Orphanet Journal of Rare Diseases

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

Jessica L. ZamboninEmail author,
Allison Bellomo,
Hilla Ben-Pazi,
David B. Everman,
Lee M. Frazer,
Michael T. Geraghty,
Amy D. Harper,
Julie R. Jones,
Benjamin Kamien,
Kristin Kernohan,
Mary Kay Koenig,
Matthew Lines,
Elizabeth Emma Palmer,
Randal Richardson,
Reeval Segel,
Mark Tarnopolsky,
Jason R. Vanstone,
Melissa Gibbons,
Abigail Collins,
Brent L. Fogel,
Care4Rare Canada Consortium,
Tracy Dudding-Byth and
Kym M. Boycott

Orphanet Journal of Rare Diseases201712:121

DOI: 10.1186/s13023-017-0672-7

Received: 14 November 2016

Accepted: 13 June 2017

Published: 28 June 2017

Abstract

Background

Spinocerebellar 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.

Results

Clinical 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.

Conclusions

Our 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.

Keywords

Human phenotype ontologies Congenital non-progressive spinocerebellar ataxia Spinocerebellar ataxia type 29 SCA29 Cerebellar atrophy ITPR1 Clinical management