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

• Published in: International journal of molecular sciences 2021-03, Vol.22 (5), p.2505
• Main Authors: Sancho, Paula, Andrés-Bordería, Amparo, Gorría-Redondo, Nerea, Llano, Katia, Martínez-Rubio, Dolores, Yoldi-Petri, María Eugenia, Blumkin, Luba, Rodríguez de la Fuente, Pablo, Gil-Ortiz, Fernando, Fernández-Murga, Leonor, Sánchez-Monteagudo, Ana, Lupo, Vincenzo, Pérez-Dueñas, Belén, Espinós, Carmen, Aguilera-Albesa, Sergio
• Format: Article
• Language: English
• Subjects: Actin; Age; Age of Onset; Amino Acid Sequence; Ataxia; Atrophy; Cell adhesion & migration; Cerebellar Ataxia - complications; Cerebellar Ataxia - congenital; Cerebellar Ataxia - genetics; Cerebellar Ataxia - pathology; Cerebellum; Child; Cognition & reasoning; Cognitive ability; Cohort Studies; Congenital diseases; Gait; Genetic Association Studies; Genotype & phenotype; Heredity; Humans; Hypotonia; Intellectual disabilities; Literature reviews; Magnetic resonance imaging; Male; Medical imaging; Mimicry; Modelling; Movement disorders; Mutation; Neurodegeneration; Neurodegenerative Diseases - complications; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - pathology; Neuroimaging; non-progressive congenital ataxia; Patients; Phenotype; Phenotypes; Phenotyping; Protein Conformation; Proteins; Sequence Homology; Spectrin; Spectrin - chemistry; Spectrin - genetics; Spectrin - metabolism; Spinocerebellar ataxia; SPTBN2 gene; Syndrome; Tremor (Muscular contraction); β-III spectrin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22052505

(1) Background: A non-progressive congenital ataxia (NPCA) phenotype caused by β-III spectrin ( ) 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 -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 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 -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.