OBJECTIVE: We aimed to analyze the clinical phenotype and the molecular characterization of GNAO1-related disorders.
METHODS: Patients were recruited in collaboration with the Spanish GNAO1 Association. For patient phenotyping, direct clinical evaluation, analysis of homemade-videos, and an online questionnaire completed by families were analyzed. We studied Gαo cellular expression, the interactions of the partner proteins, and binding to guanosine triphosphate (GTP) and G-protein-coupled receptors (GPCRs).
RESULTS: Eighteen patients with GNAO1 genetic defects had a complex neurodevelopmental disorder, epilepsy, central hypotonia, and movement disorders. Eleven patients showed neurological deterioration, recurrent hyperkinetic crisis with partial recovery, and secondary complications leading to death in three cases. Deep brain stimulation improved hyperkinetic crisis, but had inconsistent benefits in dystonia. The molecular defects caused by pathogenic Gαo were aberrant GTP binding and hydrolysis activities, an inability to interact with cellular binding partners, and reduced coupling to GPCRs. Decreased localization of Gαo in the plasma membrane was correlated with the phenotype of \"developmental and epileptic encephalopathy 17.\" We observed a genotype-phenotype correlation, pathogenic variants in position 203 were related to developmental and epileptic encephalopathy, whereas those in position 209 were related to neurodevelopmental disorder with involuntary movements. Milder phenotypes were associated with other molecular defects such as del.16q12.2q21 and I344del.
CONCLUSIONS: We highlight the complexity of the motor phenotype, which is characterized by fluctuations throughout the day, and hyperkinetic crisis with a distinct post-hyperkinetic crisis state. We confirm a molecular-based genotype-phenotype correlation for specific variants. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
目的:我们旨在分析GNAO1相关疾病的临床表型和分子特征。
方法:与西班牙GNAO1协会合作招募患者。对于患者表型,直接临床评估,分析自制视频,并对家庭填写的在线问卷进行了分析。我们研究了Gαo细胞表达,伴侣蛋白的相互作用,并与三磷酸鸟苷(GTP)和G蛋白偶联受体(GPCRs)结合。
结果:18名GNAO1基因缺陷患者患有复杂的神经发育障碍,癫痫,中枢低张力,和运动障碍。11名患者表现出神经功能恶化,反复出现的高运动型危机与部分恢复,继发并发症导致3例死亡。深部脑刺激改善了多动危象,但在肌张力障碍方面的益处不一致。致病性Gαo引起的分子缺陷是GTP结合和水解活性异常,无法与细胞结合伴侣相互作用,并减少与GPCRs的耦合。Gαo在质膜中的定位减少与发育性和癫痫性脑病17的表型相关。“我们观察到基因型-表型相关,203位的致病变异与发育性脑病和癫痫性脑病有关,而209位的患者与具有不自主运动的神经发育障碍有关。轻度表型与其他分子缺陷相关,例如del.16q12.2q21和I344del。
结论:我们强调了运动表型的复杂性,其特点是全天波动,和具有明显的后高运动危机状态的高运动危机。我们确认了特定变体的基于分子的基因型-表型相关性。©2024作者(S)。由WileyPeriodicalsLLC代表国际帕金森症和运动障碍协会出版的运动障碍。