Familial dysautonomia (FD) is an autosomal recessive disease caused by mutations in the I-B kinase complex associated protein (IKBKAP) gene sequence (Anderson et al., 2001; Slaugenhaupt et al., 2001). The disorder affects the development of sensory nerves, resulting in impaired pain and temperature perception (Riley et al., 1949), lack of visceral sensations (Norcliffe-Kaufmann et al., 2010), dysphagia and proprioceptive gait ataxia (Macefield et al., 2011). Childhood mortality is increased, with aspiration pneumonia a leading cause of death. In early adulthood, renal failure is common (Pearson et al., 1980) and eyesight deteriorates due to optic atrophy and gait ataxia worsens making walking impossible without assistance. The incidence of seizures, scoliosis, respiratory insufficiency, sleep apnea and gastrointestinal bleeds are all increased. Sudden unexpected cardiac deaths are common and there is an increased incidence of cancer. Current treatments are supportive and frequently ineffective. FD has no known cure and 50% of patients die before age 40.
A decade ago, we discovered that the disease was caused by point mutations in IKBKAP gene, leading to a deficiency of I-B kinase complex associated protein (IKAP) mainly in neuronal tissue (Slaugenhaupt et al., 2001; Mezey et al., 2003; Lee et al., 2009). Phosphatidylserine, an FDA-approved food supplement, was shown to increase protein levels in FD-derived cell lines (Keren et al., 2011) as well as in a mouse model of FD (Bochner et al., 2013). Because of the severity of FD, the availability of phosphatidylserine in health food stores and its promise as a treatment, many patients with FD are already taking it, although its safety and efficacy in this population is unknown. Thus, we propose a controlled study of phosphatidylserine to determine its safety profile and whether it has any impact on the natural history of FD.
SPECIFIC AIM 1: It is not known if phosphatidylserine increases the levels of IKBKAP mRNA in patients with FD. To determine the optimal dose of phosphatidylserine in patients with FD, (i.e., the lowest dosage at which there is maximal improvement in IKBKAP mRNA production without significant side effects) we will monitor the safety and efficacy of phosphatidylserine in an open-label dose escalation study. Safety parameters and IKBKAP mRNA levels in blood will be measured in 40 patients with FD at baseline and repeated at increasing doses of phosphatidylserine.
SPECIFIC AIM 2: In an independent long-term observational study, we will follow patients with FD of all ages who opt to take phosphatidylserine as a food supplement in their diet. Safety parameters will be measured as part of routine evaluations on an annual basis. The long-term efficacy of phosphatidylserine will be determined by evaluating the evolution of standard parameters of neurological function overtime in patients who received phosphatidylserine and comparing their progression with historical controls from the database archives.
