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Orphanet J Rare Dis. 2016 Apr 12;11:38. doi: 10.1186/s13023-016-0416-0.

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

Author information

1
Grup de Recerca en Neurologia Pediàtrica, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Pg Vall d'Hebron 119-129, 08035, Barcelona, Spain.
2
Laboratory of Molecular Neuropharmacology and Bioinformatics, Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, 08193 , Bellaterra, Barcelona, Spain.
3
Sección de Neuropediatría, Hospital Universitario Miguel Servet, P° Isabel la Católica 1,3, 50009, Zaragoza, Spain.
4
Sección de Metabolismo, Hospital Universitario Miguel Servet, P° Isabel la Católica 1,3, 50009, Zaragoza, Spain.
5
Secciones de Neuropediatría y Metabolismo, Hospital Universitario Miguel Servet, P° Isabel la Católica 1,3, 50009, Zaragoza, Spain.
6
Grup de Recerca en Neurologia Pediàtrica, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Pg Vall d'Hebron 119-129, 08035, Barcelona, Spain. amacaya@vhebron.net.
7
Pediatric Neurology Section, Hospital Universitari Vall d'Hebron, Pg Vall d'Hebron 119-129, 08035, Barcelona, Spain. amacaya@vhebron.net.

Abstract

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.

KEYWORDS:

Early infantile epileptic encephalopathy; Exome sequencing; GNAO1; Ketogenic diet

PMID:
27072799
PMCID:
PMC4830060
DOI:
10.1186/s13023-016-0416-0
[Indexed for MEDLINE]
Free PMC Article

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