The Nutritional Supplement Phosphatidylserine in Patients With Familial Dysautonomia

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.

Inclusion Criteria:

- - Diagnosis of familial dysautonomia (with mutation testing)

- Age 12 years or older

- Signed informed consent (or ascent), which will include permission to assess medical
records

Exclusion Criteria:

- Patients with significant cardiac, respiratory, or renal compromise that, in the
investigators opinion, may jeopardize their health by participating in this trial

- Patients who are currently participating in other clinical trials of compounds that my
change IKAP gene expression.

- Women who are pregnant or lactating

- Women of childbearing potential who are not using medically accepted methods of
contraception.

- Patients taking anticoagulants, such as warfarin, heparin, aspirin, pentoxifylline,
clopidogrel or ticlopidine.

- Patients taking ginko, garlic or vitamin E supplements.