• Moritz Thiel, Daniel Bamborschke, Wibke G Janzarik, Birgit Assmann, Simone Zittel, Steffi Patzer, Andrea Auhuber, Joachim Opp, Eva Matzker, Andrea Bevot, Juergen Seeger, Andreas van Baalen, Burkhard Stüve, Knut Brockmann, Sebahattin Cirak, and Anne Koy.
• Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany moritz.thiel@uk-koeln.de.
• J. Neurol. Neurosurg. Psychiatr. 2023 Oct 1; 94 (10): 806815806-815.

BackgroundPatients carrying pathogenic variants in GNAO1 often present with early-onset central hypotonia and global developmental delay, with or without epilepsy. As the disorder progresses, a complex hypertonic and hyperkinetic movement disorder is a common phenotype. A genotype-phenotype correlation has not yet been described and there are no evidence-based therapeutic recommendations.MethodsTo improve understanding of the clinical course and pathophysiology of this ultra-rare disorder, we built up a registry for GNAO1 patients in Germany. In this retrospective, multicentre cohort study, we collected detailed clinical data, treatment effects and genetic data for 25 affected patients.ResultsThe main clinical features were symptom onset within the first months of life, with central hypotonia or seizures. Within the first year of life, nearly all patients developed a movement disorder comprising dystonia (84%) and choreoathetosis (52%). Twelve (48%) patients suffered life-threatening hyperkinetic crises. Fifteen (60%) patients had epilepsy with poor treatment response. Two patients showed an atypical phenotype and seven novel pathogenic variants in GNAO1 were identified. Nine (38%) patients were treated with bilateral deep brain stimulation of the globus pallidus internus. Deep brain stimulation reduced hyperkinetic symptoms and prevented further hyperkinetic crises. The in silico prediction programmes did not predict the phenotype by the genotype.ConclusionThe broad clinical spectrum and genetic findings expand the phenotypical spectrum of GNAO1-associated disorder and therefore disprove the assumption that there are only two main phenotypes. No specific overall genotype-phenotype correlation was identified. We highlight deep brain stimulation as a useful treatment option in this disorder.© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.

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