Objective: To review the clinical phenotype and molecular findings of 125 cases with GNAO1-related disorders, delineating the typical phenotype and the phenotypic expansions and tracing future directions for research.

Background: GNAO1 encodes for the alpha subunit (Gαo) of the inhibitory heterotrimeric Go-protein complex, ubiquitously expressed in CNS and highly enriched in medium spiny neurons. Gαo is part of a complex and not well understood network of proteins involved in dopamine-mediated post-synaptic signaling and cAMP homeostasis. Genetic disorders affecting this pathway typically present during childhood with a complex hyperkinetic MD (e.g. ADCY5, GNB1, PDE2A, PDE10A). GNAO1 pathogenic variants have been associated with a complex neurological phenotype with prominent hyperkinetic MD with severe exacerbations, neurodevelopmental disorders and epilepsy.

Method: We reviewed genotypes, clinical phenotypes and response to pharmacological and surgical treatment of 125 GNAO1 patients (114 previously published and 11 novel cases).

Results: Sixty different GNAO1 pathogenic variants have been reported. The most frequent substitution affects the Glu246 residue with nearly 14% of patients carrying a variant at this position. GNAO1 is associated with a complex clinical phenotype with age of onset ranging from 0 to 12 years. Nearly 85% of patients presented mixed hyperkinetic MD associated with other recurrent features, such as axial hypotonia and developmental delay. In a subgroup of patients, life threatening paroxysmal exacerbations became so severe to require admission to intensive care units. Good response to DBS was seen in almost all of these patients. Milder phenotypes are emerging and include isolated late focal/segmental dystonia, gait abnormalities and dysarthria. MRI previously considered non specific shows, especially in severe cases, some recurrent findings.

Conclusion: Infantile or childhood onset chorea and/or dystonia, or complex hyperkinetic MD associated with hypotonia and developmental disorders should prompt a research for GNAO1 mutations. Severe MD exacerbations with multiple triggers are one of the clinical hallmarks. DBS is effective in controlling and preventing severe exacerbations and should be considered early in patients with specific GNAO1 pathogenic variants and refractory MD. Prospective and natural history studies are necessary to better define GNAO1 genotype-phenotype correlations and clarify neurological outcome.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gnao1-related-disorders-a-clinical-genetic-and-therapeutic-update/