Review articleSpinocerebellar ataxia 15: A phenotypic review and expansion
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.
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Retrocollis as the cardinal feature in a de novo ITRP1 variant
2022, Brain and DevelopmentCitation Excerpt :In 2007, Van de Leemput et al. [5] described the linkage between ITPR1 gene variants and SCA15 in humans. Additional to cerebellar ataxia, dysphagia, head and/or arm tremor, involuntary movements, oculomotor disorders, pyramidal signs and cognitive impairment have also been described [6]. SCA 29, on the other hand, is a rare disease of early-onset non-progressive cerebellar ataxia with congenital hypotonia, gross motor delay and cognitive impairment, mostly caused by ITPR1 heterozygous missense variants – although deletions and insertions have also been described [7].
Type 1 metabotropic glutamate receptor and its signaling molecules as therapeutic targets for the treatment of cerebellar disorders
2018, Current Opinion in PharmacologyCitation Excerpt :Similar upregulation of IP3R1 was observed also in mutant ATXN3 with abnormally expanded polyglutamine chain (Figure 3d and Table 1) [22•,23–25]. Deletion and missense mutation in ITPR1 cause SCA15/16, which is a neurodegenerative disorder characterized by autosomal dominant inheritance and pure cerebellar ataxia [26]. SCA15/16 is mostly caused by heterozygous deletions in ITPR1, suggesting that the decrease in IP3R1 levels and reduced IP3R1-mediated Ca2+ release from the ER underlie the pathogenesis of SCA15/16 (Figure 3e) [22•,24,25].
TRIO gene segregation in a family with cerebellar ataxia
2018, Neurologia i Neurochirurgia PolskaCitation Excerpt :Retinal abnormalities, intellectual disability (ID), and peripheral neuropathy have been associated with genetic forms of cerebellar ataxia [1]. Oculomotor disturbances, such as impaired pursuit and saccades and nystagmus, have been documented in SCA patients [6,7]. Genetic studies have shown that certain classes of SCA are caused by CAG or other trinucleotide repeat expansions, while others are due to missense mutations and deletions [1,2,4,8].