Safety and feasibility of oral zinc for patients with GNAO1-related disorders (ZINCGNAO1): an open-label, single-arm, single-centre, pilot trial in Germany

Background GNAO1 -related disorders ( GNAO1 -RD), caused by variants in GNAO1 encoding the Gαo protein, comprise a broad phenotypic spectrum including movement disorders (MD) and/or epilepsy and are typically associated with developmental delay and intellectual disability. Currently, only symptomatic treatments are available. Zinc can restore guanosine triphosphate hydrolysis and cellular interactions of dysfunctional Gαo. ZINCGNAO1 evaluated the safety and feasibility of oral zinc supplementation in GNAO1 -RD. Methods ZINCGNAO1 was a 6-month, open-label, fixed-dose, single-centre pilot trial in Germany. Eligible participants were aged 6 months to 30 years, had a genetically confirmed GNAO1 variant, at least one hallmark feature of GNAO1-RD (MD, hypotonia, epilepsy, or global developmental delay), and had a Gross Motor Function Measure-66 (GMFM-66) score of 75 or lower. Zinc acetate dihydrate was administered orally in age-dependent dosages. Primary outcomes were safety, assessed by adverse event monitoring and laboratory analyses, and feasibility, defined as treatment adherence of at least 80% of days. Exploratory secondary outcomes included changes in MD severity (Burke-Fahn-Marsden Dystonia Rating Scale-Movement Score, BFMDRS-M, Abnormal involuntary movement scale, AIMS), and related disability (BFMDRS-Disability Score), motor function (GMFM-66), quality of life (Caregiver Priorities and Child Health Index of Life with Disabilities, CPCHILD), occupational performance (Canadian Occupational Performance Measure performance and satisfaction scores, COPM-P/-S), epilepsy, and participant- or caregiver-reported outcomes. This trial was registered at ClinicalTrials.gov (NCT06412653) and the EU Clinical Trials Register (2024-512735-72-00) and is complete. Findings Between Aug 2, 2024, and Jan 27, 2025, 13 participants with 11 different genetic variants were enrolled; 11 completed the follow up of the trial. Mean age at inclusion was 8.0 years (range 0.5–25.1). Overall treatment feasibility was 84.6% (11/13). No treatment-related serious adverse events occurred, and laboratory monitoring did not identify clinically relevant safety concerns during the 6-month treatment period. Exploratory secondary outcomes showed no change in MD severity. The mean BFMDRS Disability Score decreased from 25.5 (SD 2.6) to 23.5 (SD 2.8; nominal p=0.005). Mean GMFM-66 increased from 33.1 (SD 12.8) to 37.8 (SD 12.8, nominal p=0.006). COPM-P increased from 2.6 (SD 0.8) to 3.8 (SD 1.3; nominal p=0.003), and COPM-S from 2.7 (SD 0.9) to 4.1 (SD 1.7; nominal p=0.002). CPCHILD and seizure occurrence showed no clear treatment-related change; two participants had seizures during the trial. Interpretation Our preliminary findings show that oral zinc supplementation was safe and feasible in this GNAO1 -RD population. Exploratory secondary outcomes suggested possible improvements in motor function and daily activities. Larger controlled trials are needed to assess efficacy. Funding GNAO1 -Gemeinsam nicht allein e.V.