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Spinocerebellar ataxia type 15: diagnostic assessment, frequency, and phenotypic features
  1. Matthis Synofzik1,2,
  2. Christian Beetz3,
  3. Claudia Bauer4,
  4. Michael Bonin4,
  5. Elena Sanchez-Ferrero3,
  6. Tanja Schmitz-Hübsch5,
  7. Ullrich Wüllner5,
  8. Thomas Nägele6,
  9. Olaf Riess4,
  10. Ludger Schöls1,2,
  11. Peter Bauer4
  1. 1Department of Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
  2. 2German Centre of Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany
  3. 3Institute of Clinical Chemistry, University of Jena, Jena, Germany
  4. 4Department of Medical Genetics, University of Tübingen, Tübingen, Germany
  5. 5Department of Neurology, University of Bonn, Bonn, Germany
  6. 6Department of Neuroradiology, University of Tübingen, Tübingen, Germany
  1. Correspondence to Dr Ludger Schöls, Clinical Neurogenetics, Department of Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, D 72076 Tübingen, Germany; ludger.schoels{at}uni-tuebingen.de

Abstract

Background To guide time- and cost-efficient analyses of the increasing number of autosomal-dominant spinocerebellar ataxia genes (SCAs), more information about frequency distributions, phenotypic characteristics and optimal diagnostic strategies is warranted.

Objective To assess the prevalence and phenotypic spectrum of SCA15 and to confirm multiplex ligation-dependent probe amplification (MLPA) as a robust and efficient strategy for routine molecular diagnosis.

Methods Fifty-six German SCA families negative for common repeat expansions were screened for ITPR1 deletions by MLPA. Samples with conspicuous MLPA data were additionally assessed by high-density single nucleotide polymorphism (SNP) array to confirm MLPA results and further determine the size of deletions. The phenotype of patients harbouring ITPR1 deletions was characterised by standardised clinical, electrophysiological and imaging assessment.

Results SCA15 accounted for 8.9% (5/56) of SCA families negative for common SCA repeat expansions. All deletions detected by MLPA were confirmed by SNP array. One of the ITPR1 deletions preserved exons 1 and 2 in the 5′ prime UTR of the ITPR1 gene. All patients with SCA15 (n=10) presented with slowly progressive cerebellar ataxia and vermal cerebellar atrophy, while clinical and electrophysiological signs of extracerebellar affection were mild and more variable.

Conclusions SCA15 is the most common non-trinucleotide repeat SCA in Central Europe. Screening for ITPR1 deletions should be considered in patients with slowly progressive SCA, vermal cerebellar atrophy and prominent tremor after excluding common SCA repeat expansions. Promoter and exon 2 of ITPR1 may be preserved from the deletion in some cases of SCA15.

  • Spinocerebellar ataxias
  • genetics
  • prevalence studies
  • cerebellum
  • movement disorders
  • neurology
  • movement disorders (other than Parkinson's)

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Footnotes

  • MS and ChB contributed equally to this study.

  • Funding Supported by the European Union (EUROSCA consortium; LSHM-CT-2004-503304) and the Stiftung für Pathobiochemie und Molekulare Diagnostik (to ChB). MS was supported by a grant from the Volkswagen Stiftung (Az. II/85158).

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the ethics committee at the University of Tübingen, Germany.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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