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 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.
Eur J Paediatr Neurol. 2018 May;22(3):516-524. doi: 10.1016/j.ejpn.2017.12.017. Epub 2017 Dec 30.
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.
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.
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 GABA receptor.
In the context of previous reports of an association of de novo mutations in genes encoding different subunits of the GABA 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.
早发性癫痫性脑病（EOEE）是一种严重的惊厥性疾病，其发育预后较差。尽管它与许多基因的突变有关，但仍有很大一部分患者未被诊断出来，这表明EOEE 还有许多尚未被发现的遗传原因。获得基因诊断对于了解疾病的生物学基础很重要，这对治疗和计划生育都有影响。
对一个具有阿什肯纳兹犹太血统的家族中的一名男性婴儿进行了全外显子组测序，该婴儿被诊断为 EOEE。家族中没有类似的神经系统疾病史。除了惊厥性疾病外，该患者还伴有极度肌张力低下、新生儿低体温、舞蹈样运动和视力障碍。
在 GABRA2 的一个保守结构域中发现了一个杂合错义突变 c.1003A>C，p.Asn335His，该突变为新生突变。GABRA2 编码 GABA 受体的 α2 亚基。
鉴于先前有报道称 GABA 受体不同亚基（GABRB1、GABRA1、GABRG2、GABRB3）编码基因的新生突变与常染色体显性癫痫疾病有关，我们推断 GABRA2 的新生突变可能导致伴有运动障碍和视力障碍的常染色体显性 EOEE。
