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Title: CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings
Author: Martínez Montseny, Antonio Federico
Edo, Albert
Casas Alba, Dídac
Izquierdo Serra, Mercè
Bolasell, Mercè
Conejo, David
Martorell, Loreto
Muchart López, Jordi
Carrera, Laura
Ortez, Carlos Ignacio
Nascimento, Andrés
Oliva Miguel, Baldomero
Fernández Fernández, José M.
Serrano, Mercedes
Keywords: Malalties del sistema nerviós
Nervous system Diseases
Issue Date: 13-May-2021
Publisher: MDPI
Abstract: The CACNA1A gene encodes the pore-forming alpha(1A) subunit of the voltage-gated Ca(V)2.1 Ca2+ channel, essential in neurotransmission, especially in Purkinje cells. Mutations in CACNA1A result in great clinical heterogeneity with progressive symptoms, paroxysmal events or both. During infancy, clinical and neuroimaging findings may be unspecific, and no dysmorphic features have been reported. We present the clinical, radiological and evolutionary features of three patients with congenital ataxia, one of them carrying a new variant. We report the structural localization of variants and their expected functional consequences. There was an improvement in cerebellar syndrome over time despite a cerebellar atrophy progression, inconsistent response to acetazolamide and positive response to methylphenidate. The patients shared distinctive facial gestalt: oval face, prominent forehead, hypertelorism, downslanting palpebral fissures and narrow nasal bridge. The two alpha(1A) affected residues are fully conserved throughout evolution and among the whole human Ca-V channel family. They contribute to the channel pore and the voltage sensor segment. According to structural data analysis and available functional characterization, they are expected to exert gain- (F1394L) and loss-of-function (R1664Q/R1669Q) effect, respectively. Among the CACNA1A-related phenotypes, our results suggest that non-progressive congenital ataxia is associated with developmental delay and dysmorphic features, constituting a recognizable syndromic neurodevelopmental disorder.
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It is part of: International Journal of Molecular Sciences, 2021, vol. 22, num. 10, p. 5180-5193
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ISSN: 1661-6596
Appears in Collections:Articles publicats en revistes (Biomedicina)

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