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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.

SUBMITTER: Kim SY

PROVIDER: S-EPMC7724837 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Spectrum of movement disorders in GNAO1 encephalopathy: in-depth phenotyping and case-by-case analysis.

Kim Soo Yeon SY Shim YoungKyu Y Ko Young Joon YJ Park Soojin S Jang Se Song SS Lim Byung Chan BC Kim Ki Joong KJ Chae Jong-Hee JH

Orphanet journal of rare diseases 20201209 1

<h4>Background</h4>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.<h4>Results</h4>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 med ...[more]

PMID: 33298085

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Project description:Background GNAO1 variants have been found to be associated with epileptic encephalopathies, developmental delays (DDs), and movement disorders (MDs). Therapies for patients with GNAO1 variants vary. However, treatments for GNAO1-related diseases are still in their infancy. Previous reports suggest that few pharmacological treatments are effective for patients with GNAO1 variant-related MDs. Deep brain stimulation (DBS) treatment appears to be effective, however surgical procedures and equipment failures pose risks to the patients. Effectiveness for oxcarbazepine (OXC) in GNAO1 variant-related MDs is first reported in our study, and it expand the effective drugs for MD treatment. Case Description We report the case of a 5-year-old male patient with a MD, who suffered from hypotonia and refractory choreoathetosis. The patient was found to have a DD and an intellectual disability. A de-novo variant of the GNAO1 gene (NM_138736: exom6: c.709G>A [p. Glu237Lys]) was identified by whole exome sequencing (WES) when he was 8 months old. The patient visited our hospital at the age of 4 years and 3 months because of fever and recurrent convulsions. Electroencephalogram (EEG) results show abnormal spikes, and magnetic resonance imaging (MRI) showed the enlargement of the lateral ventricles. The administration of tiapride hydrochloride, phenobarbital, midazolam, and hormones had no effect. OXC treatment was then initiated. No MD behaviors, such as rigidity and twisting of the limbs and trunk, or chorea, were observed after 10 days OXC treatment. Eventually, incremental doses of OXC were effective, and our patient achieved good control of his MD. Conclusions We are the first to demonstrate the role of OXC in alleviating MDs associated with GNAO1 mutations. This report provides a novel possibility for the clinical treatment of this rare disease. To manage MDs associated with GNAO1 mutations, we recommend that OXC treatment be attempted before invasive surgical therapy.

Project description:BackgroundThe GNAO1 gene encodes the α-subunit (Gαo) of the heterotrimeric guanine nucleotide-binding protein (G protein). The aim of this study was to explore the clinical characteristics of patients with GNAO1 pathogenic variations.MethodsTen patients with pathogenic variations in GNAO1 were enrolled from the Shenzhen Children's Hospital. Clinical data from several cases previously reported from China were also included and analyzed.ResultsTwenty-seven patients with variations in GNAO1 were analyzed (10 patients from Shenzhen Children's Hospital, 17 patients from previously published studies) including 12 boys and 15 girls. The median age of onset was 3 months with moderate to severe global developmental delay. Nineteen different GNAO1 heterozygous variants were identified. Epilepsy was observed in 18 patients (67%, 18/27), movement disorder (MD) was observed in 22 patients (81%, 22/27), and both were seen in 13 patients (48%, 13/27). Seizures typically presented as focal seizures in all patients with epilepsy. MD typically presented as dystonia and chorea. Loss-of-function (LOF) or partial loss-of-function (PLOF) mutations were more frequent in patients with developmental and epileptic encephalopathy (p = 0.029). Interictal electroencephalograms showed multifocal or diffuse epileptiform discharges. The most common magnetic resonance imaging finding was widened extracerebral space. In contrast to MD, in which improvements were not common, seizures were easily controlled by anti-seizure medications. Severe dystonia in three patients was effectively treated by deep brain stimulation. Seven (26%, 7/27) patients died of respiratory complications, status dystonicus, choreoathetosis, or sudden unexpected death in epilepsy.ConclusionWe analyzed clinical data of 27 cases of GNAO1-related encephalopathy in China. MD seemed to be the central feature and was most difficult to control. LOF or PLOF variants were significantly associated with developmental and epileptic encephalopathy. The active intervention of severe dystonia may prevent death due to status dystonicus. However, future studies with larger samples are needed to confirm these results.

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Dataset Information

Spectrum of movement disorders in GNAO1 encephalopathy: in-depth phenotyping and case-by-case analysis.

Publications

Spectrum of movement disorders in GNAO1 encephalopathy: in-depth phenotyping and case-by-case analysis.

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