Faculty Bibliography

An adolescent female with Moebius syndrome developed paroxysmal hypertension, orthostatic hypotension and autonomic symptoms. Common causes of dysautonomia were excluded by the work-up, which supported a diagnosis of baroreflex failure. Neurological testing suggested dysfunction of the tenth cranial nerve as the etiology. This report suggests that baroreflex dysfunction should be considered in Moebius syndrome patients displaying autonomic symptoms.

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::

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.

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

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

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

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