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      Heterozygous Missense Pathogenic Variants Within the Second Spectrin Repeat of SPTBN2 Lead to Infantile-Onset Cerebellar Ataxia

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          Abstract

          The term spinocerebellar ataxia encompasses a heterogeneous group of neurodegenerative disorders due to pathogenic variants in more than 100 genes, underlying 2 major groups of ataxia: autosomal dominant cerebellar ataxias (ADCA, also known as spinocerebellar ataxias [SCAs]) due to heterozygous variants or polyglutamine triplet expansions leading to adult-onset ataxia, and autosomal recessive spinocerebellar ataxias (ARCAs, also known as SCARs) due to biallelic variants, usually resulting in more severe and earlier-onset cerebellar ataxia. Certain ataxia genes, including SPTBN2 which encodes β-III spectrin, are responsible for both SCA and SCAR, depending on whether the pathogenic variant occurs in a monoallelic or biallelic state, respectively. Accordingly, 2 major phenotypes have been linked to SPTBN2: pathogenic heterozygous in-frame deletions and missense variants result in an adult-onset, slowly progressive ADCA (SCA5) through a dominant negative effect, whereas biallelic loss-of-function variants cause SCAR14, an allelic disorder characterized by infantile-onset cerebellar ataxia and cognitive impairment. Of note, 2 heterozygous missense variants (c.1438C>T, p.R480 W; c.1309C>G, p.R437G), both lying in the second spectrin repeat of SPTBN2, have been linked to infantile-onset cerebellar ataxia, similar to SCAR14. Here, we report a novel de novo heterozygous pathogenic missense variant (c.1310G>A) in SPTBN2 in a child with infantile-onset cerebellar ataxia and mild cognitive impairment. This variant affects the same R437 residue of the second spectrin repeat but results in a different amino acid change (p.R437Q). We review previously reported cases and discuss possible pathomechanisms responsible for the early-onset cerebellar phenotype due to disease-causing variants in the second spectrin repeat.

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          Author and article information

          Contributors
          (View ORCID Profile)
          Journal
          Journal of Child Neurology
          J Child Neurol
          SAGE Publications
          0883-0738
          1708-8283
          February 2020
          October 16 2019
          February 2020
          : 35
          : 2
          : 106-110
          Affiliations
          [1 ]Department of Pediatrics, Division of Pediatric Neurology, McGill University, Montreal, Quebec, Canada
          [2 ]IRCCS Policlinico San Martino, Genova, Italy
          [3 ]DINOGMI-Università degli Studi di Genova, Italy
          [4 ]McGill University Health Center (MUHC) Research Institute, Montreal, Quebec, Canada
          [5 ]Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
          Article
          10.1177/0883073819878917
          31617442
          e78b438a-f8ea-4ab7-a459-37c34902c425
          © 2020

          http://journals.sagepub.com/page/policies/text-and-data-mining-license

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