Elsevier

Neurologia i Neurochirurgia Polska

Volume 51, Issue 1, January–February 2017, Pages 86-91
Neurologia i Neurochirurgia Polska

Review article
Spinocerebellar ataxia 15: A phenotypic review and expansion

https://doi.org/10.1016/j.pjnns.2016.10.006Get rights and content

Abstract

Spinocerebellar ataxia 15 (SCA15) is a clinically heterogeneous movement disorder characterized by the adult onset of slowly progressive cerebellar ataxia. ITPR1 is the SCA15 causative gene. However, despite numerous reports of genetically-confirmed SCA15, phenotypic uncertainty persists. We reviewed the phenotypes of 60 patients for whom SCA15 was confirmed by the presence of a genetic deletion involving ITPR1. The most prevalent symptoms were gait ataxia (88.3%), dysarthria (75.0%), nystagmus (73.3%), and limb ataxia (71.7%). We also present a novel SCA15 phenotype in a woman with an ITPR1 variant found to have hydrocephalus that improved with ventriculoperitoneal shunting. This is the first reported case of hydrocephalus associated with SCA15. In this review, we analyzed previously reported SCA15 phenotypes and present a novel SCA15 phenotype. We also address important considerations for evaluating patients with complex hereditary movement disorders.

Introduction

Spinocerebellar ataxias (SCAs) are a group of complex hereditary movement disorders that are challenging to diagnose due to their clinical heterogeneity. Harding [1] stratified those with autosomal-dominant inheritance into three categories of autosomal dominant cerebellar ataxia (ADCA) based upon clinical presentation. Genetic analyses have led to improved disease classifications, which have enabled the association of SCA with specific genetic disturbances.

SCA15 was first described by Storey et al. [2] in an Australian family with “pure” cerebellar ataxia. There have been several reports of patients with SCA15, and each has been phenotypically different. However, the genetic specificity of this disease increases as the efficiency of genetic analyses improves. Genetic analysis of the original Australian family (AUS1) revealed a deletion within the region 3p24.2-3pter of the ITPR1(inositol triphosphate receptor 1) gene [3]. This was further specified within the same family by van de Leemput et al., who described a deletion involving exons 1–10 of ITPR1 and half of the neighboring SUMF1 (sulfatase modifying factor 1) gene [4]. Despite thorough reporting of SCA15 phenotypes [2], [5], [6], [7], [8], [9], [10], [11], [12], [13], there is no consensus on a specific constellation of SCA15 symptoms. Therefore, diagnosis is made by genetic analysis.

The purpose of this review is to list previously reported SCA15 phenotypes matched with the their most current genetic analyses, present a novel SCA15 phenotype, and propose a diagnostic approach to this disorder.

Section snippets

Characterizing SCA15

SCA15 is defined by a specific genetic locus. Since the locus was identified, clinicians have tried to define the SCA15 phenotype so that it may be clinically differentiable from other diseases.

Novel case of SCA15

The proband, a 59-year-old woman, presented with chronic, progressive gait ataxia. Physical examination revealed lower extremity spasticity with mild hyperreflexia, bilateral ankle clonus, and positive Babinski's sign bilaterally. She had reduced touch, pinprick, temperature, and vibration sensations in a distance-dependent manner up to the elbows and knees bilaterally. Her gait was spastic, and she had a resting tremor in her right hand. The patient's father had dementia, a shuffling gait, and

Practical application and clinical considerations

Because of the significant phenotypic variation, the diagnosis of SCA15 requires more than clinical symptomatology. Based upon our analysis of previously reported SCA15 phenotypes, we propose that SCA15 should be considered in cases of adult-onset, chronic, progressive ataxia with dysarthria and evidence suggesting an autosomal-dominant inheritance pattern. Other symptoms that should increase the suspicion for SCA15 include limb ataxia and nystagmus, but other findings including tremor,

Conclusions

SCA15 is an autosomal dominant movement disorder characterized by slowly progressive cerebellar ataxia. Like many other clinically heterogenous movement disorders, SCA15 presents a significant diagnostic challenge to clinicians. We reviewed the literature and summarized the phenotypic findings of 60 individuals with ITPR1-related ataxia. Among the reported cases, the most common findings were gait ataxia, dysarthria, nystagmus, and limb ataxia. We also presented the case of a patient with a

Authors’ contribution

PT wrote the manuscript and coordinated author contributions. KG wrote the genetics portion of the manuscript. AS obtained patient consent and coordinated scheduling for patient visits. RR aided in writing and editing the manuscript. ZW aided in editing the manuscript. All authors reviewed and agreed upon the final manuscript.

Conflict of interest

None declared.

Acknowledgement and financial support

P. Tipton has no disclosures relevant to the manuscript. K. Guthrie has no disclosures relevant to the manuscript. A. Strongosky has no disclosures relevant to the manuscript. R Reimer has no disclosures relevant to the manuscript. Z. Wszolek is supported by the NIH P50 NS072187, Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Center for Individualized Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation), and The Sol Goldman

Ethics

The work described in this article has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans; Uniform Requirements for manuscripts submitted to Biomedical journals.

References (19)

  • M.A. Knight et al.

    Spinocerebellar ataxia type 15 (SCA15) maps to 3p24.2-3pter: exclusion of the ITPR1 gene, the human orthologue of an ataxic mouse mutant

    Neurobiol Dis

    (2003)
  • A.E. Harding

    The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families, including descendants of the ‘the Drew family of Walworth’

    Brain

    (1982)
  • E. Storey et al.

    A new autosomal dominant pure cerebellar ataxia

    Neurology

    (2001)
  • J. van de Leemput et al.

    Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans

    PLoS Genet

    (2007)
  • Y. Miyoshi et al.

    A novel autosomal dominant spinocerebellar ataxia (SCA16) linked to chromosome 8q22.1-24.1

    Neurology

    (2001)
  • K. Hara et al.

    Japanese SCA families with an unusual phenotype linked to a locus overlapping with SCA15 locus

    Neurology

    (2004)
  • M.J.U. Novak et al.

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

    Mov Disord

    (2010)
  • E. Di Gregorio et al.

    Two Italian families with ITPR1 gene deletion presenting a broader phenotype of SCA15

    Cerebellum

    (2010)
  • M. Synofizik et al.

    Spinocerebellar ataxia type 15: diagnostic assessment, frequency, and phenotypic features

    J Med Genet

    (2011)
There are more references available in the full text version of this article.

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