Larasati Yonika A, Thiel Moritz, Koval Alexey, Silachev Denis N, Koy Anne, Katanaev Vladimir L
Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.
Med. 2025 Jan 10;6(1):100495. doi: 10.1016/j.medj.2024.07.023. Epub 2024 Aug 16.
De novo pathogenic variants in GNAO1-the gene encoding the major neuronal G protein Gαo-cause pediatric encephalopathies and other neurological deficiencies largely refractory to available therapies. Zn emerged to restore guanosine triphosphate hydrolysis and cellular interactions of pathogenic Gαo; dietary zinc salt supplementation improves lifespan and motoric function in a Drosophila disease model.
Using biochemical, animal, and first-in-human studies, we provide support for the patient stratification and application of zinc acetate in GNAO1-associated disorders.
We show that 16 different pathogenic missense variants cluster in three distinct groups in their responsiveness to Zn, and we provide the safety study in a mouse disease model. We further describe treatment of a 3-year-old patient with the common pathogenic GNAO1 variant c607G>A, p.Gly203Arg with oral 50 mg zinc (in the form of zinc acetate) daily, as applied in Wilson's disease. During 11 months of treatment, the patient shows cessation of daily dyskinetic crises, improved Burke-Fahn Marsden Dystonia Rating Scale movement score, reduction in epileptic seizures, and an excellent safety profile.
Our findings warrant a large-scale clinical trial and might set the new standard of care for GNAO1-related disorders.
This work was funded by the Russian Science Foundation (grant #21-15-00138) and GNAO1 España.
GNAO1基因（编码主要神经元G蛋白Gαo）中的新生致病性变异导致小儿脑病和其他神经功能缺陷，目前可用疗法对此大多难以奏效。锌已被证明可恢复致病性Gαo的三磷酸鸟苷水解和细胞相互作用；在果蝇疾病模型中，补充膳食锌盐可延长寿命并改善运动功能。
通过生化、动物和首例人体研究，我们为GNAO1相关疾病中患者分层及醋酸锌的应用提供了依据。
我们发现16种不同的致病性错义变异对锌的反应性可分为三个不同组，并在小鼠疾病模型中进行了安全性研究。我们还描述了对一名3岁患有常见致病性GNAO1变异c607G>A（p.Gly203Arg）的患者，按照威尔逊病的治疗方式，每日口服50毫克锌（醋酸锌形式）。在11个月的治疗期间，患者每日运动障碍发作停止，伯克-法恩-马斯登肌张力障碍评定量表运动评分改善，癫痫发作减少，且安全性良好。
我们的研究结果值得开展大规模临床试验，并可能为GNAO1相关疾病设定新的护理标准。
本研究由俄罗斯科学基金会（资助编号#21-15-00138）和西班牙GNAO1协会资助。
