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GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females

BACKGROUND: De novo heterozygous mutations in the GNAO1 gene, encoding the Gα o subunit of G-proteins, are the cause of a severe neurodevelopmental disorder, featuring early infantile seizures, profound cognitive dysfunction and, occasionally, movement disorder (early infantile epileptic encephalopa...

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Autores principales: Marcé-Grau, Anna, Dalton, James, López-Pisón, Javier, García-Jiménez, María Concepción, Monge-Galindo, Lorena, Cuenca-León, Ester, Giraldo, Jesús, Macaya, Alfons
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830060/
https://www.ncbi.nlm.nih.gov/pubmed/27072799
http://dx.doi.org/10.1186/s13023-016-0416-0
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author Marcé-Grau, Anna
Dalton, James
López-Pisón, Javier
García-Jiménez, María Concepción
Monge-Galindo, Lorena
Cuenca-León, Ester
Giraldo, Jesús
Macaya, Alfons
author_facet Marcé-Grau, Anna
Dalton, James
López-Pisón, Javier
García-Jiménez, María Concepción
Monge-Galindo, Lorena
Cuenca-León, Ester
Giraldo, Jesús
Macaya, Alfons
author_sort Marcé-Grau, Anna
collection PubMed
description BACKGROUND: De novo heterozygous mutations in the GNAO1 gene, encoding the Gα o subunit of G-proteins, are the cause of a severe neurodevelopmental disorder, featuring early infantile seizures, profound cognitive dysfunction and, occasionally, movement disorder (early infantile epileptic encephalopathy-17). METHODS: We report a further case of this association in a 20 month-old Spanish girl with neonatal-onset refractory seizures, progressive microcephaly, oral-lingual dyskinesia and nearly absent psychomotor development. We performed whole-exome sequencing, a computational structural analysis of the novel gene variant identified and reviewed the previously reported cases. RESULTS: Trio whole-exome-sequencing uncovered a de novo p.Leu199Pro GNAO1 mutation. Computational structural analysis indicates this novel variant adversely affects the stability of the G-protein heterotrimeric complex as a whole. Of note, our patient showed a sustained seizure reduction while on a ketogenic diet. CONCLUSIONS: With this observation, a total of twelve patients with GNAO1 encephalopathy have been reported. Oral-lingual dyskinesia and responsiveness of seizures to ketogenic diet are novel features. The distorted sex ratio (12/12 females) of the condition remains unexplained; a differential gender effect of the disruption of G-protein- mediated signal transduction on the developing brain can be hypothesized. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-016-0416-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-48300602016-04-14 GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females Marcé-Grau, Anna Dalton, James López-Pisón, Javier García-Jiménez, María Concepción Monge-Galindo, Lorena Cuenca-León, Ester Giraldo, Jesús Macaya, Alfons Orphanet J Rare Dis Research BACKGROUND: De novo heterozygous mutations in the GNAO1 gene, encoding the Gα o subunit of G-proteins, are the cause of a severe neurodevelopmental disorder, featuring early infantile seizures, profound cognitive dysfunction and, occasionally, movement disorder (early infantile epileptic encephalopathy-17). METHODS: We report a further case of this association in a 20 month-old Spanish girl with neonatal-onset refractory seizures, progressive microcephaly, oral-lingual dyskinesia and nearly absent psychomotor development. We performed whole-exome sequencing, a computational structural analysis of the novel gene variant identified and reviewed the previously reported cases. RESULTS: Trio whole-exome-sequencing uncovered a de novo p.Leu199Pro GNAO1 mutation. Computational structural analysis indicates this novel variant adversely affects the stability of the G-protein heterotrimeric complex as a whole. Of note, our patient showed a sustained seizure reduction while on a ketogenic diet. CONCLUSIONS: With this observation, a total of twelve patients with GNAO1 encephalopathy have been reported. Oral-lingual dyskinesia and responsiveness of seizures to ketogenic diet are novel features. The distorted sex ratio (12/12 females) of the condition remains unexplained; a differential gender effect of the disruption of G-protein- mediated signal transduction on the developing brain can be hypothesized. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-016-0416-0) contains supplementary material, which is available to authorized users. BioMed Central 2016-04-12 /pmc/articles/PMC4830060/ /pubmed/27072799 http://dx.doi.org/10.1186/s13023-016-0416-0 Text en © Marcé-Grau et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Marcé-Grau, Anna
Dalton, James
López-Pisón, Javier
García-Jiménez, María Concepción
Monge-Galindo, Lorena
Cuenca-León, Ester
Giraldo, Jesús
Macaya, Alfons
GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females
title GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females
title_full GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females
title_fullStr GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females
title_full_unstemmed GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females
title_short GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females
title_sort gnao1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830060/
https://www.ncbi.nlm.nih.gov/pubmed/27072799
http://dx.doi.org/10.1186/s13023-016-0416-0
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