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Spinocerebellar Ataxias in Brazil—Frequencies and Modulating Effects of Related Genes

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Abstract

This study describes the frequency of spinocerebellar ataxias and of CAG repeats range in different geographical regions of Brazil, and explores the hypothetical role of normal CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7 genes on age at onset and on neurological findings. Patients with symptoms and family history compatible with a SCA were recruited in 11 cities of the country; clinical data and DNA samples were collected. Capillary electrophoresis was performed to detect CAG lengths at SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA12, SCA17, and DRPLA associated genes, and a repeat primed PCR was used to detect ATTCT expansions at SCA10 gene. Five hundred forty-four patients (359 families) were included. There were 214 SCA3/MJD families (59.6 %), 28 SCA2 (7.8 %), 20 SCA7 (5.6 %), 15 SCA1 (4.2 %), 12 SCA10 (3.3 %), 5 SCA6 (1.4 %), and 65 families without a molecular diagnosis (18.1 %). Divergent rates of SCA3/MJD, SCA2, and SCA7 were seen in regions with different ethnic backgrounds. 64.7 % of our SCA10 patients presented seizures. Among SCA2 patients, longer ATXN3 CAG alleles were associated with earlier ages at onset (p < 0.036, linear regression). A portrait of SCAs in Brazil was obtained, where variation in frequencies seemed to parallel ethnic differences. New potential interactions between some SCA-related genes were presented.

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References

  1. Schöls L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxia: clinical features, genetics, and pathogenesis. Lancet Neurol. 2004;3(5):291–304.

    Article  PubMed  Google Scholar 

  2. Bird TD. Hereditary Ataxia Overview. 1998 Oct 28 [Updated 2012 May 31]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. http://www.ncbi.nlm.nih.gov/books/NBK1138/.

  3. Sato N, Amino T, Kobayashi K, et al. Spinocerebellar ataxia type 31 is associated with “inserted” penta-nucleotide repeats containing (TGGAA)n. Am J Hum Genet. 2009;85:544–57.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Kobayashi H, Abe K, Matsuura T, et al. Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement. Am J Hum Genet. 2011;89:121–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Sequeiros J, Martins S, Silveira I. Epidemiology and population genetics of degenerative ataxias. Handb Clin Neurol. 2012;103:227–51.

    Article  PubMed  Google Scholar 

  6. Rasmussen A, Matsuura T, Ruano L, et al. Clinical and genetic analysis of four Mexican families with spinocerebellar ataxia type 10. Ann Neurol. 2001;50(2):234–9.

    Article  CAS  PubMed  Google Scholar 

  7. Teive HA, Roa BB, Raskin S, et al. Clinical phenotype of Brazilian families with spinocerebellar ataxia 10. Neurology. 2004;63(8):1509–12.

    Article  CAS  PubMed  Google Scholar 

  8. Alonso I, Jardim LB, Artigalas O, et al. Reduced penetrance of intermediate size alleles in spinocerebellar ataxia type 10. Neurology. 2006;66(10):1602–4.

    Article  CAS  PubMed  Google Scholar 

  9. Trott A, Jardim LB, Ludwig HT, et al. Spinocerebellar ataxias in 114 Brazilian families: clinical and molecular findings. Clin Genet. 2006;70(2):173–6.

    Article  CAS  PubMed  Google Scholar 

  10. Gatto EM, Gao R, White MC, et al. Ethnic origin and extrapyramidal signs in an Argentinean spinocerebellar ataxia type 10 family. Neurology. 2007;69:216–8.

    Article  CAS  PubMed  Google Scholar 

  11. Teive HA, Munhoz RP, Arruda WO, Raskin S, Werneck LC, Ashizawa T. Spinocerebellar ataxia type 10—a review. Parkinsonism Relat Disord. 2011;17(9):655–61.

    Article  PubMed  Google Scholar 

  12. García-Murias M, Quintáns B, Arias M, et al. Costa da Morte’ ataxia is spinocerebellar ataxia 36: clinical and genetic characterization. Brain. 2012;135(Pt 5):1423–35.

    Article  PubMed  Google Scholar 

  13. Basri R, Yabe I, Soma H, Sasaki H. Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families. J Hum Genet. 2007;52:848–55.

    Article  PubMed  Google Scholar 

  14. Teive HA, Munhoz RP, Arruda WO, et al. Spinocerebellar ataxias: genotype-phenotype correlations in 104 Brazilian families. Clinics. 2012;67(5):443–9.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Ranum LPW, Chung MY, Banfi S, Bryer A, Schut LJ, Ramesar R, et al. Molecular and clinical correlations in spinocerebellar ataxia type I: evidence for familial effects on the age at onset. Am J Hum Genet. 1994;55(2):244–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Maciel P, Gaspar C, DeStefano AL, Silveira I, Coutinho P, Radvany J, et al. Correlation between CAG repeat length and clinical features in Machado–Joseph disease. Am J Hum Genet. 1995;57(1):54–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Schöls L, Amoiridis G, Büttner T, Przuntek H, Epplen JT, Riess O. Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol. 1997;42(6):924–32.

    Article  PubMed  Google Scholar 

  18. Pulst SM, Santos N, Wang D, Yang H, Huynh D, et al. Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset. Brain. 2005;128:2297–303.

    Article  PubMed  Google Scholar 

  19. Gomez CM. Spinocerebellar Ataxia Type 6. 1998 Oct 23 [Updated 2008 Jun 16]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. http://www.ncbi.nlm.nih.gov/books/NBK1140/.

  20. Michalik A, Martin J-J, Van Broeckhoven C. Spinocerebellar ataxia type 7 associated with pigmentary retinal dystrophy. Eur J Hum Genet. 2004;12(1):2–15.

    Article  CAS  PubMed  Google Scholar 

  21. Han Y, Yu L, Zheng HM, Guan YT. Clinical and genetic study of spinocerebellar ataxia type 7 in East Asian population. Chin Med J (Engl). 2010;123(16):2274–8.

    PubMed  Google Scholar 

  22. DeStefano AL, Cupples LA, Maciel P, Gaspar C, Radvany J, Dawson DM, Sudarsky L, Corwin L, Coutinho P, MacLeod P, Sequeiros J, Rouleau GA, Farrer LA. A familial factor independent of CAG repeat length influences age at onset of Machado-Joseph disease. Am J Hum Genet. 1996; 59(1):119–127.

    Google Scholar 

  23. Jardim L, Silveira I, Pereira ML, et al. Searching for modulating effects of SCA2, SCA6 and DRPLA CAG tracts on the Machado-Joseph disease (SCA3) phenotype. Acta Neurol Scand. 2003;107(3):211–4.

    Article  CAS  PubMed  Google Scholar 

  24. Bettencourt C, Raposo M, Kazachkova N, Cymbron T, Santos C, Kay T, et al. The APOE ε2 allele increases the risk of earlier age at onset in Machado-Joseph disease. Arch Neurol. 2011;68(12):1580–3.

    Article  PubMed  Google Scholar 

  25. Emmel VE, Alonso I, Jardim LB, Saraiva-Pereira ML, Sequeiros J. Does DNA methylation in the promoter region of the ATXN3 gene modify age at onset in MJD (SCA3) patients? Clin Genet. 2011;79(1):100–2.

    Article  CAS  PubMed  Google Scholar 

  26. Miller SA, Dykes DD, Polesky HF. A simple salting-out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16(3):1215.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Cagnoli C, Michielotto C, Matsuura T, Ashizawa T, Margolis RL, Holmes SE, et al. Detection of large pathogenic expansions in FRDA1, SCA10, and SCA12 genes using a simple fluorescent repeat-primed PCR assay. J Mol Diagn. 2004;6(2):96–100.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Almeida T, Alonso I, Martins S, et al. Ancestral origin of the ATTCT repeat expansion in spinocerebellar ataxia type 10 (SCA10). PLoS One. 2009;4(2):e4553

    Google Scholar 

  29. Parra FC, Amado RC, Lambertucci JR, Rocha J, Antunes CM, Pena SDJ. Color and genomic ancestry in Brazilians. PNAS. 2003;100:177–82.

    Article  CAS  PubMed  Google Scholar 

  30. Pena SDJ, Pietro GD, Fuchshuber-Moraes M, et al. (2013) The Genomic Ancestry of Individuals from Different Geographical Regions of Brazil Is More Uniform Than Expected. PLoS One 6(2):e17063. doi:10.1371/journal.pone.0017063.

  31. Andrés AM, Lao O, Soldevila M, Calafell F, Bertranpetit J. Dynamics of CAG repeat loci revealed by the analysis of their variability. Hum Mutat. 2002;21:61–70.

    Article  Google Scholar 

  32. Jardim LB, Silveira I, Pereira ML, et al. A survey of spinocerebellar ataxia in South Brazil—66 new cases with Machado-Joseph disease, SCA7, SCA8, or unidentified disease-causing mutations. J Neurol. 2001;248(10):870–6.

    Article  CAS  PubMed  Google Scholar 

  33. Trento A. Do outro lado do Atlântico—Um século de Imigração Italiana no Brasil. São Paulo: Nobel; 1988.

    Google Scholar 

  34. Filla A, Mariotti C, Caruso G, et al. Relative frequencies of CAG expansions in spinocerebellar ataxia and dentatorubropallidoluysian atrophy in 116 Italian families. Eur Neurol. 2000;44(1):31–6.

    Article  CAS  PubMed  Google Scholar 

  35. Brusco A, Gellera C, Cagnoli C, et al. Molecular genetics of hereditary spinocerebellar ataxia: mutation analysis of spinocerebellar ataxia genes and CAG/CTG repeat expansion detection in 225 Italian families. Arch Neurol. 2004;61(5):727–33.

    Article  PubMed  Google Scholar 

  36. David G, Giunti P, Abbas N, et al. The gene for autosomal dominat cerebellar ataxia type II is located in a 5-cM region in 3p12-p13: genetic and physical mapping of the SCA7 locus. Am J Hum Genet. 1996;59(6):1328–36.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Bryer A, Krause A, Bill P, et al. The hereditary adult-onset ataxias in South Africa. J Neurol Sci. 2003;216(1):47–54.

    Article  PubMed  Google Scholar 

  38. Greenberg J, Solomon GAE, Vorster AA, Heckmann J, Bryer A. Origin of the SCA7 gene mutation in South Africa: implications for molecular diagnostics. Clin Genet. 2006;70:415–7.

    Article  CAS  PubMed  Google Scholar 

  39. Teive HA, Munhoz RP, Raskin S, et al. Spinocerebellar ataxia type 10: frequency of epilpesy in a large sample of Brazilian patients. Mov Disord. 2010;25(16):2875–8.

    Article  PubMed Central  PubMed  Google Scholar 

  40. Raskin S, Ashizawa T, Teive HA, et al. Reduced penetrance in a Brazilian family with spinocerebellar ataxia type 10. Arch Neurol. 2007;64(4):591–4.

    Article  PubMed  Google Scholar 

  41. Matsuura T, Yamagata T, Burgess DL, et al. Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nat Genet. 2000;26(2):191–4.

    Article  CAS  PubMed  Google Scholar 

  42. Maruyama H, Izumi Y, Morino H, et al. Difference in disease-free survival curve and regional distribution according to subtype of spinocerebellar ataxia: a study of 1,286 Japanese patients. Am J Med Genet. 2002;114(5):578–83.

    Article  PubMed  Google Scholar 

  43. Schmitz-Hübsch T, Coudert M, Bauer P, et al. Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms. Neurology. 2008;71(13):982–9.

    Article  PubMed  Google Scholar 

  44. Jardim LB, Hauser L, Kieling C, et al. Progression rate of neurological deficits in a 10-year cohort of SCA3 patients. Cerebellum. 2010;9(3):419–28.

    Article  PubMed  Google Scholar 

  45. Jacobi H, Bauer P, Giunti P, et al. The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study. Neurology. 2011;77(11):1035–41.

    Article  CAS  PubMed  Google Scholar 

  46. du Montcel TS, Charles P, Goizet C, et al. Factors influencing disease progression in autosomal dominant cerebellar ataxia and spastic paraplegia. Arch Neurol. 2012;69(4):500–8.

    Article  Google Scholar 

  47. Uchihara T, Fujigasaki H, Koyano S, Nakamura A, Yagishita S, et al. Non-expanded polyglutamine proteins in intranuclear inclusions of hereditary ataxias—triple-labeling immunofluorescence study. Acta Neuropathol. 2001;102:149–52.

    CAS  PubMed  Google Scholar 

  48. Lessing D, Bonini NM. Polyglutamine genes interact to modulate the severity and progression of neurodegeneration in Drosophila. PLoS Biol. 2008;6(2):e29.

    Article  PubMed Central  PubMed  Google Scholar 

  49. Storey E, du Sart D, Shaw JH, Lorentzos P, Kelly L, McKinley Gardner RJ, et al. Frequency of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Australian patients with spinocerebellar ataxia. Am J Med Genet. 2000;95(4):351–7.

    Article  CAS  PubMed  Google Scholar 

  50. Jiang H, Tang B, Xu B, Zhao GH, Shen L, Tang JG, et al. Frequency analysis of autosomal dominant spinocerebellar ataxias in Han population in the Chinese mainland and clinical and molecular characterization of spinocerebellar ataxia type 6. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2005;22(1):1–4.

    PubMed  Google Scholar 

  51. Juvonen V, Hietala M, Kairisto V, Savontaus ML. The occurrence of dominant spinocerebellar ataxias among 251 Finnish ataxia patients and the role of predisposing large normal alleles in a genetically isolated population. Acta Neurol Scand. 2005;111(3):154–62.

    Article  CAS  PubMed  Google Scholar 

  52. Srivastava AK, Choudhry S, Gopinath MS, Roy S, Tripathi M, Brahmachari SK, et al. Molecular and clinical correlation in five Indian families with spinocerebellar ataxia 12. Ann Neurol. 2001;50(6):796–800.

    Article  CAS  PubMed  Google Scholar 

  53. Jin DK, Oh MR, Song SM, Koh SW, Lee M, Kim GM, et al. Frequency of spinocerebellar ataxia types 1,2,3,6,7 and dentatorubral pallidoluysian atrophy mutations in Korean patients with spinocerebellar ataxia. J Neurol. 1999;246(3):207–10.

    Article  CAS  PubMed  Google Scholar 

  54. Alonso E, Martínez-Ruano L, De Biase I, Mader C, Ochoa A, Yescas P, et al. Distinct distribution of autosomal dominant spinocerebellar ataxia in the Mexican population. Mov Disord. 2007;22(7):1050–3.

    Article  PubMed  Google Scholar 

  55. van de Warrenburg BP, Sinke RJ, Verschuuren-Bemelmans CC, Scheffer H, Brunt ER, Ippel PF, et al. Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis. Neurology. 2002;58(5):702–8.

    Article  PubMed  Google Scholar 

  56. Vale J, Bugalho P, Silveira I, Sequeiros J, Guimarães J, Coutinho P. Autosomal dominant cerebellar ataxia: frequency analysis and clinical characterization of 45 families from Portugal. Eur J Neurol. 2010;17(1):124–8.

    Article  CAS  PubMed  Google Scholar 

  57. Dragasević NT, Culjković B, Klein C, Ristić A, Keckarević M, Topisirović I, et al. Frequency analysis and clinical characterization of different types of spinocerebellar ataxia in Serbian patients. Mov Disord. 2006;21(2):187–91.

    Article  PubMed  Google Scholar 

  58. Smith DC, Bryer A, Watson LM, Greenberg LJ. Inherited polyglutamine spinocerebellar ataxias in South Africa. S Afr Med J. 2012;102(8):683–6.

    Article  CAS  PubMed  Google Scholar 

  59. Pujana MA, Corral J, Gratacòs M, Combarros O, Berciano J, Genís D, et al. Spinocerebellar ataxias in Spanish patients: genetic analysis of familial and sporadic cases. Hum Genet. 1999;104(6):516–22.

    Article  CAS  PubMed  Google Scholar 

  60. Tsai HF, Liu CS, Leu TM, Wen FC, Lin SJ, Liu CC, et al. Analysis of trinucleotide repeats in different SCA loci in spinocerebellar ataxia patients and in normal population of Taiwan. Acta Neurol Scand. 2004;109(5):355–60.

    Article  CAS  PubMed  Google Scholar 

  61. Moseley ML, Benzow KA, Schut LJ, Bird TD, Gomez CM, Barkhaus PE, et al. Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurology. 1998;51(6):1666–71.

    Article  CAS  PubMed  Google Scholar 

  62. Socal M, Emmel V, Rieder C, Hilbig A, Saraiva-Pereira M, Jardim L Intrafamilial variability of Parkinson phenotype in SCAs: Novel cases due to SCA2 and SCA3 expansions. Parkinsonism Relat Disord. 2009:15(5):374–8.

    Google Scholar 

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Acknowledgments

We would like to thank the patients and their families for taking part in this study. We would also like to thank Thais Santa Rita for her technical assistance; Vanessa Erichsen Emmel and Alexis Trott for their contribution in early stages of this project; and Pedro Braga-Neto, Isabel Cristina Neves de Souza, and Raimunda Helena Feio for their contribution in recruiting some patients. This study was supported by FAPERGS, CNPq, CAPES, INAGEMP, and FIPE-HCPA. Castilhos RM was supported by INAGEMP. Furtado GV was supported by CAPES. Gheno TC, Russo A, Saraiva-Pereira ML, and Jardim LB were supported by CNPq.

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Correspondence to Laura Bannach Jardim.

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ESM Fig. 1

Correlations between the expanded CAG repeats and ages at onset in SCA1, SCA2, SCA3/MJD, SCA6, and SCA7 patients of the present series (JPEG 18 kb)

High resolution image (TIFF 1249 kb)

ESM Fig. 2

Distribution of the normal large CAG repeats at ATXN2 and at CACNA1A genes, in 102 SCA3/MJD patients studied by the three-panels approach (first and second rows), according to the presence or absence of abnormalities of ocular movement, nystagmus, dystonic movements, palpebral retraction, and absent reflexes. Distribution of the expanded repeats at ATXN3 gene in 230 SCA3/MJD patients (third row), according to the presence or absence of abnormalities of ocular movement, dystonic movements, and absent reflexes (JPEG 19 kb)

High resolution image (TIFF 7301 kb)

ESM Fig. 3

Distribution of the large CAG repeat at ATXN1 according to the presence of ophthalmoparesis in 49 SCA2 patients (JPEG 13 kb)

High resolution image (TIFF 4115 kb)

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de Castilhos, R.M., Furtado, G.V., Gheno, T.C. et al. Spinocerebellar Ataxias in Brazil—Frequencies and Modulating Effects of Related Genes. Cerebellum 13, 17–28 (2014). https://doi.org/10.1007/s12311-013-0510-y

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