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

Anna Marc�-Grau, James Dalton, Javier L�pez-Pis�n, Mar�a Concepci�n Garc�a-Jim�nez, Lorena Monge-Galindo, Ester Cuenca-Le�n, Jes�s Giraldo, Alfons Macaya

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22 Citations (Scopus)


� 2016 Marc�-Grau et al. Background: De novo heterozygous mutations in the GNAO1 gene, encoding the Ga 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 structura 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.
Original languageEnglish
Article number38
Pages (from-to)1-9
JournalOrphanet Journal of Rare Diseases
Issue number1
Publication statusPublished - 1 Jan 2016


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


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