Adamo-Croux Marie, Angelini Chloé, Aupy Jérôme, Villard Laurent, Villeneuve Nathalie, Chefdor Arnaud, Halleb Yorsa, Colmard Maxime, Degoutin Manon, Lesca Gaetan, Charles Perrine, Keren Boris, Chemaly Nicole, Goizet Cyril, Milh Mathieu, Bar Claire
Department of Pediatric Neurology, Reference Center for Rare Epilepsies, CHU Bordeaux, Bordeaux, France.
Service de Génétique Médicale, CHU Bordeaux, Bordeaux, France.
Epilepsia. 2025 Jun 18;66(8):e187-93. doi: 10.1111/epi.18507.
Pathogenic variants in γ-aminobutyric acid type A (GABA) receptor subunit genes are increasingly associated with epilepsy and neurodevelopmental disorders. Pathogenic variants in GABRA2, encoding the α-2 subunit of GABA receptors, have been recently reported. This study aims to better delineate the phenotypic spectrum of GABRA2 pathogenic variants. We conducted a retrospective multicenter study, analyzing six new patients with GABRA2 pathogenic variants identified through a French national collaboration. Clinical, electroencephalographic (EEG), and genetic data were reviewed alongside a literature analysis of eight previously reported cases. Two distinct electroclinical phenotypes were identified. The most severe, in four of six patients, featured early infantile developmental and epileptic encephalopathy with an EEG pattern of rapid rhythms suggestive of GABAergic hyperactivity. The milder phenotype, in two of six patients, included later onset, drug-responsive epilepsy with moderate developmental delay. A literature review confirmed these phenotypes and supported genotype-phenotype correlations, with transmembrane domain variants more frequently associated with severe phenotypes. This study refines the phenotypic spectrum of GABRA2-related disorders, highlighting two distinct electroclinical phenotypes. The identification of a recognizable EEG pattern of unusual rapid rhythms for age may be a biomarker for early diagnosis of a severe phenotype and suggests a potential underlying gain-of-function mechanism, to be confirmed by functional studies.
γ-氨基丁酸A型（GABA）受体亚基基因的致病性变异与癫痫和神经发育障碍的关联日益增加。最近报道了编码GABA受体α-2亚基的GABRA2基因的致病性变异。本研究旨在更好地描绘GABRA2致病性变异的表型谱。我们进行了一项回顾性多中心研究，分析了通过法国全国合作确定的6例携带GABRA2致病性变异的新患者。同时回顾了临床、脑电图（EEG）和基因数据，并对之前报道的8例病例进行了文献分析。确定了两种不同的电临床表型。在6例患者中的4例中，最严重的表型表现为早期婴儿发育性和癫痫性脑病，脑电图模式为快速节律，提示GABA能亢进。在6例患者中的2例中，较温和的表型包括发病较晚、药物反应性癫痫以及中度发育迟缓。文献综述证实了这些表型，并支持基因型与表型的相关性，跨膜结构域变异更常与严重表型相关。本研究细化了GABRA2相关疾病的表型谱，突出了两种不同的电临床表型。识别出与年龄不相符的异常快速节律的可识别脑电图模式可能是严重表型早期诊断的生物标志物，并提示一种潜在的功能获得机制，有待功能研究证实。
