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Eur J Paediatr Neurol. 2018 May;22(3):516-524. doi: 10.1016/j.ejpn.2017.12.017. Epub 2017 Dec 30.

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

Author information

1
Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. Electronic address: naamaor@clalit.org.il.
2
Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Pediatric Epilepsy Unit, Neurological Institute, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel. Electronic address: Hagoldberg@clalit.org.il.
3
Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Neurogenetic Service, Neurological Institute, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel. Electronic address: Rachels2@clalit.org.il.
4
Raphael Recanati Genetics Institute, Rabin Medical Center- Beilinson Hospital, Petach Tikva 4941492, Israel; Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 5290002, Israel; Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva 4941492, Israel. Electronic address: lilybazak@clalit.org.il.
5
Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Raphael Recanati Genetics Institute, Rabin Medical Center- Beilinson Hospital, Petach Tikva 4941492, Israel; Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva 4941492, Israel. Electronic address: MonicaWe@clalit.org.il.
6
Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. Electronic address: NesyaKr@clalit.org.il.
7
Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. Electronic address: OdedGi@clalit.org.il.
8
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Department of Pediatrics B, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel. Electronic address: odedshv@clalit.org.il.
9
Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel. Electronic address: yahavdory@yahoo.com.
10
Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Pediatric Epilepsy Unit, Neurological Institute, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel. Electronic address: drork@clalit.org.il.
11
Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 5290002, Israel; Laboratory of Molecular Medicine, Rambam Health Care Campus, Haifa 3109601, Israel; Genomic Research Department, Emedgene Technologies, Tel Aviv, Israel. Electronic address: shaytzur@gmail.com.
12
Raphael Recanati Genetics Institute, Rabin Medical Center- Beilinson Hospital, Petach Tikva 4941492, Israel; Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva 4941492, Israel. Electronic address: NMagal@clalit.org.il.
13
Raphael Recanati Genetics Institute, Rabin Medical Center- Beilinson Hospital, Petach Tikva 4941492, Israel; Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva 4941492, Israel. Electronic address: yaelki2@clalit.org.il.
14
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Department of Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel. Electronic address: shine6@walla.co.il.
15
Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Raphael Recanati Genetics Institute, Rabin Medical Center- Beilinson Hospital, Petach Tikva 4941492, Israel; Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva 4941492, Israel. Electronic address: LinaB@clalit.org.il.

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.

KEYWORDS:

Early-onset epileptic encephalopathy (EOEE); GABRA2 gene; Whole-exome sequencing; de novo mutation

Comment in

PMID:
29422393
DOI:
10.1016/j.ejpn.2017.12.017
[Indexed for MEDLINE]

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