Spectrum of Movement Disorders in GNAO1 Encephalopathy: In-Depth Phenotyping and Case-by-Case Analysis

Abstract

Background: GNAO1 encephalopathy is a rare neurodevelopmental disorder characterized by distinct movement presentations and early onset epileptic encephalopathy. Here, we report the in-depth phenotyping of genetically confirmed patients with GNAO1 encephalopathy, focusing on movement presentations.Results: Six patients who participated in Korean Undiagnosed Disease Program were diagnosed to have pathogenic or likely pathogenic variants in GNAO1 using whole exome sequencing. All medical records and personal video clips were analyzed with a literature review. Three of the 6 patients were male. Median follow-up duration was 41 months (range, 7–78 months) and age at last examination was 7.4 years (range, 3.3–16.9 years). Initial complaints were hypotonia or developmental delay in 5 and right-hand clumsiness in 1 patient, which were noticed at median age of 3 months (range, 0–75 months). All patients showed global developmental delay and 4 had severely retarded development. Five patients (5/6, 83.3%) had many different movement symptoms with various onset and progression. The symptoms included stereotyped hands movement, non-epileptic myoclonus, dyskinesia, dystonia and choreoathetosis. Whole exome sequencing identified 6 different variants in GNAO1. Three were novel de novo variants and atypical presentation was noted in a patient. One variant turned out to be inherited from patient’s mother who had mosaic variant. Distinct and characteristics movement phenotypes in patients with variant p.Glu246Lys and p.Arg209His were elucidated by in-depth phenotyping and literature review. Conclusions: We reported 6 patients with GNAO1 encephalopathy showing an extremely diverse clinical spectrum on video. Some characteristic movement features identified by careful inspection may also provide important diagnostic insight and practice guidelines.

Fever‐Induced and Early Morning Paroxysmal Dyskinesia in a Man With GNB1 Encephalopathy

“…This unusual combination of paroxysmal motor events and the phenomenology of the interictal movement disorder observed in this patient, evoke the best characterized ADCY5 and GNAO1 phenotypes, and further defines the role of G‐protein coupled receptors signaling in the pathophysiology of PMDs 1,5,7 …”

“…This unusual combination of paroxysmal motor events and the phenomenology of the interictal movement disorder observed in this patient, evoke the best characterized ADCY5 and GNAO1 phenotypes, and further defines the role of G-protein coupled receptors signaling in the pathophysiology of PMDs. 1,5,7 More recently, childhood-onset paroxysmal dyskinesia and interictal choreodystonia, with episodes respectively during sleep or upon awakening, have been associated with biallelic PDE2A 8 and PDE10A pathogenic variants. 9 Paroxysmal dyskinesia upon morning awakening has been hypothesized to be related to imbalanced dopamine and adenosine interplay, which is modulated by Gα and Gβγ interactions, and to altered adenylyl cyclase 5 activity in MSNs.…”

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).…”

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“…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).…”