Genotype-phenotype correlations, dystonia and disease progression in spinocerebellar ataxia type 14

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DOI

  • Viorica Chelban, Department of Neurology and Neurosurgery, Institute of Emergency Medicine, Chisinau, Republic of Moldova.
  • ,
  • Sarah Wiethoff, University of Tübingen
  • ,
  • Bjørn K Fabian-Jessing
  • Nourelhoda A Haridy, Department of Neurology and Psychiatry, Assiut University Hospital, Faculty of Medicine, Assiut, Egypt.
  • ,
  • Alaa Khan, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
  • ,
  • Stephanie Efthymiou, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
  • ,
  • Esther B E Becker, Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom; Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, United Kingdom; ajm267@cam.ac.uk.
  • ,
  • Emer O'Connor, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
  • ,
  • Joshua Hersheson, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
  • ,
  • Katrina Newland, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
  • ,
  • Allan Thomas Hojland, Department of Clinical Genetics, Aalborg University Hospital, Ladegaardsgade 5, 9000, Aalborg, Denmark.
  • ,
  • Pernille A Gregersen
  • Suzanne G Lindquist, Københavns Universitet
  • ,
  • Michael B Petersen, Aalborg Universitet
  • ,
  • Jørgen E Nielsen, Neurogenetics Clinic & Research Lab, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
  • ,
  • Michael Nielsen, Aalborg Universitet
  • ,
  • Nicholas W Wood, Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, University College London, London, United Kingdom.
  • ,
  • Paola Giunti, Deparmtent of Molecular Neuroscience, Ataxia Centre UCL, Institute of Neurology, London, UK.
  • ,
  • Henry Houlden, Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, University College London, London, United Kingdom.

BACKGROUND: Spinocerebellar ataxia type 14 is a rare form of autosomal dominant cerebellar ataxia caused by mutations in protein kinase Cγ gene. Clinically, it presents with a slowly progressive, mainly pure cerebellar ataxia.

METHODS: Using next generation sequencing, we screened 194 families with autosomal dominant cerebellar ataxia and normal polyglutamine repeats. In-depth phenotyping was performed using validated clinical rating scales neuroimaging and electrophysiological investigations.

RESULTS: We identified 25 individuals from 13 families carrying pathogenic mutations in protein kinase Cγ gene. A total of 10 unique protein kinase Cγ gene mutations have been confirmed of which 5 are novel and 5 were previously described. Our data suggest that the age at onset is highly variable; disease course is slowly progressive and rarely associated with severe disability. However, one third of patients presented with a complex ataxia comprising severe focal and/or task-induced dystonia, peripheral neuropathy, parkinsonism, myoclonus, and pyramidal syndrome. The most complex phenotype is related to a missense mutation in the catalytic domain in exon 11.

CONCLUSION: We present one of the largest genetically confirmed spinocerebellar ataxia type 14 cohorts contributing novel variants and clinical characterisation. We show that although protein kinase Cγ gene mutations present mainly as slowly progressive pure ataxia, more than a third of cases had a complex phenotype. Overall, our case series extends the phenotype and suggests that protein kinase Cγ gene mutations should be considered in patients with slowly progressive autosomal dominant cerebellar ataxia, particularly when myoclonus, dystonia, or mild cognitive impairment are present in the absence of polyglutamine expansion. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

OriginalsprogEngelsk
TidsskriftMovement Disorders
Vol/bind33
Nummer7
Sider (fra-til)1119-1129
Antal sider11
ISSN0885-3185
DOI
StatusUdgivet - jul. 2018

Bibliografisk note

© 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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