GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Marcé-Grau, Anna; Dalton, James; López-Pisón, Javier; García-Jiménez, María; Monge-Galindo, Lorena; Cuenca-León, Ester; Giraldo, Jesús; Macaya, Alfons
• Is Part Of: Orphanet journal of rare diseases. Volume 11:Issue 1(2016)
• Page Start: 1
• Page End: 9
• Publication Date: 2016-12
• Subjects: Early infantile epileptic encephalopathy -- GNAO1 -- Exome sequencing -- Ketogenic diet; Rare diseases -- Periodicals; Genetic disorders -- Periodicals; Orphan drugs -- Periodicals; 616
• DOI: 10.1186/s13023-016-0416-0
• Languages: English
• ISSNs: 1750-1172

Abstract

Abstract Background De novo heterozygous mutations in theGNAO1 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 ade novo p.Leu199ProGNAO1 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 withGNAO1 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.