A de novo GABRA2 missense mutation in severe early-onset epileptic encephalopathy with a choreiform movement disorder. (May 2018)

• Record Type: Journal Article
• Authors: Orenstein, Naama; Goldberg-Stern, Hadassa; Straussberg, Rachel; Bazak, Lily; Weisz Hubshman, Monika; Kropach, Nesia; Gilad, Oded; Scheuerman, Oded; Dory, Yahav; Kraus, Dror; Tzur, Shay; Magal, Nurit; Kilim, Yael; Shkalim Zemer, Vered; Basel-Salmon, Lina
• Is Part Of: European journal of paediatric neurology. Volume 22:Number 3(2018:May)
• Page Start: 516
• Page End: 524
• Publication Date: 2018-05
• Subjects: Early-onset epileptic encephalopathy (EOEE) -- GABRA2 gene -- de novo mutation -- Whole-exome sequencing; EOEE early onset epileptic encephalopathy -- GABA gamma aminobutyric acid; Pediatric neurology -- Periodicals; Nervous System Diseases -- Periodicals; Child -- Periodicals; Infant -- Periodicals; Neurologie pédiatrique -- Périodiques; Pediatric neurology; Electronic journals; Periodicals; Electronic journals; 618.928
• DOI: 10.1016/j.ejpn.2017.12.017
• Languages: English
• ISSNs: 1090-3798

Abstract

Abstract: Background: Early-onset epileptic encephalopathy (EOEE) is a severe convulsive disorder with a poor developmental prognosis. Although it has been associated with mutations in a number of genes, the fact that there is a large proportion of patients who remain undiagnosed suggests that there are many more still-unknown genetic causes of EOEE. Achieving a genetic diagnosis is important for understanding the biological basis of the disease, with its implications for treatment and family planning. Methods: Whole-exome sequencing was performed in a family of Ashkenazi Jewish origin in which a male infant was diagnosed with EOEE. There was no family history of a similar neurologic disease. The patient had extreme hypotonia, neonatal hypothermia, choreiform movements, and vision impairment in addition to the convulsive disorder. Results: A de novo heterozygous missense mutation, c.1003A > C, p.Asn335His, was identified in a conserved domain of GABRA2 . GABRA2 encodes the α2 subunit of the GABAA receptor. Conclusions: In the context of previous reports of an association of de novo mutations in genes encoding different subunits of the GABAA receptor ( GABRB1, GABRA1, GABRG2, GABRB3 ) with autosomal dominant epileptic disorders, we conclude that a de novo mutation in GABRA2 is likely to cause autosomal dominant EOEE accompanied by a movement disorder and vision impairment. Highlights: Mutations in GABAA receptors are associated with early onset epileptic encephalopathy. GABRA2 encodes the α2 subunit of the GABAA receptor which is an important component of the gamma aminobutyric acid system. We report that a de novo mutation in GABRA2 is likely to cause autosomal dominant early onset epileptic encephalopathy. GABRA2 mutations have not been previously reported in association with human disease.