Ouahchi, K. et al. Ataxia with isolated vitamin E deficiency is caused by mutations in the -tocopherol transfer protein. Nature Genet. 9, 141-145

Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS, INSERM, ULP), Illkirch, Strasbourg, France.
Nature Genetics (Impact Factor: 29.35). 03/1995; 9(2):141-5. DOI: 10.1038/ng0295-141
Source: PubMed


Ataxia with isolated vitamin E deficiency (AVED) is an autosomal recessive neurodegenerative disease which maps to chromosome 8q13. AVED patients have an impaired ability to incorporate alpha-tocopherol into lipoproteins secreted by the liver, a function putatively attributable to the alpha-tocopherol transfer protein (alpha-TTP). Here we report the identification of three frame-shift mutations in the alpha TTP gene. A 744delA mutation accounts for 68% of the mutant alleles in the 17 families analysed and appears to have spread in North Africa and Italy. This mutation correlates with a severe phenotype but alters only the C-terminal tenth of the protein. Two other mutations were found in single families. The finding of alpha TTP gene mutations in AVED patients substantiates the therapeutic role of vitamin E as a protective agent against neurological damage in this disease.

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    • "The defective gene was excluded from the Friedreich's ataxia locus on chromosome 9q (Ben Hamida et al., 1993b) and was localized to chromosome 8q by homozygosity mapping (Ben Hamida et al., 1993a). The responsible gene was cloned as the hepatic -tocopherol transfer protein coding gene (TTPA; Arita et al., 1995) and mutations were identified (Ouahchi et al., 1995). The TTPA protein is a carrier of RRR--tocopherol, the primary vitamin E isomer in plasma. "
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    ABSTRACT: Ataxia with vitamin E deficiency is an autosomal recessive cerebellar ataxia caused by mutations in the α-tocopherol transfer protein coding gene localized on chromosome 8q, leading to lower levels of serum vitamin E. More than 91 patients diagnosed with ataxia with vitamin E deficiency have been reported worldwide. The majority of cases originated in the Mediterranean region, and the 744delA was the most common mutation among the 22 mutants previously described. We examined the clinical and molecular features of a large cohort of 132 Tunisian patients affected with ataxia with vitamin E deficiency. Of these patients, nerve conduction studies were performed on 45, and nerve biopsy was performed on 13. Serum vitamin E was dramatically reduced for 105 of the patients analysed. Molecular analysis revealed that 91.7% of the patients (n = 121) were homozygous for the 744delA mutation. Three other mutations were detected among the remaining patients (8.3%, n = 11) in the homozygous state. Two were previously reported (400C>T and 205-1G>T), and one was novel (553+1T>A). Age of onset was 13.2 ± 5.9 years, with extremes of 2 and 37 years. All described patients exhibited persistent progressive cerebellar ataxia with generally absent tendon reflexes. Deep sensory disturbances, pyramidal syndrome and skeletal deformities were frequent. Head tremor was present in 40% of the patients. Absence of neuropathy or mild peripheral neuropathy was noted in more than half of the cohort. This is the largest study of the genetic, clinical and peripheral neuropathic characteristics in patients with ataxia and vitamin E deficiency. The 744delA mutation represents the most common pathological mutation in Tunisia and worldwide, likely because of a Mediterranean founder effect. Our study led us to suggest that any patient displaying an autosomal recessive cerebellar ataxia phenotype with absent tendon reflexes and minor nerve abnormalities should first be screened for the 744delA mutation, even in the absence of a serum vitamin E measurement.
    Full-text · Article · Dec 2013 · Brain
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    • "One of the first signs of vitamin E deficiency is erythrocyte fragility closely followed by anaemia, ascites, xerophthalmia, poor growth, poor food conversion, epicarditis, and ceroid deposits in spleen and liver (Halver, 2002). Symptoms of low vitamin E levels include ataxia, anemia caused by the breakdown of red blood cells and peripheral neuropathy (Ouahchi et al., 1995). Non-specific forms of degenerative conditions have been described in several species of fish fed large quantities of polyunsaturated fatty acids with inadequate tocopherol in the ration. "
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    ABSTRACT: A quick and direct method based on RP-HPLC techniques with fluorescence detector for measuring tocopherols (α, β + γ and δ) was adapted. Validation of the Rapid RP-HPLC and RP-HPLC were also assessed. To ascertain the dietary needs for tocopherols in diets used in aquaculture, the ingredients were analyzed. Vegetable oils are probably the major dietary source of tocopherols with a variable isomer profile according to the oil identity. Application of techniques for boosting tocopherols in diet in form of Dl-α-tocopheryl acetate enabled supplementation up 100-200 mg kg-1 in commercial feed. Meanwhile, Common carp, Cyprinus carpio L. was seen to have the highest requirement for tocopherols (200-300 mg kg-1). Good performance, survival, high immune response and protection against oxidative damage to fish tissues were some of the positive functions of tocopherols in growers while high fecundity is associated with tocopherols in broodfish. Hypervitaminosis E resulted in poor growth, toxic liver reaction, and death. African catfish (Clarias gariepinus) fed high α-tocopheryl acetate dose (500 mg/kg dry feed) were observed to have significantly lower hematocrit than fish fed the basal diet. One of the first signs of vitamin E deficiency is erythrocyte fragility closely followed by anaemia, ascites, xerophthalmia, poor growth, poor food conversion, epicarditis, and ceroid deposits in spleen and liver. Dietary polyunsaturated fatty acid (PUFA) content is one of the most important effective factors on dietary vitamin E requirements in fish, which means the elevation of unsaturated fatty acids can result in increased requirements for tocopherols as intracellular antioxidants to protect the cells.
    Full-text · Article · Jan 2013
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    • "Founder mutations observed in Tunisia were also reported in populations from the Middle East such as the splice site mutation in the CA II gene responsible for carbonic anhydrase II deficiency in the Arabic peninsula [47] and the p.Q357R molecular defect in the UGT1A1 gene of the Crigler-Najjar type I syndrome in the Kuwaiti population [48]. In other cases, founder mutations are dispersed around the Mediterranean basin as illustrated by the c.744delA mutation in the TTPA gene of ataxia with isolated vitamin E deficiency [49] and the splice site defects in megaloblastic anemia 1 [50] and triple-A syndrome [51]. In other examples, the founder haplotypes are shared with populations from Europe and America, as for the Parkinson disease [52]. "
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    ABSTRACT: Background Tunisia is a North African country of 10 million inhabitants. The native background population is Berber. However, throughout its history, Tunisia has been the site of invasions and migratory waves of allogenic populations and ethnic groups such as Phoenicians, Romans, Vandals, Arabs, Ottomans and French. Like neighbouring and Middle Eastern countries, the Tunisian population shows a relatively high rate of consanguinity and endogamy that favor expression of recessive genetic disorders at relatively high rates. Many factors could contribute to the recurrence of monogenic morbid trait expression. Among them, founder mutations that arise in one ancestral individual and diffuse through generations in isolated communities. Method We report here on founder mutations in the Tunisian population by a systematic review of all available data from PubMed, other sources of the scientific literature as well as unpublished data from our research laboratory. Results We identified two different classes of founder mutations. The first includes founder mutations so far reported only among Tunisians that are responsible for 30 genetic diseases. The second group represents founder haplotypes described in 51 inherited conditions that occur among Tunisians and are also shared with other North African and Middle Eastern countries. Several heavily disabilitating diseases are caused by recessive founder mutations. They include, among others, neuromuscular diseases such as congenital muscular dystrophy and spastic paraglegia and also severe genodermatoses such as dystrophic epidermolysis bullosa and xeroderma pigmentosa. Conclusion This report provides informations on founder mutations for 73 genetic diseases either specific to Tunisians or shared by other populations. Taking into account the relatively high number and frequency of genetic diseases in the region and the limited resources, screening for these founder mutations should provide a rapid and cost effective tool for molecular diagnosis. Indeed, our report should help designing appropriate measures for carrier screening, better evaluation of diseases burden and setting up of preventive measures at the regional level.
    Full-text · Article · Aug 2012 · Orphanet Journal of Rare Diseases
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