Clinical and molecular characteristics of a Brazilian family with spinocerebellar ataxia type 1

Lopes-Cendes, Iscia; Steiner, Carlos E.; Silveira, Isabel; Pinto-Junior, Walter; Maciel, Jayme A.; Rouleau, Guy A.

doi:10.1590/S0004-282X1996000300009

Abstracts

The spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of late onset neurodegenerative disorders. To date, seven different genes causing autosomal dominant SCA have been mapped: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, SCA7 and dentatorubropallidoluysian atrophy (DRPLA). Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA1, MJD/SCA3 and DRPLA. We studied one Brazilian family segregating an autosomal dominant type of SCA. A total of ten individuals were examined and tested for the presence of the SCA1, MJD and DRPLA mutations. Three individuals, one male and two females, were considered affected based on neurological examination; ages at onset were: 32, 36 and 41 years. The first complaint in all three patients was gait ataxia which progressed slowly over the years. Six individuals showed one allele containing an expanded CAG repeat in the SCA1 gene. The mean size of the expanded allele was 48.2 CAG units. Instability of the expanded CAG tract was seen in the two transmissions that were observed in this family. In both occasions there was a contraction of the CAG tract. Our study demonstrates that SCA1 occurs in the Brazilian population. In addition, our results stress the importance of molecular studies in the confirmation of diagnosis and for pre-symptomatic testing in SCAs.

neurodegenerative disease; spinocerebellar ataxia; trinucleotide expansion

As ataxias espinocerebelares (AECs) fazem parte de um grupo de doenças neurodegenerativas que apresentam grande heterogeneidade clínica e genética. Existem até o momento sete genes mapeados responsáveis pelas AECs de transmissão autossômica dominante: SCA1, SCA2, doença de Machado-Joseph (DA/7) ou SCA3, SCA4, SCA5, SCA7 e atrofia dentatorubropalidoluisiana (ADRPL). Uma expansão de um trínucletídeo CAG foi identificada como a mutação responsável na SCA], DMJ e ADRPL. Estudamos uma família brasileira com uma forma autossômica dominante de AEC. Dez indivíduos foram examinados e amostras de sangue foram colhidas para os estudos moleculares das mutações causadoras da SCA1, DMJ e ADRPL. Três membros da família foram considerados clinicamente afetados, um indivíduo do sexo masculino e dois do sexo feminino. A idade de início dos sintomas foi 32, 36 e 41 anos. Ataxia da marcha, lentamente progressiva, foi a primeira manifestação da doença nos três pacientes. Em seis indivíduos os estudos moleculares mostraram um alelo com expansão da sequência CAG contida no gene SCA1. O tamanho médio do alelo CAG expandido foi 48,2 unidades. O alelo SCA 1 expandido apresentou instabilidade nas duas trasmissões observadas, nas quais ocorreram contrações de uma e de seis unidades CAG. O nosso estudo mostra que a SCA1 ocorre na população brasileira. Além disso, os nossos resultados reforçam a importância dos estudos moleculares na confirmação diagnostica e no diagnóstico pré-sintomático de pacientes com AEC.

doença neurodegnerativa; ataxia espinocerebelar; expansão de trínucleotídeo

Clinical and molecular characteristics of a Brazilian family with spinocerebellar ataxia type 1

Características clínicas e moleculares de uma família Brasileira com ataxia espinocerebelar tipo 1

Iscia Lopes-Cendes^I; Carlos E. Steiner^II; Isabel Silveira^III; Walter Pinto-Junior^IV; Jayme A. Maciel^V; Guy A. Rouleau^I

^IMD, Centre for Research in Neuroscience, McGill University and The Montreal General Hospital Research Institute, Montreal (CRN-MGHRI), Quebec, Canada; MD, Departamento de Genética Médica, da Faculdade de Ciências Médicas da Universidade Estadual de Campinas (FCM-UNICAMP), Campinas, São Paulo, Brazil

^IIIPharm D, CRN-MGHRI

^IVMD, PhD, Departamento de Genética Médica, FCM-UNICAMP

^VMD, PhD, Departamento de Neurologia, FCM-UNICAMP

^VIMd, PhD, CRN-MGHRI

ABSTRACT

The spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of late onset neurodegenerative disorders. To date, seven different genes causing autosomal dominant SCA have been mapped: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, SCA7 and dentatorubropallidoluysian atrophy (DRPLA). Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA1, MJD/SCA3 and DRPLA. We studied one Brazilian family segregating an autosomal dominant type of SCA. A total of ten individuals were examined and tested for the presence of the SCA1, MJD and DRPLA mutations. Three individuals, one male and two females, were considered affected based on neurological examination; ages at onset were: 32, 36 and 41 years. The first complaint in all three patients was gait ataxia which progressed slowly over the years. Six individuals showed one allele containing an expanded CAG repeat in the SCA1 gene. The mean size of the expanded allele was 48.2 CAG units. Instability of the expanded CAG tract was seen in the two transmissions that were observed in this family. In both occasions there was a contraction of the CAG tract. Our study demonstrates that SCA1 occurs in the Brazilian population. In addition, our results stress the importance of molecular studies in the confirmation of diagnosis and for pre-symptomatic testing in SCAs.

Key words: neurodegenerative disease, spinocerebellar ataxia, trinucleotide expansion.

RESUMO

As ataxias espinocerebelares (AECs) fazem parte de um grupo de doenças neurodegenerativas que apresentam grande heterogeneidade clínica e genética. Existem até o momento sete genes mapeados responsáveis pelas AECs de transmissão autossômica dominante: SCA1, SCA2, doença de Machado-Joseph (DA/7) ou SCA3, SCA4, SCA5, SCA7 e atrofia dentatorubropalidoluisiana (ADRPL). Uma expansão de um trínucletídeo CAG foi identificada como a mutação responsável na SCA], DMJ e ADRPL. Estudamos uma família brasileira com uma forma autossômica dominante de AEC. Dez indivíduos foram examinados e amostras de sangue foram colhidas para os estudos moleculares das mutações causadoras da SCA1, DMJ e ADRPL. Três membros da família foram considerados clinicamente afetados, um indivíduo do sexo masculino e dois do sexo feminino. A idade de início dos sintomas foi 32, 36 e 41 anos. Ataxia da marcha, lentamente progressiva, foi a primeira manifestação da doença nos três pacientes. Em seis indivíduos os estudos moleculares mostraram um alelo com expansão da sequência CAG contida no gene SCA1. O tamanho médio do alelo CAG expandido foi 48,2 unidades. O alelo SCA 1 expandido apresentou instabilidade nas duas trasmissões observadas, nas quais ocorreram contrações de uma e de seis unidades CAG. O nosso estudo mostra que a SCA1 ocorre na população brasileira. Além disso, os nossos resultados reforçam a importância dos estudos moleculares na confirmação diagnostica e no diagnóstico pré-sintomático de pacientes com AEC.

Palavras-chave: doença neurodegnerativa, ataxia espinocerebelar, expansão de trínucleotídeo.

Texto completo disponível apenas em PDF.

Full text available only in PDF format.

Aceite: 10-maio-1996.

Dr. Iscia Lopes-Cendes - Centre for Research in Neuroscience, The Montreal General Hospital Research Institute, Room L12-132 - 1650 Cedar Ave.-Montreal, Quebec, Canada H3G 1A4. FAX 15514 9348265. E-mail: bke6@musicb.mcgill.ca

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Publication Dates

Publication in this collection
10 Nov 2010
Date of issue
Sept 1996

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

[1] 1. Benjamin CM, Adam S, Wiggins S, Theilmann JL, Copley TT, Bloch M, Squitieri F, McKellin W, Cox S, Brown SA, Kremer HPH, Burgess M, Meshino W, Summers A, Mcgregor D, Buchanan J, Greenberg C, Carson N, Ives E, Frecker M, Welch JP, Fuller A, Rosenblatt D, Miller S, Dufresne S, Roy M, Andermann E, Prevost C, Khalifa M, Girar d K, Taylor S, Hunter A, Goldsmith C, Whelan D, Eisenberg D, Soltan H, Kane J, Shokeir MHK, Gibson A, Cardwell S, Bamforth S, Graver S, Suchowersky O, Klimek M, Garber T, Gardner HA, MacLeod P, Hayden MR. Proceed with care: direct predictive testing for Huntington disease. Am J Hum Genet 1994;55:606-617.

[2] 2. Benomar A, Krols L, Stevanin G, Cancel G, LeGern E, David G, Ouhabi H, Martin J-J, Durr A, Zaim A, Ravise N, Busque C, Penet C, Van Regemorter N, Weissenbach J, Yahyaoui M, Chkili T, Agid Y, Van Broeckhoven C, Brice A. The gene for autosomal dominant cerebellar ataxia with pigmentary macular dystrophy maps to chromosome 3p 12-p21.1Nature Genet 1995; 10:84-88.

[3] 3. Cancel G, Abbas N, Stevanin G, Durr A, Chneiweiss H, Néri C, Duyckaerts C, Penet C, Cann HM, Agid Y, Brice A. Marked phenotypic heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3/Machado-Joseph disease locus. Am J Hum Genet 1995;57:809-816.

[4] 4. Chong SS, McCall AE, Cota J, Subramony SH, Orr HT, Hughes MR, Zoghbi HY. Gametic and somatic tissue-specific heterogeneity of the expanded SCA1 CAG repeat in spinocerebellar ataxia type 1. Nature Genet 1995;10:344-350.

[5] 5. Currier RD, Subramony SH. Is it possible to differentiate clinically the ataxias ? Paper presented at the 3rd International Workshop on Machado-Joseph disease, Furnas, São Miguel, Azores, April 7-9, 1994.

[6] 6. Gardner K, Alderson K, Galster B, Kaplan C, Leppert M, Ptacek L. Autosomal dominant spinocerebellar ataxia: clinical description of a distinct hereditary ataxia and genetic localization to chromosome 16 (SCA4) in a Utah kindred [Abstract], Neurology 1994; 44 (Suppl 2):921S.

[7] 7. Gispert S, Twells R, Orozco G, Brice A, Weber J, Heredero L, Schewfler K, Riley B, Allotey R, Nothers C, Hillermann R, Lunkes A, Khati C. Stevanini G, Hernandez A, Magarino C, Klockgether T, Durr A, Chneiweiss H, Enczmann J, Farral M, Beckmann J, Mullan M, Wernet P, Agid Y, Freund H-J, Williamson R, Auburger G and Chanberlain S. Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23-24.1. Nature Genet 1993;4:295-299.

[8] 8. Giunti P, Sweeney MG, Spadaro M, Jodice C, Novelletto A, Malaspina P, Frontali M, Harding AE. The trinucleotide repeat expansion on chromosome 6p (SCA 1) in autosomal dominant cerebellar ataxias. Brain 1994; 117:645-649.

[9] 9. Gouw LG, Kaplan CD, Haines JH, Digre KB, Rutledge SL, Matilla A, Leppert M, Zoghbi HY, Ptácek LI. Retinal degeneration characterizes a spinocerebellar ataxia mapping to chromosome 3p. Nature Genet 1995;10:89-93.

[10] 10. Harding AE. Clinical features and classification of inherited ataxias. In Harding AE, Deufel T (eds). Inherited ataxias. New York: Raven Press, Adv Neurol 1993;61:1-14.

[11] 11. Housman D. Gain of glutamines, gain of function ? Nature Genet 1995;10:3-6.

[12] 12. Jodice C, Frontali M, Persichetti F, Novelletto A, Pandolfo M, Sparadaro M, Giunti P, Schinaia G, Lulli P, Malaspina P, Plasmati R, Tola R, Antonelli A, Donato SD, Morocutti C, Weissenbach J, Cann HM, Terrenato L. The gene for spinal cerebellar ataxia 1 (SCA1) is flanked by two closely linked highly polymorphic microsatellite loci. Hum Molec Genet 1993;2:1383-1387.

[13] 13. Jodice C, Malaspina P, Persichetti F, Novelletto A, Spadaro M, Giunti P, Morocutti C, Terrenato L, Harding AE, Frontali M. Effect of trinucleotide repeat length and parental sex on phenotypic variation in spinocerebellar ataxia I. Am J Hum Genet 1994;54:959-965.

[14] 14. Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I, Kimura J, Narumiya S, Kakizuka A. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nature Genet 1994;8:221-228.

[15] 15. Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, Takahashi H, Kondo R, Ishikawa A, Hayashi T, Saito M, Tomoda A, Miike T, Naito H, Ikuta F, Tsuji S. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nature Genet 1994;6:9-13.

[16] 16. Lopes-Cendes I, Andermann E, Attig E, Cendes F, Bosch S, Wagner M, Gerstenbrand F, Andermann F, Rouleau GA. 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.

[17] 17. Lopes-Cendes I, Andermann E, Rouleau GA. Evidence for the existence of a fourth dominantly inherited spinocerebellar ataxia locus. Genomics 1994,21:270-274.

[18] 18. Lopes-Cendes I, Silveira I, Maciel P, Gaspar C, Radvany J, Chitayat D, Babul R, Stewart J, Dolliver M, Robitaille Y, Rouleau G, Sequeiros J. Limits of clinical assessment in the accurate diagnosis of Machado-Joseph disease, 1996 [Submitted for publication]

[19] 19. Maciel P, Gaspar C, DeStefano A, Silveira I, Coutinho P, Radvany J, Dawson DM, Sudarsky L, Guimarães J, Loureiro JEL, Nezarati MM, Corwin LI, Lopes-Cendes I, Rooke K, Rosenberg R, MacLeod P, Farrer LA, Sequeiros J, Rouleau GA. Correlation between CAG repeat length and clinical features in Machado-Joseph disease. Am J Hum Genet 1995;57:54-61.

[20] 20. Matilla T, Volpini V, Gem's D, Roseli J, Corral J, Dávalos A, Molins A, Estivill X. Presymptomatic analysis of spinocerebellar ataxia type 1 (SCA1) via the expansion of the SCA 1 CAG-repeat in a large pedigree displaying anticipation and parental male bias. Hum Molec Genet 1993;2:2123-2128.

[21] 21. Nechiporuk A, Lopes-Cendes I, Nechiporuk T, Starkman S, Frederick T, Andermann E, Rouleau G A, Weissenbach JS, Kort E, Pulst SM. Genetic mapping of the spinocerebellar ataxia type 2 gene on human chromosome 12. Neurology 1996 [in press]

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