Infantile-onset spinocerebellar ataxia type 5 associated with a novel SPTBN2 mutation: A case report

Mizuno, Tomoko; Kashimada, Ayako; Nomura, Toshihiro; Moriyama, Kengo; Yokoyama, Haruna; Hasegawa, Setsuko; Takagi, Motoki; Mizutani, Shuki

doi:10.1016/j.braindev.2019.03.002

Cited by 15 publications

(21 citation statements)

References 10 publications

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“…As is usually the case with Mendelian disorders, AR inheritance is associated with more severe disease than AD inheritance. SCA5 is characterized by a slowly progressive pure cerebellar ataxia, and marked global cerebellar atrophy on magnetic resonance imaging (MRI) in adulthood, although early onset has also been reported [9][10][11][12]. Most patients may show ataxic gait, disabling action and postural tremor, pyramidal signs, dorsal column involvement, and gaze palsy.…”

Section: Introductionmentioning

confidence: 99%

Expanding the β-III Spectrin-Associated Phenotypes toward Non-Progressive Congenital Ataxias with Neurodegeneration

Sancho

Andrés-Bordería

Gorría-Redondo

et al. 2021

IJMS

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(1) Background: A non-progressive congenital ataxia (NPCA) phenotype caused by b-III spectrin (SPTBN2) mutations has emerged, mimicking spinocerebellar ataxia, autosomal recessive type 14 (SCAR14). The pattern of inheritance, however, resembles that of autosomal dominant classical spinocerebellar ataxia type 5 (SCA5). (2) Methods: In-depth phenotyping of two boys studied by a customized gene panel. Candidate variants were sought by structural modeling and protein expression. An extensive review of the literature was conducted in order to better characterize the SPTBN2-associated NPCA. (3) Results: Patients exhibited an NPCA with hypotonia, developmental delay, cerebellar syndrome, and cognitive deficits. Both probands presented with progressive global cerebellar volume loss in consecutive cerebral magnetic resonance imaging studies, characterized by decreasing midsagittal vermis relative diameter measurements. Cortical hyperintensities were observed on fluid-attenuated inversion recovery (FLAIR) images, suggesting a neurodegenerative process. Each patient carried a novel de novo SPTBN2 substitution: c.193A > G (p.K65E) or c.764A > G (p.D255G). Modeling and protein expression revealed that both mutations might be deleterious. (4) Conclusions: The reported findings contribute to a better understanding of the SPTBN2-associated phenotype. The mutations may preclude proper structural organization of the actin spectrin-based membrane skeleton, which, in turn, is responsible for the underlying disease mechanism.

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Section: Introductionmentioning

confidence: 99%

Expanding the β-III Spectrin-Associated Phenotypes toward Non-Progressive Congenital Ataxias with Neurodegeneration

Sancho

Andrés-Bordería

Gorría-Redondo

et al. 2021

IJMS

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“…[5][6][7] Recently, a missense variant, c.1309C>G, p.R437G, located in the region encoding the second spectrin repeat of SPTBN2 like p.R480 W, has been described in a child with infantile-onset cerebellar ataxia and cognitive impairment. 8 The severe phenotype of these children overlaps with the congenital ataxia phenotype of SCAR14, leading to speculation about the presence of either a SCA5 modifier or an undetected SPTBN2 variant in trans (e.g., deep intronic or in a noncoding regulatory region) in these patients. 7 Here, we report a novel de novo heterozygous missense variant in SPTBN2 in a 4-year-old child with infantile-onset cerebellar ataxia and mild cognitive impairment, confirming that heterozygous missense variants in the second spectrin repeat of SPTBN2 can result in a childhood onset-phenotype.…”

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confidence: 99%

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

et al. 2019

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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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“…Such points will become clearer as the number of cases reported in the literature increases over time. The differential diagnosis is increasing on a continuous basis as other rare diseases are reported [12].…”

Section: Discussionmentioning

confidence: 99%

Genetic and phenotypic features of patients with childhood ataxias diagnosed by next-generation sequencing gene panel

Arslan

Öncel

Ceylan

et al. 2020

Brain and Development

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Infantile-onset spinocerebellar ataxia type 5 associated with a novel SPTBN2 mutation: A case report

Cited by 15 publications

References 10 publications

Expanding the β-III Spectrin-Associated Phenotypes toward Non-Progressive Congenital Ataxias with Neurodegeneration

Expanding the β-III Spectrin-Associated Phenotypes toward Non-Progressive Congenital Ataxias with Neurodegeneration

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

Genetic and phenotypic features of patients with childhood ataxias diagnosed by next-generation sequencing gene panel

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