CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings

Abstract

The CACNA1A gene encodes the pore-forming α1A subunit of the voltage-gated CaV2.1 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 α1A affected residues are fully conserved throughout evolution and among the whole human CaV 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.

Genotype–phenotype relations for episodic ataxia genes: MDSGene systematic review

“…On review of the latest literature in the EA, published since the closing date of our initial systematic literature review (April 2021–June 2022), we identified a total of nine related articles (Table S4). These reported on 10 patients with novel variants in the CACNA1A [19–29]. In a case report of CACNA1A ‐related EA, dalfampridine 0.3 mg/kg was shown to resolve falls that had been unresponsive to acetazolamide (treatment was delayed due to insufficient literature on the topic) [30].…”

“…Our review of the latest literature (April 2021–June 2022) revealed a total of two related articles (Table S4). These were reported on two patients with novel variants in the PDHA1 gene [19–29].…”

“…These reported on 10 patients with novel variants in the CACNA1A [19][20][21][22][23][24][25][26][27][28][29]. In a case report of CACNA1A-related EA, dalfampridine 0.3 mg/kg was shown to resolve falls that had been unresponsive to acetazolamide (treatment was delayed due to insufficient literature on the topic) [30].…”

The Emerging Key Role of the mGluR1-PKCγ Signaling Pathway in the Pathogenesis of Spinocerebellar Ataxias: A Neurodevelopmental Viewpoint

“…In an autopsy study in early-onset SCA6, Purkinje cells were found to have reduced dendritic mass and spines, as well as reduced dendritic branching complexity [ 25 , 26 ]. Recent studies have shown that patients with CACNA1A mutations exhibit atrophy of the cerebellum during development, which is a recognizable neurodevelopmental disorder [ 27 ].…”

Meta-Analysis Identifies Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome

“…The Voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A) gene has been implicated in epileptic encephalopathy, familial hemiplegic migraine, episodic ataxia, and spinocerebellar ataxia [45,46] and has recently been reported in a small number of atypical Rett patients previously lacking known genetic mutations [47]. Voltage-sensitive calcium channels mediate the entry of calcium ions into excitatory neurons and are also involved in a variety of calcium-dependent processes, neurotransmitter release.…”