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An ITPR1 gene deletion causes spinocerebellar ataxia 15/16: A genetic, clinical and radiological description

Authors

  • Marianne J.U. Novak MRCP,

    1. Department of Neurogenetics, The National Hospital for Neurology and Neurosurgery, London, United Kingdom
    2. Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, London, United Kingdom
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  • Mary G. Sweeney BSc,

    1. Department of Neurogenetics, The National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Abi Li BSc,

    1. Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
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  • Colm Treacy MSc, RN,

    1. Department of Neurogenetics, The National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Hoskote S. Chandrashekar MD, DM,

    1. Lysholm Department of Neuroradiology, The National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Paola Giunti MD, PhD,

    1. Department of Neurogenetics, The National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Robert G. Goold PhD,

    1. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
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  • Mary B. Davis PhD,

    1. Department of Neurogenetics, The National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Henry Houlden MRCP, PhD,

    1. Department of Neurogenetics, The National Hospital for Neurology and Neurosurgery, London, United Kingdom
    2. Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
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  • Sarah J. Tabrizi FRCP, PhD

    Corresponding author
    1. Department of Neurogenetics, The National Hospital for Neurology and Neurosurgery, London, United Kingdom
    2. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
    • Box 104, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom
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  • Henry Houlden is an equal senior author.

  • Potential conflicts of interest: HH and ST are supported by MRC grants. The authors have no other financial disclosures to make and report no conflict of interest.

Abstract

the purpose of this study was to characterise a novel family with very slowly progressive pure spinocerebellar ataxia (SCA) caused by a deletion in the inositol 1,4,5-triphosphate receptor 1 (ITPR1) gene on chromosome 3. This is a detailed clinical, genetic, and radiological description of the genotype. Deletions in ITPR1 have been shown to cause SCA15/SCA16 in six families to date. A further Japanese family has been identified with an ITPR1 point mutation. The exact prevalence is as yet unknown, but is probably higher than previously thought. The clinical phenotype of the family is described, and videotaped clinical examinations are presented. Serial brain magnetic resonance imaging studies were carried out on one affected individual, and genetic analysis was performed on several family members. Protein analysis confirmed the ITPR1 deletion. Affected subjects display a remarkably slow, almost pure cerebellar syndrome. Serial magnetic resonance imaging shows moderate cerebellar atrophy with mild inferior parietal and temporal cortical volume loss. Genetic analysis shows a deletion of 346,487 bp in ITPR1 (the second largest ITPR1 deletion reported to date), suggesting SCA15 is due to a loss of ITPR1 function. Western blotting of lymphoblastoid cell line protein confirms reduced ITPR1 protein levels. SCA15 is a slowly or nonprogressive pure cerebellar ataxia, which appears to be caused by a loss of ITPR1 function and a reduction in the translated protein. Patients with nonprogressive or slowly progressive ataxia should be screened for ITPR1 defects. © 2010 Movement Disorder Society.

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