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

Autores de CIPF

• Paula Sancho Salmerón

  Autor

• Desamparados Andrés Bordería

  Autor

• María Dolores Martínez Rubio

  Autor

• Ana Sánchez Monteagudo

  Autor

• Vincenzo Lupo

  Autor

• 

  Carmen Espinós Armero

  Autor

Participantes ajenos a CIPF

• Gorria-Redondo, N
• Llano, K
• Yoldi-Petri, ME
• Blumkin, L
• de la Fuente, PR
• Gil-Ortiz, F
• Fernandez-Murga, L
• Perez-Duenas, B
• Aguilera-Albesa, S

Grupos de Investigación

• Laboratorio de Enfermedades Raras Neurodegenerativas

Abstract

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

Keywords

• SPTBN2 gene; β -III spectrin; non-progressive congenital ataxia; neurodegeneration