Dataset Information

Anoctamin 10-Related Autosomal Recessive Cerebellar Ataxia: Comprehensive Clinical Phenotyping of an Irish Sibship.

ABSTRACT: The autosomal recessive cerebellar ataxias are a heterogeneous group of neurodegenerative disorders. Mutations in the anoctamin 10 gene (ANO10) recently have been identified as a cause of autosomal recessive spinocerebellar ataxia type 10. Comprehensive phenotypic data are provided on 3 siblings with homozygous ANO10 mutations, including detailed ocular and cognitive assessments and bladder involvement not previously described in the literature. Data also are provided on unblinded therapy with coenzyme Q10, previously reported as a possible therapy in ANO10-related ataxia. A genetic diagnosis in this family was obtained through next-generation sequencing techniques after over 10 years of expensive sequencing of individual genes using the traditional Sanger approach. Greater commercial availability of gene panels will improve the ability to obtain a genetic diagnosis in the uncommon "non-Friedreich's" recessive ataxias. Clinical recognition of these recessive ataxic syndromes will also inevitably improve as the full phenotypic spectrum is identified.

SUBMITTER: Bogdanova-Mihaylova P

PROVIDER: S-EPMC6353423 | biostudies-literature | 2017 Mar-Apr

REPOSITORIES: biostudies-literature

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Anoctamin 10-Related Autosomal Recessive Cerebellar Ataxia: Comprehensive Clinical Phenotyping of an Irish Sibship.

Bogdanova-Mihaylova Petya P Austin Neil N Alexander Michael D MD Cassidy Lorraine L Early Anne A Murphy Raymond P RP Murphy Sinéad M SM Walsh Richard A RA

Movement disorders clinical practice 20160718 2

The autosomal recessive cerebellar ataxias are a heterogeneous group of neurodegenerative disorders. Mutations in the anoctamin 10 gene (<i>ANO10</i>) recently have been identified as a cause of autosomal recessive spinocerebellar ataxia type 10. Comprehensive phenotypic data are provided on 3 siblings with homozygous <i>ANO10</i> mutations, including detailed ocular and cognitive assessments and bladder involvement not previously described in the literature. Data also are provided on unblinded ...[more]

PMID: 30838263

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Project description:Background and objectivesThe term autosomal recessive cerebellar ataxia (ARCA) encompasses a diverse group of heterogeneous degenerative disorders of the cerebellum. Spinocerebellar ataxia autosomal recessive 10 (SCAR10) is a distinct classification of cerebellar ataxia caused by variants in the ANO10 gene. Little is known about the molecular role of ANO10 or its role in disease. There is a wide phenotypic spectrum among patients, even among those with the same or similar genetic variants. This study aimed to characterize the molecular consequences of variants in ANO10 and determine their pathologic significance in patients diagnosed with SCAR10.MethodsWe presented 4 patients from 4 families diagnosed with spinocerebellar ataxia with potential pathogenic variants in the ANO10 gene. Patients underwent either clinical whole-exome sequencing or screening of a panel of known neuromuscular disease genes. Effects on splicing were studied using reverse transcriptase PCR to analyze complementary DNA. Western blots were used to examine protein expression.ResultsOne individual who presented clinically at a much earlier age than typical was homozygous for an ANO10 variant (c.1864A > G [p.Met622Val]) that produces 2 transcription products by altering an exonic enhancer site. Two patients, both of Lebanese descent, had a homozygous intronic splicing variant in ANO10 (c.1163-9A > G) that introduced a cryptic splice site acceptor, producing 2 alternative transcription products and no detectable wild-type protein. Both these variants have not yet been associated with SCAR10. The remaining patient was found to have compound heterozygous variants in ANO10 previously associated with SCAR10 (c.132dupA [p.Asp45Argfs*9] and c.1537T > C [p.Cys513Arg]).DiscussionWe presented rare pathogenic variants adding to the growing list of ANO10 variants associated with SCAR10. In addition, we described an individual with a much earlier age at onset than usually associated with ANO10 variants. This expands the phenotypic and allelic heterogeneity of ANO10-associated ARCA.

Dataset Information

Anoctamin 10-Related Autosomal Recessive Cerebellar Ataxia: Comprehensive Clinical Phenotyping of an Irish Sibship.

Publications

Anoctamin 10-Related Autosomal Recessive Cerebellar Ataxia: Comprehensive Clinical Phenotyping of an Irish Sibship.

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