Cargando…
CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings
The CACNA1A gene encodes the pore-forming α(1A) subunit of the voltage-gated Ca(V)2.1 Ca(2+) 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, clinic...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153625/ https://www.ncbi.nlm.nih.gov/pubmed/34068417 http://dx.doi.org/10.3390/ijms22105180 |
_version_ | 1783698841588989952 |
---|---|
author | Martínez-Monseny, Antonio F. Edo, Albert Casas-Alba, Dídac Izquierdo-Serra, Mercè Bolasell, Mercè Conejo, David Martorell, Loreto Muchart, Jordi Carrera, Laura Ortez, Carlos I. Nascimento, Andrés Oliva, Baldo Fernández-Fernández, José M. Serrano, Mercedes |
author_facet | Martínez-Monseny, Antonio F. Edo, Albert Casas-Alba, Dídac Izquierdo-Serra, Mercè Bolasell, Mercè Conejo, David Martorell, Loreto Muchart, Jordi Carrera, Laura Ortez, Carlos I. Nascimento, Andrés Oliva, Baldo Fernández-Fernández, José M. Serrano, Mercedes |
author_sort | Martínez-Monseny, Antonio F. |
collection | PubMed |
description | The CACNA1A gene encodes the pore-forming α(1A) subunit of the voltage-gated Ca(V)2.1 Ca(2+) 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 α(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. |
format | Online Article Text |
id | pubmed-8153625 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81536252021-05-27 CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings Martínez-Monseny, Antonio F. Edo, Albert Casas-Alba, Dídac Izquierdo-Serra, Mercè Bolasell, Mercè Conejo, David Martorell, Loreto Muchart, Jordi Carrera, Laura Ortez, Carlos I. Nascimento, Andrés Oliva, Baldo Fernández-Fernández, José M. Serrano, Mercedes Int J Mol Sci Article The CACNA1A gene encodes the pore-forming α(1A) subunit of the voltage-gated Ca(V)2.1 Ca(2+) 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 α(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. MDPI 2021-05-13 /pmc/articles/PMC8153625/ /pubmed/34068417 http://dx.doi.org/10.3390/ijms22105180 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Martínez-Monseny, Antonio F. Edo, Albert Casas-Alba, Dídac Izquierdo-Serra, Mercè Bolasell, Mercè Conejo, David Martorell, Loreto Muchart, Jordi Carrera, Laura Ortez, Carlos I. Nascimento, Andrés Oliva, Baldo Fernández-Fernández, José M. Serrano, Mercedes CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings |
title | CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings |
title_full | CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings |
title_fullStr | CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings |
title_full_unstemmed | CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings |
title_short | CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings |
title_sort | cacna1a mutations causing early onset ataxia: profiling clinical, dysmorphic and structural-functional findings |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153625/ https://www.ncbi.nlm.nih.gov/pubmed/34068417 http://dx.doi.org/10.3390/ijms22105180 |
work_keys_str_mv | AT martinezmonsenyantoniof cacna1amutationscausingearlyonsetataxiaprofilingclinicaldysmorphicandstructuralfunctionalfindings AT edoalbert cacna1amutationscausingearlyonsetataxiaprofilingclinicaldysmorphicandstructuralfunctionalfindings AT casasalbadidac cacna1amutationscausingearlyonsetataxiaprofilingclinicaldysmorphicandstructuralfunctionalfindings AT izquierdoserramerce cacna1amutationscausingearlyonsetataxiaprofilingclinicaldysmorphicandstructuralfunctionalfindings AT bolasellmerce cacna1amutationscausingearlyonsetataxiaprofilingclinicaldysmorphicandstructuralfunctionalfindings AT conejodavid cacna1amutationscausingearlyonsetataxiaprofilingclinicaldysmorphicandstructuralfunctionalfindings AT martorellloreto cacna1amutationscausingearlyonsetataxiaprofilingclinicaldysmorphicandstructuralfunctionalfindings AT muchartjordi cacna1amutationscausingearlyonsetataxiaprofilingclinicaldysmorphicandstructuralfunctionalfindings AT carreralaura cacna1amutationscausingearlyonsetataxiaprofilingclinicaldysmorphicandstructuralfunctionalfindings AT ortezcarlosi cacna1amutationscausingearlyonsetataxiaprofilingclinicaldysmorphicandstructuralfunctionalfindings AT nascimentoandres cacna1amutationscausingearlyonsetataxiaprofilingclinicaldysmorphicandstructuralfunctionalfindings AT olivabaldo cacna1amutationscausingearlyonsetataxiaprofilingclinicaldysmorphicandstructuralfunctionalfindings AT fernandezfernandezjosem cacna1amutationscausingearlyonsetataxiaprofilingclinicaldysmorphicandstructuralfunctionalfindings AT serranomercedes cacna1amutationscausingearlyonsetataxiaprofilingclinicaldysmorphicandstructuralfunctionalfindings |