Zinc for GNAO1 encephalopathy: Preclinical profiling and a clinical case

Context and significanceMutations in the gene GNAO1 lead to severe and sometimes fatal pediatric encephalopathies that are poorly responsive to current treatments. The pathogenic mutations produce aberrant variants of a major neuronal signaling protein Gαo. Salts of zinc partially correct the abnormal functioning of mutant Gαo. Here, dozens of pathogenic Gαo variants are shown to fall into distinct groups in their responsiveness to zinc, providing ground for patient stratification. Zinc supplementation is safe in mouse disease models, leading to first-in-human application. A 3-year-old patient with severe GNAO1 encephalopathy on oral zinc administration shows strong improvement of motor skills, cessation of daily hyperkinetic crises, and reduction in epileptic seizures, without side effects. These findings set the new standard of care for GNAO1-related disorders.Highlights•Mutations in GNAO1 encoding neuronal Gαo lead to severe pediatric encephalopathy•Pathogenic Gαo variants stratify into 3 classes in their responsiveness to Zn2+•Zinc supplementation is safe in mouse disease models•Successful first-in-human study of zinc supplementation in GNAO1 encephalopathySummaryBackgroundDe 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. Zn2+ 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.MethodsUsing biochemical, animal, and first-in-human studies, we provide support for the patient stratification and application of zinc acetate in GNAO1-associated disorders.FindingsWe show that 16 different pathogenic missense variants cluster in three distinct groups in their responsiveness to Zn2+, 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.ConclusionsOur findings warrant a large-scale clinical trial and might set the new standard of care for GNAO1-related disorders.FundingThis work was funded by the Russian Science Foundation (grant #21-15-00138) and GNAO1 España.Graphical abstract