Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; Department of Neurosurgery, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Eur J Paediatr Neurol. 2019 Jul;23(4):657-661. doi: 10.1016/j.ejpn.2019.05.011. Epub 2019 May 24.
GRIN1 encodes the obligate subunit (GluN1) of glutamate N-methyl-d-aspartate receptor (NMDAr). Pathogenic variants in GRIN1 are a well-known cause of infantile encephalopathy characterized by profound developmental delay (DD), variable epileptic phenotypes, and distinctive behavioral abnormalities. Recently, GRIN1 has also been implicated in the pathogenesis of polymicrogyria (PMG). We investigated two patients presenting with severe intellectual disability (ID), epilepsy, stereotyped movements, and abnormal ocular movements. They showed distinctive circadian rhythm alterations and sleep-wake patterns anomalies characterized by recurrent cyclic crying or laughing spells. Genetic analysis led to the identification of two distinct de novo variants in GRIN1 affecting the same amino acid residue of an important functional protein domain. Recent advances in circadian rhythm and sleep regulation suggest that abnormal GluN1 function might play a relevant pathogenetic role for the peculiar behavioral abnormalities observed in GRIN1 patients. Our cases highlight the relevance of circadian rhythm abnormalities in epileptic children as a clue toward GRIN1 encephalopathy and expand the complex phenotypic spectrum of this severe genetic disorder.
GRIN1 编码谷氨酸 N-甲基-D-天冬氨酸受体（NMDAr）的必需亚基（GluN1）。GRIN1 中的致病变体是一种众所周知的婴儿性脑病的病因，其特征为严重的发育迟缓（DD）、多变的癫痫表型和独特的行为异常。最近，GRIN1 也与多微小脑回畸形（PMG）的发病机制有关。我们研究了两名表现为严重智力残疾（ID）、癫痫、刻板运动和异常眼球运动的患者。他们表现出明显的昼夜节律改变和睡眠-觉醒模式异常，特征为反复出现周期性哭泣或大笑发作。基因分析导致鉴定出两个不同的 GRIN1 新生变异体，影响重要功能蛋白结构域的相同氨基酸残基。昼夜节律和睡眠调节的最新进展表明，异常的 GluN1 功能可能在 GRIN1 患者观察到的特殊行为异常中发挥相关的致病作用。我们的病例强调了癫痫儿童昼夜节律异常作为 GRIN1 脑病线索的重要性，并扩展了这种严重遗传疾病的复杂表型谱。
