Zinc for GNAO1 encephalopathy: preclinical profiling and a clinical case

Abstract

Abstract De novo mutations in GNAO1 – the gene encoding the major neuronal G-protein Gαo – cause pediatric encephalopathies largely refractory to available therapies. Zn2+ emerged to restore GTP hydrolysis and cellular interactions of pathogenic Gαo; dietary Zn2+ supplementation improves lifespan and motoric function in a Drosophila disease model. Here we show that 16 different pathogenic missense mutations cluster in three distinct groups in their responsiveness to Zn2+, and provide the safety study in a mouse disease model. We further describe treatment of a 3 years-old patient with a common GNAO1 mutation c607G > A, p.Gly203Arg with oral 50mg Zn2+ daily, as applied in Wilson’s disease. During 11 months of treatment, the patient shows cessation of daily hyperkinetic crises, improved Burke-Fahn Marsden Dystonia Rating Scale movement score and general well-being, and an excellent safety profile. Our findings warrant a large-scale clinical trial and might set the new standard of care for GNAO1 encephalopathy.