Neurological Sciences

, Volume 31, Issue 4, pp 511–515 | Cite as

Ataxia with vitamin E deficiency: update of molecular diagnosis

Update in Clinical Neurogenetics


Ataxia with vitamin E deficiency (AVED) is a rare autosomal recessive neurodegenerative disease, due to mutations in TTPA gene (Arita et al. in Biochem J 306(Pt. 2):437–443, 1995; Hentati et al. in Ann Neurol 39:295–300, 1996), which encodes for α-TTP, a cytosolic liver protein that is presumed to function in the intracellular transport of α-tocopherol. This disease is characterized clinically by symptoms with often striking resemblance to those of Friedreich ataxia. The neurological symptoms include ataxia, dysarthria, hyporeflexia, and decreased vibration sense, sometimes associated with cardiomyopathy and retinitis pigmentosa (Mariotti et al. in Neurol Sci 25:130–137, 2004). Vitamin E supplementation improves symptoms and prevents disease progress (Doria-Lamba et al. in Eur J Pediatr 165(7):494–495, 2006). Over 20 mutations have been identified in patients with AVED. In the present paper we summarize the recent findings on molecular genetic of this disease including the list of the known mutations.


Ataxia Vitamin E TTPA gene Retinitis pigmentosa 


  1. 1.
    Angelini L, Erba A, Mariotti C, Gellera C, Ciano C, Nardocci N (2002) Myoclonic dystonia as unique presentation of isolated vitamin E deficiency in a young patient. Mov Disord 17(3):612–614CrossRefPubMedGoogle Scholar
  2. 2.
    Anheim M, Fleury M, Monga B, Laugel V, Chaigne D, Rodier G, Ginglinger E, Boulay C, Courtois S, Drouot N, Fritsch M, Delaunoy JP, Stoppa-Lyonnet D, Tranchant C, Koenig M (2010) Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management. Neurogenetics 11(1):1–12 (Epub 2009 May 14)CrossRefPubMedGoogle Scholar
  3. 3.
    Aparicio JM, Belanger Quintana A, Suarez L, Mayo D, Benitez J, Diaz M, Escobar H (2001) Ataxia with isolated vitamin E deficiency: case report and review of the literature. J Pediatr Gastroenterol Nutr 33:206–210CrossRefPubMedGoogle Scholar
  4. 4.
    Arita M, Sato Y, Miyata A, Tanabe T, Takahashi E, Kayden HJ, Arai H, Inoue K (1995) Human alpha-tocopherol transfer protein: cDNA cloning, expression and chromosomal localization. Biochem J 306(Pt. 2):437–443PubMedGoogle Scholar
  5. 5.
    Bellayou H, Dehbi H, Bourezgui M, Slassi I, Nadifi S (2009) Ataxia with vitamin E deficiency (AVED): an example of the contribution of research in molecular genetic to counselling in Morocco. Pathol Biol (Paris) 57(5):425–426 (Epub 2008 Nov 26)Google Scholar
  6. 6.
    Ben Hamida C, Doerflinger N, Belal S, Linder C, Reutenauer L, Dib C, Gyapay G, Vignal A, Le Paslier D, Cohen D et al (1993) Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping. Nat Genet 5:195–200CrossRefPubMedGoogle Scholar
  7. 7.
    Benomar A, Yahyaoui M, Meggouh F, Bouhouche A, Boutchich M, Bouslam N, Zaim A, Schmitt M, Belaidi H, Ouazzani R, Chkili T, Koenig M (2002) Clinical comparison between AVED patients with 744 del A mutation and Friedreich ataxia with GAA expansion in 15 Moroccan families. J Neurol Sci 198:25–29CrossRefPubMedGoogle Scholar
  8. 8.
    Bouhlal Y, Zouari M, Kefi M, Ben Hamida C, Hentati F, Amouri R (2008) Autosomal recessive ataxia caused by three distinct gene defects in a single consanguineous family. J Neurogenet 22(2):139–148CrossRefPubMedGoogle Scholar
  9. 9.
    Burck U, Goebel HH, Kuhlendahl HD, Meier C, Goebel KM (1981) Neuromyopathy and vitamin E deficiency in man. Neuropediatrics 12:267–278CrossRefPubMedGoogle Scholar
  10. 10.
    Cavalier L, Ouahchi K, Kayden HJ, Di Donato S, Reutenauer L, Mandel JL, Koenig M (1998) Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. Am J Hum Genet 62:301–310CrossRefPubMedGoogle Scholar
  11. 11.
    Cellini E, Piacentini S, Nacmias B, Forleo P, Tedde A, Bagnoli S, Ciantelli M, Sorbi S (2002) A family with spinocerebellar ataxia type 8 expansion and vitamin E deficiency ataxia. Arch Neurol 59:1952–1953CrossRefPubMedGoogle Scholar
  12. 12.
    Di Donato S, Gallera C, Mariotti C (2001) The complex clinical and genetic classification of inherited ataxias II. Autosomal recessiva atraxias. Neurol Sci 22(3):219–228 (review)CrossRefPubMedGoogle Scholar
  13. 13.
    Doria-Lamba L, De Grandis E, Cristiani E, Fiocchi I, Montaldi L, Grosso P, Gellera C (2006) Efficacious vitamin E treatment in a child with ataxia with isolated vitamin E deficiency. Eur J Pediatr 165(7):494–495 (Epub 2006 Feb 21)CrossRefPubMedGoogle Scholar
  14. 14.
    Eggermont E (2006) Recent advances in vitamin E metabolism and deficiency. Eur J Pediatr 165(7):429–434 (Epub 2006 Feb 21, review)CrossRefPubMedGoogle Scholar
  15. 15.
    Fernández-Burriel M, Martínez-Rubio D, Lupo V, Pérez-Colosía V, Piñán-López E, Palau F, Espinós C (2008) A novel delins mutation in the alpha-TTP gene in a family segregating ataxia with isolated vitamin E deficiency. Pediatr Res 64(3):262–264CrossRefPubMedGoogle Scholar
  16. 16.
    Fogel BL, Perlman S (2007) Clinical features and molecular genetics of autosomal recessive cerebellar ataxias. Lancet Neurol 6(3):245–257 (review)CrossRefPubMedGoogle Scholar
  17. 17.
    Gabsi S, Gouider-Khouja N, Belal S, Fki M, Kefi M, Turki I, Ben Hamida M, Kayden H, Mebazaa R, Hentati F (2001) Effect of vitamin E supplementation in patients with ataxia with vitamin E deficiency. Eur J Neurol 8:477–481CrossRefPubMedGoogle Scholar
  18. 18.
    Gohil K, Azzi A (2008) Reply to drug insight: antioxidant therapy in inherited ataxias. Nat Clin Pract Neurol 4(7):E1; author reply E2Google Scholar
  19. 19.
    Gotoda T, Arita M, Arai H, Inoue K, Yokota T, Fukuo Y, Yazaki Y, Yamada N (1995) Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the alpha-tocopherol-transfer protein. N Engl J Med 333:1313–1318CrossRefPubMedGoogle Scholar
  20. 20.
    Hentati A, Deng HX, Hung WY, Nayer M, Ahmed MS, He X, Tim R, Stumpf DA, Siddique T (1996) Human alpha-tocopherol transfer protein: gene structure and mutations in familial vitamin E deficiency. Ann Neurol 39:295–300CrossRefPubMedGoogle Scholar
  21. 21.
    Hoshino M, Masuda N, Ito Y, Murata M, Goto J, Sakurai M, Kanazawa I (1999) Ataxia with isolated vitamin E protei deficiency: a Japanese family carrying a novel mutation in the alpha-tocopherol transfer n gene. Ann Neurol 45(6):809–812CrossRefPubMedGoogle Scholar
  22. 22.
    Kara B, Uzümcü A, Uyguner O, Rosti RO, Koçbaş A, Ozmen M, Kayserili H (2008) Ataxia with vitamin E deficiency associated with deafness. Turk J Pediatr 50(5):471–475PubMedGoogle Scholar
  23. 23.
    Koht J, Bjørnarå KA, Jørum E, Tallaksen CM (2009) Ataxia with vitamin E deficiency in southeast Norway, case report. Acta Neurol Scand Suppl (189):42–45Google Scholar
  24. 24.
    Koenig M, Mandel JL (1997) Deciphering the cause of Friedreich ataxia. Curr Opin Neurobiol 7(5):689–694Google Scholar
  25. 25.
    Manor D, Morley S (2007) The alpha-tocopherol transfer protein. Vitam Horm 76:45–65CrossRefPubMedGoogle Scholar
  26. 26.
    Mariotti C, Gellera C, Rimoldi M, Mineri R, Uziel G, Zorzi G, Pareyson D, Piccolo G, Gambi D, Piacentini S, Squitieri F, Capra R, Castellotti B, Di Donato S (2004) Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families. Neurol Sci. 25:130–137CrossRefPubMedGoogle Scholar
  27. 27.
    Martinello F, Fardin P, Ottina M, Ricchieri GL, Koening M, Cavalier L, Trevisan CP (1998) Supplemental therapy in isolated vitamin E deficiency improves the peripheral neuropathy and prevents the progression of ataxia. J Neurol Sci 156:177–179CrossRefPubMedGoogle Scholar
  28. 28.
    Marzouki N, Benomar A, Yahyaoui M, Birouk N, Elouazzani M, Chkili T, Benlemlih M (2005) Vitamin E deficiency ataxia with (744 del A) mutation on alpha-TTP gene: genetic and clinical peculiarities in Moroccan patients. Eur J Med Genet. 48:21–28CrossRefPubMedGoogle Scholar
  29. 29.
    Meydani SN, Meydani M, Blumberg JB et al (1998) Assessment of the safety of supplementation with different amounts of vitamin E in healthy older adults. Am J Clin Nutr 68:311–318PubMedGoogle Scholar
  30. 30.
    Min KC, Kovall RA, Hendrickson WA (2003) Crystal structure of human alpha-tocopherol transfer protein bound to its ligand: implications for ataxia with vitamin E deficiency. Proc Natl Acad Sci USA 100:14713–14718CrossRefPubMedGoogle Scholar
  31. 31.
    Min CK (2007) Structure and function of alpha-tocopherol transfer protein: implications for vitamin E metabolism and AVED. Vitam Horm 76:23–43 (review)CrossRefGoogle Scholar
  32. 32.
    Morley S, Cross V, Cecchini M, Nava P, Atkinson J, Manor D (2006) Utility of a fluorescent vitamin E analogue as a probe for tocopherol transfer protein activity. Biochemistry 45(4):1075–1081CrossRefPubMedGoogle Scholar
  33. 33.
    Ouahchi K, Arita M, Kayden H, Hentati F, Ben Hamida M, Sokol R, Arai H, Inoue K, Mandel JL, Koenig M (1995) Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet 9:141–145CrossRefPubMedGoogle Scholar
  34. 34.
    Palau F, Espinós C (2006) Autosomal recessive cerebellar ataxias. Orphanet J Rare Dis 1:47CrossRefPubMedGoogle Scholar
  35. 35.
    Pang J, Kiyosawa M, Seko Y, Yokota T, Harino S, Suzuki J (2001) Clinicopathological report of retinitis pigmentosa with vitamin E deficiency caused by mutation of the alpha-tocopherol transfer protein gene. Jpn J Ophthalmol 45(6):672–676CrossRefPubMedGoogle Scholar
  36. 36.
    Ponten SC, Kwee ML, Wolters E Ch, Zijlmans JC (2007) First case of ataxia with isolated vitamin E deficiency in the Netherland. Parkinsonism Relat Disord 13(5):315–316 (Epub 2006 Oct 16)CrossRefPubMedGoogle Scholar
  37. 37.
    Qian J, Atkinson J, Manor D (2006) Biochemical consequences of heritable mutations in the alpha-tocopherol transfer protein. Biochemistry 45(27):8236–8242CrossRefPubMedGoogle Scholar
  38. 38.
    Ricciarelli R, Argellati F, Pronzato MA, Domenicotti C (2007) Vitamin E and neurodegenerative diseases. Mol Aspects Med 28(5–6):591–606 (Epub 2007 Jan 11, review)CrossRefPubMedGoogle Scholar
  39. 39.
    Roubertie A, Biolsi B, Rivier F, Humbertclaude V, Cheminal R, Echenne B (2003) Ataxia with vitamin E deficiency and severe dystonia: report of a case. Brain Dev 25(6):442–445CrossRefPubMedGoogle Scholar
  40. 40.
    Sato Y, Arai H, Miyata A, Tokita S, Yamamoto K, Tanabe T, Inoue K (1993) Primary structure of alpha-tocopherol transfer protein from rat liver. Homology with cellular retinaldehyde-binding protein. J Biol Chem. 268:17705–17710PubMedGoogle Scholar
  41. 41.
    Schuelke M, Mayatepek E, Inter M et al (1999) Treatment of ataxia in isolated vitamin E deficiency caused by α-tocopherol transfer protein deficiency. J Pediatr 134:240–244CrossRefPubMedGoogle Scholar
  42. 42.
    Schuelke M, Finckh B, Sistermans EA, Ausems MG, Hübner C, von Moers A (2000) Ataxia with vitamin E deficiency: biochemical effects of malcompliance with vitamin E therapy. Neurology 55(10):1584–1586PubMedGoogle Scholar
  43. 43.
    Shimohata T, Date H, Ishiguro H, Suzuki T, Takano H, Tanaka H, Tsuji S, Hirota K (1998) Ataxia with isolated vitamin E deficiency and retinitis pigmentosa. Ann Neurol 43:273CrossRefPubMedGoogle Scholar
  44. 44.
    Sokol RJ, Kayden HJ, Bettis DB, Traber MG, Neville H, Ringel S et al (1988) Isolated vitamin E deficiency in the absence of fat malabsorption familial and sporadic cases: characterization and investigation of causes. J Lab Clin Med 111:548–559PubMedGoogle Scholar
  45. 45.
    Tamaru Y, Hirano M, Kusaka H, Ito H, Imai T, Ueno S (1997) alpha-Tocopherol transfer protein gene: exon skipping of all transcripts causes ataxia. Neurology 49(2):584–588PubMedGoogle Scholar
  46. 46.
    Traber MG (1997) Regulation of human plasma vitamin E. Adv Pharmacol 38:49–63 (review)CrossRefPubMedGoogle Scholar
  47. 47.
    Usuki F, Maruyama K (2000) Ataxia caused by mutations in the alpha-tocopherol transfer protein gene. J Neurol Neurosurg Psychiatry 69:254–256CrossRefPubMedGoogle Scholar
  48. 48.
    Yokota T, Wada Y, Furukawa T, Tsukagoshi H, Uchihara T, Watabiki S (1987) Adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency. Ann Neurol 22:84–87CrossRefPubMedGoogle Scholar
  49. 49.
    Yokota T, Shiojiri T, Gotoda T, Arai H (1996) Retinitis pigmentosa and ataxia caused by a mutation in the gene for the α-tocopherol transfer protein. N Engl J Med 335:1770–1771Google Scholar
  50. 50.
    Yokota T, Shiojiri T, Gotoda T (1997) Friedreich-like ataxia with retinitis pigmentosa caused by the His101Gln mutation of α-tocopherol transfer protein gene. Ann Neurol 41:826–832CrossRefPubMedGoogle Scholar
  51. 51.
    Yokota T, Uchihara T, Kumagai J, Shiojiri T, Pang JJ, Arita M (2000) Postmortem study of ataxia with retinitis pigmentosa by mutation of the a-tocopherol transfer protein gene. J Neurol Neurosurg Psychiatry 68(4):521–525CrossRefPubMedGoogle Scholar
  52. 52.
    Zingg JM (2007) Vitamin E: an overview of major research directions. Mol Aspects Med 28(5–6):400–422 (Epub 2007 Jun 2)CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Dipartimento di Scienze Neurologiche, Neurochirurgiche e del ComportamentoUniversità degli Studi di SienaSienaItaly

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