Rare CACNA1A mutations leading to congenital ataxia

Izquierdo Serra, Mercè; Fernández-Fernández, José Manuel, 1967-; Serrano, Mercedes L.

doi:http://dx.doi.org/10.1007/s00424-020-02396-z

Rare CACNA1A mutations leading to congenital ataxia

Citation

Izquierdo-Serra M, Fernández-Fernández JM, Serrano M. Rare CACNA1A mutations leading to congenital ataxia. Pflugers Arch. 2020;472(7):791-809. DOI: 10.1007/s00424-020-02396-z

Abstract

Human mutations in the CACNA1A gene that encodes the pore-forming α1A subunit of the voltage-gated CaV2.1 (P/Q-type) Ca2+ channel cause multiple neurological disorders including sporadic and familial hemiplegic migraine, as well as cerebellar pathologies such as episodic ataxia, progressive ataxia, and early-onset cerebellar syndrome consistent with the definition of congenital ataxia (CA), with presentation before the age of 2 years. Such a pathological role is in accordance with the physiological relevance of CaV2.1 in neuronal tissue, especially in the cerebellum. This review deals with the report of the main clinical features defining CA, along with the presentation of an increasing number of CACNA1A genetic variants linked to this severe cerebellar disorder in the context of Ca2+ homeostasis alteration. Moreover, the review describes each pathological mutation according to structural location and known molecular and cellular functional effects in both heterologous expression systems and animal models. In view of this information in correlation with the clinical phenotype, we take into consideration different pathomechanisms underlying the observed motor dysfunction in CA patients carrying CACNA1A mutations. Present therapeutic management in CA and options for the development of future personalized treatment based on CaV2.1 dysfunction are also discussed.