Journal of Genetics

, Volume 97, Issue 1, pp 219–224 | Cite as

Genetic testing for clinically suspected spinocerebellar ataxias: report from a tertiary referral centre in India

  • Sowmya Devatha Venkatesh
  • Mahesh Kandasamy
  • Nagaraj S. Moily
  • Radhika Vaidyanathan
  • Lakshmi Narayanan Kota
  • Syama Adhikarla
  • Ravi Yadav
  • Pramod Kumar Pal
  • Sanjeev Jain
  • Meera Purushottam
Research Article

Abstract

Spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative syndromes, characterized by a wide range of muscular weakness and motor deficits, caused due to cerebellar degeneration. The prevalence of the syndromes of SCA varies across the world and is known to be linked to the instability of trinucleotide repeats within the high-end normal alleles, along with susceptible haplotype. We estimated sizes of the CAG or GAA repeat expansions at the SCA1, SCA2, SCA3, SCA12 and frataxin loci among 864 referrals of subjects to genetic counselling and testing (GCAT) clinic, National Institute of Mental Health and Neurosciences, Bengaluru, India, with suspected SCA. The most frequent mutations detected were SCA1 (\(n=100\) (11.6%)) and SCA2 (\(n=98\) (11.3%)) followed by SCA3 (\(n=40\) (4.6%)), FRDA (\(n=20\) (2.3%)) and SCA12 (\(n=8\) (0.9%)).

Keywords

CAG repeats genotyping India spinocerebellar ataxias 

Notes

Acknowledgements

We thank J. Muralidharan for excellent technical support in DNA isolation and Varalakshmi for the data entry. This work was supported by Indian Council of Medical Research (ICMR/002/208/2012/00126) for project funds and salary support for Mahesh Kandasamy, Sowmya Devatha Venkatesh and Radhika Vaidyanathan. We also thank all the patients, their family members and volunteers for their participation and cooperation.

References

  1. Bahl S., Virdi K., Mittal U., Sachdeva M. P., Kalla, A. K., Holmes S. E. et al. 2005 Evidence of a common founder for SCA12 in the Indian population. Ann. Hum. Genet. 69, 528–534.CrossRefPubMedGoogle Scholar
  2. Basri R., Yabe I., Soma H. and Sasaki H. 2007 Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families. J. Hum. Genet. 52, 848–855.CrossRefPubMedGoogle Scholar
  3. Basu P., Chattopadhyay B., Gangopadhaya P. K., Mukherjee S. C., Sinha K. K., Das S. K. et al. 2000 Analysis of CAG repeats in SCA1, SCA2, SCA3, SCA6, SCA7 and DRPLA loci in spinocerebellar ataxia patients and distribution of CAG repeats at the SCA1, SCA2 and SCA6 loci in nine ethnic populations of eastern India. Hum. Genet. 106, 597–604.CrossRefPubMedGoogle Scholar
  4. Bidichandani S. I. and Delatycki M. B. 1993 Friedreich ataxia. In Gene reviews (ed. R. A. Pagon, M. P. Adam, H. H. Ardinger, S. E. Wallace, A. Amemiya, L. J. Bean and K. Stephens). University of Washington, Seattle.Google Scholar
  5. Boonkongchuen P., Pongpakdee S., Jindahra P., Papsing C., Peerapatmongkol P., Wetchaphanphesat S. et al. 2014 Clinical analysis of adult-onset spinocerebellar ataxias in Thailand. BMC Neurol. 14, 75.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bryer A., Krause A., Bill P., Davids V., Bryant D., Butler J. et al. 2003 The hereditary adult-onset ataxias in South Africa.J. Neurol. Sci. 216, 47–54.CrossRefPubMedGoogle Scholar
  7. Chakravarty A. 2003 Friedreich’s ataxia–yesterday, today and tomorrow. Neurol. India 51, 176–182.PubMedGoogle Scholar
  8. Chakravarty A. and Mukherjee S. C. 2003 Primary degenerative cerebellar ataxias in ethnic Bengalees in West Bengal: some observations. Neurol. India 51, 227–234.PubMedGoogle Scholar
  9. Chattopadhyay B., Basu P., Gangopadhyay P. K., Mukherjee S. C., Sinha K. K., Chakraborty. et al. 2003 Variation of CAG repeats and two intragenic polymorphisms at SCA3 locus among Machado-Joseph disease/SCA3 patients and diverse normal populations from eastern India. Acta Neurol. Scand. 108, 407–414.Google Scholar
  10. Didierjean O., Cancel G., Stevanin G., Dürr A., Bürk K., Benomar A. et al. 1999 Linkage disequilibrium at the SCA2 locus. J. Med. Genet. 36, 415–417.PubMedPubMedCentralGoogle Scholar
  11. Faruq M., Scaria V., Singh I., Tyagi S., Srivastava A. K. and Mukerji M. 2009 SCA-LSVD: a repeat-oriented locus-specific variation database for genotype to phenotype correlations in spinocerebellar ataxias. Hum. Mutat. 30, 1037–1042.CrossRefPubMedGoogle Scholar
  12. Faruq M., Shakya S., Garg A. and Srivastava A. K. 2014 Spinocerebellar ataxia 2 and 12 mutations in an Indian family with cerebellar ataxia and slow saccades. Mov. Disord. Clin. Pract. 1, 267–270.CrossRefGoogle Scholar
  13. Harding A. E. 1983 Classification of the hereditary ataxias and paraplegias. Lancet 1, 1151–1155.CrossRefPubMedGoogle Scholar
  14. Hire R. R., Katrak S. M., Vaidya S., Radhakrishnan K. and Seshadri M. 2011 Spinocerebellar ataxia type 17 in Indian patients: two rare cases of homozygous expansions. Clin. Genet. 80, 472–477.CrossRefPubMedGoogle Scholar
  15. Jayadev S., Michelson S., Lipe H. and Bird T. 2006 Cambodian founder effect for spinocerebellar ataxia type 3 (Machado-Joseph disease). J. Neurol. Sci. 250, 110–113.CrossRefPubMedGoogle Scholar
  16. Kayal A. K., Goswami M., Das M. and Masaraf H. 2011 A case of spinocerebellar ataxia from ethnic tribe of Assam. Ann. Indian Acad. Neurol. 14, 122–123.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Krishna N., Mohan S., Yashavantha B. S., Rammurthy A., Kiran Kumar H. B., Mittal U. et al. 2007 SCA 1, SCA 2 & SCA 3/MJD mutations in ataxia syndromes in southern India. Indian J. Med. Res. 126, 465–470.PubMedGoogle Scholar
  18. Lee W. Y., Jin D. K., Oh M. R., Lee J. E., Song S. M., Lee E. A. et al. 2003 Frequency analysis and clinical characterization of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Korean patients. Arch. Neurol. 60, 858–868.CrossRefPubMedGoogle Scholar
  19. Martins S., Calafell F., Wong V. C. N., Sequeiros J. and Amorim A. 2006 A multistep mutation mechanism drives the evolution of the CAG repeat at MJD/SCA3 locus. Eur. J. Hum. Genet. 14, 932–940.CrossRefPubMedGoogle Scholar
  20. Martins S., Calafell F., Gaspar C., Wong V. C. N., Silveira I., Nicholson G. A. et al. 2007 Asian origin for the worldwide-spread mutational event in Machado-Joseph disease. Arch. Neurol. 64, 1502–1508.CrossRefPubMedGoogle Scholar
  21. Martins S., Soong B.-W., Wong V. C. N., Giunti P., Stevanin G. et al. 2012 Mutational origin of Machado–Joseph disease in the Australian aboriginal communities of Groote Eylandt and Yirrkala. Arch. Neurol. 69, 746–751.CrossRefPubMedGoogle Scholar
  22. Maschke M., Oehlert G., Xie T.-D., Perlman S., Subramony S. H., Kumar N. et al. 2005 Clinical feature profile of spinocerebellar ataxia type 1-8 predicts genetically defined subtypes. Mov. Disord. 20, 1405–1412.CrossRefPubMedGoogle Scholar
  23. Miller S. A., Dykes D. D. and Polesky H. F. 1988 A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 16, 1215.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Mittal U., Srivastava A. K., Jain S., Jain S. and Mukerji M. 2005a Founder haplotype for Machado-Joseph disease in the Indian population: novel insights from history and polymorphism studies. Arch. Neurol. 62, 637–640.CrossRefPubMedGoogle Scholar
  25. Mittal U., Sharma S., Chopra R., Dheeraj K., Pal P. K., Srivastava A. K. and Mukerji M. 2005b Insights into the mutational history and prevalence of SCA1 in the Indian population through anchored polymorphisms. Hum. Genet. 118, 107–114.CrossRefPubMedGoogle Scholar
  26. Mukerji M., Choudhry S., Saleem Q., Padma M. V., Maheshwari M. C. and Jain S. 2000 Molecular analysis of Friedreich’s ataxia locus in the Indian population. Acta Neurol. Scand. 102, 227–229.CrossRefPubMedGoogle Scholar
  27. Netravathi M., Pal P. K., Purushottam M., Thennarasu K., Mukherjee M. and Jain S. 2009 Spinocerebellar ataxias types 1, 2 and 3: age adjusted clinical severity of disease at presentation correlates with size of CAG repeat lengths. J. Neurol. Sci. 277, 83–86.CrossRefPubMedGoogle Scholar
  28. Pang J., Allotey R., Wadia N., Sasaki H., Bindoff L. and Chamberlain S. 1999 A common disease haplotype segregating in spinocerebellar ataxia 2 (SCA2) pedigrees of diverse ethnic origin. Eur. J. Hum. Genet. 7, 841–845.CrossRefPubMedGoogle Scholar
  29. Rossi M., Perez-Lloret S., Doldan L., Cerquetti D., Balej J., Millar Vernetti P. et al. 2014 Autosomal dominant cerebellar ataxias: a systematic review of clinical features. Eur. J. Neurol. 21, 607–615.CrossRefPubMedGoogle Scholar
  30. Ruano L., Melo C., Silva M. C. and Coutinho P. 2014 The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology 42, 174–183.CrossRefPubMedGoogle Scholar
  31. Saleem Q., Choudhry S., Mukerji M., Bashyam L., Padma M. V., Chakravarthy A. et al. 2000 Molecular analysis of autosomal dominant hereditary ataxias in the Indian population: high frequency of SCA2 and evidence for a common founder mutation. Hum. Genet. 106, 179–187.CrossRefPubMedGoogle Scholar
  32. Sequeiros J., Martins S. and Silveira I. 2012 Epidemiology and population genetics of degenerative ataxias. Handb. Clin. Neurol. 103, 227–251.CrossRefPubMedGoogle Scholar
  33. Singh I., Faruq M., Mukherjee O., Jain S., Pal P. K., Srivastav M. V. P. et al. 2010 North and south Indian populations share a common ancestral origin of Friedreich’s ataxia but vary in age of GAA repeat expansion. Ann. Hum. Genet. 74, 202–210.CrossRefPubMedGoogle Scholar
  34. Sinha K. K., Worth P. F., Jha D. K., Sinha S., Stinton V. J., Davis M. B. et al. 2004 Autosomal dominant cerebellar ataxia: SCA2 is the most frequent mutation in eastern India. J. Neurol. Neurosurg. Psychiatry 75, 448–452.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Subramony S. H. and Dürr A. 2012. Inherited ataxias. Handb. Clin. Neurol. 103 ( https://doi.org/10.1016/B978-0-444-51892-7.00051-6).
  36. Sumathipala D. S., Abeysekera G. S., Jayasekara R. W., Tallaksen C. M. E. and Dissanayake V. H. W. 2013 Autosomal dominant hereditary ataxia in Sri Lanka. BMC Neurol. 13, 39.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Sura T., Eu-Ahsunthornwattana J., Youngcharoen S., Busabaratana M., Dejsuphong D., Trachoo O. et al. 2009 Frequencies of spinocerebellar ataxia subtypes in Thailand: window to the population history? J. Hum. Genet. 54, 284–288.CrossRefPubMedGoogle Scholar
  38. Tan E. K. 2003 Autosomal dominant spinocerebellar ataxias: an Asian perspective. Can. J. Neurol. Sci. 30, 361–367.CrossRefPubMedGoogle Scholar
  39. Tan E. K., Law H. Y., Zhao Y., Lim E., Chan L. L., Chang H. M. et al. 2000 Spinocerebellar ataxia in Singapore: predictive features of a positive DNA test? Eur. Neurol. 44, 168–171.CrossRefPubMedGoogle Scholar
  40. Tang B., Liu C., Shen L., Dai H., Pan Q., Jing L. et al. 2000 Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds. Arch. Neurol. 57, 540–544.CrossRefPubMedGoogle Scholar
  41. Wadia N., Pang J., Desai J., Mankodi A., Desai M. and Chamberlain S. 1998 A clinicogenetic analysis of six Indian spinocerebellar ataxia (SCA2) pedigrees. The significance of slow saccades in diagnosis. Brain. 121, 2341–2355.CrossRefPubMedGoogle Scholar
  42. Wang J., Wu Y., Lei L., Shen L., Jiang H., Zhou Y. et al. 2010 Polynucleotide repeat expansion of nine spinocerebellar ataxia subtypes and dentatorubral-pallidoluysian atrophy in healthy Chinese Han population. Chin. J. Med. Genet. 27, 501–505.Google Scholar
  43. Wu Y. R., Lin H. Y., Chen C. M., Gwinn-Hardy K., Ro L. S., Wang Y. C. et al. 2004 Genetic testing in spinocerebellar ataxia in Taiwan: expansions of trinucleotide repeats in SCA8 and SCA17 are associated with typical Parkinson’s disease. Clin. Genet. 65, 209–214.CrossRefPubMedGoogle Scholar
  44. Yabe I., Sasaki H., Matsuura T., Takada A., Wakisaka A., Suzuki Y. et al. 1998 SCA6 mutation analysis in a large cohort of the Japanese patients with late-onset pure cerebellar ataxia. J. Neurol. Sci. 156, 89–95.CrossRefPubMedGoogle Scholar

Copyright information

© Indian Academy of Sciences 2018

Authors and Affiliations

  • Sowmya Devatha Venkatesh
    • 1
    • 2
  • Mahesh Kandasamy
    • 1
    • 2
    • 3
  • Nagaraj S. Moily
    • 1
    • 4
  • Radhika Vaidyanathan
    • 2
    • 5
  • Lakshmi Narayanan Kota
    • 2
  • Syama Adhikarla
    • 2
  • Ravi Yadav
    • 6
  • Pramod Kumar Pal
    • 1
    • 6
  • Sanjeev Jain
    • 1
    • 2
  • Meera Purushottam
    • 1
    • 2
  1. 1.Department of Psychiatry, Genetic Testing and Counselling ClinicNational Institute of Mental Health and NeurosciencesBengaluruIndia
  2. 2.Department of Psychiatry, Molecular Genetics LaboratoryNational Institute of Mental Health and NeurosciencesBengaluruIndia
  3. 3.Laboratory of Stem Cells and Neuroregeneration, Department of Animal Science, School of Life SciencesBharathidasan UniversityTiruchirappalliIndia
  4. 4.University of MelbourneMelbourneAustralia
  5. 5.Department of PsychologyFlorida State UniversityTallahasseeUSA
  6. 6.Department of NeurologyNational Institute for Mental Health and NeurosciencesBengaluruIndia

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