Felicia B Axelrod, M.D.

Kinetin Improves IKBKAP mRNA Splicing in Patients With Familial Dysautonomia
Axelrod FB; Liebes L; Simson GG; Mendoza S; Mull J; Leyne M; Norcliffe-Kaufmann L; Kaufmann H; Slaugenhaupt SA
2011 Nov;70(5):480-483, Pediatric research
Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-kappa-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients. ABBREVIATIONS::
— id: 139909, year: 2011, vol: 70, page: 480, stat: Journal Article,

Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome
Freeman R; Wieling W; Axelrod FB; Benditt DG; Benarroch E; Biaggioni I; Cheshire WP; Chelimsky T; Cortelli P; Gibbons CH; Goldstein DS; Hainsworth R; Hilz MJ; Jacob G; Kaufmann H; Jordan J; Lipsitz LA; Levine BD; Low PA; Mathias C; Raj SR; Robertson D; Sandroni P; Schondorff R; Stewart JM; van Dijk JG
2011 Apr 26;161(1-2):46-48, Autonomic neuroscience
— id: 126645, year: 2011, vol: 161, page: 46, stat: Journal Article,

Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome
Freeman, Roy; Wieling, Wouter; Axelrod, Felicia B; Benditt, David G; Benarroch, Eduardo; Biaggioni, Italo; Cheshire, William P; Chelimsky, Thomas; Cortelli, Pietro; Gibbons, Christopher H; Goldstein, David S; Hainsworth, Roger; Hilz, Max J; Jacob, Giris; Kaufmann, Horacio; Jordan, Jens; Lipsitz, Lewis A; Levine, Benjamin D; Low, Phillip A; Mathias, Christopher; Raj, Satish R; Robertson, David; Sandroni, Paola; Schatz, Irwin; Schondorff, Ron; Stewart, Julian M; van Dijk, J Gert
2011 Apr;21(2):69-72, Clinical autonomic research
— id: 146236, year: 2011, vol: 21, page: 69, stat: Journal Article,

Cardiovascular and neuroendocrine features of Panayiotopoulos syndrome in three siblings
Gonzalez-Duarte, Alejandra; Norcliffe-Kaufmann, Lucy; Martinez, Jose; Rodriguez, Alcibiades J; Kuzniecky, Ruben; Axelrod, Felicia; Kaufmann, Horacio
2011 Jul;21(3):296-300, Epilepsy & behavior
OBJECTIVE: Panayiotopoulos syndrome is a benign idiopathic childhood epilepsy characterized by altered autonomic activity at seizure onset. METHODS: Three siblings with Panayiotopoulos syndrome underwent 24-hour EEG recording and head-up tilt testing with continuous blood pressure and RR interval monitoring. Plasma catecholamines and vasopressin were measured while supine, upright, and during a typical seizure. RESULTS: Patient 1, a 12-year-old girl, had a history of involuntary lacrimation, abdominal pain, and recurrent episodes of loss of muscle tone and unresponsiveness followed by somnolence. Her EEG revealed bilateral frontotemporal spikes. Patient 2, a 10-year-old boy, had episodic headaches with pinpoint pupils, skin flushing of the face, trunk, and extremities, purple discoloration of hands and feet, diaphoresis, nausea, and vomiting. Tilt testing triggered a typical seizure after 9minutes; there was a small increase in blood pressure (+5/4mm Hg, systolic/diastolic) and pronounced increases in heart rate (+59bpm) and norepinephrine (+242pg/mL), epinephrine (+175pg/mL), and vasopressin (+22.1pg/mL) plasma concentrations. Serum glucose was elevated (206mg/dL). His EEG revealed right temporal and parietal spikes. Patient 3, an 8-year-old boy, had a history of restless legs at night, enuresis, night terrors, visual hallucinations, cyclic abdominal pain, and nausea. His EEG showed bitemporal spikes. CONCLUSION: Hypertension, tachycardia, and the release of vasopressin suggest activation of the central autonomic network during seizures in familial Panayiotopoulos syndrome. These autonomic and neuroendocrine features may be useful in the diagnosis and may have therapeutic implications
— id: 136485, year: 2011, vol: 21, page: 296, stat: Journal Article,

Bursts of muscle sympathetic nerve activity are absent in familial dysautonomia
Macefield V.G.; Norcliffe-Kaufmann L.J.; Axelrod F.B.; Kaufmann H.
2011 ;21(4):219-219, Clinical autonomic research
Familial dysautonomia is an hereditary sensory and autonomic neuropathy (HSAN type III), expressed at birth, that is associated with reduced or absent pain and temperature sensibilities, postural hypotension, absent baroreflex function and labile blood pressure that increases markedly during emotional excitement (Norcliffe-Kaufmann et al. 2010). Given the absent baroreflex function we tested the hypothesis that cardiac-locked bursts of muscle sympathetic nerve activity (MSNA) are absent in familial dysautonomia. Tungsten microelectrodes were inserted percutaneously into muscle or cutaneous fascicles of the common peroneal nerve in 10 patients with FD. Spontaneous bursts of MSNA were absent, but we found evidence of tonically firing sympathetic neurones that increased during emotional arousal. Conversely, skin sympathetic nerve activity (SSNA) appeared normal. We conclude that the loss of phasic bursts of MSNA and the loss of baroreflex modulation of muscle vasoconstrictor drive contributes to the poor control of blood pressure in familial dysautonomia
— id: 137865, year: 2011, vol: 21, page: 219, stat: Journal Article,

Can loss of muscle spindle afferents explain the ataxic gait in Riley-Day syndrome?
Macefield, Vaughan G; Norcliffe-Kaufmann, Lucy; Gutierrez, Joel; Axelrod, Felicia B; Kaufmann, Horacio
2011 Nov;134(Pt 11):3198-3208, Brain
The Riley-Day syndrome is the most common of the hereditary sensory and autonomic neuropathies (Type III). Among the well-recognized clinical features are reduced pain and temperature sensation, absent deep tendon reflexes and a progressively ataxic gait. To explain the latter we tested the hypothesis that muscle spindles, or their afferents, are absent in hereditary sensory and autonomic neuropathy III by attempting to record from muscle spindle afferents from a nerve supplying the leg in 10 patients. For comparison we also recorded muscle spindles from 15 healthy subjects and from two patients with hereditary sensory and autonomic neuropathy IV, who have profound sensory disturbances but no ataxia. Tungsten microelectrodes were inserted percutaneously into fascicles of the common peroneal nerve at the fibular head. Intraneural stimulation within muscle fascicles evoked twitches at normal stimulus currents (10-30 microA), and deep pain (which often referred) at high intensities (1 mA). Microneurographic recordings from muscle fascicles revealed a complete absence of spontaneously active muscle spindles in patients with hereditary sensory and autonomic neuropathy III; moreover, responses to passive muscle stretch could not be observed. Conversely, muscle spindles appeared normal in patients with hereditary sensory and autonomic neuropathy IV, with mean firing rates of spontaneously active endings being similar to those recorded from healthy controls. Intraneural stimulation within cutaneous fascicles evoked paraesthesiae in the fascicular innervation territory at normal stimulus intensities, but cutaneous pain was never reported during high-intensity stimulation in any of the patients. Microneurographic recordings from cutaneous fascicles revealed the presence of normal large-diameter cutaneous mechanoreceptors in hereditary sensory and autonomic neuropathy III. Our results suggest that the complete absence of functional muscle spindles in these patients explains their loss of deep tendon reflexes. Moreover, we suggest that their ataxic gait is sensory in origin, due to the loss of functional muscle spindles and hence a compromised sensorimotor control of locomotion
— id: 146233, year: 2011, vol: 134, page: 3198, stat: Journal Article,

Clinical Neuro-ophthalmic Findings in Familial Dysautonomia
Mendoza-Santiesteban CE; Hedges TR 3rd; Norcliffe-Kaufmann L; Warren F; Reddy S; Axelrod FB; Kaufmann H
2011 Sep 13;:?-?, Journal of neuroophthalmology
BACKGROUND:: To define the clinical neuro-ophthalmic abnormalities of patients with familial dysautonomia (FD). METHODS:: Sixteen patients (32 eyes) with the clinical and molecular diagnoses of FD underwent thorough neuro-ophthalmic clinical evaluation. RESULTS:: Visual acuity ranged from 0.05 to 1.0 decimal units and was reduced in 15 of 16 patients. Mild to moderate corneal opacities were found in most patients but were visually significant in only 2 eyes. Red-green color vision was impaired in almost all cases. Depression of the central visual fields was present on automated visual fields in all patients, even in those with normal visual acuity. Temporal optic nerve pallor was present in all cases and was associated with retinal nerve fiber layer loss in the papillomacular region. Various ocular motility abnormalities also were observed. CONCLUSION:: Patients with FD have a specific type of optic neuropathy with predominant loss of papillomacular nerve fibers, a pattern similar to other hereditary optic neuropathies caused by mutations either in nuclear or in mitochondrial DNA, affecting mitochondrial protein function. Defects of eye movements, particularly saccades, also appear to be a feature of patients with FD
— id: 146235, year: 2011, vol: , page: ?, stat: Journal Article,

Assessing autonomic dysfunction symptoms in children: a pilot study
Ming, Xue; Bain, Jennifer M; Smith, Douglas; Brimacombe, Michael; Gold von-Simson, Gabrielle; Axelrod, Felicia B
2011 Apr;26(4):420-427, Journal of child neurology
As a screening tool to identify symptoms of autonomic dysfunction, the Pediatric Autonomic Symptoms Scale was administered to parents of children with familial dysautonomia, autism spectrum disorders, and age-matched controls. The total scores for the presence of symptoms were compared among the 3 groups for each section and overall. The Pediatric Autonomic Symptoms Scale distinguished controls from children with familial dysautonomia and autism spectrum disorders with scores from each section and overall scores. Familial dysautonomia children scored significantly higher in visceral symptoms, while children with autism spectrum disorders scored significantly higher in psychosocial symptoms. In familial dysautonomia, the concordance for the presence of symptoms within sections and overall scores ranged from 71% to 100%. The concordance for absence of autonomic dysfunction symptoms in controls ranged from 75% to 87.5%. The Pediatric Autonomic Symptoms Scale is comprehensive and can profile autonomic dysfunction in the 2 neurodevelopmental disorders. Its usefulness in other pediatric disorders remains to be studied
— id: 138324, year: 2011, vol: 26, page: 420, stat: Journal Article,

Hyper-dopaminergic vomiting crises in familial dysautonomia
Norcliffe-Kaufmann L.J.; Axelrod F.B.; Kaufmann H.
2011 ;21(4):244-245, Clinical autonomic research
Background: Patients with familial dysautonomia have a selective defect in the afferent neurons of the baroreflex. Failure to sense blood pressure result in the unregulated release of plasma catecholamines and volatile blood pressure. One of the most disabling features of familial dysautonomia are the recurrent attacks of nausea, retching and vomiting triggered by emotional or physiological stressors and associated with hypertension, tachycardia and psychomotor agitation. A pronounced surge in circulating norepinephrine during these crises readily explains the hypertension, but the cause of the nausea and vomiting remains unknown. Methods: Seven patients with familial dysautonomia (mean age 17 +/- 3 years, 4 females) confirmed by genetic testing were studied. We monitored blood pressure and heart rate and measured plasma catecholamines when they were feeling well and during typical vomiting crises triggered by emotionally charged situations. Results: When the patients were feeling well, average supine blood pressure was 124 +/- 7/64 +/- 5 mmHg with a heart rate of 81 +/- 3 beats/min. All patients experienced typical crises when they complained of severe nausea and were retching loudly. Vomiting was prevented by the fundoplication surgery. During crises, all patients were hypertensive (180 +/- 9/116 +/- 4 mmHg) and tachycardic (124 +/- 4 beats/min) but denied feeling palpitations. While supine, plasma norepinephrine levels increased from 130 +/- 42 to 772 +/- 151 pg/ml (p<0.002), plasma epinephrine levels increased from 20 +/- 5 to 63 pg/ml, and plasma dopamine levels increased markedly from 22 +/- 2 to 96 +/- 20 pg/ml. Conclusions: Our finding of high levels of circulating dopamine during crises in patients with familial dysautonomia suggest that the severe nausea and vomiting is due to activation of dopamine receptors in the chemoreceptor trigger zone
— id: 137864, year: 2011, vol: 21, page: 244, stat: Journal Article,

The norepinephrine paradox in hereditary sensory and autonomic neuropathy type IV
Norcliffe-Kaufmann L.J.; Axelrod F.B.; Kaufmann H.
2011 ;21(4):286-286, Clinical autonomic research
Background: Hereditary sensory and autonomic neuropathy type IV (HSAN-IV) is a recessive disease caused by mutations affecting the tyrosine kinase receptor. The disorder affects the development of sensory and sudomotor sympathetic nerve fibers resulting in complete insensitivity to pain and anhidrosis. However, little is known about the cardiovascular autonomic phenotype of the disorder. Methods: We measured blood pressure, heart rate and catecholamines, vasopressin, endothelin and renin activity in plasma while supine and after 10 min of passive upright tilt in 10 patients with typical clinical features of HSAN-IV and diagnostic confirmation with genetic testing (mean age 9 +/- 2 years old, 4 females). Results: In the supine position, blood pressures (104 +/- 5/ 58 +/- 4 mmHg) and heart rates (87 +/- 9 beats/min) were normal. During upright tilt, mean arterial blood pressure changed little (-5 +/- 5 mmHg, p = 0.17) and heart rate increased appropriately (+23 +/- 5 beat/min, p<0.001). In all patients, plasma norepinephrine levels were low or undetectable while in the supine position (31 +/- 3 pg/ml) and failed to increase with upright tilt (4 +/- 5 pg/ml). Plasma renin activity levels increased slightly from 2.0 +/- 0.6 to 3.6 +/- 1.1 pg/ml with head-up tilt (+68 +/- 33 D%, p<0.03). Plasma vasopressin increased little and endothelin levels were essentially unchanged during upright tilt. Conclusions: Patients with HSAN-IV have very low levels of norepinephrine while supine and upright, but do not have orthostatic hypotension. Other vasoactive peptides involved in orthostatic blood pressure maintenance are not increased. These results challenge our current concepts of the role of norepinephrine in the regulation of blood pressure. The mechanism by which patients with HSAN-IV maintain their blood pressure is unknown
— id: 137861, year: 2011, vol: 21, page: 286, stat: Journal Article,

Developmental abnormalities, blood pressure variability and renal disease in Riley Day syndrome
Norcliffe-Kaufmann L; Axelrod FB; Kaufmann H
2011 Dec 1;:?-?, Journal of human hypertension
Riley Day syndrome, commonly referred to as familial dysautonomia (FD), is a genetic disease with extremely labile blood pressure owing to baroreflex deafferenation. Chronic renal disease is very frequent in these patients and was attributed to recurrent arterial hypotension and renal hypoperfusion. Aggressive treatment of hypotension, however, has not reduced its prevalence. We evaluated the frequency of kidney malformations as well as the impact of hypertension, hypotension and blood pressure variability on the severity of renal impairment. We also investigated the effect of fludrocortisone treatment on the progression of renal disease. Patients with FD appeared to have an increased incidence of hydronephrosis/reflux and patterning defects. Patients <4 years old had hypertension and normal estimated glomerular filtration rates (eGFR). Patients with more severe hypertension and greater variability in their blood pressure had worse renal function (both, P<0.01). In contrast, there was no relationship between eGFR and the lowest blood pressure recorded during upright tilt. The progression of renal disease was faster in patients receiving fludrocortisone (P<0.02). Hypertension precedes kidney disease in these patients. Moreover, increased blood pressure variability as well as mineralocorticoid treatment accelerate the progression of renal disease. No association was found between hypotension and renal disease in patients with FD.Journal of Human Hypertension advance online publication, 1 December 2011; doi:10.1038/jhh.2011.107
— id: 146234, year: 2011, vol: , page: ?, stat: Journal Article,

Is end-tidal CO2 a valid measurement to assess hypoventilation in patients with familial dysautonomia?
Perez M.A.; Norcliffe-Kaufmann L.J.; Reyes J.; Axelrod F.B.; Kaufmann H.
2011 ;21(4):286-286, Clinical autonomic research
Background: Patients with familial dysautonomia (FD) fail to increase respiratory drive in response to low oxygen and high CO₂ levels. Many hypoventilate and have frequent apneic events during sleep, a time associated with an increased incidence of sudden death. To assess the need for non-invasive ventilation, patients with FD routinely undergo sleep studies with end-tidal CO₂ monitoring. Because most have severe lung disease, it is not known, however, whether end-tidal CO₂ levels accurately reflect arterial blood CO₂ levels. Methods: We studied 88 patients with FD (mean age 25 +/- 1, 45; females:43 males). We measured the partial pressure of CO₂ in blood obtained from the radial artery at the wrist (ABL80 FLEX, Radiometer, Denmark). End-tidal CO₂ was continuously sampled from a nasal canula (infrared analysis 5200 Ohmeda, USA). The average CO₂ value obtained over 10 full tidal breaths was used. All measurements were obtained during relaxed spontaneous breathing in the supine position. The relationship between end-tidal and arterial CO₂ measurements was examined using Pearson correlations. Results: All patients had a history of at least one aspiration pneumonia. The average partial pressure of oxygen in arterial blood was 87 +/- 2 mmHg. Thirty-one patients (36%) had arterial oxygen levels B80 mmHg. The average partial pressure of CO₂ was 43 +/- 0.4 mmHg (range 34-57 mmHg). Thirty-four patients (39%) had hypercapnia with CO₂ in arterial blood >=45 mmHg. Measurements of end-tidal CO₂ correlated tightly with CO₂ measured in arterial blood (y = 0.88x + 2.23, R² = 0.50, p<0.001). Conclusions: Our results show that in patients with FD, despite severe lung disease, the partial pressure of CO₂ measured in expired air (i.e. end tidal CO₂) accurately reflects the partial pressure ofCO₂ in arterial blood. Monitoring end tidal CO₂ is critically important to determine the potential role of apnea/hypoventilation in sudden death during sleep
— id: 137860, year: 2011, vol: 21, page: 286, stat: Journal Article,

Complicated peptic ulcer disease in three patients with familial dysautonomia
Wan, David W; Levy, Joseph; Ginsburg, Howard B; Kaufmann, Horacio; Axelrod, Felicia B
2011 Aug;45(7):611-613, Journal of clinical gastroenterology
Familial dysautonomia (FD) is an autosomal recessive disorder characterized by autonomic and sensory neuropathy. Owing to pervasive dysfunction, the disease has protean clinical manifestations, affecting the ocular, gastrointestinal, pulmonary, orthopedic, vasomotor, and neurologic systems. The gastrointestinal perturbations, including dysphagia, gastroesophageal dysmotility, gastroesophageal reflux, and vomiting crises, are among the earliest signs. Here, we present the first 3 instances of gastric ulcers in patients with FD and discuss their common presenting features and the special management that was required
— id: 138323, year: 2011, vol: 45, page: 611, stat: Journal Article,

Neuroimaging supports central pathology in familial dysautonomia
Axelrod, Felicia B; Hilz, Max J; Berlin, Dena; Yau, Po Lai; Javier, David; Sweat, Victoria; Bruehl, Hannah; Convit, Antonio
2010 Feb;257(2):198-206, Journal of neurology
Familial dysautonomia (FD) is a hereditary peripheral and central nervous system disorder with poorly defined central neuropathology. This prospective pilot study aimed to determine if MRI would provide objective parameters of central neuropathology. There were 14 study subjects, seven FD individuals (18.6 +/- 4.2 years, 3 female) and seven controls (19.1 +/- 5.8 years, 3 female). All subjects had standardized brain MRI evaluation including quantitative regional volume measurements, diffusion tensor imaging (DTI) for assessment of white matter (WM) microstructural integrity by calculation of fractional anisotropy (FA), and proton MR spectroscopy ((1)H MRS) to assess neuronal health. The FD patients had significantly decreased FA in optic radiation (p = 0.009) and middle cerebellar peduncle (p = 0.004). Voxel-wise analysis identified both GM and WM microstructural damage among FD subjects as there were nine clusters of WM FA reductions and 16 clusters of GM apparent diffusion coefficient (ADC) elevations. Their WM proportion was significantly decreased (p = 0.003) as was the WM proportion in the frontal region (p = 0.007). (1)H MRS showed no significant abnormalities. The findings of WM abnormalities and decreased optic radiation and middle cerebellar peduncle FA in the FD study group, suggest compromised myelination and WM micro-structural integrity in FD brains. These neuroimaging results are consistent with clinical visual abnormalities and gait disturbance. Furthermore the frontal lobe atrophy is consistent with previously reported neuropsychological deficits
— id: 104788, year: 2010, vol: 257, page: 198, stat: Journal Article,

Olfactory stem cells, a new cellular model for studying molecular mechanisms underlying familial dysautonomia
Boone, Nathalie; Loriod, Beatrice; Bergon, Aurelie; Sbai, Oualid; Formisano-Treziny, Christine; Gabert, Jean; Khrestchatisky, Michel; Nguyen, Catherine; Feron, Francois; Axelrod, Felicia B; Ibrahim, El Cherif
2010 ;5(12):e15590-e15590, PLoS ONE
BACKGROUND: Familial dysautonomia (FD) is a hereditary neuropathy caused by mutations in the IKBKAP gene, the most common of which results in variable tissue-specific mRNA splicing with skipping of exon 20. Defective splicing is especially severe in nervous tissue, leading to incomplete development and progressive degeneration of sensory and autonomic neurons. The specificity of neuron loss in FD is poorly understood due to the lack of an appropriate model system. To better understand and modelize the molecular mechanisms of IKBKAP mRNA splicing, we collected human olfactory ecto-mesenchymal stem cells (hOE-MSC) from FD patients. hOE-MSCs have a pluripotent ability to differentiate into various cell lineages, including neurons and glial cells. METHODOLOGY/PRINCIPAL FINDINGS: We confirmed IKBKAP mRNA alternative splicing in FD hOE-MSCs and identified 2 novel spliced isoforms also present in control cells. We observed a significant lower expression of both IKBKAP transcript and IKAP/hELP1 protein in FD cells resulting from the degradation of the transcript isoform skipping exon 20. We localized IKAP/hELP1 in different cell compartments, including the nucleus, which supports multiple roles for that protein. We also investigated cellular pathways altered in FD, at the genome-wide level, and confirmed that cell migration and cytoskeleton reorganization were among the processes altered in FD. Indeed, FD hOE-MSCs exhibit impaired migration compared to control cells. Moreover, we showed that kinetin improved exon 20 inclusion and restores a normal level of IKAP/hELP1 in FD hOE-MSCs. Furthermore, we were able to modify the IKBKAP splicing ratio in FD hOE-MSCs, increasing or reducing the WT (exon 20 inclusion):MU (exon 20 skipping) ratio respectively, either by producing free-floating spheres, or by inducing cells into neural differentiation. CONCLUSIONS/SIGNIFICANCE: hOE-MSCs isolated from FD patients represent a new approach for modeling FD to better understand genetic expression and possible therapeutic approaches. This model could also be applied to other neurological genetic diseases
— id: 122564, year: 2010, vol: 5, page: e15590, stat: Journal Article,

Supine squatting supports cardiovascular recovery of familial dysautonomia patients
Ehmann E.C.; Marthol H.; Baltadzhieva R.; Mller S.; Axelrod F.B.; Hilz M.J.
2010 ;17:550-550, European journal of neurology
Background: Familial Dysautonomia (FD) is associated with severe orthostatic hypotension (OH) which improves with reclining, squatting or abdominal compression. Combined reclining and splanchnic compression (supinesquatting) might promote cardiovascular recovery. Objective: To evaluate recovery-times of blood pressure (BP) and superior-mesenteric-artery (SMA) blood-flow upon supine positioning after OH, without and with supinesquatting. Methods: In 11 FDs (18+/-4 years) and 12 age-matched controls, we recorded heart rate (HR) BP, cross-sectional SMA-area and SMA-mean velocity (SMA-Vel) using Doppler-ultrasound. We assessed SMA-blood-flow (SMABF) as SMA-Vel X SMA-area, and SMA-resistance as MBP/SMA-BF-ratio. We determined parameters during 5minutes supine position, at 90degree head-up tilt (standing), upon return to supine without, and in a second trial with supine-squatting. BP-recovery-times were defined as times from tilting-back until BP returned to baseline values minus 2SD. Results: In FDs, BP during standing (95.0+/-26.0mmHg) was lower than supine BP (147.0+/-17.3mmHg, p<0.05). In controls, standing did not change BP.Without squatting, BP recovery-times were longer in FDs than controls (85.4+/-60.9s vs. 12.6+/-27.3s; p<0.05). With squatting, recovery-times of patients (36.6+/-49.5s) and controls (26.0+/-44.8s) were similar. Upon standing, both groups decreased SMA-Area, SMA-Vel, SMA-BF (p<0.05). FDs had slightly lower SMAVel and significantly lower SMA-BF with than without supine-squatting. Only controls increased their SMAresistance upon standing. SMA-resistance decreased upon return to supine without squatting in both groups but increased in FDs during supine squatting. Conclusion: Supine-squatting shortens recovery-times after OH, very likely because of increased SMA-resistance, reduced splanchnic pooling and increased blood redistribution to heart and brain
— id: 113824, year: 2010, vol: 17, page: 550, stat: Journal Article,

DIAGNOSIS OF FAMILIAL DYSAUTONOMIA IN THE UK: THE NEED FOR INCREASED AWARNESS
Maayan, C.; Gerson-Sofer, N.; Brogan, P.; Rosenfeld, N.; Norcliffe-Kaufmann, L.; Kaufmann, H.; Axelrod, F.
2010 DEC ;99(6):79-79, Acta paediatrica
— id: 121342, year: 2010, vol: 99, page: 79, stat: Journal Article,

Respiratory alterations during sleep in familial dysautonomia
Moeller S.; Axelrod F.B.; Rapoport D.M.; Ayappa I.; Buechner S.; Sczepanska H.; Dimitrov N.; Hilz M.J.
2010 ;17:549-549, European journal of neurology
Introduction: Sudden death during sleep is a risk in familial dysautonomia (FD). Respiratory abnormalities might contribute to fatalities. Objective: This study was performed to assess respiratory abnormalities in FD during sleep. Methods: In 11 FD patients (5 females, 28+/-11 years) and 11 age- and sex-matched controls (6 females, 28+/-11 years), we recorded polysomnographic signals during one night, and assessed sleep latency, REMlatency, sleep stages, number of sleep cycles and apnoeas.Apnoea responses were classified as oxygen desaturation (<=4% SatO2-decrease within 30sec) or arousals (<=3sec abrupt shift in electroencephalographic frequencies to alpha- or theta-activity or frequencies >16Hz). Chi²-test compared numbers of patients and controls with apnoea, desaturation or arousal. U-test assessed differences in frequencies of individual apnoeas, desaturations or arousals between patients and controls (significance: p<0.05). Results: 10 patients and 4 controls had apnoeas (p<0.05). 9 patients and 1 control developed deoxygenation (p<0.05); 3 patients and 1 control had arousals. Apnoea frequency (median, 25^th percentile; 75^th percentile, range) was higher in patients (8; 5; 18; 0-28) than in controls (0; 0; 1; 0-2; p<0.05). Apnoea-induced desaturations also were more frequent in patients (6; 2; 10; 0-26) than in controls (0; 0; 0; 0-1; p<0.05) while arousal frequency was similar in patients (0; 0; 1; 0-2) and controls (0, 0, 0, 0-1). Conclusion: High frequency of sleep apnoeas and deoxygenation in FD patients may cause fatalities, as deoxygenation which induces hypoventilation, arterial hypotension, and bradyarrhythmia in FD patients (Bernardi et al. Am J Respir Crit Care Med. 2003;167:141-9)
— id: 113823, year: 2010, vol: 17, page: 549, stat: Journal Article,

Volatile hypertension is a risk factor for renal failure in patients with familial dysautonomia
Norcliffe-Kaufmann L.; Voustianiouk A.; Axelrod F.; Kaufmann H.
2010 ;20(2):144-144, Clinical autonomic research
Renal failure is a common problem in patients with familial dysautonomia (FD). By age 25, 20% of patients with FD have end stage renal disease. To determine the role of arterial hypertension in the development and progression of kidney disease, we compared glomerular filtration rate (Cockcroft-Gault equation) over time in 50 patients with FD according to their level of arterial hypertension throughout childhood (until age 15). In addition, to assess the possible impact of increased blood pressure variability on renal function we examined the relationship between the standard deviation of ambulatory blood pressure over 24-h, an indicator of blood pressure volatility, and glomerular filtration rate. Patients with average systolic blood pressure[180 mmHg during childhood (stage III and IV hypertension American Heart Association) had a faster decline in glomerular filtration rate over time than patients with lower blood pressures (Kaplan-Meyer survival curve). There was an inverse relationship between the standard deviation of ambulatory blood pressure over 24-h and glomerular filtration rate, i.e., patients with higher standard deviation had lower glomerular filtration rates (y = - 3.3044x + 167.54, R² = 0.1949, p<0.01). Our results indicate that arterial hypertension during childhood and the magnitude of blood pressure volatility are risk factors for the development of renal failure in patients with familial dysautonomia. Prospective studies are warranted to determine whether controlling hypertension and blood pressure variability can delay the onset or slow the progression of renal failure in these patients
— id: 134744, year: 2010, vol: 20, page: 144, stat: Journal Article,

Afferent baroreflex failure in familial dysautonomia
Norcliffe-Kaufmann, Lucy; Axelrod, Felicia; Kaufmann, Horacio
2010 Nov 23;75(21):1904-1911, Neurology
BACKGROUND: Familial dysautonomia (FD) is due to a genetic deficiency of the protein IKAP, which affects development of peripheral neurons. Patients with FD display complex abnormalities of the baroreflex of unknown cause. METHODS: To test the hypothesis that the autonomic phenotype of FD is due to selective impairment of afferent baroreceptor input, we examined the autonomic and neuroendocrine responses triggered by stimuli that either engage (postural changes) or bypass (cognitive/emotional) afferent baroreflex pathways in 50 patients with FD and compared them to those of normal subjects and to those of patients with pure autonomic failure (PAF), a disorder with selective impairment of efferent autonomic neurons. RESULTS: During upright tilt, in patients with FD and in patients with PAF blood pressure fell markedly but the heart rate increased in PAF and decreased in FD. Plasma norepinephrine levels failed to increase in both groups. Vasopressin levels increased appropriately in patients with PAF but failed to increase in patients with FD. Head-down tilt increased blood pressure in both groups but increased heart rate only in patients with FD. Mental stress evoked a marked increase in blood pressure and heart rate in patients with FD but little change in those with PAF. CONCLUSION: The failure to modulate sympathetic activity and to release vasopressin by baroreflex-mediated stimuli together with marked sympathetic activation during cognitive tasks indicate selective failure of baroreceptor afference. These findings indicate that IKAP is critical for the development of afferent baroreflex pathways and has therapeutic implications in the management of these patients
— id: 114841, year: 2010, vol: 75, page: 1904, stat: Journal Article,

RENAL DISEASE IN FAMILIAL DYSAUTONOMIA: TWO CASE REPORTS OF SUCCESSFUL TRANSPLANTS
Rekhtman, Y; Bomback, AS; Nash, MA; Cohen, SD; Jan, D; Axelrod, FB; Radhakrishnan, J; Appel, GB
2010 APR ;55(4):A94-A94, American journal of kidney diseases
— id: 110123, year: 2010, vol: 55, page: A94, stat: Journal Article,

Renal transplantation in familial dysautonomia: report of two cases and review of the literature
Rekhtman, Yelena; Bomback, Andrew S; Nash, Martin A; Cohen, Scott D; Matalon, Albert; Jan, Dominique M; Kaufmann, Horacio; Axelrod, Felicia B; Radhakrishnan, Jai; Appel, Gerald B
2010 Sep;5(9):1676-1680, Clinical journal of the American Society of Nephrology : CJASN.
BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) is an increasingly recognized complication of familial dysautonomia (FD), a neurodevelopmental disorder with protean systemic manifestations that are the result of sensory and autonomic dysfunction. Progressive renal dysfunction occurs due to chronic volume depletion and cardiovascular lability with supine hypertension and orthostatic hypotension. By age 25, nearly one-half of all patients with FD will have reached stage 3 CKD. Furthermore, dialysis for ESRD in FD patients is associated with multiple complications and poor outcomes. Design, settings, participants, & measurements: We report two patients with FD who developed ESRD at ages 27 and 16, respectively, and underwent renal transplantation. Transplant was performed after 3 months on intermittent hemodialysis (HD) in the first case and after 1 month on twice-weekly continuous veno-venous hemodialysis (CVVHD) in the second case. RESULTS: Both patients tolerated surgery well and have maintained good graft function at 20 and 24 months posttransplantation, respectively. Symptomatic and functional improvements have included lower supine BP and increased sensitivity to antihypertensive agents. CONCLUSIONS: As general supportive care improves the lifespan of FD patients, issues related to the management of ESRD will become more important. Renal transplantation provides a viable alternative to dialysis for FD patients with ESRD
— id: 138213, year: 2010, vol: 5, page: 1676, stat: Journal Article,

Pregabalin: a new approach to treatment of the dysautonomic crisis
Axelrod, Felicia B; Berlin, Dena
2009 Aug;124(2):743-746, Pediatrics
Nausea and dysautonomic crises severely limit function and quality of life for a large number of individuals with familial dysautonomia. We treated a small cohort of 15 patients with familial dysautonomia who suffered frequent dysautonomic crises with pregabalin. Nausea and overt crises markedly decreased in 13 (87%) of these patients and the overall assessments of benefit were extremely favorable, suggesting that pregabalin may be a potentially useful therapeutic agent for this disorder
— id: 101321, year: 2009, vol: 124, page: 743, stat: Journal Article,

Peripheral arthropathy in hereditary sensory and autonomic neuropathy types III and IV
Feldman, David S; Ruchelsman, David E; Spencer, Daniel B; Straight, Joseph J; Schweitzer, Mark E; Axelrod, Felicia B
2009 Jan-Feb;29(1):91-97, Journal of pediatric orthopedics
BACKGROUND: To determine the features of the underlying destructive arthropathy in the peripheral joints of children with hereditary sensory and autonomic neuropathy (HSAN) type III and to compare and contrast this to the arthropathy noted in HSAN type IV, as both groups experience decreased pain perception. METHODS: From a database of 547 patients with HSAN type III and 32 patients with HSAN type IV, we performed a retrospective chart review and radiographic analysis of all patients who presented with joint swelling and deformity. Underlying joint pathology was classified as either osteonecrosis or Charcot arthropathy. RESULTS: In the HSAN type III population, 44 (8%; 22 males and 22 females) of the 547 patients had clinical evidence of arthropathy. In 42 patients, 48 joints demonstrated radiographic evidence of osteonecrosis; 45 (94%) of the 48 joints with osteonecrosis occurred in the lower extremity. In each case of osteonecrosis of the knee (n = 19), isolated involvement of the lateral distal femoral condyle was seen consisting of varying sizes of posterolateral osteochondral fragmentation. In the 32 patients comprising the HSAN type IV population, 18 (56%) were found to have radiographic findings consistent with Charcot arthropathy in a total of 30 affected joints. One patient demonstrated Charcot arthropathy of the spine and subsequent progressive spondylolisthesis. Nine patients (12 joints) also demonstrated osteomyelitis. CONCLUSIONS: In patients with HSAN type III, osteonecrosis is the initial lesion preceding destructive arthropathy. Osteonecrosis and osteochondral fragmentation were always isolated at the lateral distal femoral condyle in the knee. This pathology may be amenable to surgical reconstruction and fixation to stabilize the knee and prevent further degeneration. Hereditary sensory and autonomic neuropathy type IV was most commonly associated with Charcot arthropathy or joint subluxation and dislocation. Late secondary changes at the articular surface may make radiographic distinction difficult. Charcot arthropathy affected both sides of the involved joint with evidence of collapse and fragmentation. With osteonecrosis, the articular process was found to be more focal
— id: 93224, year: 2009, vol: 29, page: 91, stat: Journal Article,

Dysautonomia: familial
Gold-von Simson G; Axelrod FB; Slaugenhaupt SA
Encyclopedia of neuroscience Berlin: Elsevier, 2009,
— id: 5627, year: 2009, vol: , page: 737, stat: Chapter,

Kinetin in familial dysautonomia carriers: implications for a new therapeutic strategy targeting mRNA splicing
Gold-von Simson, Gabrielle; Goldberg, Judith D; Rolnitzky, Linda M; Mull, James; Leyne, Maire; Voustianiouk, Andrei; Slaugenhaupt, Susan A; Axelrod, Felicia B
2009 Mar;65(3):341-346, Pediatric research
Familial dysautonomia (FD) is caused by an intronic splice mutation in the IkappaB kinase-associated protein gene (IKBKAP) that leads to partial skipping of exon 20 and tissue-specific reduction of IkappaB kinase-associated protein/elongator protein 1 (IKAP/ELP-1 protein). Kinetin increases IKBKAP mRNA and protein expression in FD cell lines. To determine whether oral kinetin alters IKBKAP splicing in vivo, we administered kinetin to 29 healthy carriers of the major FD mutation for 8 d. Adverse effects, kinetin, and IKBKAP mRNA levels were monitored. In the highest dosing cohorts (23.5 mg/kg/d), the target plasma kinetin level was achieved in 91% of subjects at 2 h. After 8 d, IKBKAP mRNA expression in leukocytes increased as kinetin levels increased. There is a linear association between log plasma kinetin level and corresponding log change from baseline in IKBKAP mRNA expression that allows estimation of IKBKAP mRNA levels because of kinetin ingestion. Adverse effects were transient and mild. This is the first report of in vivo IKBKAP splicing modification and strongly suggests kinetin's therapeutic potential in FD and perhaps in other splicing disorders. Furthermore, our findings support our hypothesis that treatments, which target a particular splicing mutation, can be successfully developed
— id: 104339, year: 2009, vol: 65, page: 341, stat: Journal Article,

Neoplasia in familial dysautonomia: a 20-year review in a young patient population
Gold-von Simson, Gabrielle; Romanos-Sirakis, Eleny; Maayan, Channa; Axelrod, Felicia B
2009 Dec;155(6):934-936, Journal of pediatrics
We reviewed the charts of all patients with familial dysautonomia (n = 631) and found that 2% had been diagnosed with tumors. We hypothesize that the IkappaB Kinase-associated protein gene mutation, which causes aberrant RNA splicing in patients with familial dysautonomia, may contribute to tumorigenesis in this genetically homogenous patient population
— id: 105345, year: 2009, vol: 155, page: 934, stat: Journal Article,

The R3 component of the electrically elicited blink reflex is present in patients with congenital insensitivity to pain
Tellez, Maria J; Axelrod, Felicia; Kaufmann, Horacio
2009 Jan;141(1-2):178-180, Pain
To clarify whether the R3 component of the electrically elicited blink reflex is a nociceptive response we studied two patients with congenital insensitivity to pain due to the impaired development of Adelta and C nerve fibers (hereditary sensory and autonomic neuropathy types III and IV). We postulated that if the R3 component is a nociceptive reflex, it should be absent in these patients. The R3 responses were elicited in both sides in both the patients at all intensities, strongly suggesting that the R3 component of the blink reflex is not a nociceptive response
— id: 94974, year: 2009, vol: 141, page: 178, stat: Journal Article,

Hereditary Sensory and Autonomic Neuropathy IV
Axelrod, Felicia B; Gold-von Simson, Gabrielle; Oddoux, Carole
GeneReviews Seattle WA : University of Washington, 2008,
Disease characteristics. Hereditary sensory and autonomic neuropathy type IV (HSAN IV) is characterized by congenital profound sensory loss affecting perception of pain and temperature, and absence of sweating. Secondary consequences of reduced pain perception include: oral self-mutilation (biting of tongue, lips, and buccal mucosa); fingertip biting; repeated bone fractures and joint trauma. Anhidrosis results in poor thermoregulation in hot environmental conditions and can cause recurrent febrile episodes. Although developmental milestones are usually normal to only mildly delayed, learning problems can be severe. Hyperactivity and emotional lability are common. Diagnosis/testing. Axon flare after intradermal histamine phosphate injection is absent, a finding in all HSAN types that is not specific to HSAN IV. Mutations in NTRK1 (TRKA), the only gene known to be associated with HSAN IV, are identified by sequence analysis in almost all individuals meeting HSAN IV diagnostic criteria. Management. Treatment of manifestations: prevention of self-mutilation by smoothing or extracting teeth; prevention of secondary severe or debilitating orthopedic problems by daily evaluation for early signs of unrecognized injury; control of hyperthermia with acetaminophen and/or ibuprofen or direct cooling in a bath or cooling blanket; prevention of neurotrophic keratitis with tarsorrhaphy, corneal patch graft, keratoplasty, and/or scleral bandage lens. Antipsychotic and/or ADHD medications in conjunction with behavior modification as needed. Interventions for behavioral, developmental, and motor delays; educational and social support for school-age children and adolescents. Prevention of secondary complications: attention to temperature management during the perioperative period. Surveillance: annual evaluations with ophthalmology, dentistry, and orthopedics. Agents/circumstances to avoid: hot, dry climates; high-impact activities and sports; inadequate sedation in the postoperative period. Testing of relatives at risk: clarify the genetic status of at-risk infants by molecular genetic testing for the family-specific mutations in order to prevent hyperpyrexia in those who are affected. Genetic counseling. HSAN IV is inherited in an autosomal recessive manner. Uniparental disomy (UPD) has been reported. Each child of known carriers has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible once the disease-causing mutations have been identified in a family
— id: 5308, year: 2008, vol: , page: ?, stat: Chapter,

IKBKAP mRNA in peripheral blood leukocytes: a molecular marker of gene expression and splicing in familial dysautonomia
Gold-von Simson, Gabrielle; Leyne, Maire; Mull, James; Rolnitzky, Linda M; Goldberg, Judith D; Berlin, Dena; Axelrod, Felicia B; Slaugenhaupt, Susan A
2008 Feb;63(2):186-190, Pediatric research
The common familial dysautonomia (FD) mutation results in tissue specific mis-splicing with reduced amount of wild-type (WT) IkappaB kinase associated protein gene (IKBKAP) mRNA and ELP1. ELP1 is a subunit of Elongator, formerly called the IkappaB kinase associated protein (IKAP) protein. We measured IKBKAP mRNA in peripheral blood leukocytes to determine whether FD subjects and carriers have characteristic levels. Estimated mean IKBKAP mRNA levels, measured by quantitative PCR and expressed as amount relative to the noncarrier average, were significantly different for the two groups when not adjusted for age and sex (p < 0.001): FD subjects 0.23, 95% confidence interval (CI) (0.19, 0.28); carriers 0.58, 95% CI (0.50, 0.68); or adjusted for age and sex (p < 0.001): FD subjects 0.21, 95% CI (0.16, 0.26); carriers 0.66, 95% CI (0.55, 0.79). Comparison of IKBKAP mRNA levels of the 22 FD subjects and their related carriers showed a strong correlation, providing evidence for genetic control of splicing efficiency. IKBKAP mRNA levels were not higher in those subjects using tocotrienols or epigallocatechin gallate. Levels of IKBKAP mRNA in peripheral blood leukocytes can be used to assess molecular response to therapies aimed at enhancing exon 20 inclusion and increasing cellular levels of ELP1/IKAP
— id: 78635, year: 2008, vol: 63, page: 186, stat: Journal Article,

Cardiac sympathetic hypo-innervation in familial dysautonomia
Goldstein, David S; Eldadah, Basil; Sharabi, Yehonatan; Axelrod, Felicia B
2008 Jun;18(3):115-119, Clinical autonomic research
OBJECTIVE: Familial dysautonomia (FD) involves incomplete development of the sympathetic nervous system. Whether such loss extends to sympathetic innervation of the heart has been unknown. This study used 6-[(18)F]fluorodopamine neuroimaging to assess cardiac sympathetic innervation and function in FD. METHODS: Six adult FD patients underwent thoracic PET scanning for 30 minutes after i.v. 6-[(18)F]fluorodopamine injection, as did healthy volunteers without (N = 21) or with (N = 10) pre-treatment by desipramine, which interferes with neuronal uptake and thereby simulates effects of noradrenergic denervation. Effective rate constants for uptake and loss were calculated using a single compartment pharmacokinetic model. RESULTS: FD patients had decreased uptake and accelerated loss of 6-[(18)F]fluorodopamine-derived radioactivity in the interventricular myocardial septum (P = 0.009, P = 0.05) and ventricular free wall (P = 0.007, P < 0.001), compared to untreated controls. Desipramine-treated subjects had decreased uptake but normal loss of 6-[(18)F]fluorodopamine-derived radioactivity. CONCLUSIONS: FD involves cardiac noradrenergic hypo-innervation. Since accelerated loss of 6-[(18)F]fluorodopamine-derived radioactivity cannot be explained by decreased neuronal uptake alone, FD may also involve augmented NE loss from extant terminals
— id: 122565, year: 2008, vol: 18, page: 115, stat: Journal Article,

Plasma catechols in familial dysautonomia: a long-term follow-up study
Goldstein, David S; Holmes, Courtney; Axelrod, Felicia B
2008 Sep;33(9):1889-1893, Neurochemical research
This study tested whether familial dysautonomia (FD) involves progressive loss of noradrenergic nerves. Plasma levels of catechols, including dihydroxyphenylglycol (DHPG), norepinephrine (NE), dopamine (DA), and DOPA, were measured in 7 adult patients with FD and 50 healthy control subjects. FD patients were re-tested after a mean follow-up period of 13 years. Compared to controls, FD patients had low plasma levels of DHPG (P < 0.001), high DOPA and DA levels (P = 0.01, P = 0.0002), and high NE:DHPG (P < 0.0001), DA:NE (P = 0.0003), and DOPA:DHPG (P < 0.0001) ratios. At follow-up there were no changes in plasma levels of individual catechols; however, there were further increases in DOPA:DHPG ratios (mean 24 +/- 7%, P = 0.01). In FD, plasma catechol profiles are sufficiently stable, at least over a decade, to be used as a biomarker of disease involvement. An increasing DOPA:DHPG ratio suggests slight but consistent, progressive loss of noradrenergic neurons
— id: 122566, year: 2008, vol: 33, page: 1889, stat: Journal Article,

Advanced electrocardiographic predictors of mortality in familial dysautonomia
Solaimanzadeh, I; Schlegel, T T; Feiveson, A H; Greco, E C; DePalma, J L; Starc, V; Marthol, H; Tutaj, M; Buechner, S; Axelrod, F B; Hilz, M J
2008 Dec 15;144(1-2):76-82, Autonomic neuroscience
OBJECTIVE: To identify electrocardiographic predictors of mortality in patients with familial dysautonomia (FD). METHODS: Ten-minute resting high-fidelity 12-lead electrocardiograms (ECGs) were obtained from 14 FD patients and 14 age/gender-matched healthy subjects. Multiple conventional and advanced ECG parameters were studied for their ability to predict mortality over a subsequent 4.5-year period, including representative parameters of heart rate variability (HRV), QT variability (QTV), T-wave complexity, signal averaged ECG, and 3-dimensional ECG. RESULTS: Four of the 14 FD patients died during the follow-up period, three with concomitant pulmonary disorder. Of the ECG parameters studied, increased non-HRV-correlated QTV and decreased HRV were the most predictive of death. Compared to controls as a group, FD patients also had significantly increased ECG voltages, JTc intervals and waveform complexity, suggestive of structural heart disease. CONCLUSION: Increased QTV and decreased HRV are markers for increased risk of death in FD patients. When present, both markers may reflect concurrent pathological processes, especially hypoxia due to pulmonary disorders and sleep apnea
— id: 104791, year: 2008, vol: 144, page: 76, stat: Journal Article,

Hereditary sensory and autonomic neuropathies: types II, III, and IV
Axelrod, Felicia B; Gold-von Simson, Gabrielle
2007 ;2:39-39, Orphanet journal of rare diseases
ABSTRACT: The hereditary sensory and autonomic neuropathies (HSAN) encompass a number of inherited disorders that are associated with sensory dysfunction (depressed reflexes, altered pain and temperature perception) and varying degrees of autonomic dysfunction (gastroesophageal reflux, postural hypotention, excessive sweating). Subsequent to the numerical classification of four distinct forms of HSAN that was proposed by Dyck and Ohta, additional entities continue to be described, so that identification and classification are ongoing. As a group, the HSAN are rare diseases that affect both sexes. HSAN III is almost exclusive to individuals of Eastern European Jewish extraction, with incidence of 1 per 3600 live births. Several hundred cases with HSAN IV have been reported. The worldwide prevalence of HSAN type II is very low. This review focuses on the description of three of the disorders, HSAN II through IV, that are characterized by autosomal recessive inheritance and onset at birth. These three forms of HSAN have been the most intensively studied, especially familial dysautonomia (Riley-Day syndrome or HSAN III), which is often used as a prototype for comparison to the other HSAN. Each HSAN disorder is likely caused by different genetic errors that affect specific aspects of small fiber neurodevelopment, which result in variable phenotypic expression. As genetic tests are routinely used for diagnostic confirmation of HSAN III only, other means of differentiating between the disorders is necessary. Diagnosis is based on the clinical features, the degree of both sensory and autonomic dysfunction, and biochemical evaluations, with pathologic examinations serving to further confirm differences. Treatments for all these disorders are supportive
— id: 75413, year: 2007, vol: 2, page: 39, stat: Journal Article,

A reinforced suture line prevents recurrence after fundoplication in patients with familial dysautonomia
Nadler, Evan P; Leung, Sam; Axelrod, Felicia B; Ginsburg, Howard B
2007 Apr;42(4):653-656, Journal of pediatric surgery
BACKGROUND/PURPOSE: Long-term follow-up of fundoplication in patients with familial dysautonomia (FD) has revealed a high rate of recurrent gastroesophageal reflux. This may be because of the unique characteristics of patients with FD which include autonomic denervation accompanied by cyclic vomiting and retching. We reviewed our results with adaptations to the Nissen fundoplication to determine which would be most effective in preventing the need for reoperation. METHODS: We reviewed the records of 108 patient with FD who underwent fundoplication by a single pediatric surgeon from November 1978 to July 1, 2004. Patients were divided into 4 groups based on the operative technique: standard Nissen fundoplication, Nissen with a posterior gastropexy, Nissen with posterior gastropexy and a superior anchoring suture, and Nissen with a reinforced suture line in addition to the previous modifications. Demographic data and surgical outcomes were abstracted. RESULTS: Patients who underwent a Nissen fundoplication with a reinforced suture line were significantly less likely to require a reoperation for recurrent reflux than any other patients (P = .05, Fisher's Exact test) despite the fact that they were younger than patients who underwent a standard Nissen alone. CONCLUSION: The addition of a reinforced suture line to the standard Nissen fundoplication decreases the failure rate for patients with gastroesophageal reflux and FD. A reinforced suture line may be an attractive modification for patients where the fundoplication may be under continued physical stress caused by autonomic perturbations, or other conditions such as uncontrolled seizures or progressive neurologic decline
— id: 72541, year: 2007, vol: 42, page: 653, stat: Journal Article,

A world without pain or tears
Axelrod, Felicia B
2006 Apr;16(2):90-97, Clinical autonomic research
The world of the child with familial dysautonomia (FD), a genetic disorder affecting development of the sensory and autonomic nervous system, is not idyllic. However, over the last 35 years advances in supportive treatments have improved morbidity and mortality. Recent genetic breakthroughs have further expanded thinking about this disorder and suggested innovative approaches to modifying genetic expression. This article reviews the current supportive treatment modalities and their rationale, as well as the suggested new treatments that may alter the function and prognosis of an individual affected with FD
— id: 71304, year: 2006, vol: 16, page: 90, stat: Journal Article,

Pediatric autonomic disorders
Axelrod, Felicia B; Chelimsky, Gisela G; Weese-Mayer, Debra E
2006 Jul;118(1):309-321, Pediatrics
The scope of pediatric autonomic disorders is not well recognized. The goal of this review is to increase awareness of the expanding spectrum of pediatric autonomic disorders by providing an overview of the autonomic nervous system, including the roles of its various components and its pervasive influence, as well as its intimate relationship with sensory function. To illustrate further the breadth and complexities of autonomic dysfunction, some pediatric disorders are described, concentrating on those that present at birth or appear in early childhood
— id: 67006, year: 2006, vol: 118, page: 309, stat: Journal Article,

Prevalence and severity of renal disease in familial dysautonomia
Elkayam, Lior; Matalon, Albert; Tseng, Chi-Hong; Axelrod, Felicia
2006 Nov;48(5):780-786, American journal of kidney diseases
BACKGROUND: One of the less well-defined complications of familial dysautonomia (FD) is chronic kidney disease (CKD). The goal of this report is to better define the prevalence and severity of kidney disease in this population and identify associated risk factors. METHODS: We conducted a retrospective analysis of the database of the Dysautonomia Treatment and Evaluation Center at New York University School of Medicine for patients with FD who were seen at ages 15, 20, 25, 30, 35, and 40 years. Estimated glomerular filtration rate (GFR) was compared with that of the general population. Changes in mean blood pressure from supine to erect at ages 15 and 20 years were analyzed for patients who eventually required dialysis therapy and compared with those of the other patients with FD. Percentage of patients requiring dialysis and duration of treatment also were analyzed. RESULTS: Mean estimated GFR of each predefined age group was considerably less than that of the general population starting at age 15 years (P < 0.001). Patients with FD were more likely to develop stage 3, 4, or 5 CKD than the general population. Of patients who remained alive at age 25 years, 19% eventually required dialysis. Those who required dialysis therapy were less likely to have had a feeding gastrostomy tube placed (P < 0.001) and had much more pronounced postural changes in blood pressure (P < 0.0001) by age 15 years. For those requiring dialysis therapy, average duration of treatment was 9 months. CONCLUSION: Patients with FD are far more likely than the general population to develop CKD. Patients with FD who eventually required dialysis showed a greater degree of orthostatic hypotension and were significantly less likely to have had a feeding gastrostomy tube placed for hydration before the age of 15 years. Dialysis therapy is not well tolerated in this population
— id: 71302, year: 2006, vol: 48, page: 780, stat: Journal Article,

Familial dysautonomia: update and recent advances
Gold-von Simson, Gabrielle; Axelrod, Felicia B
2006 Jul;36(6):218-237, Current problems in pediatric & adolescent health care
— id: 69023, year: 2006, vol: 36, page: 218, stat: Journal Article,

Cushing syndrome from topical foam steroid use in an adolescent male
Gold-von Simson, Gabrielle; Kohn, Brenda; Axelrod, Felicia B
2006 Jan-Feb;45(1):97-100, Clinical pediatrics
— id: 64783, year: 2006, vol: 45, page: 97, stat: Journal Article,

Anesthesia management of familial dysautonomia
Ngai, Jennie; Kreynin, Ilya; Kim, Jung T; Axelrod, Felicia B
2006 Jun;16(6):611-620, Paediatric anesthesia
Familial dysautonomia (FD) is an autosomal recessive inherited disorder, predominantly affecting the Ashkenazi Jewish population that is characterized by sensory and autonomic neuropathy. The protean manifestations and perturbations result in high morbidity and mortality. However, as a result of supportive measures and centralized care, survival has improved. As surgical options are increasing to symptomatically treat FD, anesthesiologists need to be familiar with this disorder. Because the Dysautonomia Center at NYU Medical Center is a referral center for FD patients, we have attained considerable anesthetic experience with FD. This article reviews clinical features of FD that could potentially affect anesthetic management and outlines our present practices
— id: 68934, year: 2006, vol: 16, page: 611, stat: Journal Article,

Familial dysautonomia's impact on quality of life in childhood, adolescence, and adulthood
Sands, Stephen A; Giarraffa, Philip; Jacobson, Colleen M; Axelrod, Felicia B
2006 Apr;95(4):457-462, Acta paediatrica
AIM: To evaluate the quality of life (QoL) of children, adolescents, and adults treated for familial dysautonomia (FD), a pervasive neurological disorder. METHODS: The Child Health Questionnaire was completed by parents of 71 patients, while an additional 74 patients completed the Short Form--36. RESULTS: FD imposed a greater physical than psychosocial burden on the child, while the young adults reported both mental and physical quality of life within the average range. Self-esteem was problematic and improved with age, while both groups reported lowering physical quality of life as they grew older, with worsening general health that limited their role at school or work. CONCLUSION: Younger FD patients should be closely monitored for lowered self-esteem and referred for counseling when appropriate, while physical and occupational therapy should be provided in advance of expected lowered physical QoL and role fulfillment with increasing age. This becomes important as the need for additional surgical interventions, such as fundoplication with gastrostomy or spinal fusion, contribute to lower physical functioning. Given the high degree of parental involvement required for the varied manifestations of this multisystem disorder, the need for continued parental assessment and psycho-education about this chronic medical illness is warranted
— id: 71303, year: 2006, vol: 95, page: 457, stat: Journal Article,

Effect of physical countermaneuvers on orthostatic hypotension in familial dysautonomia
Tutaj, Marcin; Marthol, Harald; Berlin, Dena; Brown, Clive M; Axelrod, Felicia B; Hilz, Max J
2006 Jan;253(1):65-72, Journal of neurology
Familial dysautonomia (FD) patients frequently experience debilitating orthostatic hypotension. Since physical countermaneuvers can increase blood pressure (BP) in other groups of patients with orthostatic hypotension, we evaluated the effectiveness of countermaneuvers in FD patients. In 17 FD patients (26.4 +/- 12.4 years, eight female), we monitored heart rate (HR), blood pressure (BP), cardiac output (CO), total peripheral resistance (TPR) and calf volume while supine, during standing and during application of four countermaneuvers: bending forward, squatting, leg crossing, and abdominal compression using an inflatable belt. Countermaneuvers were initiated after standing up,when systolic BP had fallen by 40mmHg or diastolic BP by 30mmHg or presyncope had occurred. During active standing, blood pressure and TPR decreased, calf volume increased but CO remained stable.Mean BP increased significantly during bending forward (by 20.0 (17 - 28.5) mmHg; P = 0.005) (median (25(th) - 75(th) quartile)), squatting (by 50.8 (33.5 - 56) mmHg; P = 0.002), and abdominal compression (by 5.8 (-1 - 34.7) mmHg; P = 0.04) - but not during leg-crossing. Squatting and abdominal compression also induced a significant increase in CO (by 18.1 (-1.3 - 47.9) % during squatting (P = 0.02) and by 7.6 (0.4 - 19.6) % during abdominal compression (P=0.014)). HR did not change significantly during the countermaneuvers. TPR increased significantly only during squatting (by 37.2 (11.8 - 48.2) %; P = 0.01). However, orthopedic problems or ataxia prevented several patients from performing some of the countermaneuvers. Additionally, many patients required assistance with the maneuvers. Squatting, bending forward and abdominal compression can improve orthostatic BP in FD patients, which is achieved mainly by an increased cardiac output. Squatting has the greatest effect on orthostatic blood pressure in FD patients. Suitability and effectiveness of a specific countermaneuver depends on the orthopedic or neurological complications of each FD patient and must be individually tested before a therapeutic recommendation can be given
— id: 68219, year: 2006, vol: 253, page: 65, stat: Journal Article,

Fludrocortisone in patients with familial dysautonomia--assessing effect on clinical parameters and gene expression
Axelrod, Felicia B; Goldberg, Judith D; Rolnitzky, Linda; Mull, James; Mann, Sandra P; Gold von Simson, Gabrielle; Berlin, Dena; Slaugenhaupt, Susan A
2005 Aug;15(4):284-291, Clinical autonomic research
The common familial dysautonomia (FD) mutation causes a splicing defect that leads to production of both wild-type (WT) and mutant (MU) IKBKAP mRNA. Because drugs may alter splicing, seven drugs, fludrocortisone, midodrine, diazepam, albuterol, clonidine, caffeine, and dopamine were screened. Since only fludrocortisone negatively altered gene expression, we assessed fludrocortisone's efficacy in treating postural hypotension, and its effect on survival and secondary long-term FD problems. For 341 FD patients we obtained demographic data and clinical information from the last Center evaluation (most current or prior to death) including mean blood pressures (supine, 1 min erect and 5 min erect) and history regarding syncope and presyncope symptoms. For 175 fludrocortisone-treated patients, data from the evaluation prior to start of fludrocortisone and from the last Center evaluation were compared. The fludrocortisone-treated patient cohort was compared to the nontreated patient cohort with respect to overall survival and event-free survival for crisis frequency, worsening gait, frequent fractures, spine curvature, renal insufficiency, and pacemaker insertion. Overall survivals of patients on fludrocortisone alone, on fludrocortisone and midodrine, and on neither drug were compared. Cumulative survival was significantly higher in fludrocortisone-treated patients than in non-treated patients during the first decade. In subsequent decades, the addition of midodrine improved cumulative survival. Fludrocortisone significantly increased mean blood pressures and decreased dizziness and leg cramping, but not headaches or syncope. Fludrocortisone was associated with more long-term problems, which may reflect more symptomatic status associated with longer survival. Our data suggest that fludrocortisone has clinical efficacy despite negative in vitro observations on gene expression
— id: 58717, year: 2005, vol: 15, page: 284, stat: Journal Article,

Assessing efficacy of high-frequency chest wall oscillation in patients with familial dysautonomia
Giarraffa, Philip; Berger, Kenneth I; Chaikin, Alice A; Axelrod, Felicia B; Davey, Cynthia; Becker, Brian
2005 Nov;128(5):3377-3381, Chest
STUDY OBJECTIVE: To determine the benefits of daily use of high-frequency chest wall oscillation (HFCWO) in familial dysautonomia (FD) patients with lung disease. DESIGN: Pulmonary function tests, chest radiographs, and blood tests were performed on entry to the study. A retrospective chart review of 12 months prior to entry provided baseline data regarding respiratory illnesses, medications, doctor visits, hospitalizations, and absenteeism. Daily logs provided prospective data on these parameters as well as HFCWO usage. Evaluations were performed at 1, 3, 6, 9, and 12 months for pulse oximetry, spirometry, and log review. At the exit evaluation, blood tests and chest radiographs were repeated. PATIENTS: Fifteen FD patients with history of lung disease requiring daily inhalation therapy (7 female and 8 male; age range, 11 to 33 years) were enrolled in a 1-year clinical trial of HFCWO therapy. Two subjects withdrew after 3 months and 6 months, respectively. Each individual served as his/her own control. RESULTS: Oxygen saturation improved by 1 month (median, 97.5%; interquartile range [IQR], 96 to 98%; vs median, 94%; IQR, 89 to 96%) and was sustained at exit evaluation (median, 98%; IQR, 98 to 98%) [p = 0.004]. Median FVC and peak expiratory flow rate (PEFR) were the pulmonary function measures with sustained improvement from baseline to exit (p = 0.02 and p = 0.03, respectively). When retrospective and prospective data were compared, all measured health outcomes improved significantly, including pneumonias (p = 0.0156), hospitalizations (p = 0.0161), antibiotic courses (p = 0.0005), antibiotic days (p = 0.0002), doctor visits (p = 0.0005), and absenteeism (p = 0.0002). CONCLUSION: In this limited study of FD patients, HFCWO effected significant improvements in all measured health outcomes and oxygen saturation; FVC and PEFR were the pulmonary function measures demonstrating sustained improvement
— id: 61272, year: 2005, vol: 128, page: 3377, stat: Journal Article,

Familial dysautonomia
Axelrod, Felicia B
2004 Mar;29(3):352-363, Muscle & nerve
Familial dysautonomia (FD) is a neurodevelopmental genetic disorder within the larger classification of hereditary sensory and autonomic neuropathies, each caused by a different genetic error. The FD gene has been identified as IKBKAP. Mutations result in tissue-specific expression of mutant IkappaB kinase-associated protein (IKAP). The genetic error probably affects development, as well as maintenance, of neurons because there is neuropathological and clinical progression. Pathological alterations consist of decreased unmyelinated and small-fiber neurons. Clinical features reflect widespread involvement of sensory and autonomic neurons. Sensory loss includes impaired pain and temperature appreciation. Autonomic features include dysphagia, vomiting crises, blood pressure lability, and sudomotor dysfunction. Central dysfunction includes emotional lability and ataxia. With supportive treatment, prognosis has improved greatly. About 40% of patients are over age 20 years. The cause of death is usually pulmonary failure, unexplained sudden deaths, or renal failure. With the discovery of the genetic defect, definitive treatments are anticipated
— id: 42583, year: 2004, vol: 29, page: 352, stat: Journal Article,

Sudomotor function in familial dysautonomia
Bickel, A; Axelrod, F B; Marthol, H; Schmelz, M; Hilz, M J
2004 Feb;75(2):275-279, Journal of neurology neurosurgery & psychiatry
BACKGROUND: Patients with familial dysautonomia (FD) manifest episodic hyperhidrosis despite the reduction of sudomotor fibres and sweat glands associated with this autonomic neuropathy. We assessed peripheral sudomotor nerve fibre and sweat gland function to determine if this symptom was due to peripheral denervation hypersensitivity. METHODS: In 14 FD patients and 11 healthy controls, direct and axon reflex mediated sweat responses were determined by measuring transepidermal water loss (TEWL) after application of acetylcholine via a microdialysis membrane, a novel method to evaluate sudomotor function in neuropathy patients. Results were compared with data from conventional quantitative sudomotor axon reflex testing (QSART). Using microdialysis, interstitial fluid was analysed for plasma proteins to evaluate protein extravasation induced by acetylcholine as an additional parameter of C-fibre function. RESULTS: Although reduced axon reflex sweating was expected in FD patients, neither direct or axon reflex mediated sweat responses, nor acetylcholine induced protein extravasation differed between control and patient groups. However, the baseline resting sweat rate was higher in FD patients than controls (p<0.05). TEWL and QSART test results correlated (r = 0.64, p = 0.01), proving the reliability of TEWL methodology in evaluating sudomotor function. CONCLUSION: The finding of normal direct and axon reflex mediated sweat output in FD patients supports our hypothesis that, in a disorder with severe sympathetic nerve fibre reduction, sudomotor fibres, but not the sweat gland itself, exhibit chemical hypersensitivity. This might explain excessive episodic hyperhidrosis in situations with increased central sympathetic outflow
— id: 68228, year: 2004, vol: 75, page: 275, stat: Journal Article,

Growth hormone treatment in children with familial dysautonomia
Kamboj, Manmohan K; Axelrod, Felicia B; David, Raphael; Geffner, Mitchell E; Novogroder, Michael; Oberfield, Sharon E; Turco, John H; Maayan, Channa; Kohn, Brenda
2004 Jan;144(1):63-67, Journal of pediatrics
OBJECTIVE: To assess experience with growth hormone (GH) therapy in patients with familial dysautonomia (FD).Study design Of 580 patients with FD registered at the Dysautonomia Center at New York University Medical Center, 13 patients (8 males, 5 females) aged 1.10 to 15.10 years received GH treatment. GH doses ranged from 0.2 to 0.3 mg/kg/wk; one patient received 0.14 mg/kg/wk. Information regarding auxologic data, skeletal age, pubertal status, and spinal deformity before and after GH therapy was obtained from center records and treating endocrinologists. Growth velocity was analyzed before and during GH treatment at 0 to 6 months, 6 to 12 months, 1 to 2 years, and >2 years. RESULTS: Before GH therapy, growth velocity was <5 cm/y in 10 patients and 5 to 6 cm/y in three patients. In the first six months of GH therapy, growth velocity exceeded pretreatment rates in all but one patient; 10 patients achieved an annualized growth rate >7 cm/y. Six of nine patients treated for more than one year grew >5 cm/y. Less than optimal treatment responses were attributed to poor compliance, intercurrent illness, scoliosis, or advanced puberty. CONCLUSION: The data demonstrate that GH treatment in patients with FD may increase growth velocity, at least in the short term. This experiential data supports a future prospective study
— id: 42620, year: 2004, vol: 144, page: 63, stat: Journal Article,

Rescue of a human mRNA splicing defect by the plant cytokinin kinetin
Slaugenhaupt, Susan A; Mull, James; Leyne, Maire; Cuajungco, Math P; Gill, Sandra P; Hims, Matthew M; Quintero, Fabiola; Axelrod, Felicia B; Gusella, James F
2004 Feb 15;13(4):429-436, Human molecular genetics
The defective splicing of pre-mRNA is a major cause of human disease. Exon skipping is a common result of splice mutations and has been reported in a wide variety of genetic disorders, yet the underlying mechanism is poorly understood. Often, such mutations are incompletely penetrant, and low levels of normal transcript and protein are maintained. Familial dysautonomia (FD) is caused by mutations in IKBKAP, and all cases described to date involve an intron 20 mutation that results in a unique pattern of tissue-specific exon skipping. Accurate splicing of the mutant IKBKAP allele is particularly inefficient in the nervous system. Here we show that treatment with the plant cytokinin kinetin alters splicing of IKBKAP. Kinetin significantly increases inclusion of exon 20 from the endogenous gene, as well as from an IKBKAP minigene. By contrast the drug does not enhance inclusion of alternatively spliced exon 31 in MYO5A. Benzyladenine, the most closely related cytokinin, showed a similar but less dramatic effect. Our findings reveal a remarkable impact on splicing fidelity by these small molecules, which therefore provide new tools for the dissection of mechanisms controlling tissue-specific pre-mRNA splicing. Further, kinetin should be explored as a treatment for increasing the level of normal IKAP in FD, and for other splicing disorders that may share a similar mechanism
— id: 71305, year: 2004, vol: 13, page: 429, stat: Journal Article,

Sympathetic and parasympathetic baroreflex dysfunction in familial dysautonomia
Stemper, B; Bernardi, L; Axelrod, F B; Welsch, G; Passino, C; Hilz, M J
2004 Oct 26;63(8):1427-1431, Neurology
OBJECTIVE: To assess the possible abnormalities in the baroreflex modulation of both the heart and the arterial vasculature, in order to better evaluate the role of baroreflex abnormalities in the generation of the cardiovascular symptoms and complications affecting the familial dysautonomia (FD) patient. METHODS: Twenty-one FD patients and 22 controls underwent 3 minutes of passive head-up tilt (HUT) and baroreceptor stimulation by means of sinusoidal neck suction (NS; 0 to -30 mm Hg; 0.1 Hz [LF] and 0.2 Hz [HF]). Respiration was maintained constant during NS at 15 breaths/minute. The authors monitored RR-intervals (RRI), blood pressure (BP) (Colin), and respiration. NS induced changes of RRI and BP were determined by spectral analysis. RESULTS: HUT showed orthostatic hypotension without compensatory tachycardia in FD patients but not in controls. LF-NS increased LF power of RRI and BP and HF-NS increased HF power of RRI in controls, but not in FD patients. CONCLUSIONS: Familial dysautonomia patients have a widespread baroreflex abnormality, involving both the efferent sympathetic arm on the resistance vessels, and the sympathetic and parasympathetic efferent arms on the heart. Therefore, the abnormalities in the control of blood pressure-i.e., supine hypertension, orthostatic hypotension, blood pressure lability-and heart rate-i.e., bradyarrhythmias-are likely due to baroreflex abnormalities
— id: 68224, year: 2004, vol: 63, page: 1427, stat: Journal Article,

Inherited autonomic neuropathies
Axelrod, Felicia B; Hilz, Max J
2003 Mar-Apr;23(4):381-390, Seminars in neurology
Inherited autonomic neuropathies are a rare group of disorders associated with sensory dysfunction. As a group they are termed the 'hereditary sensory and autonomic neuropathies' (HSAN). Classification of the various autonomic and sensory disorders is ongoing. In addition to the numerical classification of four distinct forms proposed by Dyck and Ohta (1975), additional entities have been described. The best known and most intensively studied of the HSANs are familial dysautonomia (Riley-Day syndrome or HSAN type III) and congenital insensitivity to pain with anhidrosis (HSAN type IV). Diagnosis of the HSANs depends primarily on clinical examinations and specific sensory and autonomic assessments. Pathologic examinations are helpful in confirming the diagnosis and in differentiating between the different disorders. In recent years identification of specific genetic mutations for some disorders has aided diagnosis. Replacement or definitive therapies are not available for any of the disorders so that treatment remains supportive and directed toward specific symptoms
— id: 46215, year: 2003, vol: 23, page: 381, stat: Journal Article,

Respiratory and cerebrovascular responses to hypoxia and hypercapnia in familial dysautonomia
Bernardi, Luciano; Hilz, Max; Stemper, Brigitte; Passino, Claudio; Welsch, Goetz; Axelrod, Felicia B
2003 Jan 15;167(2):141-149, American journal of respiratory & critical care medicine
Although cardiorespiratory complications contribute to the high morbidity/mortality of familial dysautonomia (FD), the mechanisms remain unclear. We evaluated respiratory, cardiovascular, and cerebrovascular control by monitoring ventilation, end-tidal carbon dioxide (CO2-et), oxygen saturation, RR interval, blood pressure (BP), and midcerebral artery flow velocity (MCFV) during progressive isocapnic hypoxia, progressive hyperoxic hypercapnia, and during recovery from moderate hyperventilation (to simulate changes leading to respiratory arrest) in 22 subjects with FD and 23 matched control subjects. Subjects with FD had normal ventilation, higher CO2-et, lower oxygen saturation, lower RR interval, and higher BP. MCFV was also higher but depended on the higher baseline CO2-et. In the FD group, whereas hyperoxic hypercapnia induced normal cardiovascular and ventilatory responses, progressive hypoxia resulted in blunted increases in ventilation, paradoxical decreases in RR interval and BP, and lack of MCFV increase. Hyperventilation induced a longer hypocapnia-induced apneic period (51.5 +/- 9.9 versus 11.2 +/- 5.5 seconds, p < 0.008) with profound desaturation (to 75.8 +/- 3.5%), marked BP decrease, and RR interval increase. Subjects with FD develop central depression in response to even moderate hypoxia with lack of expected change in cerebral circulation, leading to hypotension, bradycardia, hypoventilation, and potentially respiratory arrest. Higher resting BP delays occurrence of syncope during hypoxia. Therapeutic measures preventing hypoxia/hypocapnia may correct cardiovascular accidents in patients with FD
— id: 37074, year: 2003, vol: 167, page: 141, stat: Journal Article,

Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia
Cuajungco, Math P; Leyne, Maire; Mull, James; Gill, Sandra P; Lu, Weining; Zagzag, David; Axelrod, Felicia B; Maayan, Channa; Gusella, James F; Slaugenhaupt, Susan A
2003 Mar;72(3):749-758, American journal of human genetics
We recently identified a mutation in the I-kappa B kinase associated protein (IKBKAP) gene as the major cause of familial dysautonomia (FD), a recessive sensory and autonomic neuropathy. This alteration, located at base pair 6 of the intron 20 donor splice site, is present on >99.5% of FD chromosomes and results in tissue-specific skipping of exon 20. A second FD mutation, a missense change in exon 19 (R696P), was seen in only four patients heterozygous for the major mutation. Here, we have further characterized the consequences of the major mutation by examining the ratio of wild-type to mutant (WT:MU) IKBKAP transcript in EBV-transformed lymphoblast lines, primary fibroblasts, freshly collected blood samples, and postmortem tissues from patients with FD. We consistently found that WT IKBKAP transcripts were present, albeit to varying extents, in all cell lines, blood, and postmortem FD tissues. Further, a corresponding decrease in the level of WT protein is seen in FD cell lines and tissues. The WT:MU ratio in cultured lymphoblasts varied with growth phase but not with serum concentration or inclusion of antibiotics. Using both densitometry and real-time quantitative polymerase chain reaction, we found that relative WT:MU IKBKAP RNA levels were highest in cultured patient lymphoblasts and lowest in postmortem central and peripheral nervous tissues. These observations suggest that the relative inefficiency of WT IKBKAP mRNA production from the mutant alleles in the nervous system underlies the selective degeneration of sensory and autonomic neurons in FD.Therefore, exploration of methods to increase the WT:MU IKBKAP transcript ratio in the nervous system offers a promising approach for developing an effective therapy for patients with FD
— id: 34733, year: 2003, vol: 72, page: 749, stat: Journal Article,

Genetic disorders as models to understand autonomic dysfunction
Axelrod, Felicia B
2002 May;12 Suppl 1:I1-I1, Clinical autonomic research
— id: 71306, year: 2002, vol: 12 Suppl 1, page: I1, stat: Journal Article,

Hereditary sensory and autonomic neuropathies. Familial dysautonomia and other HSANs
Axelrod, Felicia B
2002 May;12 Suppl 1(1):I2-14, Clinical autonomic research
— id: 39619, year: 2002, vol: 12 Suppl 1, page: I2, stat: Journal Article,

Survival in familial dysautonomia: Impact of early intervention
Axelrod, Felicia B; Goldberg, Judith D; Ye, Xiang Y; Maayan, Channa
2002 Oct;141(4):518-523, Journal of pediatrics
OBJECTIVE: To assess the effectiveness of advances in supportive centralized care on survival and function in patients with familial dysautonomia (FD). STUDY DESIGN: From September l, 1969 through January 1, 2001. Five hundred fifty-one patients with FD entered the Dysautonomia Center. We divided the group into two cohorts: the first cohort (n = 227) entered until March 1, 1981, and the second cohort (n = 324) entered after March 1, 1981. Survival curves were compared by using log-rank tests. Demographic and disease characteristics were examined, including gender, geographic location, age at entry, birth weight, breath-holding history, age of walking, causes of death, and social data. RESULTS: For both cohorts age at entry was the primary variable that influenced survival; mortality increased by 3% per year. Survival time lengthened for cohort 2 when survival time was defined as time from entry into the Center to last observation or death; in cohort 2, mortality was 73% that of cohort 1 even after adjustment for age at entry. Although survival improved, causes of death were unchanged; sleep deaths and sudden deaths remained frequent. CONCLUSION: Our data indicate that the more recent cohort patients were younger at the time of entry and had improved survival, which suggests that early access to centralized and more advanced treatment appreciably benefits patients with familial dysautonomia
— id: 39450, year: 2002, vol: 141, page: 518, stat: Journal Article,

Dermal microdialysis provides evidence for hypersensitivity to noradrenaline in patients with familial dysautonomia
Bickel, A; Axelrod, F B; Schmelz, M; Marthol, H; Hilz, M J
2002 Sep;73(3):299-302, Journal of neurology neurosurgery & psychiatry
OBJECTIVES: To use the technique of dermal microdialysis to examine sensitivity of skin vessels to noradrenaline (NA) in patients with familial dysautonomia (FD) and in healthy controls. METHODS: In 14 patients with FD and 12 healthy controls, plasma extravasation, local laser Doppler blood flow, and skin blanching were observed before, during, and after application of 10(-6) M NA through a microdialysis membrane, located intradermally in the skin of the lower leg. RESULTS: Maximum local vasoconstriction measured by laser Doppler blood flow did not differ between patients with FD and controls. In contrast, patients with FD had an earlier onset of vasoconstriction (p = 0.02). Moreover, reaction to NA was more prominent and prolonged in FD, shown by a larger zone of skin blanching around the microdialysis membrane (p < 0.001) and delayed reduction of the protein content in the dialysate after termination of NA application (p = 0.03). CONCLUSION: These data support the hypothesis that peripheral blood vessels of patients with FD show a denervation hypersensitivity to catecholamines. This may be one mechanism contributing to the major hypertension that frequently occurs during 'dysautonomic crises' in FD
— id: 37010, year: 2002, vol: 73, page: 299, stat: Journal Article,

Sympathetic and parasympathetic pupillary dysfunction in familial dysautonomia
Dutsch, M; Hilz, M J; Rauhut, U; Solomon, J; Neundorfer, B; Axelrod, F B
2002 Mar 15;195(1):77-83, Journal of the neurological sciences
Objective assessment of autonomic dysfunction in familial dysautonomia (FD) is largely based on the analysis of cardiovascular responses to challenge maneuvers such as orthostatic stress. Infrared pupillometry (IPM) provides an additional reliable method for cranial autonomic evaluation and has the advantage of requiring minimal cooperation.This study was performe to determine whether IPM contributes to the assessment of autonomic function in FD patients.In 14 FD patients and 14 healthy controls, we studied absolute and relative light reflex amplitude, pupillary constriction velocity (v(constr)), pupillary diameter, early and late pupillary re-dilatation velocity (v(dil 1), v(dil 2)) after dark adaptation. Prior to IPM, all patients had an ophthamological examination to evaluate refraction and corneal integrity.In comparison to controls, patients had a significant reduction of the parameters reflecting parasympathetic pupillary function (absolute light reflex amplitude 1.34plus minus0.21 vs. l.86plus minus0.14 mm, relative light reflex amplitude 22.74plus minus7.11% vs. 30.76plus minus3.57%, v(constr) 3.75plus minus1.09 vs. 5.80plus minus0.59 mm/s) and of the parameters reflecting sympathetic pupillary function (diameter 5.69plus minus0.66 vs. 6.35plus minus0.60 mm, v(dil 1) 1.29plus minus0.23 vs. 1.95plus minus0.23 mm/s, v(dil 2) 0.64plus minus0.13 vs. 0.72plus minus0.l2 mm/s; Mann--Whitney U-test: p<0.05).The non-invasive technique of IPM demonstrates dysfunction not only of the cranial parasympathetic, but also of the cranial sympathetic nervous system and, thus, further characterizes autonomic dysfunction in FD
— id: 25656, year: 2002, vol: 195, page: 77, stat: Journal Article,

Cold pressor test demonstrates residual sympathetic cardiovascular activation in familial dysautonomia
Hilz, M J; Axelrod, F B; Braeske, K; Stemper, B
2002 Apr 15;196(1-2):81-89, Journal of the neurological sciences
In familial dysautonomia (FD), i.e. Riley-Day-syndrome, sympathetic cardiovascular function, as well as afferent temperature and pain mediating neurons, are significantly reduced. Thus, it was questioned if cold pressor test (CPT), which normally enhances sympathetic outflow and induces peripheral vasoconstriction by the activation of thermo- and nociceptive system activation, could be used to assess sympathetic function in FD.To evaluate whether CPT can be used to assess sympathetic activation in FD, we performed CPT in 15 FD patients and 18 controls. After a 35-min resting period, participants immersed their right hand and arm up to the elbow into 0-1 degrees C cold water while we monitored heart rate (HR), respiration, beat-to-beat radial artery blood pressure (BP), and laser Doppler skin blood flow (SBF) at the right index finger pulp. From these measurements, heart rate variability parameters were calculated: root mean square of successive differences (RMSSD), coefficient of variation (CV), low and high frequency (LF, HF) power spectra of the electrocardiogram (ECG).All participants perceived cold stimulation and indicated discomfort. In controls, SBF decreased and HR and BP increased rapidly upon CPT. After 60 s, SBF indicated secondary vasodilatation in six controls, BP rise attenuated and HR returned to baseline in all controls. In the patients, SBF remained unchanged, HR and BP increased significantly, but after 50-60 s of CPT and changes were lower than in controls (p<0.05). RMSSD and CV decreased and LF increased significantly only in the controls.We conclude that CPT activates sympathetic HR and BP modulation despite impaired pain and temperature perception in FD patients. BP increase in the presence of almost unchanged SBF might be due to HR increase and to nociceptive arousal and emotionally induced catecholamine release as seen in emotional crises of FD patients. CPT assesses sympathetic cardiovascular responses independently from baroreflex function, which is compromised in FD
— id: 37017, year: 2002, vol: 196, page: 81, stat: Journal Article,

Transcranial Doppler sonography during head up tilt suggests preserved central sympathetic activation in familial dysautonomia
Hilz, M J; Axelrod, F B; Haertl, U; Brown, C M; Stemper, B
2002 May;72(5):657-660, Journal of neurology neurosurgery & psychiatry
OBJECTIVE: Cerebral autoregulation was assessed by transcranial Doppler sonography in 10 patients with familial dysautonomia and 10 age matched controls. METHODS: Blood pressure, heart rate, and middle cerebral artery blood flow velocity (CBFV) were simultaneously recorded when supine and during 180 seconds of head up tilt. Cerebrovascular resistance (CVR) was calculated from CBFV and mean blood pressure was adjusted to brain level. RESULTS: In the controls, mean blood pressure remained stable during tilt, but heart rate increased significantly. In the patients with familial dysautonomia, mean (SD) blood pressure decreased by 15.0 (10.8)% (p < 0.05). Heart rate remained unchanged. In controls, systolic and mean CBFV decreased by 9.1 (4.7)% and 9.4 (7.0)%, respectively, while diastolic CBFV remained stable. In the patients, diastolic and mean CBFV decreased continuously by 32.1 (13.9)% and by 14.8 (31.4)%. Supine CVR was 28% higher in patients than in controls and decreased significantly less during head up tilt. CONCLUSIONS: Tilt evokes orthostatic hypotension without compensatory tachycardia in patients with familial dysautonomia owing to decreased peripheral sympathetic innervation. High supine CVR values and relatively preserved CVR during tilt suggest preserved central sympathetic activation in familial dysautonomia, assuring adaptation of cerebrovascular autoregulation to chronic supine hypertension and orthostatic hypotension
— id: 37016, year: 2002, vol: 72, page: 657, stat: Journal Article,

Valsalva maneuver suggests increased rigidity of cerebral resistance vessels in familial dysautonomia
Hilz, M J; Axelrod, F B; Steingrueber, M; Stemper, B
2002 Oct;12(5):385-392, Clinical autonomic research
In familial dysautonomia (FD), cerebral autoregulation (CA) must adjust cerebral blood flow to extreme and rapid fluctuations in systemic blood pressure. Compromised CA during systemic blood pressure (BP) fluctuations might contribute to central autonomic dysfunction in FD.To evaluate CA during rapid BP changes, we monitored heart rate (HR), radial artery BP and middle cerebral artery blood flow velocity (CBFV), using transcranial Doppler sonography, in eight FD patients and twelve age-matched controls in supine position at baseline and during a Valsalva maneuver (VM, 40 mmHg expiratory pressure for 15 seconds). The best of four VM recordings was analyzed. We calculated two autoregulation parameters. CA(II) reflects BP related autoregulatory CBFV increase in late phase II of VM. CA(II) = [(CBFV(II late)-CBFV(II early))/CBFV(II early)]/[(BP(II late)-BP(II early))/BP(II early)]. CA(IV) reflects BP and HR related autoregulatory CBFV increase in phase IV of VM. CA(IV) = (CBFV(IV)/CBFV(I))/(BP(IV)/BP(I))/(HR(IV)/HR(I)). Baseline systemic BP, but not CBFV, was higher in the patients than the controls. During VM, both groups had similar CBFV and BP values, but CAIV and especially CA(II) were significantly lower in the patients than the controls. We have documented that FD patients maintain stable CBFV during rapid BP fluctuations associated with early and late phase II and phase IV of VM suggesting that small intracerebral vessels of FD patients are less responsive to rapid systemic blood pressure fluctuations. To compensate for decreased sympathetic vascular innervation, we propose that FD patients may alter the myogenic component of CA by vessel wall thickening resulting in increased rigidity of intracerebral resistance vessels. The resulting vasoconstriction would allow maintenance of normal baseline CBFV in spite of chronic recumbent hypertension
— id: 37007, year: 2002, vol: 12, page: 385, stat: Journal Article,

Stability of autonomic cardiovascular modulation and baroreflex function during Sildenafil use and physical challenge
Hilz, MJ; Stemper, B; Brys, M; Marthol, H; Franta, R; Axelrod, FB
2002 ;58(7):A348-A349, Neurology
— id: 104750, year: 2002, vol: 58, page: A348, stat: Journal Article,

Extensive Riga-Fede disease of the lip and tongue
Zaenglein, Andrea L; Chang, Mary Wu; Meehan, Shane A; Axelrod, Felicia B; Orlow, Seth J
2002 Sep;47(3):445-447, Journal of the American Academy of Dermatology
Riga-Fede disease presents in early infancy and is characterized by firm, verrucous plaques arising on the oral mucosal surfaces. These histologically benign lesions occur as a result of repetitive trauma of the oral mucosal surfaces by the teeth. Early recognition of this entity is important, because it may be the presenting sign of an underlying neurologic disorder. We report the case of a 10-month-old boy with extensive Riga-Fede disease involving the lip and tongue that prompted a diagnosis of congenital autonomic dysfunction with universal pain loss
— id: 34782, year: 2002, vol: 47, page: 445, stat: Journal Article,

Nonspinal orthopaedic problems in familial dysautonomia (Riley-Day syndrome)
Laplaza, F J; Turajane, T; Axelrod, F B; Burke, S W
2001 Mar-Apr;21(2):229-232, Journal of pediatric orthopedics
Familial dysautonomia (FD) is a rare autosomal recessive disease occurring in Ashkenazi Jews. It affects the autonomic, central, and peripheral nervous systems. The purpose of this study was to assess the prevalence and characteristics of orthopedic deformities, other than spinal deformities, in this population. A retrospective review of the medical records and radiographs of 182 patients was made. Three main groups of orthopaedic conditions were evaluated: (a) Fractures: 60% of the patients had one or more fractures; the average fracture rate was 1.4/patient. (b) Neuropathic joints: 11% of the cases had one or more neuropathic joints, the knee being the most common. (c) Other musculoskeletal deformities: 26% of the patients had one or more deformities. Lower extremity rotational problems and foot anomalies accounted for most of these deformities. Patients with FD have a higher prevalence of fractures and neuropathic joints than do their peers. The fracture pattern also is different, with a higher incidence of proximal femoral fractures
— id: 122567, year: 2001, vol: 21, page: 229, stat: Journal Article,

Cytomegalovirus infectivity in whole blood following leukocyte reduction by filtration
Lipson SM; Shepp DH; Match ME; Axelrod FB; Whitbread JA
2001 Jul;116(1):52-55, American journal of clinical pathology
Cytomegalovirus (CMV) may be transmitted by transfusion of whole blood and cellular components processed according to standard processing procedures. A need exists to develop new procedures to remove CMV and other leukocyte-borne viruses from donor blood. Ten patients (AIDS/bone marrow transplants) who were CMV antigenemic (virus subsequently confirmed by isolation), donated 50 mL of venous blood within 24 to 72 hours of the initial antigen detection. Twenty-five-milliliter aliquots of each specimen were passed through Purecell Neo Neonatal Leukocyte Reduction Filters (Pall, East Hills, NY). The remaining 25-mL nonfiltered aliquots, as well as the blood filtrates, were subjected to infectivity endpoint determinations. The Purecell Neo filter effected a 3 to 4 log10 leukocyte reduction. CMV input titers ranged from less than 10 to 7.3 x 10(1) median tissue culture infectious dose (TCID50) per milliliter. CMV was not isolated from any postfiltration effluent (i.e., leukocytes, erythrocytes, or plasma). CMV DNA was not detected by nested polymerase chain reaction in 8 of 10 postfiltrate blood specimens. The Purecell Neo filter was efficacious in eliminating or significantly reducing viral (CMV) load in venous blood
— id: 21131, year: 2001, vol: 116, page: 52, stat: Journal Article,

Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia
Slaugenhaupt, S A; Blumenfeld, A; Gill, S P; Leyne, M; Mull, J; Cuajungco, M P; Liebert, C B; Chadwick, B; Idelson, M; Reznik, L; Robbins, C; Makalowska, I; Brownstein, M; Krappmann, D; Scheidereit, C; Maayan, C; Axelrod, F B; Gusella, J F
2001 Mar;68(3):598-605, American journal of human genetics
Familial dysautonomia (FD; also known as 'Riley-Day syndrome'), an Ashkenazi Jewish disorder, is the best known and most frequent of a group of congenital sensory neuropathies and is characterized by widespread sensory and variable autonomic dysfunction. Previously, we had mapped the FD gene, DYS, to a 0.5-cM region on chromosome 9q31 and had shown that the ethnic bias is due to a founder effect, with >99.5% of disease alleles sharing a common ancestral haplotype. To investigate the molecular basis of FD, we sequenced the minimal candidate region and cloned and characterized its five genes. One of these, IKBKAP, harbors two mutations that can cause FD. The major haplotype mutation is located in the donor splice site of intron 20. This mutation can result in skipping of exon 20 in the mRNA of patients with FD, although they continue to express varying levels of wild-type message in a tissue-specific manner. RNA isolated from lymphoblasts of patients is primarily wild-type, whereas only the deleted message is seen in RNA isolated from brain. The mutation associated with the minor haplotype in four patients is a missense (R696P) mutation in exon 19, which is predicted to disrupt a potential phosphorylation site. Our findings indicate that almost all cases of FD are caused by an unusual splice defect that displays tissue-specific expression; and they also provide the basis for rapid carrier screening in the Ashkenazi Jewish population
— id: 122569, year: 2001, vol: 68, page: 598, stat: Journal Article,

Impaired cardiovascular responses during hypoxic chemoreceptor stimulation in familial dysautonomia
Stemper, B; Hilz, MJ; Bernardi, L; Welsch, G; Passino, C; Axelrod, FB
2001 ;56(8):A426-A426, Neurology
— id: 104754, year: 2001, vol: 56, page: A426, stat: Journal Article,

Ictal SPECT during autonomic crisis in familial dysautonomia
Axelrod FB; Zupanc M; Hilz MJ; Kramer EL
2000 Jul 12;55(1):122-125, Neurology
The authors report results of SPECT cerebral perfusion studies in two patients with familial dysautonomia (FD) during dysautonomic crises and when clinically stable. SPECT imaging studies used 99mTc ethylene cysteine dimer. During dysautonomic crises, regions in the temporoparietal and frontal lobes had increased uptake. Uptake in these areas was less during asymptomatic periods. Episodic asymmetric cerebral perfusion during crises especially affecting the frontal and temporal lobes is suggestive of ictal activity
— id: 11600, year: 2000, vol: 55, page: 122, stat: Journal Article,

Intranasal midazolam and familial dysautonomia
Axelrod, F B; Maayan, C
2000 Oct;23(4):369-369, Pediatric neurology
— id: 122568, year: 2000, vol: 23, page: 369, stat: Journal Article,

Cloning, mapping, and expression of a novel brain-specific transcript in the familial dysautonomia candidate region on chromosome 9q31
Chadwick, B P; Leyne, M; Gill, S; Liebert, C B; Mull, J; Mezey, E; Robbins, C M; Pinkett, H W; Makalowska, I; Maayan, C; Blumenfeld, A; Axelrod, F B; Brownstein, M; Gusella, J F; Slaugenhaupt, S A
2000 Jan;11(1):81-83, Mammalian genome
— id: 122571, year: 2000, vol: 11, page: 81, stat: Journal Article,

Spinal deformity in familial dysautonomia. Prevalence, and results of bracing
Hayek, S; Laplaza, F J; Axelrod, F B; Burke, S W
2000 Nov;82-A(11):1558-1562, Journal of bone & joint surgery (American volume)
BACKGROUND: Familial dysautonomia (Riley-Day syndrome) is an autosomal recessive disorder primarily affecting individuals of Ashkenazi Jewish extraction. It affects the autonomic, central, and peripheral nervous systems. Spinal deformity (mainly scoliosis) is the most common orthopaedic problem in patients with familial dysautonomia. The objectives of our study were to document the prevalence of spinal deformity in a referral center for familial dysautonomia and to determine the effectiveness of bracing. METHODS: We performed a retrospective radiographic and clinical study of 123 patients with familial dysautonomia who had survived to the age of twenty years or older. RESULTS: One hundred and two (83 percent) of the 123 patients had spinal deformity: sixty-nine (56 percent) had scoliosis only, thirty-one (25 percent) had scoliosis as well as kyphosis, and two (2 percent) had kyphosis only. Scoliosis was diagnosed by the age of ten years in sixty-four (52 percent) of the patients. Of the sixty-five patients who were treated with bracing, fifty-eight (89 percent) had progression and twenty-four (37 percent) underwent spinal arthrodesis. No risk factors for the presence or progression of the curves could be found. CONCLUSIONS: The prevalence of spinal deformity in patients with familial dysautonomia who had lived for at least twenty years was found to be 83 percent. By the age of ten years, 52 percent of the patients had scoliosis and 21 percent had kyphosis with or without scoliosis. Bracing was found to be of limited effectiveness as a definitive treatment for spinal deformity. The curve progressed despite bracing in fifty-eight (89 percent) of sixty-five patients
— id: 122570, year: 2000, vol: 82-A, page: 1558, stat: Journal Article,

Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31
Blumenfeld, A; Slaugenhaupt, S A; Liebert, C B; Temper, V; Maayan, C; Gill, S; Lucente, D E; Idelson, M; MacCormack, K; Monahan, M A; Mull, J; Leyne, M; Mendillo, M; Schiripo, T; Mishori, E; Breakefield, X; Axelrod, F B; Gusella, J F
1999 Apr;64(4):1110-1118, American journal of human genetics
Familial dysautonomia (FD) is an autosomal recessive disorder characterized by developmental arrest in the sensory and autonomic nervous systems and by Ashkenazi Jewish ancestry. We previously had mapped the defective gene (DYS) to an 11-cM segment of chromosome 9q31-33, flanked by D9S53 and D9S105. By using 11 new polymorphic loci, we now have narrowed the location of DYS to <0.5 cM between the markers 43B1GAGT and 157A3. Two markers in this interval, 164D1 and D9S1677, show no recombination with the disease. Haplotype analysis confirmed this candidate region and revealed a major haplotype shared by 435 of 441 FD chromosomes, indicating a striking founder effect. Three other haplotypes, found on the remaining 6 FD chromosomes, might represent independent mutations. The frequency of the major FD haplotype in the Ashkenazim (5 in 324 control chromosomes) was consistent with the estimated DYS carrier frequency of 1 in 32, and none of the four haplotypes associated with FD was observed on 492 non-FD chromosomes from obligatory carriers. It is now possible to provide accurate genetic testing both for families with FD and for carriers, on the basis of close flanking markers and the capacity to identify >98% of FD chromosomes by their haplotype
— id: 122575, year: 1999, vol: 64, page: 1110, stat: Journal Article,

Cloning, genomic organization and expression of a putative human transmembrane protein related to the Caenorhabditis elegans M01F1.4 gene
Chadwick, B P; Gill, S; Leyne, M; Mull, J; Liebert, C B; Robbins, C M; Pinkett, H W; Makalowska, I; Maayan, C; Blumenfeld, A; Axelrod, F B; Brownstein, M; Slaugenhaupt, S A
1999 Nov 15;240(1):67-73, Gene
A novel human transcript CG-2 (C9ORF5), was isolated from the familial dysautonomia candidate region on 9q31 using a combination of cDNA selection and exon trapping. CG-2 was detected as a relatively abundant 8kb transcript in all adult and fetal tissues with the exception of adult thymus. Genomic analysis of CG-2 identified 18 exons that span more than 110kb. The gene encodes a 911-amino-acid protein with a predicted molecular weight of 101kDa and a hypothetical pI of 9.03. Sequence analysis of CG-2 indicates that it is likely to encode a transmembrane protein. Here, we assess CG-2 as a candidate for familial dysautonomia
— id: 122572, year: 1999, vol: 240, page: 67, stat: Journal Article,

Cloning, mapping, and expression of two novel actin genes, actin-like-7A (ACTL7A) and actin-like-7B (ACTL7B), from the familial dysautonomia candidate region on 9q31
Chadwick, B P; Mull, J; Helbling, L A; Gill, S; Leyne, M; Robbins, C M; Pinkett, H W; Makalowska, I; Maayan, C; Blumenfeld, A; Axelrod, F B; Brownstein, M; Gusella, J F; Slaugenhaupt, S A
1999 Jun 15;58(3):302-309, Genomics
Two novel human actin-like genes, ACTL7A and ACTL7B, were identified by cDNA selection and direct genomic sequencing from the familial dysautonomia candidate region on 9q31. ACTL7A encodes a 435-amino-acid protein (predicted molecular mass 48.6 kDa) and ACTL7B encodes a 415-amino-acid protein (predicted molecular mass 45. 2 kDa) that show greater than 65% amino acid identity to each other. Genomic analysis revealed ACTL7A and ACTL7B to be intronless genes contained on a common 8-kb HindIII fragment in a 'head-to-head' orientation. The murine homologues were cloned and mapped by linkage analysis to mouse chromosome 4 in a region of gene order conserved with human chromosome 9q31. No recombinants were observed between the two genes, indicating a close physical proximity in mouse. ACTL7A is expressed in a wide variety of adult tissues, while the ACTL7B message was detected only in the testis and, to a lesser extent, in the prostate. No coding sequence mutations, genomic rearrangements, or differences in expression were detected for either gene in familial dysautonomia patients
— id: 122573, year: 1999, vol: 58, page: 302, stat: Journal Article,

Electrocardiographic repolarization abnormalities in familial dysautonomia: an indicator of cardiac autonomic dysfunction
Glickstein, J S; Axelrod, F B; Friedman, D
1999 Apr;9(2):109-112, Clinical autonomic research
OBJECTIVE: Electrocardiographic repolarization intervals were evaluated to determine the extent of cardiac autonomic dysfunction in patients with familial dysautonomia (FD) and to determine if any of these intervals could serve as a possible predictor of clinical symptoms. METHODS: Thirty-seven electrocardiograms of patients with FD were retrospectively evaluated. QT, JT, rate-corrected QT and JT intervals were calculated as well as QT and QTC dispersion. Results were compared to normative data and electrocardiograms of 20 age-matched control subjects. OBSERVATIONS: In the FD group, prolongation of QTC (>450 msec) was noted in 5/37 (13.5%) patients, as compared to 0/20 normal controls (p = NS), and prolongation of JTc (>340 msec) in 16/37 (43.3%) patients, as compared to 0/20 normal controls (p < 0.001). QT and QTC dispersion were abnormal in 3/37 (8.1%) and 5/37 (13.5%), respectively. In the 16 FD patients with prolonged JTc, six had a positive history of syncope, whereas none of the 21 with normal JTc had syncope or symptoms suggesting arrhythmia (p < 0.003). The positive predictive value of having syncope or symptoms suggestive of arrhythmia with an abnormal JTc is 37.5% (95% CI [15%, 65%]). The negative predictive value is 100% (95% CI [87%, 100%]). CONCLUSION: In the FD population, the electrocardiographic measure of repolarization that was most frequently abnormal was the JTc interval . Prolongation of the JTc interval was significantly more frequent than prolongation of the QTC interval (p < 0.001) QT and QTC dispersions were less significantly affected in the FD population, indicating uniform ventricular recovery time. These results suggest that a prolonged JTc interval may be a more sensitive indicator of abnormal ventricular repolarization and cardiac autonomic dysfunction. Due to the known sympathetic denervation inherent in patients with FD, they are at risk for unopposed parasympathetic predominance. FD patients, therefore, are more likely to have brady arrhythmias and asystole rather than polymorphic ventricular tachycardia. The increased incidence of syncope in patients with prolonged JTc suggests that this measure may serve as a helpful marker to predict which FD patients are at increased risk of serious clinical sequelae including bradyarrhythmias with asystole or sudden death
— id: 122574, year: 1999, vol: 9, page: 109, stat: Journal Article,

Sympathetic skin response differentiates hereditary sensory autonomic neuropathies III and IV
Hilz MJ; Stemper B; Axelrod FB
1999 May 12;52(8):1652-1657, Neurology
OBJECTIVE: To evaluate whether sympathetic skin response (SSR) differs in patients with hereditary sensory autonomic neuropathy (HSAN) types III and IV. BACKGROUND: HSAN types III and IV are rare autosomal recessive disorders that cause many similar autonomic, sensory, and motor dysfunctions, but different sweating characteristics. HSAN III patients have preserved and at times, excessive sweating, whereas anhidrosis is characteristic of HSAN IV. SSR reflects the integrity of sympathetic sudomotor fibers and the activation of sweat glands through the change in skin resistance in response to an arousal stimulus. Therefore, SSR is a test method that might facilitate differential diagnosis of HSAN III and IV. METHODS: In 17 HSAN III patients (eight women, nine men; mean age, 20.65+/-5.45 years) and seven HSAN IV patients (five girls, two boys; mean age, 10.0+/-5.45 years) SSR was recorded from the palms and soles after repeated electrical, acoustic, and inspiratory gasp stimulations. In addition, all subjects underwent a neurologic examination; studies of median, peroneal motor, and sural nerve conduction velocities; and determination of vibratory and thermal perception thresholds. RESULTS: Although clinical differences were appreciated between the two types of HSANs, both HSANs had evidence of small-fiber involvement. Both HSANs had abnormal temperature and pain perception. In contrast, SSR was preserved in all HSAN III and absent in all HSAN IV patients. CONCLUSION: SSR provides another parameter to improve differentiation of HSAN III from HSAN IV, and also gives us additional information regarding sympathetic sudomotor fiber function in these developmental diseases
— id: 6114, year: 1999, vol: 52, page: 1652, stat: Journal Article,

Mendelian diseases among Roman Jews: implications for the origins of disease alleles
Oddoux C; Guillen-Navarro E; Ditivoli C; Dicave E; Cilio MR; Clayton CM; Nelson H; Sarafoglou K; McCain N; Peretz H; Seligsohn U; Luzzatto L; Nafa K; Nardi M; Karpatkin M; Aksentijevich I; Kastner D; Axelrod F; Ostrer H
1999 Dec;84(12):4405-4409, Journal of clinical endocrinology & metabolism
The Roman Jewish community has been historically continuous in Rome since pre-Christian times and may have been progenitor to the Ashkenazi Jewish community. Despite a history of endogamy over the past 2000 yr, the historical record suggests that there was admixture with Ashkenazi and Sephardic Jews during the Middle Ages. To determine whether Roman and Ashkenazi Jews shared common signature mutations, we tested a group of 107 Roman Jews, representing 176 haploid sets of chromosomes. No mutations were found for Bloom syndrome, BRCA1, BRCA2, Canavan disease, Fanconi anemia complementation group C, or Tay-Sachs disease. Two unrelated individuals were positive for the 3849 + 10C->T cystic fibrosis mutation; one carried the N370S Gaucher disease mutation, and one carried the connexin 26 167delT mutation. Each of these was shown to be associated with the same haplotype of tightly linked microsatellite markers as that found among Ashkenazi Jews. In addition, 14 individuals had mutations in the familial Mediterranean fever gene and three unrelated individuals carried the factor XI type III mutation previously observed exclusively among Ashkenazi Jews. These findings suggest that the Gaucher, connexin 26, and familial Mediterranean fever mutations are over 2000 yr old, that the cystic fibrosis 3849 + 10kb C->T and factor XI type III mutations had a common origin in Ashkenazi and Roman Jews, and that other mutations prevalent among Ashkenazi Jews are of more recent origin
— id: 8259, year: 1999, vol: 84, page: 4405, stat: Journal Article,

Genetic heterogeneity in hereditary and autonomic sensory neuropathy type 4 (HSAN4)
Oddoux, C; Wang, J; Clayton, CM; Hilz, M; Cilio, R; Bertini, E; Mayaan, C; Blumenfeld, A; Axelrod, F; Ostrer, H
1999 OCT ;65(4):A482-A482, American journal of human genetics
— id: 53834, year: 1999, vol: 65, page: A482, stat: Journal Article,

Familial dysautonomia: a 47-year perspective. How technology confirms clinical acumen
Axelrod FB
1998 Mar;132(3 Pt 2):S2-S5, Journal of pediatrics
A historical perspective of familial dysautonomia is presented, highlighting the early contributions of Dr. Joseph Dancis. As further investigations proceeded, his original observations have withstood the test of time and may contribute to determining the molecular abnormality in this rare genetic disorder. Dr. Dancis's work in this area serves as a model of how observations based on clinical acumen and critical thinking can be verified by future technological advances
— id: 7493, year: 1998, vol: 132, page: S2, stat: Journal Article,

Genotype and phenotype in familial dysautonomia
Axelrod FB; Goldstein DS; Holmes C; Kopin IJ
1998 ;42:925-928, Advances in pharmacology (New York)
— id: 7494, year: 1998, vol: 42, page: 925, stat: Journal Article,

Electrocardiographic repolarization abnormalities in familial dysautonomia: An indicator of autonomic dysfunction
Glickstein, JS; Axelrod, F; Friedman, D
1998 SEP ;102(3):687-687, Pediatrics
— id: 53762, year: 1998, vol: 102, page: 687, stat: Journal Article,

Normative values of vibratory perception in 530 children, juveniles and adults aged 3-79 years
Hilz MJ; Axelrod FB; Hermann K; Haertl U; Duetsch M; Neundorfer B
1998 Aug 14;159(2):219-225, Journal of the neurological sciences
Impaired vibratory perception is an early and frequent finding in various neuropathies. Quantitative vibratory threshold assessment refines the diagnosis of neuropathies but is based on psychophysical techniques requiring patient cooperation. Large, age and sex matched normative data bases are needed to better identify abnormal vibratory perception. In this study vibratory perception was tested at the second metacarpal bone and above the first metatarsal bone of 530 children, juveniles and adults aged 3.3-79.2 years. Thresholds assessed with a 128 Hz graded Rydel-Seiffer tuning fork, TF, were compared to three Vibrameter values, the vibration perception thresholds, VPT, determined with increasing vibration stimuli, the vibration disappearance threshold, VDT, determined with decreasing supraliminal stimuli, and the vibration threshold VT which equals the mean of VPT and VDT. The influence of gender, age, body height, weight and skin temperature at the tested site on thresholds was studied. Retest reliability was tested in 73 children aged 3.3-6.9 years and in 20 volunteers aged 5.2-66.1 years who were also tested for the influence of pretest skin warming on thresholds and for differences between results of the left and right body side. TF, VPT, VDT, VT were closely correlated with each other (Spearman: -0.67<Rs<-0.47; P<0.01). The skin temperature, body side, weight and height did not influence thresholds. In adults, thresholds increased with age and were higher in men above the age of 50 than in women of the same age. Thresholds at the feet were higher than at the hands (Wilcoxon: P<0.001). Retest reliability was high and did not depend on the retest interval. The study provides important normative data for the widespread use of quantitative vibration testing
— id: 7600, year: 1998, vol: 159, page: 219, 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,

Assessing microcirculation in familial dysautonomia by laser Doppler flowmeter
Weiser M; Hilz MJ; Bronfin L; Axelrod FB
1998 Feb;8(1):13-23, Clinical autonomic research
Microcirculatory vasomotor responses to an alpha-adrenergic agonist and an antagonist were assessed in 11 familial dysautonomia and nine control subjects by laser Doppler flowmetry. Using two iontophoresis machines, blood flow in the midclavicular areas was continuously monitored by two channel laser Doppler flowmeter. Simultaneously, the alpha-antagonist (0.5 mM phentolamine hydrochloride) and a control solution (0.9% saline) were iontophoresed at 200 microA for 15 min. The alpha-agonist (0.5 mM norepinephrine bitartrate) was then iontophoresed (20 microA) to both pretreated areas for progressively longer pulses separated by 3-min observation intervals (15, 30, 60, 90, 120 s). The familial dysautonomia subject group had higher mean baseline perfusion with widely fluctuating baselines, especially on the phentolamine pretreated side (P = 0.03). Saline iontophoresis significantly increased perfusion in the control group, but not in the familial dysautonomia group (ANOVA: P = 0.02 and 0.15, respectively). There was > 100% increase in flow by the end of the saline observation period in seven of nine controls, but in only three of 11 familial dysautonomia subjects. Phentolamine iontophoresis differentiated familial dysautonomia subjects into responders and nonresponders by 7-8 min when all nine control subjects, but only five of 11 familial dysautonomia subjects, had > 200% increase in blood flow. Irrespective of pretreatment type, norepinephrine decreased blood flow in both familial dysautonomia and control groups (ANOVA: P < 0.0001), but the final mean change after saline was greater in the control group, P = 0.02. The final mean changes of flow after phentolamine pretreatment were not different between the two groups and were comparable to the familial dysautonomia group's smaller response after saline pretreatment. Higher baseline perfusion suggests dilation may be intrinsic to familial dysautonomia vasculature. Two populations of familial dysautonomia subjects are noted; those who like controls increase blood flow with iontophoresis of the alpha-antagonist and those who are refractory. In addition, in familial dysautonomia subjects, the microcirculatory constrictive response to alpha-agonist iontophoresis is less than that observed for controls. These data suggest that some familial dysautonomia subjects may have decreased or dysfunctional adrenoceptors as well as decreased innervation
— id: 7846, year: 1998, vol: 8, page: 13, stat: Journal Article,

Electrocardiographic measures and heart rate variability in patients with familial dysautonomia
Axelrod FB; Putman D; Berlin D; Rutkowski M
1997 Mar-Apr;88(2):133-140, Cardiology
Cardiovascular abnormalities are prominent in the genetic disorder, familial dysautonomia (FD). To determine if autonomic dysfunction involves cardiac, as well as peripheral vascular integrity, noninvasive tests were performed in 10 FD patients and 8 healthy control subjects while supine and at 90 degrees tilt. Simultaneous blood pressure (BP) and heart rate (HR) and QTc were obtained, while performing signal-averaged electrocardiography (SAECG) and heart rate variability (HRV). FD subjects were tested on 2 separate days, before and 1 h after oral fludrocortisone or midodrine; controls were tested once without medication. With tilt, all FD subjects decreased mean BP > or = 24 mm Hg by 5 min. On SAECG, 70% of supine FD subjects had a prolonged tQRS; only 2 FD subjects shortened tQRS with tilt. The QTc interval was prolonged (> 440 ms) in 2 supine FD subjects; with tilt, the QTc prolonged in a third. Frequency domain analysis of HRV revealed that mid (MF) and high frequency band areas were significantly decreased when supine, but not when upright. On time domain analysis, the pNN50 was significantly decreased in FD subjects (8.9 +/- 1.7 vs. 17.7 +/- 3.6%, p < 0.01). Fludrocortisone lowered supine BP and HR and increased supine MF area. Midodrine raised supine and erect BP, lowered erect HR, and shortened erect QTc. Although all FD subjects have abnormal orthostatic BP and HR responses, cardiac tone, as assessed by electrocardiographic and HRV responses, varies. Prolongation of the tQRS appears to be a sensitive but not specific indicator of autonomic dysfunction. QTc prolongation may indicate more extensive sympathetic dysfunction. HRV data suggest some FD patients have abnormalities in parasympathetic, as well as sympathetic, cardiac tone
— id: 7106, year: 1997, vol: 88, page: 133, 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,

Genetic evidence for a common origin among Roman Jews and Ashkenazi Jews
Oddoux, C; Guillen-Navarro, E; Clayton, CM; Nelson, H; Peretz, H; Seligsohn, U; Luzzatto, L; Nardi, M; Karpatkin, M; DiTivoli, C; DiCave, E; Axelrod, F; Ostrer, H
1997 OCT ;61(4):A207-A207, American journal of human genetics
— id: 53606, year: 1997, vol: 61, page: A207, stat: Journal Article,

Pattern of plasma levels of catecholamines in familial dysautonomia
Axelrod FB; Goldstein DS; Holmes C; Berlin D; Kopin IJ
1996 Aug;6(4):205-209, Clinical autonomic research
This report extends previous investigations of endogenous catecholamine levels in patients with orthostatic hypotension due to familial dysautonomia (FD), to define better the neurochemical phenotype and elucidate possible pathophysiological mechanisms. Ten FD patients (age 26.1 +/- 2.6 (SEM) years) and eight control subjects (age 29.5 +/- 3.7 years) were studied. Heart rate, blood pressure and venous blood samples were obtained while supine and after 5 min in the upright position. Plasma levels of dihydroxyphenylalanine (DOPA), noradrenaline (NA), adrenaline (A), dopamine (DA), dihydroxyphenylglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC) were measured. When supine, the FD group had greater NA and DOPA levels, and lower DHPG levels. Plasma NA did not increase with erect posture in FD patients. Individual FD mean blood pressures were correlated positively with plasma NA levels when supine and with plasma DA and DOPAC when upright. In FD, DOPA:DHPG ratios were above the range found in normal subjects or that reported in patients with acquired forms of dysautonomia regardless of posture, whereas DOPAC:DHPG ratios remained normal. Thus FD patients have a characteristic neurochemical pattern which probably reflects either decreased vesicular storage of catecholamines or limited oxidative deamination despite normal or increased tyrosine hydroxylation
— id: 12558, year: 1996, vol: 6, page: 205, stat: Journal Article,

Allgrove syndrome: documenting cholinergic dysfunction by autonomic tests
Chu ML; Berlin D; Axelrod FB
1996 Jul;129(1):156-159, Journal of pediatrics
We describe two Hispanic adolescents with Allgrove syndrome (alacrima, achalasia, and sensorimotor polyneuropathy) in whom we documented cholinergic dysfunction by cardiovascular autonomic tests. Both patients had orthostatic hypotension and decreased heart rate variability
— id: 6987, year: 1996, vol: 129, page: 156, stat: Journal Article,

Quantitative thermal perception testing in preschool children
Hilz MJ; Glorius SE; Schweibold G; Neuner I; Stemper B; Axelrod FB
1996 Mar;19(3):381-383, Muscle & nerve
— id: 7002, year: 1996, vol: 19, page: 381, 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,

Preliminary observations on the use of midodrine in treating orthostatic hypotension in familial dysautonomia
Axelrod FB; Krey L; Glickstein JS; Allison JW; Friedman D
1995 Oct 5;55(1-2):29-35, Journal of the autonomic nervous system
Midodrine, a peripheral alpha-adrenergic agonist, was evaluated in 7 female and 2 male patients with familial dysautonomia (FD), a disorder characterized by decreased sympathetic innervation. Prior to and after three months of midodrine treatment, each patient's response to postural change was assessed by arteriosonde readings of blood pressure and heart rate, corrected QT-interval measurements, Doppler evaluation of renal blood flow and circulating atrial natriuretic peptide (ANP) levels. The initial midodrine dose (2.5 mg three times daily) was raised until subjective symptoms improved. Doses were reduced if patients felt jittery or developed erect hypertension (systolic > 180 mmHg or diastolic > 110 mmHg). Midodrine, at an average dose of 0.25 mg/kg per day, improved subjective symptoms in all patients. With treatment, magnitude of blood pressure responses was variable. Although mean erect blood pressure did not increase significantly for the aggregate, it did increase in six of nine patients. In addition, the QTc interval normalized and erect renal perfusion improved. Changes in supine mean blood pressure and supine circulating ANP correlated directly. We judge midodrine to be useful in management of orthostatic hypotension in patients with familial dysautonomia
— id: 6803, year: 1995, vol: 55, page: 29, stat: Journal Article,

Blood center perspective: defining the ideal platelet concentrate
Axelrod, F B; Ooley, P W
1995 ;10(3):128-130, Journal of clinical apheresis
During the past two decades, an increased demand for platelets has challenged blood collection centers to produce a safe and readily available supply. Defining the ideal platelet for transfusion is a process that cannot be decided by a single entity. Collection centers are only one member of a partnership which involves the donor, transfusion service, hospital administration, clinicians, and patients. Regulatory definitions exist to help guide collection centers to the minimum acceptable criteria for the production of platelets, but in reality, the standard by which clinicians judge the efficacy of the product is most important
— id: 122579, year: 1995, vol: 10, page: 128, stat: Journal Article,

[Localization of the familial dysautonomia gene to chromosome 9q31-33 and the development of a genetic test for the disease]
Blumenfeld, A; Axelrod, F B; Tamper, V; Maayan, C
1995 Jan 15;128(2):97-100, Harefuah: journal of the Israeli Medical Association
— id: 122578, year: 1995, vol: 128, page: 97, stat: Journal Article,

Prenatal diagnosis of familial dysautonomia by analysis of linked CA-repeat polymorphisms on chromosome 9q31-q33
Eng, C M; Slaugenhaupt, S A; Blumenfeld, A; Axelrod, F B; Gusella, J F; Desnick, R J
1995 Nov 20;59(3):349-355, American journal of medical genetics
Familial Dysautonomia (FD) is an autosomal recessive sensory neuropathy that affects about 1 in 3,700 individuals of Ashkenazi Jewish ancestry. The underlying biochemical and genetic defects are unknown, thereby precluding prenatal diagnosis in at-risk families. Recently, the FD gene (DYS) was mapped with strong linkage disequilibrium to polymorphic markers in the chromosome 9 region q31-q33. In this report, the use of these markers for the prenatal diagnosis of FD by linkage analysis in families with a previously affected child was evaluated. Genomic DNA from appropriate family members was analyzed to construct haplotypes using informative CA repeat polymorphisms closely linked to and flanking the FD locus. The calculation of risk for the prenatal diagnoses was performed by linkage analysis. All seven FD families were informative for the closely linked polymorphic markers and fetal diagnoses were made in eight pregnancies. Six fetal diagnoses were predicted with > 98% accuracy, while two with recombinations were predicted with at least 88% and 92% accuracy. Use of these closely linked markers permitted the reliable prenatal diagnosis of FD in families with a previously affected child
— id: 122576, year: 1995, vol: 59, page: 349, 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,

Prenatal diagnostic testing for familial dysautonomia using linked genetic markers
Oddoux C; Reich E; Axelrod F; Blumenfeld A; Maayan C; Slaugenhaupt S; Gusella J; Ostrer H
1995 Sep;15(9):817-826, Prenatal diagnosis
Familial dysautonomia (FD), a recessively inherited disease, has been mapped to chromosome 9q31. Highly polymorphic dinucleotide repeat markers flanking the genetic locus and at the same genetic location have been identified. We describe the prenatal diagnosis of FD using linkage and linkage disequilibrium analyses with these markers. Twelve families were analysed for informativeness and of these, seven went on to have prenatal testing (a total of eight fetuses tested). All of these fetuses were predicted to be heterozygous unaffected (FD carriers). Seven fetuses have come to term and are normal. In the absence of a recombinant proband, a panel of three proximal and three distal markers is sufficient to provide informative flanking markers and an 87-96 per cent likelihood of a highly predictive test. In an additional family at 1:4 risk for FD, no DNA was available from the propositus. This family was analysed using linkage disequilibrium to the :18 allele of the tightly linked marker D9S58 in conjunction with linkage analysis using data from two unaffected children. Prenatal diagnosis in this family indicated an affected fetus
— id: 6853, year: 1995, vol: 15, page: 817, stat: Journal Article,

The human gene for neurotrophic tyrosine kinase receptor type 2 (NTRK2) is located on chromosome 9 but is not the familial dysautonomia gene
Slaugenhaupt, S A; Blumenfeld, A; Liebert, C B; Mull, J; Lucente, D E; Monahan, M; Breakefield, X O; Maayan, C; Parada, L; Axelrod, F B
1995 Feb 10;25(3):730-732, Genomics
The neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene is a member of the trk family of tyrosine protein kinases, which encode receptors for the nerve growth factor-related proteins known as neurotrophins. The neurotrophins and their receptors have long been considered candidate genes for familial dysautonomia (FD), a hereditary sensory neuropathy resulting from the congenital loss of both sensory and autonomic neurons. The DYS gene has recently been mapped to human chromosome 9q31-q33, and therefore we set out to determine the chromosomal localization of the candidate gene NTRK2. A mouse trkB probe was hybridized to both somatic cell hybrids containing human chromosome 9 and a human chromosome 9 flow-sorted cosmid library. The human homologue of trkB, NTRK2, was assigned to chromosome 9. To localize the NTRK2 gene further, a dinucleotide repeat polymorphism was identified within a cosmid that contains NTRK2 exon sequences. This marker was genotyped in the CEPH reference pedigrees and places the NTRK2 gene near D9S1 on the proximal long arm of human chromosome 9. The NTRK2 gene is located approximately 22 cm proximal to DYS and shows several recombinants in disease families. Therefore, the NTRK2 gene can now be excluded as a candidate gene for familial dysautonomia
— id: 122577, year: 1995, vol: 25, page: 730, stat: Journal Article,

EVALUATION OF CANDIDATE GENES FOR FAMILIAL DYSAUTONOMIA
SLAUGENHAUPT, SA; LIEBERT, CB; MULL, J; MACCORMACK, K; LEBEL, A; OLEARY, K; LUCENTE, D; MCCORMICK, MK; BUCKLER, AJ; MAAYAN, C; AXELROD, F; BLUMENFELD, A; GUSELLA, JF
1995 OCT ;57(4):1569-1569, American journal of human genetics
— id: 86715, year: 1995, vol: 57, page: 1569, stat: Journal Article,

Atrial natriuretic peptide response to postural change and medication in familial dysautonomia
Axelrod FB; Krey L; Glickstein JS; Friedman D; Weider J; Metakis LJ; Porges VM; Mineo M; Notterman D
1994 Dec;4(6):311-318, Clinical autonomic research
Circulating atrial natriuretic peptide (ANP) was assayed before and after postural change and exercise in 54 patients with familial dysautonomia (FD) and 20 controls. ANP levels were compared with blood pressure, heart rate, plasma catecholamines and parameters of renal function. Compared with controls supine FD subjects had elevated blood pressures, heart rates and ANP levels (39 +/- 4 pg/ml vs. 23 +/- 3 pg/ml, p < 0.01). With the erect posture and exercise in FD subjects, blood pressure fell below control values, with ANP lowered. In FD subjects, blood pressure was correlated with ANP levels when supine and when erect and with heart rate post exercise. In controls, ANP levels did not correlate with other parameters. In FD patients on metoclopramide, supine and erect blood pressure and ANP levels were higher. FD subjects treated with fludrocortisone, had elevated supine and erect noradrenaline (p < 0.05 and p = 0.06); and those on diazepam had lower erect and post exercise noradrenaline (p < 0.05), but ANP levels were similar. In conclusion, sympathetic denervation may increase FD patients' responsiveness to other regulators of cardiovascular integrity, such as ANP. In addition, circulating ANP and catecholamines in FD subjects appear to be influenced by commonly used medications, such as metoclopramide
— id: 6572, year: 1994, vol: 4, page: 311, stat: Journal Article,

The effects of postural change and exercise on renal haemodynamics in familial dysautonomia
Axelrod FB; Glickstein JS; Weider J; Gluck MC; Friedman D
1993 Jun;3(3):195-200, Clinical autonomic research
Cardiovascular instability is a prominent manifestation of familial dysautonomia [FD] while renal insufficiency occurs in a large number of adult FD patients. To determine if there was a causative relationship, renal artery blood flow velocity using Doppler technology, was recorded and the ratio of the peak systolic velocity (point A) to the end diastolic velocity (point B) was calculated. The A/B ratio was assessed in response to change of position and exercise, and was correlated with renal function, heart rate and systemic blood pressure. Studies were performed in 54 FD patients with a mean age of 24 years +/- 9.8 years, and 20 controls, with a mean age of 24.7 +/- 7.6 years. In the supine position, the mean A/B ratios were not significantly different, but FD subjects had a significantly higher mean blood pressure and heart rate than controls. When erect and post exercise, the mean A/B ratios in FD subjects were significantly higher than controls, p = 0.0004 and p = 0.0001, respectively. In contrast to controls, when FD subjects were standing erect and post exercise, mean blood pressure decreased significantly without a significant change in heart rate. When FD subjects were divided into two groups based on their creatinine clearance value, the group with the lower creatinine clearances had a significantly greater fall in diastolic pressure when they moved from the supine to the erect position. Our results indicate that noninvasive Doppler techniques are helpful in detecting changes in renal blood flow in subjects with familial dysautonomia.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 6311, year: 1993, vol: 3, page: 195, stat: Journal Article,

The growing practice of "splitting" double-dose apheresis platelet products
Axelrod, F B
1993 Oct;14(4):364-368, Transfusion science
— id: 122580, year: 1993, vol: 14, page: 364, stat: Journal Article,

Exclusion of familial dysautonomia from more than 60% of the genome
Blumenfeld, A; Axelrod, F B; Trofatter, J A; Maayan, C; Lucente, D E; Slaugenhaupt, S A; Liebert, C B; Ozelius, L J; Haines, J L; Breakefield, X O
1993 Jan;30(1):47-52, Journal of medical genetics
Familial dysautonomia (FD) is a recessive neurological disorder that affects the development of the sensory and autonomic nervous system. The gene defect appears to be limited to the Ashkenazi Jewish population, where the carrier frequency is 1 in 30. One hundred and ninety-one marker loci representing all autosomes were tested for linkage with the FD genetic defect in 23 families. A combination of pairwise and multipoint analyses excluded the FD gene from at least 60% of the autosomal genome. The program EXCLUDE predicted regions of chromosomes 2, 4, 5q, 9, or 10 as the most promising locations for future analyses
— id: 122582, year: 1993, vol: 30, page: 47, stat: Journal Article,

Localization of the gene for familial dysautonomia on chromosome 9 and definition of DNA markers for genetic diagnosis
Blumenfeld, A; Slaugenhaupt, S A; Axelrod, F B; Lucente, D E; Maayan, C; Liebert, C B; Ozelius, L J; Trofatter, J A; Haines, J L; Breakefield, X O
1993 Jun;4(2):160-164, Nature genetics
Familial dysautonomia (DYS), the Riley-Day syndrome, is an autosomal recessive disorder characterized by developmental loss of neurons from the sensory and autonomic nervous system. It is limited to the Ashkenazi Jewish population, where the carrier frequency is 1 in 30. We have mapped the DYS gene to chromosome 9q31-q33 by linkage with ten DNA markers in 26 families. The maximum lod score of 21.1 with no recombinants was achieved with D9S58. This marker also showed strong linkage disequilibrium with DYS, with one allele present on 73% of affected chromosomes compared to 5.4% of controls (chi 2 = 3142, 15 d.f. p < 0.0001). D9S53 and D9S105 represent the closest flanking markers for the disease gene. This localization will permit prenatal diagnosis of DYS in affected families and aid the isolation of the disease gene
— id: 122581, year: 1993, vol: 4, page: 160, stat: Journal Article,

THE GENE FOR FAMILIAL DYSAUTONOMIA IS LINKED TO CHROMOSOME-9 AND SHOWS STRONG LINKAGE DISEQUILIBRIUM WITH D9S58
Blumenfeld, A; Slaugenhaupt, SA; Lucente, DE; Axelrod, FB; Liebert, CB; Maayan, C; Monahan, M; Trofatter, JA; Haines, JL; Breakefield, XO; Gusella, JF
1993 AUG ;64(2):108-108, Cytogenetics & cell genetics
— id: 130394, year: 1993, vol: 64, page: 108, stat: Journal Article,

Abnormalities of the corrected QT interval in familial dysautonomia: an indicator of autonomic dysfunction
Glickstein JS; Schwartzman D; Friedman D; Rutkowski M; Axelrod FB
1993 Jun;122(6):925-928, Journal of pediatrics
We report abnormalities in corrected QT intervals with changes in position and after exercise in patients with familial dysautonomia and confirm the previously reported finding of abnormal heart rate and blood pressure responses. Prolonged corrected QT intervals (> 440 msec) with lack of appropriate shortening with exercise is a noninvasive means of demonstrating an aberration in autonomic regulation of cardiac conduction
— id: 13143, year: 1993, vol: 122, page: 925, stat: Journal Article,

Don't forget the SOPCAB!
Axelrod, F B; Pepkowitz, S H; Goldfinger, D
1992 Feb;32(2):190-191, Transfusion
— id: 122584, year: 1992, vol: 32, page: 190, stat: Journal Article,

Respiratory system stability and abnormal carbon dioxide homeostasis
Maayan, C; Carley, D W; Axelrod, F B; Grimes, J; Shannon, D C
1992 Mar;72(3):1186-1193, Journal of applied physiology (Bethesda)
We have tested the hypothesis that interactions among eight parameters of the respiratory and cardiovascular systems that determine the loop gain (LG) of the respiratory CO2 feedback control system might account for the degree of stability or instability of breathing patterns in healthy sleeping volunteers as well as in familial dysautonomia (FD) and congenital central hypoventilation syndrome (CCHS) patients. The predictability of cycle duration was tested as well. We measured the values of CO2 sensitivity, CO2 delivery capacity in the circulation, circulation delay, mean lung volume for CO2, and mixed venous PCO2 in 8 FD patients, 2 CCHS patients, and 19 healthy controls. The values of these parameters were used in a mathematical model to compute the LG of the respiratory control system during sleep for each epoch of respiration analyzed. The strength of the ventilatory oscillations (R) was quantified using power density spectra of the ventilation time series. All subjects were studied at inspiratory O2 concentrations (FIO2) of 0.21 and 0.15; CCHS patients and controls were also studied at 0.12 FIO2 to examine the effect of steady-state hypoxia on respiratory system stability. In 2 FD patients, LG was elevated at both levels of FIO2 and periodic breathing was observed; the values of R were elevated. Elevated mixed venous PCO2 and reduced CO2 delivery capacity were chiefly responsible for the abnormally high LG observed. In three healthy volunteers, high LG and unstable patterns were associated with high chemosensitivity. The CCHS patients, however, remained stable even at 0.12 FIO2 because LG remained equivalent to zero due to a lack of chemosensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 122583, year: 1992, vol: 72, page: 1186, stat: Journal Article,

Transient third-degree atrioventricular block in a 4-year-old child with familial dysautonomia
Rutkowski M; Axelrod FB; Danilowicz D
1992 Jul;13(3):184-186, Pediatric cardiology
The case of a transient third degree atrioventricular block in a 4-year-old patient with familial dysautonomia is reported. A review of the literature follows with analysis of the significance of arrhythmias in the natural history of the patient with familial dysautonomia
— id: 13532, year: 1992, vol: 13, page: 184, stat: Journal Article,

Fundoplication and gastrostomy in familial dysautonomia
Axelrod FB; Gouge TH; Ginsburg HB; Bangaru BS; Hazzi C
1991 Mar;118(3):388-394, Journal of pediatrics
Fundoplication with gastrostomy has become a frequent treatment for patients with familial dysautonomia, so we evaluated the use of both procedures in 65 patients. Although patients differed widely in presenting signs and age, from 5 weeks to 40 years, gastroesophageal reflux was documented in 95% of patients by cineradiography or pH monitoring. Panendoscopy was a useful adjunct. Preoperative symptoms of gastroesophageal reflux included vomiting, respiratory infections, and exaggerated autonomic dysfunction. Severe oropharyngeal incoordination frequently coexisted and resulted in misdirected swallows with aspiration, dependence on gavage feedings, or poor weight gain and dehydration. Follow-up after surgical correction ranged from 3 months to 11 years; 55 patients (85%) were available for a 1-year postoperative assessment. We had no instances of surgical death. The long-term mortality rate was 14%, primarily related to severe preexisting respiratory disease. Beyond the first postoperative year, 30 patients had pneumonia attributed to continued aspiration, exacerbation of preexisting lung disease, or recurrence of gastroesophageal reflux. Of 11 patients who vomited postoperatively, six had recurrence of reflux. Recurrence of gastroesophageal reflux was documented in eight patients (12%), and we revised the fundoplication in three patients. The number of patients with cyclic crises was reduced from 18 to 7; retching replaced overt vomiting in all but two of these seven patients, neither of whom had recurrence of reflux. Because oropharyngeal incoordination was prominent, concomitant use of gastrostomy and an antireflux procedure was especially effective in the treatment of younger patients with familial dysautonomia, before the development of severe respiratory disease. Despite the development of severe morning nausea in 15 patients, the combination procedure resulted in significantly improved nutritional status, decreased vomiting, and decreased respiratory problems. Appropriate use of gastrostomy feedings also contributed to success of the operation. The generally good outcome of fundoplication with gastrostomy confirms the benefit of this procedure in familial dysautonomia
— id: 14114, year: 1991, vol: 118, page: 388, stat: Journal Article,

Establishment of a schedule of optimal preoperative collection of autologous blood
Axelrod, F B; Pepkowitz, S H; Goldfinger, D
1989 Oct;29(8):677-680, Transfusion
Autologous blood donation prior to elective surgery can protect patients from unnecessary exposure to allogeneic blood. However, the inappropriate use of autologous blood programs, which results in the collection of excessive quantities of blood or of the collection of any blood prior to low-risk surgical procedures, can be wasteful and potentially hazardous. All patients donating autologous blood at a large institution during a period of three months were studied in an effort to develop a schedule of optimal preoperative collection of autologous blood (SOPCAB), which is similar to a maximum surgical blood order schedule. Some 461 consecutive autologous donations from 264 patients were investigated. For certain surgical procedures, primarily the cardiac and orthopedic procedures, undercollection appeared to be the most common problem. For other procedures (laminectomies, nasal surgery), overcollection was more common. A model is presented for the careful scrutiny of autologous blood collection and use to allow for the creation of a SOPCAB for patients undergoing elective surgery
— id: 122585, year: 1989, vol: 29, page: 677, stat: Journal Article,

Anesthesia in familial dysautonomia
Axelrod FB; Donenfeld RF; Danziger F; Turndorf H
1988 Apr;68(4):631-635, Anesthesiology
— id: 11129, year: 1988, vol: 68, page: 631, stat: Journal Article,

THE AUTONOMIC NERVOUS SYSTEM AND ADRENAL FUNCTION CORTISOL RESPONSE TO ACTH IN FAMILIAL DYSAUTONOMIA FD
SKLAR C A; AXELROD F B
1988 ;3(1):33-36, Journal of pediatric endocrinology & metabolism
Studies in animals and limited data from the human suggest a role for the peripheral autonomic nervous system in the regulation of adrenocortical function. To elucidate further the relationship between adrenal function and the autonomic sympathetic nervous system, we have assessed the cortisol response to prolonged infusion (8 hrs) of ACTH in five patients with familial dysautonomia (FD). Baseline cortisol levels were similar in FD patients and controls. Following the ACTH infusion, the rise from basal to peak cortisol levels was significant for the patients (15.7 .+-. 2.7 vs 44.1 .+-. 4.6 ug/dl, p < .002) and the controls (12.5 .+-. 1.0 vs 42.5 .+-. 1.8 ug/dl, p < .001). The patients' mean cortisol concentrations at 2, 4, 6, and 8 hours during the infusion were not significantly different from those of the controls. The results of this study indicate that the sympathetic nervous system does not appear to play a significant role in the control of glucocorticoid synthesis or release in man
— id: 98831, year: 1988, vol: 3, page: 33, stat: Journal Article,

Bradycardia associated with hiatal hernia and gastroesophageal reflux relieved by surgery
Axelrod FB; Maayan C; Hazzi C; Bangaru BS; Shannon DC
1987 Feb;82(2):159-161, American journal of gastroenterology
A man known to have familial dysautonomia presented with a cardiac arrhythmia due to development of hiatal hernia and gastroesophageal reflux. Preoperative symptoms and assessment are described including use of power spectrum analysis of heart rate fluctuations which was consistent with enhanced parasympathetic stimulation. After surgical repair of hiatal hernia and fundoplication, bradycardia resolved, gastroesophageal reflux symptoms subsided, and the power spectrum analysis of heart rate confirmed decreased parasympathetic influence. Power spectrum analysis proved to be a useful adjunct in confirming preoperative autonomic imbalance and assessing the postoperative result. It is concluded that in individuals with disorders such as familial dysautonomia that are associated with autonomic dysfunction, cardiac arrhythmias may be a sign of esophageal pathology. Thus, cardiac evaluations should be accompanied by investigation of gastroesophageal structure and function and appropriate treatment may prevent a catastrophic arrhythmia
— id: 66511, year: 1987, vol: 82, page: 159, stat: Journal Article,

Disproportionate outdating of group A blood
Axelrod, F B; Grindon, A J; Vroon, D H
1987 May-Jun;27(3):219-221, Transfusion
The authors studied the factors responsible for the disproportionate outdating of group A blood compared with group O blood over a 6-month interval. Distribution, transfusion, and outdate data for 99,251 units of blood were collected from representative hospitals within the region served by the Atlanta Regional Red Cross Blood Center. Factors evaluated included: neonatal transfusion of type O blood to type A recipients; use of type O blood in emergencies or due to group-specific shortages; demographic donor and recipient differences; and blood importing practices. Of 43,757 group O units (44.1% of total) available for distribution, 2050 (4.7%) were outdated, compared with 3908 (10.7%) of 36,501 group A units (36.8% of total). One thousand two hundred and seventy-nine units of type O blood were transfused to recipients who were not type O, including 842 group A neonatal patients. A larger inner-city hospital, where 46.8 percent of recipients were group O and 29.2 percent were group A, accounted for 180 more group O and 509 fewer group A transfusions than would be expected if donor-recipient ABO distributions were the same. Three hundred and seventy-four more group A units were imported than were needed. ABO-mismatched transfusions due to shortage or emergency were insignificant. It was concluded that increased use of group O blood for neonatal transfusions, donor-recipient differences in blood group frequencies, and blood importing practices are the major factors that increase the rate of group A outdating
— id: 122587, year: 1987, vol: 27, page: 219, stat: Journal Article,

Optic nerve dysfunction in familial dysautonomia
Diamond GA; D'Amico RA; Axelrod FB
1987 Dec 15;104(6):645-648, American journal of ophthalmology
We examined 12 patients with familial dysautonomia who had clear corneas to determine if there was any optic nerve involvement. The patients ranged in age from 6 to 34 years. Visual acuity ranged from 20/20 to 20/100. Nineteen eyes of 12 patients (79%) had abnormal (mean +/- 3 S.D.) pattern reversal visual-evoked potentials as compared to 50 control eyes (P100 = 98.8 msec; S.D., +/- 4.5 msec). P100 latency appeared to worsen with age. Exodeviation was present in seven patients (58%) and correlated with visual acuity and P100 latency. Ophthalmoscopic examination showed some degree of optic nerve pallor in all eyes
— id: 24781, year: 1987, vol: 104, page: 645, stat: Journal Article,

Evaluation of autonomic dysfunction in familial dysautonomia by power spectral analysis
Maayan, C; Axelrod, F B; Akselrod, S; Carley, D W; Shannon, D C
1987 Nov;21(1):51-58, Journal of the autonomic nervous system
We examined the nature and extent of the autonomic control defect in patients with autonomic dysfunction using power spectral analysis of heart rate fluctuations. Heart rate variability and respiratory patterns were monitored and discrete blood pressure measurements were made during supine and standing positions in 10 ambulatory patients with familial dysautonomia and in controls. Postural hypotension without compensatory tachycardia was confirmed in the patients upon standing. The balance between sympathetic and parasympathetic activity was compared in both positions by quantifying the power of the low (0.04-0.095 Hz) and high (respiratory) frequency fluctuations in instantaneous heart rate. After changing from supine to standing position there was a small decrease in the low frequency power of heart rate fluctuations in the patients as opposed to a significant increase in controls. The mean power of fluctuations occurring at high frequency decreased only slightly in the patients compared to a marked decrease in the controls. We conclude that the fall in blood pressure, lack of appropriate heart rate modulation, and failure to increase low frequency heart rate power which occurred in the patients upon standing, are all due to lack of increased sympathetic output under the influence of gravity. The failure to decrease power in the respiratory frequency peak in the patients, suggests an abnormal retention of parasympathetic activity. This may be explained by parasympathetic compensation for the substantial sympathetic loss, or by a lack of appropriate inhibition of parasympathetic tone from baroreceptors or supraspinal structures
— id: 122586, year: 1987, vol: 21, page: 51, stat: Journal Article,

DNA polymorphisms for the nerve growth factor receptor gene exclude its role in familial dysautonomia
Breakefield XO; Ozelius L; Bothwell MA; Chao MV; Axelrod F; Kramer PL; Kidd KK; Lanahan AA; Johnson DE; Ross AH; et al
1986 Dec;3(6):483-494, Molecular biology & medicine
Alleles for the single human nerve growth factor receptor gene (NGFR) on chromosome 17q can be distinguished by two polymorphic restriction sites for XmnI and one for HincII. The combined information content for haplotypes is quite high, making the NGFR locus an excellent genetic marker. Two of these polymorphisms were used to follow the inheritance of NGFR alleles in families with two or more members affected with familial dysautonomia. This rare disease is inherited in an autosomal recessive mode in the Ashkenazic Jewish population. Affected individuals show a severe depletion of NGF-dependent nerve populations from birth. Linkage analysis excluded a role for NGFR in this disease with odds of greater than 10(6):1 against the dysautonomia gene being within 1 centiMorgan of the mutation. In a previous study the gene for the beta subunit of NGF (NGFB) was also excluded in this disease. A possible role for other genes involved in NGF action or those coding for other developmentally determining neuronal factors is indicated
— id: 14708, year: 1986, vol: 3, page: 483, stat: Journal Article,

Congenital sensory neuropathies. Diagnostic distinction from familial dysautonomia
Axelrod, F B; Pearson, J
1984 Oct;138(10):947-954, American journal of diseases of children
Among congenital sensory neuropathies there are several variants that share features of diminished pain sensitivity and/or autonomic dysfunction with familial dysautonomia but can be shown to be distinct from this entity by clinical and pathologic criteria. Recognition of the unique nature of each disease type is an essential prerequisite for genetic and causative studies. We reviewed the diagnostic tests that can be used in the clinical evaluation of sensory and autonomic function. Based on this process of evaluation, we studied 13 patients who were initially considered to have familial dysautonomia but who were later shown to have five distinct syndromes that were confirmed by neuropathologic studies
— id: 122588, year: 1984, vol: 138, page: 947, stat: Journal Article,

Structural gene for beta-nerve growth factor not defective in familial dysautonomia
Breakefield, X O; Orloff, G; Castiglione, C; Coussens, L; Axelrod, F B; Ullrich, A
1984 Jul;81(13):4213-4216, Proceedings of the National Academy of Sciences of the United States of America
The developmental loss of neurons in sympathetic, sensory, and some parasympathetic ganglia in familial dysautonomia suggests an inherited defect in the action of beta-nerve growth factor (beta-NGF). The role of this growth factor in dysautonomia has been difficult to resolve as there is no known source of authentic human beta-NGF. The availability of a cloned DNA probe for the human beta-NGF gene has allowed identification of some copies of the gene (alleles) in six affected families. Alleles differ in the length of restriction endonuclease fragments that hybridize to DNA probes for the gene. In two families, affected children did not inherit the same two alleles at the beta-NGF locus. Since this disease is transmitted in an autosomal recessive manner, affected children must share the same alleles at the locus causing the disease. This analysis excludes the beta-NGF gene region as the cause of this neurologic disease but does not eliminate other genes involved in beta-NGF action, such as those coding for processing enzymes, receptors, or other subunits of the NGF complex
— id: 122589, year: 1984, vol: 81, page: 4213, stat: Journal Article,

Congenital autonomic dysfunction with universal pain loss
Axelrod, F B; Cash, R; Pearson, J
1983 Jul;103(1):60-64, Journal of pediatrics
Three patients who appear to have a previously undescribed congenital neuropathy are described. None is of Ashkenazi Jewish extraction, but each seems to fulfill the clinical diagnostic criteria for familial dysautonomia. All lack overflow tears, fungiform papillae, and deep-tendon reflexes; intradermal administration of histamine did not produce an axon flare. Intraocular instillation of dilute mecholyl produced miosis in the one patient tested. In contrast to patients with familial dysautonomia, the three patients had universal loss of pain sensation, profound hypotonia, and unusual facies. Pathologic examination of the sural nerve in one patient was not consistent with the usual findings in familial dysautonomia. These patients are believed to have a previously undescribed congenital neuropathy
— id: 122591, year: 1983, vol: 103, page: 60, stat: Journal Article,

Congenital sensory neuropathy with skeletal dysplasia
Axelrod, F B; Pearson, J; Tepperberg, J; Ackerman, B D
1983 May;102(5):727-730, Journal of pediatrics
— id: 122592, year: 1983, vol: 102, page: 727, stat: Journal Article,

Physical therapy management of familial dysautonomia
Ganz, S B; Levine, D B; Axelrod, F B; Kahanovitz, N
1983 Jul;63(7):1121-1124, Physical therapy
This paper describes physical therapy programs to assist physical therapists in the rehabilitation of patients with familial dysautonomia. There have been no reports in the literature about a physical therapy program for patients with this disease. A retrospective analysis of the clinical manifestations in 80 patients in a dysautonomia clinic was performed. Scoliosis and kyphosis were found in 92 percent of the patients, 93 percent had ataxia, 74 percent had feeding difficulties, 69 percent had frequent pneumonias, and 63 percent exhibited delayed developmental milestones. Cardiovascular, gastrointestinal, pulmonary, musculoskeletal, and neurological symptoms and treatments are discussed
— id: 122590, year: 1983, vol: 63, page: 1121, stat: Journal Article,

Gastroesophageal fundoplication and gastrostomy in familial dysautonomia
Axelrod FB; Schneider KM; Ament ME; Kutin ND; Fonkalsrud EW
1982 Mar;195(3):253-258, Annals of surgery
Gastric and esophageal dysfunction are components of familial dysautonomia. The limited success of various medical management programs, has led to two types of surgical intervention. Experience with nine patients who had gastrostomy alone and 12 patients who had gastroesophageal fundoplication is reviewed. Both surgical procedures decreased frequency of vomiting and pneumonias and had positive effects on weight gain. Although 'dysautonomic crises' are not eliminated, sufficient modification in character occurs so that associated risks are lessened. It is suggested that if medical management cannot control recurrent pneumonia, postprandial vomiting, esophageal bleeding, and/or inadequate weight gain, then the patient should be evaluated for fundoplication and/or gastrostomy
— id: 22206, year: 1982, vol: 195, page: 253, stat: Journal Article,

Familial dysautonomia: a prospective study of survival
Axelrod, F B; Abularrage, J J
1982 Aug;101(2):234-236, Journal of pediatrics
— id: 122594, year: 1982, vol: 101, page: 234, stat: Journal Article,

Retroperitoneal actinomycosis: a rare manifestation of an uncommon disease
Axelrod, F B; Fonda, J N; Bradley, E L 3rd
1982 Sep;75(9):1156-1157, Southern medical journal
— id: 122593, year: 1982, vol: 75, page: 1156, stat: Journal Article,

Caring for a child with familial dysautonomia (a treatment manual)
Axelrod, Felicia B
New York NY : Dysautonomia Treatment & Evaluation Center, 1982,
— id: 2238, year: 1982, vol: , page: , stat: ,

Aseptic necrosis in familial dysautonomia
Mitnick JS; Axelrod FB; Genieser NB; Becker M
1982 Jan;142(1):89-91, Radiology
— id: 63017, year: 1982, vol: 142, page: 89, stat: Journal Article,

Progressive sensory loss in familial dysautonomia
Axelrod, F B; Iyer, K; Fish, I; Pearson, J; Sein, M E; Spielholz, N
1981 Apr;67(4):517-522, Pediatrics
Clinical variability in sensory impairment was demonstrated among 75 patients with familial dysautonomia. Older patients had a greater tendency toward increased dysfunction in pain sensation, joint position and Romberg's sign, and vibratory sense. Significant worsening with increased age was supported by retesting of 53 patients after a five-year interval. Sensory and motor axon loss were indicated by electrodiagnostic testing of peripheral nerves and abnormal cortical somatosensory evoked potentials. Familial dysautonomia is a hereditary disease with variable penetrance which involves both failure of intrauterine development of neurons and their postnatal maintenance
— id: 122595, year: 1981, vol: 67, page: 517, stat: Journal Article,

The pupil in familial dysautonomia
Korczyn, A D; Rubenstein, A E; Yahr, M D; Axelrod, F B
1981 May;31(5):628-629, Neurology
We performed infrared pupillography on 10 patients with familial dysautonomia. Pupillary constriction to light and accommodation was normal. There was no evidence for light-near dissociation, and tonic responses were not observed. Dilatation in darkness was normal. Ocular application of dilute pilocarpine produced miosis in all patients. Supersensitivity of the pupil to muscarinic agents in familial dysautonomia is unlikely to be explained by parasympathetic denervation. Possible explanations for this phenomenon include diminished lacrimation and corneal ulcerations
— id: 90871, year: 1981, vol: 31, page: 628, stat: Journal Article,

Personality development and familial dysautonomia
Clayson, D; Welton, W; Axelrod, F B
1980 Feb;65(2):269-274, Pediatrics
The study sought to establish baselines for personality and frequency of psychopathology in familial dysautonomia (FD). Fifty FD patients, aged 6 to 28 years, served as subjects. FD subjects in all age ranges manifest neurotic patterns, but show no greater incidence of more severe pathology than is found in the general population. the arrested psychologic development seen in FD is described, together with the phenomenon of periodic lapses in judgment. The organic impairment of cognitive functions is discussed. Recommendations for treatment are proposed
— id: 122596, year: 1980, vol: 65, page: 269, stat: Journal Article,

Renal disease in familial dysautonomia
Pearson, J; Gallo, G; Gluck, M; Axelrod, F
1980 Jan;17(1):102-112, Kidney international
A study of renal disease in familial dysautonomia identified excess glomerulosclerosis in 10 or 13 autopsied and biopsied patients. Sympathetic nerve terminals could not be found on renal vessels in biopsied tissue; they were invariably demonstrable in controls. Altered renovascular responsivity to systemic hypotension in familial dysautonomia may lead to ischemia and subsequent sclerosis of glomeruli. Review of 79 living outpatients showed that clinically overt renal disease was rare in familial dysautonomia. Nevertheless, frequent observations of elevations of serum creatinine concentrations (32% of patients) and blood urea concentrations (76% of patients) indicated a high prevalence of abnormality. An association was found between hypotension and renal dysfunction
— id: 76976, year: 1980, vol: 17, page: 102, stat: Journal Article,

THE PUPIL IN FAMILIAL DYSAUTONOMIA
RUBENSTEIN, AE; KORCZYN, AD; YAHR, MD; AXELROD, FB
1980 ;30(4):428-428, Neurology
— id: 102340, year: 1980, vol: 30, page: 428, stat: Journal Article,

Intellectual development and familial dysautonomia
Welton, W; Clayson, D; Axelrod, F B; Levine, D B
1979 May;63(5):708-712, Pediatrics
The study examined adaptive trends in cognitive development among individuals with familial dysautonomia and sought to establish new base rates of intelligence for the dysautonomic population. Fifty-two subjects, aged 6 to 28 years, were administered the Wechsler scales of intelligence. The results indicate that there is less cognitive impairment than previous research would suggest, and that more dysautonomic children are capable of adjusting to standard school programs than was heretofore thought possible. Specific deficits seen in this population are discussed along with a rationale for deleting the term retarded where most of these individuals are concerned
— id: 122597, year: 1979, vol: 63, page: 708, stat: Journal Article,

Orthopedic management of familial dysautonomia
Thorne, R P; Levine, D B; Axelrod, F B
1978 Sep;5(9):37-39, ONA journal
— id: 122598, year: 1978, vol: 5, page: 37, stat: Journal Article,