Genotype–phenotype correlation and treatment effects in young patients withGNAO1-associated disorders

Abstract

BackgroundPatients carrying pathogenic variants inGNAO1often 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 forGNAO1patients 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 inGNAO1were 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 ofGNAO1-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.

GNAO1 Mutations Affecting the N‐Terminal α‐Helix of Gαo Lead to Parkinsonism

“…Gα subunits contain a Ras‐like domain (RD), an α‐helical domain (AHD), and an N‐terminal α‐helix (αN) 22 . We highlighted the singular position of Leu13 and Leu23 alongside 45 missense mutations reported in GNAO1 patients 4,23,24 . Whereas GNAO1 mutations spread over the RD and AHD (red colored, Fig.…”

“…Because parkinsonism was not seen in the cohort we recently reported, 4 we further analyzed the Gαo L13P mutant to better understand its genotype–phenotype correlation. We also included L23P, as it was associated with a similar phenotype 3 …”

“…GNAO1 disorders are thus classified as “developmental and epileptic encephalopathy 17” (OMIM‐615473) and “neurodevelopmental disorder with involuntary movements” (OMIM‐617493). However, recent GNAO1 variants were linked to milder adolescent/adult‐onset dystonia 3,4 . As clinical presentations are very heterogeneous, GNAO1 disorders seem to represent a continuous phenotypic spectrum rather than two distinct phenotypes 4 …”

“…However, recent GNAO1 variants were linked to milder adolescent/adult‐onset dystonia 3,4 . As clinical presentations are very heterogeneous, GNAO1 disorders seem to represent a continuous phenotypic spectrum rather than two distinct phenotypes 4 …”

Dyskinetic crisis in GNAO1-related disorders: clinical perspectives and management strategies

“…The data extracted from the literature review are presented in Supplementary Data . It is important to reference the various terms used in the literature to describe this movement disorder phenomenon: continuous, generalized involuntary movements ( 3 ), exacerbation of dyskinesia ( 18 , 19 ), acute exacerbation ( 9 , 20 ), episodes of dyskinetic movement ( 8 , 21 ), severe episodes of paroxysmal choreoathetosis ( 12 ), worsening of extrapyramidal symptomatology ( 22 ), dyskinetic episodes ( 13 ), paroxysmal episodes ( 13 ), chorea episodes ( 23 ), movement disorder fluctuations ( 24 , 25 ), recurrent episodes of hyperkinesia ( 26 ), intermittent hyperkinesia ( 27 ), episodic deterioration of the movement disorders ( 28 ), worsening of hyperkinetic movement ( 29 ), hyperkinetic crisis ( 26 , 30 ), dyskinetic crisis ( 2 ), dystonic-dyskinetic movements ( 31 ), and spells ( 6 ). In its most severe manifestation, this motor phenomenon has been referred to as dyskinetic status ( 13 , 24 , 32 ), hyperkinetic state ( 26 ), status dystonicus ( 10 , 33 , 34 ), dystonic storm ( 4 , 5 ), intractable dystonia ( 35 ), or a movement disorder emergency ( 13 ).…”