Martínez Monseny, Antonio FedericoEdo, AlbertCasas Alba, DídacIzquierdo Serra, MercèBolasell, MercèConejo, DavidMartorell, LoretoMuchart, JordiCarrera, LauraOrtez, CarlosNascimento, AndrésOliva Miguel, BaldomeroFernández-Fernández, José Manuel, 1967-Serrano Masip, Mercedes2021-06-042021-06-042021Martínez-Monseny AF, Edo A, Casas-Alba D, Izquierdo-Serra M, Bolasell M, Conejo D, Martorell L, Muchart J, Carrera L, Ortez CI, Nascimento A, Oliva B, Fernández-Fernández JM, Serrano M. CACNA1A mutations causing early onset ataxia: profiling clinical, dysmorphic and structural-functional findings. Int J Mol Sci. 2021;22(10):5180. DOI: 10.3390/ijms221051801422-0067http://hdl.handle.net/10230/47763The 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.application/pdfeng© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).info:eu-repo/semantics/articlehttp://dx.doi.org/10.3390/ijms22105180CACNA1A geneCaV2.1 (P/Q-type) voltage-dependent calcium channelAtaxiaCerebellar atrophyDysmorphic traitsEarly-onset cerebellar ataxiainfo:eu-repo/semantics/openAccess