Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia

Jessica L Zambonin,Melissa Gibbons,Julie R Jones,Randal Richardson,Mary Kay Koenig,Elizabeth E Palmer ,Lee M Frazer,Benjamin Kamien,Kristin D Kernohan ,Jason Vanstone ,Hilla Ben‐Pazi ,Mark A Tarnopolsky ,Matthew A Lines ,Brent L Fogel,Tracy Dudding‐Byth ,David B Everman,Allison Bellomo,Michael T Geraghty,Reeval Segel,Abigail Collins,Amy Harper ,Kym M Boycott

doi:10.1186/s13023-017-0672-7

Abstract

BackgroundSpinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible.ResultsClinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3–12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort.ConclusionsOur findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural history of SCA29 through prospective studies is an important next step in better understanding the condition.

Highlights

Spinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment
Participants in this study were identified retrospectively based on a deleterious-appearing variant in Inositol 1 (ITPR1) identified by whole exome sequencing and clinical features overlapping with SCA29; as a result, recruitment bias cannot be excluded
Molecular findings Our cohort consisted of 9 males and 12 females with heterozygous mutations identified in ITPR1 from 15 unrelated families, including 2 families that had been previously reported [2, 3]

Summary

Introduction

Spinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. ITPR1 encodes a ligand-gated Ca2+ channel, inositol 1,4,5-trisphosphate receptor type 1, localized to the endoplasmic reticulum (ER) membrane, and is highly expressed in Purkinje cells in the cerebellum, where it regulates ER-stored Ca2+release Both missense mutations that were previously reported in SCA29 were localized to the coupling/regulatory domain of the ITPR1 gene product, and are hypothesized to alter calcium channel function [3]. Heterozygous deletions of this gene were already known to cause SCA15, an adult-onset, slowly-progressive ataxia. Improved understanding of SCA29 will facilitate early diagnosis and targeted intervention

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