Zinc for GNAO1 encephalopathy: Preclinical profiling and a clinical case.

Background: 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.

Methods: Using biochemical, animal, and first-in-human studies, we provide support for the patient stratification and application of zinc acetate in GNAO1-associated disorders.

Findings: 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.

Conclusions: Our findings warrant a large-scale clinical trial and might set the new standard of care for GNAO1-related disorders.

Funding: This work was funded by the Russian Science Foundation (grant #21-15-00138) and GNAO1 España.