Expanding the β‐iii spectrin‐associated phenotypes toward non‐progressive congenital ataxias with neurodegeneration

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


(1) Background: A non‐progressive congenital ataxia (NPCA) phenotype caused by β‐III spectrin (SPTBN2) mutations has emerged, mimicking spinocerebellar ataxia, autosomal recessive type 14 (SCAR14). The pattern of inheritance, however, resembles that of autosomal dominant clas-sical 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 neurodegen-erative 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 del-eterious. (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 spec-trin‐based membrane skeleton, which, in turn, is responsible for the underlying disease mechanism.

Original languageEnglish
Article number2505
Pages (from-to)1-11
Number of pages11
JournalInternational Journal of Molecular Sciences
Issue number5
StatePublished - 1 Mar 2021


  • Neurodegeneration
  • Non‐progressive congenital ataxia
  • SPTBN2 gene
  • β‐III spectrin


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