KOLODNY, EH
1978 NOV ;12(4):509-509, Pediatric research
— id: 75001, year: 1978, vol: 12, page: 509, stat: Journal Article,

Effects of diet and behavior therapy on social and motor behavior of retarded phenylketonuric adults: an experimental analysis
Marholin, D 2nd; Pohl, R E 3rd; Stewart, R M; Touchette, P E; Townsend, N M; Kolodny, E H
1978 Mar;12(3):179-187, Pediatric research
The effects of a low phenylalanine diet on six retarded phenylketonuric adults were assessed. An ABA individual-subject design was used in experiment I to assess the effects of a low phenylalanine diet on social and motor behavior. Following a baseline during which the subjects ingested a normal phenylalanine diet (phase A), a low phenylalanine diet (phase B) was administered in a double blind fashion. Finally, the baseline condition (phase A) was reinstated (normal diet). The low phenylalanine diet resulted in few significant behavioral changes for those subjects with which proper methodologic controls were employed. However, for two of six subjects motor behavior, including stereotypy and tremor, seem to have ameliorated. In experiment II, applied behavior analysis techniques, including differential reinforcement of other behavior and time out, were combined to radically reduce the frequency of stereotypy and self-abuse exhibited by one of the six subjects of experiment I
— id: 75093, year: 1978, vol: 12, page: 179, stat: Journal Article,

LEUKOCYTE BETA-GLUCOSIDASE IN GAUCHER DISEASE
RAGHAVAN, SS; TOPOL, J; KOLODNY, EH
1978 NOV ;37(6):1767-1767, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 75000, year: 1978, vol: 37, page: 1767, stat: Journal Article,

Mannosidosis. New clinical presentation, enzyme studied, and carbohydrate analysis
Kistler, J P; Lott, I T; Kolodny, E H; Friedman, R B; Nersasian, R; Schnur, J; Mihm, M C; Dvorak, A M; Dickersin, R
1977 Jan;34(1):45-51, Archives of neurology
Mannosidosis is a rare inborn error of metabolism characterized by deficiency of the lysosomal enzyme alpha-mannosidase and widespread storage of complex carbohydrate, which is enriched in mannose. Two affected unrelated males, aged 6 and 26 years, are reported. Both had a nonprogressive encephalopathy with moderately severe mental retardation. The older patient showed several unique features, including massive gingival hyperplasia associated with histiocytes containing large amounts of a material with the staining characteristics of glycoprotein. The best determinant of mannose storage proved to be the ratio of mannose to other carbohydrates in urinary polysaccharides. The enzyme deficiency in this disease is most convincingly demonstrated at pH values below 4.0. The ability of zinc to activate the mutant enzyme in vitro offers a possible mode of therapy for this disease. Retarded individuals with a Hurler-like appearance and gum hyperplasia of unknown cause should be screened for alpha-mannosidase deficiency
— id: 75096, year: 1977, vol: 34, page: 45, stat: Journal Article,

Carrier screening techniques for Tay-Sachs and other lysosomal storage diseases
Kolodny, E H
1977 ;18:213-219, Progress in clinical & biological research
— id: 75095, year: 1977, vol: 18, page: 213, stat: Journal Article,

ENZYMATIC DIAGNOSIS IN ATYPICAL CASES OF KRABBES DISEASE AND METACHROMATIC LEUKODYSTROPHY
KOLODNY, EH; GAJEWSKI, A
1977 NOV ;27(3):190-191, Human heredity
— id: 75003, year: 1977, vol: 27, page: 190, stat: Journal Article,

STEROID HEXOSAMINIDASE ACTIVITY IN SANDHOFF-JATZKEWITZ DISEASE - IDENTITY WITH HEXOSAMINIDASE-C
KOLODNY, EH; KOSHI, DL; FUKUSHIMA, KK
1977 NOV ;27(3):191-191, Human heredity
— id: 75004, year: 1977, vol: 27, page: 191, stat: Journal Article,

MANNOSIDOSIS - REPLY
LOTT, IT; KOLODNY, EH; DICKERSIN, R
1977 NOV ;34(10):650-651, Archives of neurology
— id: 75002, year: 1977, vol: 34, page: 650, stat: Journal Article,

GM1-ganglioside beta-galactosidase in leukocytes and cultured fibroblasts
Raghavan, S A; Gajewski, A; Kolodny, E H
1977 Nov 15;81(1):47-56, Clinica chimica acta
GM1-ganglioside hydrolysis by leukocytes and fibroblasts, tissues easily obtainable from patients, was investigated using 3H-labeled GM1 and was found to be at least as active as that reported for any other tissue. Sodium taurocholate was required for the reaction, the crude bile salt at an optimum concentration of 0.4% producing twice as much activity as pure taurocholate at its optimum concentration of 0.8%. Leukocyte GM1-ganglioside beta-galactosidase and 4-MU-beta-gal cleaving activities were similar, 134.5 +/- 23.3 and 179.8 +/- 25.4 nmol/h/mg protein, respectively. In cultured skin fibroblasts and amniotic fluid cells these enzyme activities were 4 to 5 times higher. Homozygotes for GM1-gangliosidosis showed negligible activity while in heterozygotes the leukocyte GM1-cleaving activity was reduced to one-third of control values. In leukocytes from patients with four other sphingolipid storage diseases the activity was either normal (Krabbe's, Tay-Sachs, Metachromatic leukodystrophy) or increased (adult Gaucher's)
— id: 75094, year: 1977, vol: 81, page: 47, stat: Journal Article,

NEURONAL MORPHOLOGY IN ISOLATED CORTEX IN KRABBES DISEASE - GOLGI STUDY
WILLIAMS, RS; KOLODNY, EH; CAVINESS, VS
1977 NOV ;36(3):637-637, Journal of neuropathology & experimental neurology
— id: 75005, year: 1977, vol: 36, page: 637, stat: Journal Article,

Current concepts in genetics. Lysosomal storage diseases
Kolodny, E H
1976 May 27;294(22):1217-1220, New England journal of medicine
— id: 75099, year: 1976, vol: 294, page: 1217, stat: Journal Article,

Arylsulfatases A and B in metachromatic leukodystrophy and Maroteaux-Lamy syndrome: studies with 4-methylumelliferyl sulfate
Kolodny, E H; Mumford, R A
1976 ;68:239-251, Advances in experimental medicine & biology
Metachromatic leukodystrophy and Maroteaux-Lamy syndrome can be diagnosed by assay of leukocyte or fibroblast arylsulfatase A and B activity with the fluorogenic substrate 4-methylumbelliferyl sulfate. The arylsulfatases are extracted into a 27000 x g supernatant by sonication in 0.9% sodium chloride and then separated with CM-32 on columns or in test tubes. In 0.05 M sodium acetate pH 6.0, arylsulfatase A is not absorbed while arylsulfatase B is retained by the resin. The arylsulfatase B is then eluted from the resin with 0.3 M sodium chloride. The arylsulfatase A activity obtained from normal leukocytes and fibroblasts is linear for the initial 10 minutes of the reaction, is stimulated 3-fold by 6 mM lead acetate and inhibited 80% by 0.24 mM silver nitrate. After separation with CM-32, the arylsulfatase B activity is stimulated 3-fold by Triton X-100 (0.1%). Arylsulfatase A but not arylsulfatase B is destroyed by heat (60 degrees). Both leukocyte and fibroblast arylsulfatase A activity was reduced to 11% of control values in metachromatic leukodystrophy. Essentially no arylsulfatase B activity was detected in cells from patients with Maroteaux-Lamy syndrome. Metachromatic leukodystrophy heterozygotes but not Maroteaux-Lamy syndrome heterozygotes can also be distinguished by this method. A heat inactivation technique utilizing the differential thermal stabilities of the two enzymes for diagnosis of patients with Marotezux-Lamy syndrome is also described. The advantages of these 4-methylumbelliferyl sulfate assay procedures over the p-nitrocatechol sulfate method of assay are greater sensitivity, selectivity for the desired enzyme and potential for use in large scale testing
— id: 75102, year: 1976, vol: 68, page: 239, stat: Journal Article,

Human leukocyte acid hydrolases: characterization of eleven lysosomal enzymes and study of reaction conditions for their automated analysis
Kolodny, E H; Mumford, R A
1976 Jul 15;70(2):247-257, Clinica chimica acta
The optimal reaction conditions and kinetic properties of eleven leukocyte acid hydrolases determined with the use of fluorigenic derivatives of 4-methyl-umbelliferone are described. The enzymes studied were acid phosphatase, aryl sulfatase, alpha- and beta-glucosidase, alpha- and beta-galactosidase, alpha-mannosidase, N-acetyl-beta-glucosaminidase, N-acetyl-beta-galactosaminidase, beta-glucuronidase and alpha-fucosidase. More than 90% of the activity of each enzyme was released into a 27,000 X g supernatant by a double sonication procedure employing 0.9% sodium chloride and 0.1% Triton X-100. The Km values obtained were similar to those previously reported for chromogenic subtrates. A single Km value could not be derived for beta-galactosidase because its double reciprocal plot was not linear. All enzymes could be measured with less than 10 mug of protein within 15 min. Activators and inhibitors studied included the chloride salts of Na+, K+, Zn2+, Ca2+, Mg2+, Hg2+, and Fe2+ as well as p-chloromercuriphenysulfonate, glutathione, BAL, EDTA, EGTA, Triton X-100 and sodium taurocholate. The reaction conditions described in this report can be used for the diagnosis of various lysosomal storage diseases and should facilitate the development of automated procedures for the analysis of these eleven enzyme activities with small quantities of blood
— id: 75097, year: 1976, vol: 70, page: 247, stat: Journal Article,

Adrenoleukodystrophy: a clinical, pathological and biochemical study
Schaumburg, H H; Powers, J M; Raine, C S; Johnson, A B; Kolodny, E H; Kishimoto, Y; Igarashi, M; Suzuki, K
1976 ;68:379-387, Advances in experimental medicine & biology
— id: 75101, year: 1976, vol: 68, page: 379, stat: Journal Article,

The pituitary-thyroid axis in adults with phenylketonuria
Stewart, R M; Hemli, S; Daniels, G H; Kolodny, E H; Maloof, F
1976 Jun;42(6):1179-1181, Journal of clinical endocrinology & metabolism
Serum thyroxine and triiodothyronine levels in 15 adult phenylketonuric patients on an unrestricted diet were normal despite reduced circulating tyrosine levels. Serum thyrotropin levels were normal in the basal state or in response to thyrotropin-releasing hormone in selected patients tested. These results support and extend previous observations of normal thyroid function in phenylketonuria
— id: 75098, year: 1976, vol: 42, page: 1179, stat: Journal Article,

Cholesterol metabolism in cultured fibroblasts in adrenoleukodystrophy
Yavin, E; Milunsky, A; DeLong, G R; Nash, A H; Kolodny, E H
1976 May;10(5):540-545, Pediatric research
The basic biochemical defect of X-linked adrenoleukodystrophy (sudanophilic leukodystrophy, Schilder's disease) is unknown. To investigate reported abnormalities in cholesterol metabolism in vitro, we examined cultured skin fibroblasts of four patients and four normal control subjects. The kinetics of retention and accumulation of [14C]cholesterol by these cells was studied. After 3 days of exposure to tracer amounts of [14C]cholesterol, an apparent steady state between the medium and cellular cholesterol was established. The specific radioactivity expressed per mg of protein was similar for both Schilder and control fibroblasts. tafter labeling the pre-existing cellular cholesterol pool, the rate of loss of label was followed up for a 6-day period. About 23% and 14%, respectively, of the cellular radioactivity in both Schilder's disease and control cells were released into the medium after the consecutive change with fresh nonlabeled medium. No significant differences in [14C]cholesterol rates of uptake or release were observed between control and Schilder's disease fibroblasts. About 44% of the labeled cholesterol was present in an esterfied form after incubation in the presence of unheated serum in both Schilder's and control cultures
— id: 75100, year: 1976, vol: 10, page: 540, stat: Journal Article,

The preparation of Tay-Sachs ganglioside specifically labeled in either the N-acetylneuraminosyl or N-acetylgalactosaminyl portion of the molecule
Tallman, J F; Kolodny, E H; Brady, R O
1975 ;35:541-548, Methods in enzymology
— id: 75103, year: 1975, vol: 35, page: 541, stat: Journal Article,

MACULAR CHERRY-RED SPOT, MYOCLONIC EPILEPSY, AND NEUROVISCERAL STORAGE IN A 17-YEAR-OLD GIRL
GOLDSTEI.ML; KOLODNY, EH; GASCON, GG; GILLES, FH
1974 NOV ;30(5):420-420, Archives of neurology
— id: 75006, year: 1974, vol: 30, page: 420, stat: Journal Article,

Macular cherry-red spot, myoclonic epilepsy, and neurovisceral storage in a 17-year-old girl
Goldstein, M L; Kolodny, E H; Gascon, G G; Gilles, F H
1974 ;99:110-112, Transactions of the American Neurological Association
— id: 75105, year: 1974, vol: 99, page: 110, stat: Journal Article,

Steroid hexosaminidase activity in Tay-Sachs and Sandhoff-Jatzkewitz diseases
Tomasi, L G; Fukushima, D K; Kolodny, E H
1974 Dec;24(12):1158-1165, Neurology
— id: 75104, year: 1974, vol: 24, page: 1158, stat: Journal Article,

STEROID HEXOSAMINIDASE ACTIVITY IN TAY-SACHS AND SANDHOFF-JATZKEWITZ DISEASES
TOMASI, L; KOLODNY, EH; FUKUSHIM.DK
1974 NOV ;24(4):369-370, Neurology
— id: 75007, year: 1974, vol: 24, page: 369, stat: Journal Article,

Gm2-gangliosidosis: studies in cultured fibroblasts
Kolodny, E H; Milunsky, A; Sheng, G S
1973 Mar;9(2):130-135, Birth defects original articles series
— id: 75106, year: 1973, vol: 9, page: 130, stat: Journal Article,

GM2-GANGLIOSIDOSIS WITHOUT DEFICIENCY IN ARTIFICIAL SUBSTRATE CLEAVING ACTIVITY OF HEXOSAMINIDASES A AND B
KOLODNY, EH; WALD, I; MOSER, HW; COGAN, DG; KUWABARA, T
1973 NOV ;23(4):427-&, Neurology
— id: 75008, year: 1973, vol: 23, page: 427, stat: Journal Article,

Disorders of ganglioside metabolism
Brady, R O; Kolodny, E H
1972 ;8:225-241, Progress in medical genetics
— id: 75108, year: 1972, vol: 8, page: 225, stat: Journal Article,

Clinical and biochemical genetics of the lipidoses
Kolodny, E H
1972 Jul;9(3):251-271, Seminars in hematology
— id: 75107, year: 1972, vol: 9, page: 251, stat: Journal Article,

MORPHOLOGIC STUDIES IN O VARIANT OF GM2-GANGLIOSIDOSIS
KOLODNY, EH; ASTROM, KE; CAUFIELD, JB; HYMAN, VC; RICHARDS.EP
1972 NOV ;66(3):A12-&, American journal of pathology
— id: 75009, year: 1972, vol: 66, page: A12, stat: Journal Article,

Properties of a particle-bound enzyme from rat intestine that cleaves sialic acid from Tay-Sachs ganglioside
Kolodny, E H; Kanfer, J; Quirk, J M; Brady, R O
1971 Mar 10;246(5):1426-1431, Journal of biological chemistry
— id: 75110, year: 1971, vol: 246, page: 1426, stat: Journal Article,

Circular dichroism of gangliosides from normal and Tay-Sachs tissues
Stone, A L; Kolodny, E H
1971 Jul;6(3):274-279, Chemistry & physics of lipids
— id: 75109, year: 1971, vol: 6, page: 274, stat: Journal Article,

GANGLIOSIDE METABOLISM IN VIRALLY TRANSFORMED AND CHEMICALLY INDUCED HEPATOMA CELL LINES
BRADY, RO; MORA, PT; KOLODNY EH; BUREK C
1970 NOV ;29(2):A410-&, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 129586, year: 1970, vol: 29, page: A410, stat: Journal Article,

Enzymatic block in the synthesis of gangliosides in DNA virus-transformed tumorigenic mouse cell lines
Cumar, F A; Brady, R O; Kolodny, E H; McFarland, V W; Mora, P T
1970 Oct;67(2):757-764, Proceedings of the National Academy of Sciences of the United States of America
The ganglioside pattern of both SV40- and polyoma virus-transformed mouse cell lines differs from that of the parent cell lines or of cell lines that have transformed spontaneously in tissue culture. This is manifested by a dramatic decrease of gangliosides with an oligosaccharide chain larger than sialyllactose. Present investigations indicate that this change probably cannot be attributed to excessive catabolism of gangliosides, but is caused by impaired synthesis of tri- and tetrahexosyl gangliosides in the virus-transformed cell lines. We present evidence for the block of a required step for the biosynthesis of these ganglioside homologs. The block involves the enzyme catalyzing the transfer of N-acetylgalactosamine from uridine diphosphate N-acetylgalactosamine to hematosides (N-glycolylneuraminyl or N-acetylneuraminylgalactosylglucosyl ceramide). This well-defined enzymatic change opens the way for studies of the biochemical mechanism of the alteration of cell membranes which occurs after transformation by the tumorigenic DNA viruses polyoma and SV40
— id: 75114, year: 1970, vol: 67, page: 757, stat: Journal Article,

Further studies on the elucidation of the enzymatic defect in Tay-Sachs disease
Kolodny, E H; Brady, R O
1970 Apr;20(4):388-388, Neurology
— id: 75115, year: 1970, vol: 20, page: 388, stat: Journal Article,

Preparation of radioactive Tay-Sachs ganglioside labeled in the sialic acid moiety
Kolodny, E H; Brady, R O; Quirk, J M; Kanfer, J N
1970 Mar;11(2):144-149, Journal of lipid research
A procedure is described for the preparation of Tay-Sachs ganglioside specifically labeled in the sialic acid portion of the molecule. Rat brain gangliosides were labeled biosynthetically by the intracranial injection of N-acetyl-(3)H-D-mannosamine. Radioactive gangliosides were isolated and selectively degraded with bacterial neuraminidase and rat liver beta-galactosidase to Tay-Sachs ganglioside-(3)H. Radioactivity in the labeled product was confined to the N-acetyl-neuraminic acid portion of the molecule
— id: 75116, year: 1970, vol: 11, page: 144, stat: Journal Article,

Prenatal genetic diagnosis (second of three parts)
Milunsky, A; Littlefield, J W; Kanfer, J N; Kolodny, E H; Shih, V E; Atkins, L
1970 Dec 24;283(26):1441-1447, New England journal of medicine
— id: 75112, year: 1970, vol: 283, page: 1441, stat: Journal Article,

Prenatal genetic diagnosis. I
Milunsky, A; Littlefield, J W; Kanfer, J N; Kolodny, E H; Shih, V E; Atkins, L
1970 Dec 17;283(25):1370-1381, New England journal of medicine
— id: 75113, year: 1970, vol: 283, page: 1370, stat: Journal Article,

Prenatal genetic diagnosis. 3
Milunsky, A; Littlefield, J W; Kanvfer, J N; Kolodny, E H; Shih, V E; Atkins, L
1970 Dec 31;283(27):1498-1504, New England journal of medicine
— id: 75111, year: 1970, vol: 283, page: 1498, stat: Journal Article,

Demonstration of an alteration of ganglioside metabolism in Tay-Sachs disease
Kolodny, E H; Brady, R O; Volk, B W
1969 Oct 22;37(3):526-531, Biochemical & biophysical research communications
— id: 75117, year: 1969, vol: 37, page: 526, stat: Journal Article,

STUDIES ON METABOLISM OF TAY-SACHS GANGLIOSIDE
KOLODNY, EH; BRADY, RO; QUIRK, JM; KANFER, JN
1969 NOV ;28(2):596-&, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 75010, year: 1969, vol: 28, page: 596, stat: Journal Article,

Granulomatous angiitis of the central nervous system
Kolodny, E H; Rebeiz, J J; Caviness, V S Jr; Richardson, E P Jr
1968 Nov;19(5):510-524, Archives of neurology
— id: 75118, year: 1968, vol: 19, page: 510, stat: Journal Article,

Granulomatous angiitis of the central nervous system
Kolodny, E H; Rebeiz, J J; Caviness, V S; Richardson, E P
1968 Jan;27(1):125-126, Journal of neuropathology & experimental neurology
— id: 75119, year: 1968, vol: 27, page: 125, stat: Journal Article,

Corticodentatonigral degeneration with neuronal achromasia
Rebeiz, J J; Kolodny, E H; Richardson, E P Jr
1968 Jan;18(1):20-33, Archives of neurology
— id: 75120, year: 1968, vol: 18, page: 20, stat: Journal Article,

WEEKLY CLINICOPATHOLOGICAL EXERCISES - CASE 35-1967
CASTLEMA.B; MCNEELY, BU; FISHER, CM; RICHARDS.EP; KOLODNY, EH; MOMOSE, J; ADAMS, RD; BALLANTI.HT; DOCTOROF.SJ; HEYL, JT
1967 NOV ;277(8):423-&, New England journal of medicine
— id: 75011, year: 1967, vol: 277, page: 423, stat: Journal Article,

Corticodentatonigral degeneration with neuronal achromasia: a progressive disorder of late adult life
Rebeiz, J J; Kolodny, E H; Richardson, E P Jr
1967 ;92:23-26, Transactions of the American Neurological Association
— id: 75121, year: 1967, vol: 92, page: 23, stat: Journal Article,

Refsum's syndrome with corneal involvement
Baum, J L; Tannenbaum, M; Kolodny, E H
1965 Oct;60(4):699-708, American journal of ophthalmology
— id: 75122, year: 1965, vol: 60, page: 699, stat: Journal Article,

REFSUM'S SYNDROME: REPORT OF A CASE INCLUDING ELECTRON MICROSCOPIC STUDIES OF THE LIVER
KOLODNY, E H; HASS, W K; LANE, B; DRUCKER, W D
1965 Jun;12:583-596, Archives of neurology
— id: 75123, year: 1965, vol: 12, page: 583, stat: Journal Article,

Effect of phlorizin on hepatic glucose output
KOLODNY EH; KLINE R; ALTSZULER N
1962 Jan;202:149-154, American journal of physiology
— id: 61916, year: 1962, vol: 202, page: 149, stat: Journal Article,

INFLUENCE OF PHLORIZIN ON CARBOHYDRATE METABOLISM
KOLODNY, EH; ALTSZULER, N; KLINE, R
1962 NOV ;21(2):81-&, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 75012, year: 1962, vol: 21, page: 81, stat: Journal Article,