GNAO1-related movement disorder: An update on phenomenology, clinical course, and response to treatments

Aim: To evaluate clinical phenotype and molecular findings of 157 cases with GNAO1 pathogenic or likely pathogenic variants delineating the clinical spectrum, course, and response to treatments.Method: Clinical phenotype, genetic data, and pharmacological and surgical treatment history of 11 novel cases and 146 previously published patients were analyzed.Results: Complex hyperkinetic movement disorder (MD) characterizes 88% of GNAO1 patients. Severe hypotonia and prominent disturbance of postural control seem to be hallmarks in the early stages preceding the hyperkinetic MD. In a subgroup of patients, paroxysmal exacerbations became so severe as to require admission to intensive care units (ICU). Almost all patients had a good response to deep brain stimulation (DBS). Milder phenotypes with late-onset focal/segmental dystonia, mild to moderate intellectual disability, and other minor neurological signs (i.e., parkinsonism and myoclonus) are emerging. MRI, previously considered noncontributory to a diagnosis, can show recurrent findings (i.e., cerebral atrophy, myelination and/or basal ganglia abnormalities). Fifty-eight GNAO1 pathogenic variants, including missense changes and a few recurrent splice site defects, have been reported. Substitutions at residues Gly203, Arg209 and Glu246, together with the intronic c.724-8G > A change, account for more than 50% of cases.Interpretation: Infantile or childhood-onset complex hyperkinetic MD (chorea and/or dystonia) with or without paroxysmal exacerbations, associated hypotonia, and developmental disorders should prompt research for GNAO1 mutations. DBS effectively controls and prevents severe exacerbations and should be considered early in patients with specific GNAO1 variants and refractory MD. Prospective and natural history studies are necessary to define genotype-phenotype correlations further and clarify neurological outcomes.

Automated summary

To evaluate the clinical spectrum, course, and response to treatments of GNAO1 pathogenic or likely pathogenic variants, researchers analyzed the clinical phenotype, genetic data, and treatment history of 157 cases. The study found that hyperkinetic movement disorder characterized most of the patients, with severe hypotonia and disturbances of postural control in the early stages. Deep brain stimulation showed a good response in almost all patients, and milder phenotypes with late-onset dystonia and other neurological signs were also observed.