Gabrielle Gold-Von Simson, 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,

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,

NHE3 expression and SIDS
Bowers, Megan; Gold-von Simson, Gabrielle
2010 Sep;157(3):516-516, Journal of pediatrics
— id: 111964, year: 2010, vol: 157, page: 516, 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,

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,

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,

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,

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,

Pacemakers in patients with familial dysautonomia--a review of experience with 20 patients
Gold-von Simson, Gabrielle; Rutkowski, Monika; Berlin, Dena; Axelrod, Felicia B
2005 Feb;15(1):15-20, Clinical autonomic research
Familial dysautonomia (FD) is a genetic disease associated with a high incidence of sudden death. If fatal bradyarrhythmia is an etiological factor then the incidence of sudden death should decrease after pacemaker placement. Retrospective review of 596 registered FD patients revealed that 22 FD patients (3.7%) had pacemakers placed between December 1984 and June 2003. Clinical and electrocardiographic indications for placement and demographic data were assessed for 20 of the 22 patients (10 males, 10 females, ages 4 to 48 years). Two patients were excluded because of insufficient data. Prior to pacemaker placement, presenting symptoms were syncope and cardiac arrest, 16/20 (80%) and 6/20 (30 %), respectively. Asystole was the most frequent electrocardiographic finding and was documented in 17/20 patients (85 %). Other electrocardiographic abnormalities included bradycardia, AV block, prolonged QTc and prolonged JTc. The average duration of pacemaker utilization was 5.7 years (range 5 months to 14.5 years). Complications included infection (1 patient) and wire migration (2 patients). In the one patient with infection, the pacemaker was permanently removed. This patient then experienced multiple syncopal episodes and death. There were 7 other deaths. Three deaths occurred suddenly without preceding events, and 4 patients had non-cardiac causes of death. None of these 7 deceased patients had recurrence of syncope after pacemaker placement. In the 12 surviving patients, 6 had recurrence of syncope but none had cardiac arrest. Pacemaker placement may protect FD patients from fatal bradyarrhythmia and may decrease the incidence of syncope. However, data are limited and prospective analysis is needed
— id: 55964, year: 2005, vol: 15, page: 15, stat: Journal Article,