title: GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females.
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.
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Marcé-Grau
authors.affiliation: Laboratory of Molecular Neuropharmacology and Bioinformatics, Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, 08193 , Bellaterra, Barcelona, Spain.
authors.forename: James
authors.initials: J
authors.lastname: Dalton
authors.affiliation: Sección de Neuropediatría, Hospital Universitario Miguel Servet, P° Isabel la Católica 1,3, 50009, Zaragoza, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: López-Pisón
authors.affiliation: Sección de Metabolismo, Hospital Universitario Miguel Servet, P° Isabel la Católica 1,3, 50009, Zaragoza, Spain.
authors.forename: María Concepción
authors.initials: MC
authors.lastname: García-Jiménez
authors.affiliation: Secciones de Neuropediatría y Metabolismo, Hospital Universitario Miguel Servet, P° Isabel la Católica 1,3, 50009, Zaragoza, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Monge-Galindo
authors.affiliation: 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.
authors.forename: Ester
authors.initials: E
authors.lastname: Cuenca-León
authors.affiliation: Laboratory of Molecular Neuropharmacology and Bioinformatics, Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, 08193 , Bellaterra, Barcelona, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Giraldo
authors.affiliation: 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.|Pediatric Neurology Section, Hospital Universitari Vall d'Hebron, Pg Vall d'Hebron 119-129, 08035, Barcelona, Spain. amacaya@vhebron.net.
authors.forename: Alfons
authors.initials: A
authors.lastname: Macaya
mesh_terms: D000328:Adult; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001927:Brain Diseases; D059472:Exome / Q000235:genetics; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D056004:Molecular Dynamics Simulation; D055815:Young Adult
chemical_list: C584143:GNAO1 protein, human; D019206:GTP-Binding Protein alpha Subunits, Gi-Go
keywords: Early infantile epileptic encephalopathy; Exome sequencing; GNAO1; Ketogenic diet