Ataxias cerebelares hereditárias: do martelo ao gen

Arruda, Walter Oleschko; Teive, Hélio A. Ghizoni

doi:10.1590/S0004-282X1997000400027

Resumos

As heredoataxias constituem grupo complexo de doenças neurodegenerativas hereditárias, para o qual várias formas de classificação clínica e patológica foram propostas com sucesso variável. O desenvolvimento das técnicas de biologia molecular trouxe informações importantes que têm permitido caracterizar geneticamente as ataxias cerebelares hereditárias. O reconhecimento das doenças causadas por expansões de trinucleotídeos abre novo capítulo para a pesquisa sobre outros mecanismos de doenças, como na ataxia de Friedreich e nas várias formas de ataxia cerebelar autossômica dominante(SCAl a SCA7), das quais a doença de Machado-Joseph / SCA3 parece ser a mais comum no nosso meio. A deficiência familial de vitamina E (cromossomo 8q) leva a quadro semelhante ao da ataxia de Friedreich (cromossomo 9p), mas responde à reposição oral de tocoferol. Formas familiais de ataxia periódica com (cromossomo 12p) ou sem (cromossomo 19p) mioquimia foram caracterizadas, a primeira resultado de mutações dos gens de canais de potássio. Os portadores do gen da ataxia-teleangiectasia (cromossomo 1 lq) representam 1-3% da população e são suscetíveis aos efeitos oncogênicos da radiação iônica. Sem olvidar da importância da avaliação clínica neurológica, a avaliação genética laboratorial passa a ser valiosa ferramenta para o diagnóstico e aconselhamento genético, além do melhor entendimento da patogênese dessas doenças.

ataxia cerebelar; doenças cerebelares; trinucleotídeos; genética

The hereditary ataxias comprise a complex group of neurological disorders involving the cerebellum and its connections. Several classifications based on clinical and/or pathological data have been only partially successful. Recent progress in molecular genetics has identified the genic loci of hereditary ataxias and has allowed a more precise diagnosis of distinct genetic diseases. Trinucleotide repeat expansions has been recognized as a mechanism of disease in some autosomal dominant spinocerebellar ataxias (ADCA) (SCA1 to SCA7), including Machado-Joseph disease / SCA3, probably the most common form of ADCA in South Brazil, and Friedreich ataxia (GAA expansion - chromosome 9p). Familial alpha-tocopherol deficiency (chromosome 8q) may have a Friedreich ataxia phenotype and responds to the oral supplementaion with vitamin E. Familial episodic ataxias with (EA1 - chromosome 12p) and without (chromosome 19p - EA2) myokimia were identified, the first one caused by point mutations in the gene encoding the KCNA1 potassium voltage-gated channel. The gene responsible for ataxia-teleangiectasia (chromosome 1 lq) was found to encode a putative DNA binding protein kinase (ATM), related to the cell cycle control. One to 3% of the population are heterozygotic ATM gen carry and pose a higher risk of cancer when exposed to ionizing radiation. Molecular biology has provided us with useful tools to diagnosis and genetic counseling and, hopefully, will provide us with a better understanding of the pathogenesis and eventual treatment of the several forms of hereditary ataxias.

cerebellar ataxia; cerebellar diseases; trinucleotides; genetics

Ataxias cerebelares hereditárias: do martelo ao gen

Hereditary cerebellar ataxias from neurological hammer to genetics

Walter Oleschko Arruda^I; Hélio A. Ghizoni Teive^II

^IProfessor Assistente de Neurologia do Departamento de Clínica Médica do Hospital de Clínicas da Universidade Federal do Paraná (UFPR), Neurologista da Unidade de Ciências Neurológicas do Hospital das Nações / Hospital Vita, Curitiba

^IIProfessor Assistente de Neurologia do Departamento de Clínica Médica do Hospital da Clínicas da UFPR, Curitiba

RESUMO

As heredoataxias constituem grupo complexo de doenças neurodegenerativas hereditárias, para o qual várias formas de classificação clínica e patológica foram propostas com sucesso variável. O desenvolvimento das técnicas de biologia molecular trouxe informações importantes que têm permitido caracterizar geneticamente as ataxias cerebelares hereditárias. O reconhecimento das doenças causadas por expansões de trinucleotídeos abre novo capítulo para a pesquisa sobre outros mecanismos de doenças, como na ataxia de Friedreich e nas várias formas de ataxia cerebelar autossômica dominante(SCAl a SCA7), das quais a doença de Machado-Joseph / SCA3 parece ser a mais comum no nosso meio. A deficiência familial de vitamina E (cromossomo 8q) leva a quadro semelhante ao da ataxia de Friedreich (cromossomo 9p), mas responde à reposição oral de tocoferol. Formas familiais de ataxia periódica com (cromossomo 12p) ou sem (cromossomo 19p) mioquimia foram caracterizadas, a primeira resultado de mutações dos gens de canais de potássio. Os portadores do gen da ataxia-teleangiectasia (cromossomo 1 lq) representam 1-3% da população e são suscetíveis aos efeitos oncogênicos da radiação iônica. Sem olvidar da importância da avaliação clínica neurológica, a avaliação genética laboratorial passa a ser valiosa ferramenta para o diagnóstico e aconselhamento genético, além do melhor entendimento da patogênese dessas doenças.

Palavras-chave: ataxia cerebelar, doenças cerebelares, trinucleotídeos, genética.

ABSTRACT

The hereditary ataxias comprise a complex group of neurological disorders involving the cerebellum and its connections. Several classifications based on clinical and/or pathological data have been only partially successful. Recent progress in molecular genetics has identified the genic loci of hereditary ataxias and has allowed a more precise diagnosis of distinct genetic diseases. Trinucleotide repeat expansions has been recognized as a mechanism of disease in some autosomal dominant spinocerebellar ataxias (ADCA) (SCA1 to SCA7), including Machado-Joseph disease / SCA3, probably the most common form of ADCA in South Brazil, and Friedreich ataxia (GAA expansion - chromosome 9p). Familial alpha-tocopherol deficiency (chromosome 8q) may have a Friedreich ataxia phenotype and responds to the oral supplementaion with vitamin E. Familial episodic ataxias with (EA1 - chromosome 12p) and without (chromosome 19p - EA2) myokimia were identified, the first one caused by point mutations in the gene encoding the KCNA1 potassium voltage-gated channel. The gene responsible for ataxia-teleangiectasia (chromosome 1 lq) was found to encode a putative DNA binding protein kinase (ATM), related to the cell cycle control. One to 3% of the population are heterozygotic ATM gen carry and pose a higher risk of cancer when exposed to ionizing radiation. Molecular biology has provided us with useful tools to diagnosis and genetic counseling and, hopefully, will provide us with a better understanding of the pathogenesis and eventual treatment of the several forms of hereditary ataxias.

Key-words: cerebellar ataxia, cerebellar diseases, trinucleotides, genetics.

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Aceite: 12-agosto-1997.

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Referências bibliográficas

1. Allotey R, Twells R, Cemal C, et al. The spinocerebellar ataxia II locus is located within a 3-cM interval on chromosome 12q23-24.1 Am J Hum Genet 1995;57:185-189.
2. Arruda WO. Classificação das ataxias cerebelares hereditárias. Arq Neuropsiquiatr 1991;49:57-65.
3. Arruda WO, Petzl-Erler ML, Cardoso MA, Lehner T, Ott J. Late onset autosomal dominant cerebellar ataxia: a family description and linkage analysis with the HLA system. Arq Neuropsiquiatr 1991;49:285-291.
4. Baloh RW, Yue Q, Furman JM, Nelson SF. Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p. Ann Neurol 1997;41:8-16.
5. Belal S, Cancel G, Stevanin G, et al. Clinical and genetic analysis of a Tunisian family with autosomal dominant cerebellar ataxia type 1 linked to the SCA2 locus. Neurology 1994;44:1423-1426.
6. Ben Hamida C, Doerflinger N, Belal S, et al. Localization of Friedreich ataxia phenotype with selective vitamina E deficiency to chromosome 8q by homozigosity mapping. Nat Genet 1993;5:195-200.
7. Benomar A, Krols L, Stevanin G, et al. The gene for autosomal dominant cerebellar ataxia with pigmentary macular dystrophy maps to chromosome 3pl2-p21.1. Nat Genet 1995;10:84-88.
8. Brice A, Cancel G, Durr A, et al. SCA2 (spinocerebellar ataxia 2): another unstable CAG expansion. Molecular and clinical analysis of 101 patients. Neurology 1997;48(Suppl):A210.
9. Browne D, Gancher ST, Nutt JG, et al. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA 1. Nat Genet 1994;8:136-140.
10. Bürk K, Abele M, Fetter M, et al. Autosomal dominant cerebellar ataxia type I: clinical features and MRI in families with SCAl, SCA2 and SCA3. Brain 1996;119:1497-1505.
11. Burke JR, Winfield MS, Lewis KE et al. The Haw River syndrome: dentatorubral-pallidoluysian atrophy (DRPLA) in an African-American family. Nat Genet 1994;7:521-524.
12. Campuzano V, Montermini L, Molto MD, et al. Friedreich's ataxia: autosomal recessive disease caused by an introni GAA triplet repeat expansion. Science 1996;271:1423-1426.
13. Cancel G, Abbas N, Stevanin G, et al. Marked pheonotypic heterogeneity associated with expansion of a CAG reapeat sequence at the spinocerebellar ataxia 31 Machado-Joseph disease locus. Am J Hum Genet 1995;57:809-816.
14. Chamberlain S, Shaw J, Rowland A. et al. Mapping of mutation causing Friedreich's ataxia to human chromosome 9. Nature 1988;334:248-250.
15. Chung M-y, Ranum LPW, Duvick L, et al. Analysis of the CAG repeat expansion in spinocerebellar ataxia type 1: evidence for a possible mechanism predisposing to instability. Nat Genet 1993;5:254-258.
16. Claus D. Zur Differentialdiagnostik der Friedreich Ataxic Nervenarzt 1986;60:26-31.
17. Coutinho P, Andrade C. Autosomal dominant system degeneration in Portuguese families of the Azores Islands. Neurology 1978;28:703-709.
18. David G, Giubti P, Abbas N, et al. The gene for autosomal dominant cerebellar ataxia type II is located ina 5-cM region in 3pl2-pl3: genetic and physical mapping of the SCA7 locus. Am J Hum Genet 1996;59:1328-1336.
19. Dubourg O, Durr A, Cancel G, et al. Analysis of the SCAl CAG repeat in a large number of families with dominant ataxia: clinical and molecular correlations. Ann Neurol 1995;37:176-180.
20. Durr A, Cossee M, Agid Y, et al. Clinical and genetic abnormalities in patients with Friedreich's ataxia. N Engl J Med 1996.335:1169-1175.
21. Durr A, Smadja D, Cancel G, et al. Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies). Clinical and neuropathological analysis of 53 patients from thre unrelated SCA2 families. Brain 1995;118:1573-1581.
22. Enevoldson TP, Sanders MD, Harding AE. Autosomal dominant cerebellar ataxia qith pigmentary macular dystrophy: a clinical and genetic study of eight families. Brain 1994;117:445-460.
23. Farlow MR, DeMyer W, DIouhy S, Hodes ME. X-linked recessive inheritance of ataxia and adult-onset dementia: clinical features and preliminary linkage studies. Neurology 1987;37:602-607.
24. Filia A, De Michele G, Banfi S, et al. Has spinocerebellar ataxia type 2 a distinct phenotype? Genetic and clinical study of an Italian family. Neurology 1995;45:793-796.
25. Frontali M, Spadaro M, Giunti P, et al. Autosomal dominant pure cerebellar ataxia: neurological and genetic study. Brain 1992;115:1647-1654.
26. Gardner K, Alderson K, Galster B, et al. Autosomal dominant spinocerebellar ataxia: clinical description of a distinct hereditary ataxia and genetic localization to chromosome 16 (SCA4) in a Utah kindred. Neurology 1994;44(Suppl 2): A361.
27. Gatti RA, Berkel I, Boder E, et al. Localization of an ataxia-teleangiectasia gene to chromosome Uq22-23. Nature 1988;336:577-580.
28. Gatti RA, Boder E, Vinters HV, et al. Ataxia-teleangiectasia: an interdisciplinary approach to pathogenesis. Medicine 1991;70:99-119.
29. Genis D, Junck L, Fink JK. Machado-Joseph disease and SCA3: the genotype meets the phenotype. Neurology 1996;46:4-8.
30. Geschwind D, Perlman S, Pulst S. Frequency and clinical pheonotype of mutations in the gene for spinocerebellar ataxia type 2 (SCA2). Neurology 1997;48 (Suppl):A176.
31. Gispert S, Twells R, Orozco G, et al. Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23-24.1. Nat Genet 1993;4:295-299.
32. Giunti P, Sweeney MG, Harding AE. Detection of the Machado-Joseph disease I spinocerebellar ataxia three nucleotide repeat in families with autosomal dominant motor disorders, including the Drew family of Walworth. Brain 1995;118:1077-1085.
33. Gouw LG, Digre KB, Harris CP, et al. Autosomal dominant cerebellar ataxia with retinal degeneration: clinical, neuropathologic, and genetic analysis of a large kindred. Neurology 1994;44:1441-1447.
34. Harding AE. Early onset cerebellar ataxia with retained tendon reflexes: a clinical and genetic study of a disorder distinct from Friedreich's ataxia. J Neurol Neurosurg Psychiatry 1981;44:503-508.
35. Harding AE. The hereditary ataxias and related disorders. Edinburgh: Churchill-Linvingstone, 1984:266.
36. Harding AE, Matthews S, Jones S, et al. Spinocerebellar degeneration associated with a selective defect of vitamin E absorption. N Engl J Med 1985;313:32-35.
37. Hentati A, Deng HX, Hung WY, et al. Human alpha-tocopherol transfer protein: gene structure and mutations in familial vitamin E deficiency. Ann Neurol 1996;39:295-300.
38. Hoffman PM, Stuart WH, Earle KM, et al. Hereditary late onset cerebellar degeneration. Neurology 1971; 21:771-775.
39. Jackson JF, Currier RD, Terasaki PI, Morton NE. Spinocerebelar ataxia and HLA linkage: risk prediction by HLA typing. N Engl J Med 1977;296:1138-1141.
40. Jodice C, Frontali M, Parsichetti F, et al. The gene for spinal cerebellar ataxia 1 (SCA1) is flanked by two closely linked highly polymorphic microsatellite loci. Hum Mol Genet 1993;2:1383-1387.
41. Klostermann W, Zuhlke C, Heide W, et.al. Slow saccades and other eye movement disorders in spinocerebellar atrophy type 1. J Neurol 1997;244:105-111.
42. Koskinen T, Santavuori P, Sainio K, et al. Infantile onset spinocerebellar ataxia with sensory neuropathy: a new inherited disease. J Neurol Sci 1994,121:50-56.
43. Krendel DA, Gilchrest JM, Johnson AO, Bossen EH. Isolated deficiency of vitamin E with progressive neurologic deterioration. Neurology 1987;37:538-540.
44. La Spada AR, Paulson HL, Fischbeck KH. Trinucleotide repeat expansion neurological disease. Ann Neurol 1994;36:814-822.
45. Lima L, Coutinho P. Clinical criteria for diagnosis of Machado-Joseph disease: report of a non-Azorean Portuguese family. Neurology 1980;30:319-322.
46. Lopes-Cendes I, Andermann E, Attig E, et al. Confirmation of the SCA-2 locus as an alternative locus for dominantly inherited spinocerebellar ataxias and refinement of the candidate region. Am J Hum Genet 1994;54:774-781.
47. Lopes-Cendes I, Andermann E, Nechiporuk A, et al. Frequency and molecular characteristics of the spinocerebellar ataxia type 2 mutation. Neurology 1997;48(Suppl):A177.
48. Lopes-Cendes I, Silveira I, Maciel P, et al. Limits of clinical assessment in the accurate diagnosis of Machado-Joseph disease. Arch Neurol 1996;53:1168-1174.
49. Manila T, McCall A, Subramony SH, Zoghbi HY. Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado-Joseph disease. Ann Neurol 1995;38:68-72.
50. Middleton LT, Christodoulou K. Classification of autossomal recessive spinocerebellar ataxias (ARSCA) based on recent genetic studies. Neurology 1997;48 (Suppl):A177.
51. Nagafuchi S, Yanagisawa H, Sato K, et al. Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Genomics 1994;6:14-18.
52. Nakano KK, Dawson DM, Spence A. Machado disease: a hereditary ataxia in Portuguese immigrants to Massachusetts. Neurology 1972;22:49-55.
53. Nielsen JE, Sorensen SA, Hasholt L, Norremolle A. Dentatorubral-pallidoluysian atrophy: clinical features of a five-generation Danish family. Mov Disord 1996;11:533-541.
54. Nikali K, Isosomppi J, Lonqvist T et al. Toward cloning of a novel ataxia gene: refined assingment and physical map of IOSCA locus (SCA8) on 10q24. Genomics 1997; 39:185-191.
55. Nikali K, Suomalainen A, Terwilliger J, et al. Random search for shared chromosomal regions in four affected individuals: the assignment of a new hereditary ataxia locus. Am J Hum Genet 1995; 56:1088-1095.
56. Orozco DG, Nodarse FA, Cordovés SR, Augurger G. Autosomal dominant cerebellar ataxia: clinical analysis of 263 patients from a homogeneous population in Holguin, Cuba. Neurology 1990;40:1369-1375.
57. Orr HT, Chung M, Banfi S, et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 1993;4:221-226.
58. Ranum LPW, Lundgren JK, Schut LI, et al. Spinocerebellar ataxia type I and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia. Am J Hum Genet 1995;57:603-608.
59. Ranum LPW, Schutt LJ, Lundgren JK, et al. Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nat Genet 1994;8:280-284.
60. Richter RB. Late cortical cerebellar atrophy: a form of hereditary cerebellar ataxia. J Human Genet 1950;2:1-6.
61. Romanul FCA, Fowler HL, Radvany J, et al. Azorean disease of the nervous system. N Engl J Med 1977;296:1505-1508.
62. Rosenberg RN. Autosomal dominant cerebellar phenotypes: the genotype has settled the issue. Neurology 1995;45:1-5.
63. Rosenberg RN. DNA-tripIet repeats and neurologic diseases. N Engl J Med 1996; 335:1222-1224.
64. Rosenberg RN, Nyhan WL, Bay C, Shore P. Autosomal dominant striatonigral degeneration. Neurology 1976;26:703-714.
65. Roses AD. From genes to mechanisms to therapies: lessons to be learned from neurological diseases. Nature Med 1996;2:267-269.
66. Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia teleangiectasia gene with a product similar to PI-3 kinase. Science 1995;268:1749-1753.
67. Sequeiros J, Coutinho P. Epidemiology and clinical aspects of Machado-Joseph disease. In: Harding AE, Deufel T. Inherited ataxias. Adv Neurol 1993,61:139-153.
68. Silveira I, Lopes-Cendes I, Kish S, et al. Frequency of spinocerebellar type I, dentatorubropallidoluyisian atrophy, and Machado-Joseph disease in a large group of spinocerebellar atrophy patients. Neurology 1996;46:214-218.
69. Sokol RJ, Kayden HJ, Betas DB, et al. Isolated vitamin E deficiency in the absence of fat-mal-absorption - familial and sporadic cases: caracterization and investigation of causes. J Lab Clin Med 1988;111:548-559.
70. Spira PJ, McLeod JG, Evans WA. A spinocerebellar degeneration with X-linked inheritance. Brain 1979;102:27-41.
71. Stevanin G, Cancel G, Durr A, et al. The gene for spinal cerebellar ataxia 3 (SCA3) is located in a region of ~3 cM on chromosome 14q24.3-q32.2 Am J Hum Genet 1995;56:193-201.
72. Suzuki Y, Sasaki H, Wakisaka A, et al. Spinocerebellar ataxia I (SCA-I) in the Japanese: analysis of CAG trinucleotide repeat expansion and instability of the repeat for paternal transmission. Jap J Hum Genet 1995;40:131-143.
73. Takano T, Yamanouchi Y, Nagafuchi S, Yamada M. Assignment of the dentatorubral and pallidoluysian atrophy (DRPLA) gene to I2pl3.31 by fluorescence in situ hybridization. Genomics 1996;32:171-172.
74. Takano H, Ikeuchi T, Igarashi S. et al. A molecular genetic study on autosomal dominant ataxias in Japanese: comparison of the prevalence and CAG repeat expansions amons spinocerebellar ataxia (SCAl), spinocerebellar ataxia type 2 (SCA2), Machado-Joseph disease (MJD) and dentatotrubral-pallidoluysian atrophy (DRPLA). Neurology 1997;48(Suppl):A209.
75. Takiyama Y, Igarishi S, Rogaeva EA, et al. Evidence for inter-generational instability in the CAG reapeats in the MJD I gene and for conserved haplotype at flanking markers amongst Japanese and Caucasian subsjects with Machado-Joseph disease. Hum Mol Genet 1995; 4:1137-1146.
76. Takiyama Y, Nishisawa M, Tanaka H, et al. The gene for Machado-Joseph disease maps to chromosome 14q. Nat Genet 1993;3:300-304.
77. Teh BT, Silburn P, Lindblad K, et al. Familial periodic cerebellar ataxia without myokymia maps to a 19 cM region on 19pl3. Am J Hum Genet 1996;56:1443-1449.
78. Teive HAG, Arruda WO, Trevisol PCB, et al. Spinocerebellar ataxia: a genetic study in 30 Brazilian families. Neurology 1997;48(Suppl):A177.
79. Titica J, Van Bogaert L. Heredo-degenerative hemiballismus. Brain 1946;69:251-263.
80. Twist EC, Casabon LK, Ruttledge MH et al. Machado-Joseph disease maps to the same region of chromosome 14 as the spinocerebellar ataxia type 3 locus. J Med Genet 1995;32:25-31.
81. Vlghetto A, Froment JC, Trillet M, Aimard G. Magnetic resonance imaging in familial paroxysmal ataxia. Arch Neurol 1988;45:547-549.
82. Warner TT, Lennox GG, Janota I, Harding AE. Autosomal dominant dentatorubropallidoluysian atrophy in the United Kingdom. Mov Disord 1994;9:289-296.
83. Yakura H, Wasisaka A, Fujimori S, Itakura K. Hereditary ataxia and HLA genotypes. N Engl J Med 1974;291:154-155.
84. Yokota T, Wada Y, Furukawa T, et al. Adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency. Ann Neurol 1987;22:84-87.
85. Zappacosta B, Gellera C, Mazzuchelli F, et al. Clinical and genetic studies in Italian autosomal dominant cerebellar ataxias. Neurology 1997;48(Suppl):A177.
86. Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha-la-voltage-dependent calcium channel. Nat Genet 1997;15:62-69.

Datas de Publicação

Publicação nesta coleção
18 Out 2010
Data do Fascículo
Set 1997

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Allotey R, Twells R, Cemal C, et al. The spinocerebellar ataxia II locus is located within a 3-cM interval on chromosome 12q23-24.1 Am J Hum Genet 1995;57:185-189.

[2] 2. Arruda WO. Classificação das ataxias cerebelares hereditárias. Arq Neuropsiquiatr 1991;49:57-65.

[3] 3. Arruda WO, Petzl-Erler ML, Cardoso MA, Lehner T, Ott J. Late onset autosomal dominant cerebellar ataxia: a family description and linkage analysis with the HLA system. Arq Neuropsiquiatr 1991;49:285-291.

[4] 4. Baloh RW, Yue Q, Furman JM, Nelson SF. Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p. Ann Neurol 1997;41:8-16.

[5] 5. Belal S, Cancel G, Stevanin G, et al. Clinical and genetic analysis of a Tunisian family with autosomal dominant cerebellar ataxia type 1 linked to the SCA2 locus. Neurology 1994;44:1423-1426.

[6] 6. Ben Hamida C, Doerflinger N, Belal S, et al. Localization of Friedreich ataxia phenotype with selective vitamina E deficiency to chromosome 8q by homozigosity mapping. Nat Genet 1993;5:195-200.

[7] 7. Benomar A, Krols L, Stevanin G, et al. The gene for autosomal dominant cerebellar ataxia with pigmentary macular dystrophy maps to chromosome 3pl2-p21.1. Nat Genet 1995;10:84-88.

[8] 8. Brice A, Cancel G, Durr A, et al. SCA2 (spinocerebellar ataxia 2): another unstable CAG expansion. Molecular and clinical analysis of 101 patients. Neurology 1997;48(Suppl):A210.

[9] 9. Browne D, Gancher ST, Nutt JG, et al. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA 1. Nat Genet 1994;8:136-140.

[10] 10. Bürk K, Abele M, Fetter M, et al. Autosomal dominant cerebellar ataxia type I: clinical features and MRI in families with SCAl, SCA2 and SCA3. Brain 1996;119:1497-1505.

[11] 11. Burke JR, Winfield MS, Lewis KE et al. The Haw River syndrome: dentatorubral-pallidoluysian atrophy (DRPLA) in an African-American family. Nat Genet 1994;7:521-524.

[12] 12. Campuzano V, Montermini L, Molto MD, et al. Friedreich's ataxia: autosomal recessive disease caused by an introni GAA triplet repeat expansion. Science 1996;271:1423-1426.

[13] 13. Cancel G, Abbas N, Stevanin G, et al. Marked pheonotypic heterogeneity associated with expansion of a CAG reapeat sequence at the spinocerebellar ataxia 31 Machado-Joseph disease locus. Am J Hum Genet 1995;57:809-816.

[14] 14. Chamberlain S, Shaw J, Rowland A. et al. Mapping of mutation causing Friedreich's ataxia to human chromosome 9. Nature 1988;334:248-250.

[15] 15. Chung M-y, Ranum LPW, Duvick L, et al. Analysis of the CAG repeat expansion in spinocerebellar ataxia type 1: evidence for a possible mechanism predisposing to instability. Nat Genet 1993;5:254-258.

[16] 16. Claus D. Zur Differentialdiagnostik der Friedreich Ataxic Nervenarzt 1986;60:26-31.

[17] 17. Coutinho P, Andrade C. Autosomal dominant system degeneration in Portuguese families of the Azores Islands. Neurology 1978;28:703-709.

[18] 18. David G, Giubti P, Abbas N, et al. The gene for autosomal dominant cerebellar ataxia type II is located ina 5-cM region in 3pl2-pl3: genetic and physical mapping of the SCA7 locus. Am J Hum Genet 1996;59:1328-1336.

[19] 19. Dubourg O, Durr A, Cancel G, et al. Analysis of the SCAl CAG repeat in a large number of families with dominant ataxia: clinical and molecular correlations. Ann Neurol 1995;37:176-180.

[20] 20. Durr A, Cossee M, Agid Y, et al. Clinical and genetic abnormalities in patients with Friedreich's ataxia. N Engl J Med 1996.335:1169-1175.

[21] 21. Durr A, Smadja D, Cancel G, et al. Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies). Clinical and neuropathological analysis of 53 patients from thre unrelated SCA2 families. Brain 1995;118:1573-1581.

[22] 22. Enevoldson TP, Sanders MD, Harding AE. Autosomal dominant cerebellar ataxia qith pigmentary macular dystrophy: a clinical and genetic study of eight families. Brain 1994;117:445-460.

[23] 23. Farlow MR, DeMyer W, DIouhy S, Hodes ME. X-linked recessive inheritance of ataxia and adult-onset dementia: clinical features and preliminary linkage studies. Neurology 1987;37:602-607.

[24] 24. Filia A, De Michele G, Banfi S, et al. Has spinocerebellar ataxia type 2 a distinct phenotype? Genetic and clinical study of an Italian family. Neurology 1995;45:793-796.

[25] 25. Frontali M, Spadaro M, Giunti P, et al. Autosomal dominant pure cerebellar ataxia: neurological and genetic study. Brain 1992;115:1647-1654.

[26] 26. Gardner K, Alderson K, Galster B, et al. Autosomal dominant spinocerebellar ataxia: clinical description of a distinct hereditary ataxia and genetic localization to chromosome 16 (SCA4) in a Utah kindred. Neurology 1994;44(Suppl 2): A361.

[27] 27. Gatti RA, Berkel I, Boder E, et al. Localization of an ataxia-teleangiectasia gene to chromosome Uq22-23. Nature 1988;336:577-580.

[28] 28. Gatti RA, Boder E, Vinters HV, et al. Ataxia-teleangiectasia: an interdisciplinary approach to pathogenesis. Medicine 1991;70:99-119.

[29] 29. Genis D, Junck L, Fink JK. Machado-Joseph disease and SCA3: the genotype meets the phenotype. Neurology 1996;46:4-8.

[30] 30. Geschwind D, Perlman S, Pulst S. Frequency and clinical pheonotype of mutations in the gene for spinocerebellar ataxia type 2 (SCA2). Neurology 1997;48 (Suppl):A176.

[31] 31. Gispert S, Twells R, Orozco G, et al. Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23-24.1. Nat Genet 1993;4:295-299.

[32] 32. Giunti P, Sweeney MG, Harding AE. Detection of the Machado-Joseph disease I spinocerebellar ataxia three nucleotide repeat in families with autosomal dominant motor disorders, including the Drew family of Walworth. Brain 1995;118:1077-1085.

[33] 33. Gouw LG, Digre KB, Harris CP, et al. Autosomal dominant cerebellar ataxia with retinal degeneration: clinical, neuropathologic, and genetic analysis of a large kindred. Neurology 1994;44:1441-1447.

[34] 34. Harding AE. Early onset cerebellar ataxia with retained tendon reflexes: a clinical and genetic study of a disorder distinct from Friedreich's ataxia. J Neurol Neurosurg Psychiatry 1981;44:503-508.

[35] 35. Harding AE. The hereditary ataxias and related disorders. Edinburgh: Churchill-Linvingstone, 1984:266.

[36] 36. Harding AE, Matthews S, Jones S, et al. Spinocerebellar degeneration associated with a selective defect of vitamin E absorption. N Engl J Med 1985;313:32-35.

[37] 37. Hentati A, Deng HX, Hung WY, et al. Human alpha-tocopherol transfer protein: gene structure and mutations in familial vitamin E deficiency. Ann Neurol 1996;39:295-300.

[38] 38. Hoffman PM, Stuart WH, Earle KM, et al. Hereditary late onset cerebellar degeneration. Neurology 1971; 21:771-775.

[39] 39. Jackson JF, Currier RD, Terasaki PI, Morton NE. Spinocerebelar ataxia and HLA linkage: risk prediction by HLA typing. N Engl J Med 1977;296:1138-1141.

[40] 40. Jodice C, Frontali M, Parsichetti F, et al. The gene for spinal cerebellar ataxia 1 (SCA1) is flanked by two closely linked highly polymorphic microsatellite loci. Hum Mol Genet 1993;2:1383-1387.

[41] 41. Klostermann W, Zuhlke C, Heide W, et.al. Slow saccades and other eye movement disorders in spinocerebellar atrophy type 1. J Neurol 1997;244:105-111.

[42] 42. Koskinen T, Santavuori P, Sainio K, et al. Infantile onset spinocerebellar ataxia with sensory neuropathy: a new inherited disease. J Neurol Sci 1994,121:50-56.

[43] 43. Krendel DA, Gilchrest JM, Johnson AO, Bossen EH. Isolated deficiency of vitamin E with progressive neurologic deterioration. Neurology 1987;37:538-540.

[44] 44. La Spada AR, Paulson HL, Fischbeck KH. Trinucleotide repeat expansion neurological disease. Ann Neurol 1994;36:814-822.

[45] 45. Lima L, Coutinho P. Clinical criteria for diagnosis of Machado-Joseph disease: report of a non-Azorean Portuguese family. Neurology 1980;30:319-322.

[46] 46. Lopes-Cendes I, Andermann E, Attig E, et al. Confirmation of the SCA-2 locus as an alternative locus for dominantly inherited spinocerebellar ataxias and refinement of the candidate region. Am J Hum Genet 1994;54:774-781.

[47] 47. Lopes-Cendes I, Andermann E, Nechiporuk A, et al. Frequency and molecular characteristics of the spinocerebellar ataxia type 2 mutation. Neurology 1997;48(Suppl):A177.

[48] 48. Lopes-Cendes I, Silveira I, Maciel P, et al. Limits of clinical assessment in the accurate diagnosis of Machado-Joseph disease. Arch Neurol 1996;53:1168-1174.

[49] 49. Manila T, McCall A, Subramony SH, Zoghbi HY. Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado-Joseph disease. Ann Neurol 1995;38:68-72.

[50] 50. Middleton LT, Christodoulou K. Classification of autossomal recessive spinocerebellar ataxias (ARSCA) based on recent genetic studies. Neurology 1997;48 (Suppl):A177.

[51] 51. Nagafuchi S, Yanagisawa H, Sato K, et al. Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Genomics 1994;6:14-18.

[52] 52. Nakano KK, Dawson DM, Spence A. Machado disease: a hereditary ataxia in Portuguese immigrants to Massachusetts. Neurology 1972;22:49-55.

[53] 53. Nielsen JE, Sorensen SA, Hasholt L, Norremolle A. Dentatorubral-pallidoluysian atrophy: clinical features of a five-generation Danish family. Mov Disord 1996;11:533-541.

[54] 54. Nikali K, Isosomppi J, Lonqvist T et al. Toward cloning of a novel ataxia gene: refined assingment and physical map of IOSCA locus (SCA8) on 10q24. Genomics 1997; 39:185-191.

[55] 55. Nikali K, Suomalainen A, Terwilliger J, et al. Random search for shared chromosomal regions in four affected individuals: the assignment of a new hereditary ataxia locus. Am J Hum Genet 1995; 56:1088-1095.

[56] 56. Orozco DG, Nodarse FA, Cordovés SR, Augurger G. Autosomal dominant cerebellar ataxia: clinical analysis of 263 patients from a homogeneous population in Holguin, Cuba. Neurology 1990;40:1369-1375.

[57] 57. Orr HT, Chung M, Banfi S, et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 1993;4:221-226.

[58] 58. Ranum LPW, Lundgren JK, Schut LI, et al. Spinocerebellar ataxia type I and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia. Am J Hum Genet 1995;57:603-608.

[59] 59. Ranum LPW, Schutt LJ, Lundgren JK, et al. Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nat Genet 1994;8:280-284.

[60] 60. Richter RB. Late cortical cerebellar atrophy: a form of hereditary cerebellar ataxia. J Human Genet 1950;2:1-6.

[61] 61. Romanul FCA, Fowler HL, Radvany J, et al. Azorean disease of the nervous system. N Engl J Med 1977;296:1505-1508.

[62] 62. Rosenberg RN. Autosomal dominant cerebellar phenotypes: the genotype has settled the issue. Neurology 1995;45:1-5.

[63] 63. Rosenberg RN. DNA-tripIet repeats and neurologic diseases. N Engl J Med 1996; 335:1222-1224.

[64] 64. Rosenberg RN, Nyhan WL, Bay C, Shore P. Autosomal dominant striatonigral degeneration. Neurology 1976;26:703-714.

[65] 65. Roses AD. From genes to mechanisms to therapies: lessons to be learned from neurological diseases. Nature Med 1996;2:267-269.

[66] 66. Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia teleangiectasia gene with a product similar to PI-3 kinase. Science 1995;268:1749-1753.

[67] 67. Sequeiros J, Coutinho P. Epidemiology and clinical aspects of Machado-Joseph disease. In: Harding AE, Deufel T. Inherited ataxias. Adv Neurol 1993,61:139-153.

[68] 68. Silveira I, Lopes-Cendes I, Kish S, et al. Frequency of spinocerebellar type I, dentatorubropallidoluyisian atrophy, and Machado-Joseph disease in a large group of spinocerebellar atrophy patients. Neurology 1996;46:214-218.

[69] 69. Sokol RJ, Kayden HJ, Betas DB, et al. Isolated vitamin E deficiency in the absence of fat-mal-absorption - familial and sporadic cases: caracterization and investigation of causes. J Lab Clin Med 1988;111:548-559.

[70] 70. Spira PJ, McLeod JG, Evans WA. A spinocerebellar degeneration with X-linked inheritance. Brain 1979;102:27-41.

[71] 71. Stevanin G, Cancel G, Durr A, et al. The gene for spinal cerebellar ataxia 3 (SCA3) is located in a region of ~3 cM on chromosome 14q24.3-q32.2 Am J Hum Genet 1995;56:193-201.

[72] 72. Suzuki Y, Sasaki H, Wakisaka A, et al. Spinocerebellar ataxia I (SCA-I) in the Japanese: analysis of CAG trinucleotide repeat expansion and instability of the repeat for paternal transmission. Jap J Hum Genet 1995;40:131-143.

[73] 73. Takano T, Yamanouchi Y, Nagafuchi S, Yamada M. Assignment of the dentatorubral and pallidoluysian atrophy (DRPLA) gene to I2pl3.31 by fluorescence in situ hybridization. Genomics 1996;32:171-172.

[74] 74. Takano H, Ikeuchi T, Igarashi S. et al. A molecular genetic study on autosomal dominant ataxias in Japanese: comparison of the prevalence and CAG repeat expansions amons spinocerebellar ataxia (SCAl), spinocerebellar ataxia type 2 (SCA2), Machado-Joseph disease (MJD) and dentatotrubral-pallidoluysian atrophy (DRPLA). Neurology 1997;48(Suppl):A209.

[75] 75. Takiyama Y, Igarishi S, Rogaeva EA, et al. Evidence for inter-generational instability in the CAG reapeats in the MJD I gene and for conserved haplotype at flanking markers amongst Japanese and Caucasian subsjects with Machado-Joseph disease. Hum Mol Genet 1995; 4:1137-1146.

[76] 76. Takiyama Y, Nishisawa M, Tanaka H, et al. The gene for Machado-Joseph disease maps to chromosome 14q. Nat Genet 1993;3:300-304.

[77] 77. Teh BT, Silburn P, Lindblad K, et al. Familial periodic cerebellar ataxia without myokymia maps to a 19 cM region on 19pl3. Am J Hum Genet 1996;56:1443-1449.

[78] 78. Teive HAG, Arruda WO, Trevisol PCB, et al. Spinocerebellar ataxia: a genetic study in 30 Brazilian families. Neurology 1997;48(Suppl):A177.

[79] 79. Titica J, Van Bogaert L. Heredo-degenerative hemiballismus. Brain 1946;69:251-263.

[80] 80. Twist EC, Casabon LK, Ruttledge MH et al. Machado-Joseph disease maps to the same region of chromosome 14 as the spinocerebellar ataxia type 3 locus. J Med Genet 1995;32:25-31.

[81] 81. Vlghetto A, Froment JC, Trillet M, Aimard G. Magnetic resonance imaging in familial paroxysmal ataxia. Arch Neurol 1988;45:547-549.

[82] 82. Warner TT, Lennox GG, Janota I, Harding AE. Autosomal dominant dentatorubropallidoluysian atrophy in the United Kingdom. Mov Disord 1994;9:289-296.

[83] 83. Yakura H, Wasisaka A, Fujimori S, Itakura K. Hereditary ataxia and HLA genotypes. N Engl J Med 1974;291:154-155.

[84] 84. Yokota T, Wada Y, Furukawa T, et al. Adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency. Ann Neurol 1987;22:84-87.

[85] 85. Zappacosta B, Gellera C, Mazzuchelli F, et al. Clinical and genetic studies in Italian autosomal dominant cerebellar ataxias. Neurology 1997;48(Suppl):A177.

[86] 86. Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha-la-voltage-dependent calcium channel. Nat Genet 1997;15:62-69.