title: 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.
authors.affiliation: The Israeli Familial Dysautonomia Center at the Department of Pediatrics, Hadassah University Hospital Mount Scopus, Hebrew University-Hadassah Medical School, Jerusalem, Israel. david.cheishvili@mcgill.ca.|Department of Rehabilitation, Hadassah University Hospital Mount Scopus, Hebrew University-Hadassah Medical School, Jerusalem, Israel. david.cheishvili@mcgill.ca.|Department of Pharmacology & Therapeutics, McGill University Medical School, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada. david.cheishvili@mcgill.ca.|Department of Developmental Biology and Cancer Research, The Hebrew University, Hadassah School of Medicine, Jerusalem, Israel. david.cheishvili@mcgill.ca.
authors.forename: David
authors.initials: D
authors.lastname: Cheishvili
authors.affiliation: The Israeli Familial Dysautonomia Center at the Department of Pediatrics, Hadassah University Hospital Mount Scopus, Hebrew University-Hadassah Medical School, Jerusalem, Israel.|Department of Rehabilitation, Hadassah University Hospital Mount Scopus, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Channa
authors.initials: C
authors.lastname: Maayan
authors.affiliation: The Israeli Familial Dysautonomia Center at the Department of Pediatrics, Hadassah University Hospital Mount Scopus, Hebrew University-Hadassah Medical School, Jerusalem, Israel.|Department of Rehabilitation, Hadassah University Hospital Mount Scopus, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Naama
authors.initials: N
authors.lastname: Holzer
authors.affiliation: Department of Developmental Biology and Cancer Research, The Hebrew University, Hadassah School of Medicine, Jerusalem, Israel.
authors.forename: Jeanna
authors.initials: J
authors.lastname: Tsenter
authors.affiliation: Department of Pharmacology & Therapeutics, McGill University Medical School, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada.
authors.forename: Elad
authors.initials: E
authors.lastname: Lax
authors.affiliation: Department of Pharmacology & Therapeutics, McGill University Medical School, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Petropoulos
authors.affiliation: Department of Developmental Biology and Cancer Research, The Hebrew University, Hadassah School of Medicine, Jerusalem, Israel.
authors.forename: Aharon
authors.initials: A
authors.lastname: Razin
mesh_terms: D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000097:blood; D002648:Child; D002675:Child, Preschool; D004402:Dysautonomia, Familial / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D010865:Pilot Projects; D024508:Tocotrienols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D035602:Transcriptional Elongation Factors; D014815:Vitamins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D002352:Carrier Proteins; C114720:Elp1 protein, human; D024508:Tocotrienols; D035602:Transcriptional Elongation Factors; D014815:Vitamins
keywords: Familial dysautonomia; IKAP; IKBKAP; Tocotrienol