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

(1) Background: A non-progressive congenital ataxia (NPCA) phenotype caused by β-III spectrin (<i>SPTBN2</i>) mutations has emerged, mimicking spinocerebellar ataxia, autosomal recessive type 14 (SCAR14). The pattern of inheritance, however, resembles that of autosomal dominant classical...

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Main Authors: Paula Sancho, Amparo Andrés-Bordería, Nerea Gorría-Redondo, Katia Llano, Dolores Martínez-Rubio, María Eugenia Yoldi-Petri, Luba Blumkin, Pablo Rodríguez de la Fuente, Fernando Gil-Ortiz, Leonor Fernández-Murga, Ana Sánchez-Monteagudo, Vincenzo Lupo, Belén Pérez-Dueñas, Carmen Espinós, Sergio Aguilera-Albesa
Format: Article
Language:English
Published: MDPI AG 2021-03-01
Series:International Journal of Molecular Sciences
Subjects:
<i>SPTBN2</i> gene
β-III spectrin
non-progressive congenital ataxia
neurodegeneration
Online Access:https://www.mdpi.com/1422-0067/22/5/2505
Description
Summary:(1) Background: A non-progressive congenital ataxia (NPCA) phenotype caused by β-III spectrin (<i>SPTBN2</i>) 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 <i>SPTBN2</i>-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 <i>SPTBN2</i> 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 <i>SPTBN2</i>-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.
ISSN:1661-6596
1422-0067

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