GNAO1-Associated Movement Disorder.
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ABSTRACT:
SUBMITTER: Dhamija R
PROVIDER: S-EPMC6353469 | biostudies-literature | 2016 Nov-Dec
REPOSITORIES: biostudies-literature
Publications
<i>GNAO1</i>-Associated Movement Disorder.
Dhamija Radhika R Mink Jonathan W JW Shah Binit B BB Goodkin Howard P HP
Movement disorders clinical practice 20160311 6
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Project description:ObjectiveTo define molecular mechanisms underlying the clinical spectrum of epilepsy and movement disorder in individuals with de novo mutations in the GNAO1 gene.MethodsWe identified all GNAO1 mutations reported in individuals with epilepsy (early infantile epileptiform encephalopathy 17) or movement disorders through April 2016; 15 de novo mutant alleles from 25 individuals were introduced into the Gαo subunit by site-directed mutagenesis in a mammalian expression plasmid. We assessed protein expression and function in vitro in HEK-293T cells by Western blot and determined functional Gαo-dependent cyclic adenosine monophosphate (cAMP) inhibition with a coexpressed α2A adrenergic receptor.ResultsOf the 15 clinical GNAO1 mutations studied, 9 show reduced expression and loss of function (LOF; <90% maximal inhibition). Six other mutations show variable levels of expression but exhibit normal or even gain-of-function (GOF) behavior, as demonstrated by significantly lower EC50 values for α2A adrenergic receptor-mediated inhibition of cAMP. The GNAO1 LOF mutations are associated with epileptic encephalopathy while GOF mutants (such as G42R, G203R, and E246K) or normally functioning mutants (R209) were found in patients with movement disorders with or without seizures.ConclusionsBoth LOF and GOF mutations in Gαo (encoded by GNAO1) are associated with neurologic pathophysiology. There appears to be a strong predictive correlation between the in vitro biochemical phenotype and the clinical pattern of epilepsy vs movement disorder.
| S-EPMC5580866 | biostudies-literature
Project description:BackgroundInfants and children with dominant de novo mutations in GNAO1 exhibit movement disorders, epilepsy, or both. Children with loss-of-function (LOF) mutations exhibit Epileptiform Encephalopathy 17 (EIEE17). Gain-of-function (GOF) mutations or those with normal function are found in patients with Neurodevelopmental Disorder with Involuntary Movements (NEDIM). There is no animal model with a human mutant GNAO1 allele.ObjectivesHere we develop a mouse model carrying a human GNAO1 mutation (G203R) and determine whether the clinical features of patients with this GNAO1 mutation, which includes both epilepsy and movement disorder, would be evident in the mouse model.MethodsA mouse Gnao1 knock-in GOF mutation (G203R) was created by CRISPR/Cas9 methods. The resulting offspring and littermate controls were subjected to a battery of behavioral tests. A previously reported GOF mutant mouse knock-in (Gnao1+/G184S), which has not been found in patients, was also studied for comparison.ResultsGnao1+/G203R mutant mice are viable and gain weight comparably to controls. Homozygotes are non-viable. Grip strength was decreased in both males and females. Male Gnao1+/G203R mice were strongly affected in movement assays (RotaRod and DigiGait) while females were not. Male Gnao1+/G203R mice also showed enhanced seizure propensity in the pentylenetetrazole kindling test. Mice with a G184S GOF knock-in also showed movement-related behavioral phenotypes but females were more strongly affected than males.ConclusionsGnao1+/G203R mice phenocopy children with heterozygous GNAO1 G203R mutations, showing both movement disorder and a relatively mild epilepsy pattern. This mouse model should be useful in mechanistic and preclinical studies of GNAO1-related movement disorders.
| S-EPMC6347370 | biostudies-literature
Project description:GNAO1-associated disorders are ultra-rare autosomal dominant conditions, which can manifest, depending on the exact pathogenic variant in GNAO1, as a spectrum of neurological phenotypes, including epileptic encephalopathy, developmental delay with movement disorders, or late-onset dystonia. There are currently no effective treatments available, apart from symptomatic options. In this work, we suggest harnessing personalized RNA therapy to treat GNAO1 patients and focus specifically on a recurrent pathogenic variant (E246K). We systemically screened allele-specific antisense oligonucleotides (ASOs) targeting the mutated allele to identify a potent and specific sequence using both reporter-based platforms and a patient-derived cellular model. We show that reduction of mutated GNAO1 in vitro by knockout or by ASO has a beneficial functional outcome, which can be measured by cAMP accumulation and gene expression changes. We established a Gnao1-E246K mouse model that shows a neurological phenotype, which partially recapitulates the human condition. Due to sequence similarity, the mouse can be treated with the selected ASO to test treatment efficacy in animal models, as shown in vitro using murine neural progenitor cells. Our results demonstrate a beneficial effect for the reduction of mutated GNAO1 by ASO in patient-derived models, demonstrating its feasibility as a therapeutic approach.
| S-EPMC11787015 | biostudies-literature
Project description:BackgroundGNAO1-related neurodevelopmental disorder is a heterogeneous condition characterized by hypotonia, developmental delay, epilepsy, and movement disorder. This study aims to better understand the spectrum of epilepsy associated with GNAO1 variants and experience with anti-seizure medications, and to review published epilepsy phenotypes in GNAO1.MethodsAn online survey was distributed to caregivers of individuals diagnosed with GNAO1 pathogenic variants, and a literature review was conducted.ResultsFifteen respondents completed the survey with the median age of 39 months, including a novel variant p.Q52P. Nine had epilepsy - six had onset in the first week of life, three in the first year of life - but two reported no ongoing seizures. Seizure types varied. Individuals were taking a median of 3 seizure medications without a single best treatment. Our cohort was compared to a literature review of epilepsy in GNAO1. In 86 cases, 38 discrete variants were described; epilepsy is reported in 53 % cases, and a developmental and epileptic encephalopathy in 36 %.ConclusionsWhile GNAO1-related epilepsy is most often early-onset and severe, seizures may not always be drug resistant or lifelong. Experience with anti-seizure medications is varied. Certain variant "hotspots" may correlate with epilepsy phenotype though genotype-phenotype correlation is poorly understood.
| S-EPMC9841045 | biostudies-literature
Project description:GNAO1 encephalopathy is a neurodevelopmental disorder with a spectrum of symptoms that include dystonic movements, seizures and developmental delay. While numerous GNAO1 mutations are associated with this disorder, the functional consequences of pathological variants are not completely understood. Here, we deployed the invertebrate C. elegans as a whole-animal behavioral model to study the functional effects of GNAO1 disorder-associated mutations. We tested several pathological GNAO1 mutations for effects on locomotor behaviors using a combination of CRISPR/Cas9 gene editing and transgenic overexpression in vivo. We report that all three mutations tested (G42R, G203R and R209C) result in strong loss of function defects when evaluated as homozygous CRISPR alleles. In addition, mutations produced dominant negative effects assessed using both heterozygous CRISPR alleles and transgenic overexpression. Experiments in mice confirmed dominant negative effects of GNAO1 G42R, which impaired numerous motor behaviors. Thus, GNAO1 pathological mutations result in conserved functional outcomes across animal models. Our study further establishes the molecular genetic basis of GNAO1 encephalopathy, and develops a CRISPR-based pipeline for functionally evaluating mutations associated with neurodevelopmental disorders.
| S-EPMC8863422 | biostudies-literature
Project description:In 1949, Cade described "sedative effects" after injecting guinea pigs intraperitoneally with lithium (LTM) carbonate. Based on his experiments, he began treating psychiatric patients with LTM. This literature review aims to evaluate the clinical epidemiological profile, pathological mechanisms, and management of LTM-associated movement disorder (MD). Relevant reports in six databases (Excerpta Medica, Google Scholar, Latin American and Caribbean Health Sciences Literature, Medline, Scientific Electronic Library Online, and ScienceDirect) were identified and assessed by two reviewers without language restriction from 1949 to 2021. A total of 250 reports containing 1100 individuals who developed MD associated with LTM were identified. The MDs encountered 148 parkinsonism (PKN), 114 dyskinesia (DKN), 97 myoclonus, 22 dystonia (DTN), 20 Creutzfeldt-Jakob-like syndrome, 11 akathisia, 10 restless legs syndrome (RLS) symptoms, 6 tics, 5 cerebellar syndromes, and 3 stuttering. In the subgroup of cases not clearly defined, there were 320 individuals with extrapyramidal symptoms, 135 with DTN, 37 with DKN, 24 with PKN, and 7 with RLS. Other 141 individuals were only described as presenting an abnormal involuntary movement without further explanation. The mean age was 53.06 years (standard deviation [SD]: 15.64) and the predominant sex was female, i.e., 56.20% (154/274). The mean LTM dose was 963.03 mg/day (SD: 392.03). The mean serum LTM level was 1.53 mEq/L (SD: 1.08). The median onset time was 3 months (1 day to 40 years). The mean recovery time was 0.94 months (SD: 0.87). 45.94% had a full recovery. LTM-induced MD was extensively reported in the literature. Only general terms were used in the majority of the reports. LTM polytherapy probably affected the identification of the MD cause.
| S-EPMC9336594 | biostudies-literature
Project description:Phenytoin (PHT) was first synthesized as a barbiturate derivative and was approved in 1953 by the Food and Drug Administration. This work aimed to review the pathophysiology, epidemiology, clinical presentation, and treatment of PHT-associated movement disorders (MDs). Studies were searched in relevant databases (ScienceDirect, Google Scholar, Excerpta Medica, Latin American and Caribbean Health Sciences Literature, Medline, and Scientific Electronic Library Online) and were selected by two reviewers irrespective of language between 1963 and 2021. Papers of PHT-induced ataxia alone or tremor were excluded. In total, 127 reports with 219 individuals who developed MDs associated with PHT were encountered. MDs found: 126 dyskinesias, 49 myoclonus, 19 dystonia, 14 parkinsonism, 6 tics, 3 stuttering, and 2 restless legs syndrome. The mean age was 35 years (standard deviation [SD]: 23.5) and the predominant sex was male (53.4%). The mean PHT dose when the MD took place was 370.4 mg (SD: 117.5). A serum PHT concentration was reported in 103 cases, ranging from 4 to 110 μg/mL (median: 27.7 μg/mL). No significant relationship was found between PHT dose and age or PHT level. The mean onset time of PHT-associated MD was 23.4 months (SD: 4.4). The mean recovery time after MD management was 3.7 weeks (SD: 1.1). Regarding management, the most common form was PHT withdrawal in 90.4%. 86.3% of the individuals recovered fully. PHT-induced MD was extensively reported in the literature. Only general terms were used in the majority of the reports. The mechanisms underlying the adverse events caused by PHT probably depend on the presence of predisposing factors.
| S-EPMC9791846 | biostudies-literature
Project description:BackgroundFluoroquinolones (FQNs) are related to several central nervous system side effects. This review aims to evaluate the clinical-epidemiological profile, pathophysiological mechanisms, and management of FQNs-associated movement disorders (MDs).MethodsTwo reviewers identified and assessed relevant reports in six databases without language restriction between 1988 and 2022.ResultsA total of 45 reports containing 51 cases who developed MDs secondary to FQNs were reported. The MDs included 25 myoclonus, 13 dyskinesias, 7 dystonias, 2 cerebellar syndromes, 1 ataxia, 1 tic, and 2 undefined cases. The FQNs reported were ciprofloxacin, ofloxacin, gatifloxacin, moxifloxacin, levofloxacin, gemifloxacin, and pefloxacin. The mean and median age were 64.54 (SD: 15.45) and 67 years (range: 25-87 years). The predominant sex was male (54.16%). The mean and median time of MD onset were 6.02 (SD: 10.87) and 3 days (range: 1-68 days). The mean and median recovery time after MD treatment was 5.71 (SD: 9.01) and 3 days (range: 1-56 days). A complete recovery was achieved within one week of drug withdrawal in 80.95% of the patients. Overall, 95.83% of the individuals fully recovered after management.ConclusionsFuture cases need to describe the long-term follow-up of the individuals. Additionally, FQN-induced myoclonus should include electrodiagnostic studies.
| S-EPMC10303425 | biostudies-literature
Project description:BackgroundGNAO1 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 descriptionWe 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.ConclusionsWe 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.
| S-EPMC9561508 | biostudies-literature
Project description:BackgroundGNAO1 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.ResultsSix 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.ConclusionsWe 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.
| S-EPMC7724837 | biostudies-literature