The Nutritional Supplement Phosphatidylserine in Patients With Familial Dysautonomia
Keywords
Abstract
Description
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.
Dates
Last Verified: | 04/30/2019 |
First Submitted: | 10/15/2014 |
Estimated Enrollment Submitted: | 10/26/2014 |
First Posted: | 10/27/2014 |
Last Update Submitted: | 05/07/2019 |
Last Update Posted: | 05/09/2019 |
Actual Study Start Date: | 10/31/2011 |
Estimated Primary Completion Date: | 11/30/2019 |
Estimated Study Completion Date: | 11/30/2019 |
Condition or disease
Intervention/treatment
Drug: Phosphatidylserine
Phase
Arm Groups
Arm | Intervention/treatment |
---|---|
Experimental: Phosphatidylserine Phosphatidylserine titration from 300, 600 and 800 mg/day
duration: 6 months | Drug: Phosphatidylserine Phosphatidylserine will be titrated starting at 300mg/day dose for two months to 600mg/day dose for 2 months, then 800 mg/day dose for a final 2 month period. |
Eligibility Criteria
Ages Eligible for Study | 12 Years To 12 Years |
Sexes Eligible for Study | All |
Accepts Healthy Volunteers | Yes |
Criteria | 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. |
Outcome
Primary Outcome Measures
1. Change from baseline in blood lab values at every 2 month interval [measurements will be taken at baseline and at two months intervals for the first 6 months, then at yearly intervals for up to 5 years]
2. Change from baseline in adverse events measures at every 2 month interval [measurements will be taken at baseline and at two months intervals for the first 6 months, then at yearly intervals for up to 5 years]
3. Change from baseline in physical exam measures at every 2 month interval [measurements will be taken at baseline and at two months intervals for the first 6 months, then at yearly intervals for up to 5 years]
4. Change from baseline in 12 lead ECG measures at every 2 month interval [measurements will be taken at baseline and at two months intervals for the first 6 months, then at yearly intervals for up to 5 years]
5. Change from baseline in vital signs measures at every 2 month interval [measurements will be taken at baseline and at two months intervals for the first 6 months, then at yearly intervals for up to 5 years]
Secondary Outcome Measures
1. Change from baseline in efficacy measures [measurements will be taken at baseline and at two months intervals for the first 6 months, then at yearly intervals for up to 5 years]