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. 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.
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.
RESULTS: We 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.
CONCLUSIONS: Our findings warrant a large-scale clinical trial and might set the new standard of care for GNAO1-related disorders.
BACKGROUND: This work was funded by the Russian Science Foundation (grant #21-15-00138) and GNAO1 España.

A lumbar puncture can be used to measure the concentrations of drugs and/or pharmacodynamic biomarkers during clinical trials of central nervous system drugs. We report a case of a post lumbar puncture headache (PLPH) in a first-in-human study, which was reported as a serious adverse event. A 20-year-old man received 200 mg of the investigational product (IP) for 7 days and underwent a lumbar puncture for cerebrospinal fluid sampling before IP administration (Day 1, pre-dose) and after 7 days and multiple IP administrations (Day 7, 1 hour post-dose). After discharge on Day 8, the subject complained of headache, nausea, vomiting, neck stiffness, and numbness of the extremities. The symptoms occurred when he got up and disappeared after he remained in the supine position for several minutes. Five days later, he visited the neurology clinic of the main hospital. The neurologist recommended hospitalization for further evaluation and symptom management, and the subject was then admitted to the hospital. There were no abnormal findings in vital signs, laboratory results, or brain-computed tomography. His symptoms disappeared during the hospitalization period. It was important to distinguish whether the headache was IP-related or lumbar puncture-related. Therefore, knowledge of clinical characteristics and differential diagnosis of PLPH is paramount. Furthermore, if severe PLPH occurs, a consultation with a neurologist and imaging studies should be considered for a differential diagnosis of PLPH.