Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1^−/− mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy.

中文翻译：

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双等位基因 GAD1 变异引起的婴儿早发性癫痫和发育迟缓。

γ-氨基丁酸 (GABA) 和谷氨酸是大脑中最丰富的氨基酸神经递质。GABA 是一种抑制性神经递质，由谷氨酸脱羧酶 (GAD) 合成。其主要同工型 GAD67 在 CNS 中贡献高达 90% 的碱基水平 GABA，并由GAD1基因编码。GAD1的破坏导致抑制性和兴奋性神经递质失衡，并且由于Gad1 ^-/-小鼠在新生儿期死于严重的腭裂，因此无法确定任何潜在的神经功能障碍。此外，人们对 GAD1 破坏对人类的影响知之甚少。在这里，我们展示了来自六个无关家庭的六个受影响的个体，携带双等位基因GAD1变异型，表现为发育性和癫痫性脑病，其特征是早发性癫痫和肌张力减退，并伴有其他可变的非中枢神经系统表现，如骨骼异常、畸形特征和腭裂。我们的研究结果强调了GAD1在癫痫发作诱导、神经元和神经元外发育中的重要作用，并将GAD1作为与发育性和癫痫性脑病相关的新基因引入。