Dados do Trabalho

Título

PHENOTYPIC VARIABILITY ASSOCIATED CACNA1A GENE: A CASE SERIES

Apresentação dos casos

Introduction: The CACNA1A gene encodes calcium-permeable ion channels with high expression in neuronal tissue. Rare mutations in this gene have been associated with the following phenotypes: episodic ataxia type 2 (EA2); familial hemiplegic migraine with and without ataxia; developmental and epileptic encephalopathy 42 (DEE42); and spinocerebellar ataxia type 6 (SCA6). This case series describes 5 patients with mutations in the CACNA1A gene and different phenotypes. All phenotypes are of autosomal dominant inheritance. Case series: This case series presents 5 patients, all male, ranging in age from 3 to 42 years. All had progressive ataxia and four had neurodevelopmental delay (NDD) and congenital hypotonia. Three patients had the phenotype of episodic ataxia type 2, two of them with a pathogenic variant in deletion in very close regions, one at amino acid position 1501 and the other at position 1502, with a similar clinical presentation and evolution. The third patient, whose symptoms began at 11 years of age, with predominance of epileptic seizures and an exome with variant c.1594G>A, had the phenotype epileptic encephalopathy type 42 and the only adult patient, with onset of ataxia at 36 years of age, had the phenotype spinocerebellar ataxia 6 with exome Chr19: c.2010G>C.

Discussão

EA2 is a progressive paroxysmal disorder associated with congenital hypotonia, NDD, and movement disorders, beginning in childhood and adolescence. DEE42 is characterized by early onset difficult-to-control epilepsy, NDD and signs of pyramidal release. SCA6 is a progressive cerebellar ataxia of adult onset, which may be associated with hemiplegic migraine and/or sensory neuropathy.

Comentários finais

Phenotypic heterogeneity may be associated with the different variants, as there are cases in the literature with the same variant and mild or severe phenotype in the same family, probably due to polygenic and/or environmental interactions.

Referências

Indelicato, E., & Boesch, S. (2021). From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing. Frontiers in neurology, 12, 639994. https://doi.org/10.3389/fneur.2021.639994

Izquierdo-Serra, M., Fernández-Fernández, J. M., & Serrano, M. (2020). Rare CACNA1A mutations leading to congenital ataxia. Pflugers Archiv : European journal of physiology, 472(7), 791–809. https://doi.org/10.1007/s00424-020-02396-z

Myers, Candace T. et al. De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies. The American Journal of Human Genetics, Volume 99, Issue 2, 287 - 298. https://doi.org/10.1016/j.ajhg.2016.06.003

Sintas, C., Carreño, O., Fernàndez-Castillo, N., Corominas, R., Vila-Pueyo, M., Toma, C., Cuenca-León, E., Barroeta, I., Roig, C., Volpini, V., Macaya, A., & Cormand, B. (2017). Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia. Scientific reports, 7(1), 2514. https://doi.org/10.1038/s41598-017-02554-x

Yuan, X., Zheng, Y., Gao, F., Sun, W., Wang, Z., & Zhao, G. (2022). Case Report: A Novel CACNA1A Mutation Caused Flunarizine-Responsive Type 2 Episodic Ataxia and Hemiplegic Migraine With Abnormal MRI of Cerebral White Matter. Frontiers in neurology, 13, 899813. https://doi.org/10.3389/fneur.2022.899813

Palavras Chave

ataxias; Epileptic encephalopathy; CACNA1A