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 α–tocopherol into lipoproteins secreted by the liver, a function putatively attributable to the α–tocopherol transfer protein (α–TTP). Here we report the identification of three frame–shift mutations in the αTTP 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 αTTP gene mutations in AVED patients substantiates the therapeutic role of vitamin E as a protective agent against neurological damage in this disease.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Muller, D.P., Lloyd, J.K. & Wolff, O.H. Vitamin E and neurological function. Lancet 1, 225–228 (1983).
Burck, U., Goebel, H.H., Kuhlendahl, H.D., Meier, C. & Goebel, K.M. Neuromyopathy and vitamin E deficiency in man. Neuropediatrics 12, 267–278 (1981).
Harding, A.E., Matthews, S., Jones, S., Ellis, C.J., Booth, I.W. & Muller, D.P. Spinocerebellar degeneration associated with a selective defect of vitamin E absorption. N. Engl. J. Med. 313, 32–35 (1985).
Krendel, D.A., Gilchrist, J.M., Johnson, A.O. & Bossen, E.H. Isolated deficiency of vitamin E with progressive neurologic deterioration. Neurology 37, 538–540 (1987).
Yokota, T., Wada, Y., Furukawa, T., Tsukagoshi, H., Uchihara, T. & Watabiki, S. Adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency. Ann. Neurol. 22, 84–87 (1987).
Stumpf D.A. et al. Friedreich's disease: V. Variant form with vitamin E deficiency and normal fat absorption. Neurology 37, 68–74 (1987).
Sokol, R.J. et al. Isolated vitaminE deficiency in the absence of fat malabsorption — familial and sporadic cases: characterization and investigation of causes. J. lab. clin. Med. 111, 548–559 (1988).
Laplante, P., Vanasse, M., Michaud, J., Geoffroy, G. & Brochu, P. A progressive neurological syndrome associated with an isolated vitamin E deficiency. Can. J. Neurol. Sci. 11, 561–564 (1984).
Kohlschütter, A., Hubner, C., Jansen, W. & Lindner, S.G. A treatable familial neuromyopathy with vitamin E deficiency, normal absorption, and evidence of increased consumption of vitamin E. J. Inher. Metab. 11, 149–152 (1988).
Trabert, W., Stober, T., Mielke, V., Siu Heck, F. & Schimrigk, K. Isolierter Vitamin-E-Managel. Fortschr. Neurol. Psychiat. 57, 495–501 (1989).
Ben Hamida, M. et al. Friedreich's ataxia phenotype not linked to chromosome 9 and associated with selective autosomal recessive vitamin E deficiency in two inbred Tunisian families. Neurology 43, 2179–2183 (1993).
Ben Hamida, C. et al. Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping. Nature Genet. 5, 195–200 (1993).
Dærflinger, N. et al. Ataxia with vitamin E deficiency: refinement of genetic localisation and analysis of linkage disequilibrium using new markers in 14 families. Am. J. hum. Genet. (in the press).
Traber, M.G. et al. Impaired ability of patients with familial isolated vitamin E deficiency to incorporate α-tocopherol into lipoproteins secreted by the liver. J. clin. Invest. 85, 397–407 (1990).
Traber, M.G. et al. Impaired discrimination between stereoisomers of α-tocopherol in patients with familial isolated vitamin E deficiency. J. Lipid Res. 34, 201–210 (1993).
Traber, M.G., Ramakrishnan, R. & Kayden, H.J. Human plasma vitamin E kinetics demonstrate rapid recycling of plasma RRR-α-tocopherol. Proc. natn. Acad. Sci. U.S.A. 91, 10005–10008 (1994).
Kayden, H.J. The neurologic syndrome of vitamin E deficiency: a significant cause of ataxia. Neurology 43, 2167–2169 (1993).
Mowri, H., Nakagawa, Y., Inoue, K. & Nojima, S. Enhancement of the transfer of α-tocopherol between liposomes and mitochondria by rat-liver protein (s). Eur. J Biochem. 117, 537–542 (1981).
Behrens, W.A. & Madere, R. Transfer of a-tocopherol to microsomes mediated by partially purified liver α-tocopherol binding protein. Nutr. Res. 2, 611–618 (1982).
Sato, Y., Hagiwara, K., Arai, H. & Inoue, K. Purification and characterization of the α-tocopherol transfer protein from rat liver. FEBS 288, 41–45 (1991).
Sato, Y. et al. Primary structure of α-tocopherol transfer protein from rat liver. J. biol. Chem. 268, 17705–17710 (1993).
Arita, M. et al. Human α-tocopherol transfer protein-cDNA cloning, expression and chromosomal localisation. Biochem. J. (in the press).
Cohen, D., Chumakov, I. & Weissenbach, J. A first-generation physical map of the human genome. Nature 366, 698–701 (1993).
Sirugo, G. et al. Friedreich ataxia locus in Louisiana Acadians: Demonstration of a founder effect by analysis of microsatellite-generated extended haplotypes. Am. J. hum. Genet. 50, 559–566 (1992).
Hästbacka, J., de la Chapelle, A., Kaitila, I., Sistonen, P., Weaver, A. & Lander, E.S. Linkage disequilibrium mapping in isolated founder population: diastrophic dysplasia in Finland. Nature Genet. 2, 204–211 (1993).
Amiel, J. et al. Familial isolated vitamin Edeficiency. Study of a multiplex family with a 5 years therapeutic followup. J. inher. Metab. (in the press).
Kayden, H.J. & Traber, M.G., bsorption, lipoprotein transport, and regulation of plasma concentrations of vitamin E in humans. J. Lipid Res. 34, 343–358 (1993).
Sharp, D. et al. Cloning and gene defects in microsomal triglycerides transfer protein associated with abetalipoproteinaemia. Nature 365, 65–69 (1993).
Di Mascio, P., Murphy, M.E. & Sies, H. Antioxidant defense systems: the role of carotenoids, tocopherols, and thiols. Am. J. clin. Nutr. 53, 194S–200S (1991).
Schubert, D., Kimura, H. & Maher, P. Growth factors and vitamin E modify neuronal glutamate toxicity. Proc. natn. Acad. Sci. U.S.A. 89, 8264–8267 (1992).
Rosen, D.R. et al. Mutation in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993).
Duclos, F., Rodius, F., Wrogemann, K., Mandel, J.-L. & Koenig, M., The Friedreich ataxia region: characterization of two novel genes and reduction of the critical region to 300 kb. Hum. molec. Genet. 3, 909–914 (1994).
About this article
Cite this article
Ouahchi, K., Arita, M., Kayden, H. et al. Ataxia with isolated vitamin E deficiency is caused by mutations in the α–tocopherol transfer protein. Nat Genet 9, 141–145 (1995). https://doi.org/10.1038/ng0295-141
Neurología (English Edition) (2021)
Genetic Variants Shaping Inter-individual Differences in Response to Dietary Intakes—A Narrative Review of the Case of Vitamins
Frontiers in Nutrition (2020)
Scientific Reports (2020)
Acta Neurologica Belgica (2020)