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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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.

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