Tocotrienol Treatment in Familial Dysautonomia: Open-Label Pilot Study

Abstract

Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy, primarily presented in Ashkenazi Jews. The most common mutation in FD patients results from a single base pair substitution of an intronic splice site in the IKBKAP gene which disrupts normal mRNA splicing and leads to tissue-specific reduction of IKBKAP protein (IKAP). To date, treatment of FD patients remains preventative, symptomatic and supportive. Based on previous in vitro evidence that tocotrienols, members of the vitamin E family, upregulate transcription of the IKBKAP gene, we aimed to investigate whether a similar effects was observed in vivo. In the current study, we assessed the effects of tocotrienol treatment on FD patients' symptoms and IKBKAP expression in white blood cells. The initial daily doses of 50 or 100 mg tocotrienol, doubled after 3 months, was administered to 32 FD patients. Twenty-eight FD patients completed the 6-month study. The first 3 months of tocotrienol treatment was associated with a significant increase in IKBKAP expression level in FD patients' blood. Despite doubling the dose after the initial 3 months of treatment, IKBKAP expression level returned to baseline by the end of the 6-month treatment. Clinical improvement was noted in the reported clinical questionnaire (with regard to dizziness, bloching, sweating, number of pneumonia, cough episodes, and walking stability), however, no significant effect was observed in any clinical measurements (weight, height, oxygen saturation, blood pressure, tear production, histamine test, vibration threshold test, nerve conduction, and heart rate variability) following Tocotrienol treatment. In conclusion, tocotrienol treatment appears significantly beneficial by clinical evaluation for some FD patients in a few clinical parameters; however it was not significant by clinical measurements. This open-label study shows the complexity of effect of tocotrienol treatment on FD patients' clinical outcomes and on IKBKAP expression level compared to in vitro results. A longitudinal study with an increased sample size is required in the future to better understand tocotrienol affect on FD patients.

<em>IKBKAP/ELP1</em> gene mutations: mechanisms of familial dysautonomia and gene-targeting therapies

“…This study demonstrated that tocotrienol mediated: 1) reduction in the number of pneumonias; 2) reduced sweating, blotching and dizziness; and 3) increased stability in walking. 76 After 3 months of the tocotrienol therapy, a significant increase in the expression of the exon 20-containing ELP1 transcript was detected in peripheral blood cells of these patients. For reasons that are unclear, no increase in the exon 20-containing ELP1 transcript in the peripheral blood cells was detected at the 6-month time point.…”

“…The tocotrienol-mediated reduction in the frequency of pneumonias 76 and hypertensive crises, 73 which are the leading causes of death in FD patients, 14 , 77 strongly support their continued administration. The tocotrienol-mediated increased tear production 73 – 75 has helped FD patients avoid the recurrent corneal abrasions/ulcers that typically result from the lack of tear production.…”

“…The results of a second clinical trial, which assessed the impact of tocotrienol ingestion on a cohort of 28 FD patients, were recently published. 76 The participants in this open label study ingested either 50 or 100 mg of tocotrienols for an initial 3-month period and then either 100 or 200 mg of tocotrienols for a second 3-month period. This study demonstrated that tocotrienol mediated: 1) reduction in the number of pneumonias; 2) reduced sweating, blotching and dizziness; and 3) increased stability in walking.…”

“…The tocotrienol-mediated increased tear production 73 – 75 has helped FD patients avoid the recurrent corneal abrasions/ulcers that typically result from the lack of tear production. 57 The observed tocotrienol-mediated increased stability in walking, 76 reduced sweating and blotching 76 and increased lacrimation 73 – 75 suggest improvement in sympathetic and parasympathetic neuronal function. These findings demonstrate the in vivo impact of the tocotrienols and suggest that the long-term ingestion of the tocotrienols may preserve neuronal function and extend the life span of FD patients.…”

Proteasome inhibitors to alleviate aberrant IKBKAP mRNA splicing and low IKAP/hELP1 synthesis in familial dysautonomia

“…Although its efficacy in FD remains controversial (Lee et al, 2009), its anticancer properties have been in part related to proteasome inhibition (Chen et al, 2011;Modernelli et al, 2015). Therefore, a rational approach to reduce carfilzomib toxicity while maintaining splicing profile improvement and proteasome blocking could be to combine this drug with EGCG or with tocotrienols, members of the vitamin E family, that have been shown to upregulate IKBKAP transcription and to provide clinical benefit to FD patients (Anderson et al, 2003b;Cheishvili et al, 2016).…”