Cortical Myoclonus in a Young Boy with GOSR2 Mutation Mimics Chorea.
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ABSTRACT:
SUBMITTER: van Egmond ME
PROVIDER: S-EPMC6353358 | biostudies-literature | 2015 Mar
REPOSITORIES: biostudies-literature
Publications
Cortical Myoclonus in a Young Boy with <i>GOSR2</i> Mutation Mimics Chorea.
van Egmond Martje E ME Kuiper Anouk A Elting Jan Willem J JWJ Brouwer Oebele F OF de Koning Tom J TJ Tijssen Marina A J MAJ
Movement disorders clinical practice 20150224 1
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Project description:The progressive myoclonus epilepsies (PMEs) are a group of predominantly recessive disorders that present with action myoclonus, tonic-clonic seizures, and progressive neurological decline. Many PMEs have similar clinical presentations yet are genetically heterogeneous, making accurate diagnosis difficult. A locus for PME was mapped in a consanguineous family with a single affected individual to chromosome 17q21. An identical-by-descent, homozygous mutation in GOSR2 (c.430G>T, p.Gly144Trp), a Golgi vesicle transport gene, was identified in this patient and in four apparently unrelated individuals. A comparison of the phenotypes in these patients defined a clinically distinct PME syndrome characterized by early-onset ataxia, action myoclonus by age 6, scoliosis, and mildly elevated serum creatine kinase. This p.Gly144Trp mutation is equivalent to a loss of function and results in failure of GOSR2 protein to localize to the cis-Golgi.
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Project description:Myoclonus is characterized by sudden, brief involuntary movements, and its presence is debilitating. We identified a family suffering from adult onset, cortical myoclonus without associated seizures. We performed clinical, electrophysiological, and genetic studies to define this phenotype.A large, 4-generation family with a history of myoclonus underwent careful questioning, examination, and electrophysiological testing. Thirty-five family members donated blood samples for genetic analysis, which included single nucleotide polymorphism mapping, microsatellite linkage, targeted massively parallel sequencing, and Sanger sequencing. In silico and in vitro experiments were performed to investigate functional significance of the mutation.We identified 11 members of a Canadian Mennonite family suffering from adult onset, slowly progressive, disabling, multifocal myoclonus. Somatosensory evoked potentials indicated a cortical origin of the myoclonus. There were no associated seizures. Some severely affected individuals developed signs of progressive cerebellar ataxia of variable severity late in the course of their illness. The phenotype was inherited in an autosomal dominant fashion. We demonstrated linkage to chromosome 16q21-22.1. We then sequenced all coding sequence in the critical region, identifying only a single cosegregating, novel, nonsynonymous mutation, which resides in the gene NOL3. Furthermore, this mutation was found to alter post-translational modification of NOL3 protein in vitro.We propose that familial cortical myoclonus is a novel movement disorder that may be caused by mutation in NOL3. Further investigation of the role of NOL3 in neuronal physiology may shed light on neuronal membrane hyperexcitability and pathophysiology of myoclonus and related disorders.
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Project description:Biallelic variants in the Golgi SNAP receptor complex member 2 gene (GOSR2) have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a GOSR2-related disorder and novel genetic and clinical findings. The first patient, a male compound heterozygous for the GOSR2 splice site variant c.336+1G>A and the novel c.364G>A,p.Glu122Lys missense variant showed global developmental delay and seizures at the age of 2 years, followed by myoclonus at the age of 8 years with partial response to clonazepam. The second patient, a female homozygous for the GOSR2 founder variant p.Gly144Trp, showed only mild fine motor developmental delay and generalized tonic-clonic seizures triggered by infections during adolescence, with seizure remission on levetiracetam. The associated movement disorder progressed atypically slowly during adolescence compared to its usual speed, from initial intention tremor and myoclonus to ataxia, hyporeflexia, dysmetria, and dystonia. These findings expand the genotype-phenotype spectrum of GOSR2-related disorders and suggest that GOSR2 should be included in the consideration of monogenetic causes of dystonia, global developmental delay, and seizures.
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Project description:Myoclonus dystonia is a childhood-onset hyperkinetic movement disorder with a combined motor and psychiatric phenotype. It represents one of the few autosomal dominant inherited dystonic disorders and is caused by mutations in the ε-sarcoglycan (SGCE) gene. Work to date suggests that dystonia is caused by disruption of neuronal networks, principally basal ganglia-cerebello-thalamo-cortical circuits. Investigation of cortical involvement has primarily focused on disruption to interneuron inhibitory activity, rather than the excitatory activity of cortical pyramidal neurons. Here, we have sought to examine excitatory cortical glutamatergic activity using two approaches: the CRISPR/Cas9 editing of a human embryonic cell line, generating an SGCE compound heterozygous mutation, and three patient-derived induced pluripotent stem cell lines, each gene edited to generate matched wild-type SGCE control lines. Differentiation towards a cortical neuronal phenotype demonstrated no significant differences in either early- (PAX6, FOXG1) or late-stage (CTIP2, TBR1) neurodevelopmental markers. However, functional characterization using Ca2+ imaging and microelectrode array approaches identified an increase in network activity, while single-cell patch clamp studies found a greater propensity towards action potential generation with larger amplitudes and shorter half-widths associated with SGCE mutations. Bulk RNA sequencing analysis identified gene ontological enrichment for 'neuron projection development', 'synaptic signalling' and 'synaptic transmission'. Examination of dendritic morphology found SGCE mutations to be associated with a significantly higher number of branches and longer branch lengths, together with longer ion-channel dense axon initial segments, particularly towards the latter stages of differentiation (Days 80 and 100). Gene expression and protein quantification of key synaptic proteins (synaptophysin, synapsin and PSD95), AMPA and NMDA receptor subunits found no significant differences between the SGCE mutation and matched wild-type lines. By contrast, significant changes to synaptic adhesion molecule expression were identified, namely higher presynaptic neurexin-1 and lower postsynaptic neuroligin-4 levels in the SGCE mutation carrying lines. Our study demonstrates an increased intrinsic excitability of cortical glutamatergic neuronal cells in the context of SGCE mutations, coupled with a more complex neurite morphology and disruption to synaptic adhesion molecules. These changes potentially represent key components to the development of the hyperkinetic clinical phenotype observed in myoclonus dystonia, as well a central feature to the wider spectrum of dystonic disorders, potentially providing targets for future therapeutic development.
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Project description:We report the case of a 12-year-old boy with a glucokinase (GCK) mutation, and diabetes with hyperinsulinemia and insulin resistance. For 4 years, the patient intermittently received insulin medications Actrapid HM and Protaphane HM (total dose 5 U/day), with glycated hemoglobin (HbA1c) levels of 6.6%-7.0%. After extensive screening the patient was found to carry a heterozygous mutation (p.E256K) in GCK (MIM #138079, reference sequence NM_000162.3). Insulin therapy was replaced by metformin at 1,700 mg/day. One year later, his HbA1c level was 6.9%, postprandial glycemia at 120 min of oral glucose tolerance test was 15.4 mmol/L, hyperinsulinemia had increased to 508.9 mU/L, homeostasis model assessment index was 114.2 and the Matsuda index was 0.15. Insulin resistance was confirmed by a hyperinsulinemic euglycemic clamp test - M-index was 2.85 mg/kg/min. This observation is a rare case of one of the clinical variants of diabetes, which should be taken into account by a vigilant endocrinologist due to the need for nonstandard diagnostic and therapeutic approaches.
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Project description:BackgroundHemizygous mutations in GRIA3 encoding the GluA3 subunit of the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor are known to be associated with neurodevelopmental disorders, including intellectual disability, hypotonia, an autism spectrum disorder, sleep disturbances, and epilepsy in males.ObjectiveTo describe a new and consistent phenotype in 4 affected male patients associated with an undescribed deleterious variant in GRIA3.MethodsWe evaluated a large French family in which segregate a singular phenotype according to an apparent X-linked mode of inheritance. Molecular analyses using next generation sequencing and in vitro functional studies using 2-electrode voltage clamp recordings on Xenopus laevis oocytes and a β-lactamase reporter assay in transfected human embryonic kidney (HEK293) cells were performed.ResultsIn addition to mild intellectual disability and dysarthria, affected patients presented a tightly consistent early-onset movement disorder combining an exaggerated startle reflex with generalized chorea and multifocal myoclonus. The unreported GRIA3 missense variant c.2477G > A; p.(Gly826Asp) affecting the fourth transmembrane domain of the protein was identified in index patients and their unaffected mothers. Functional studies revealed that variant receptors show decreased current response evoked by agonist (ie, kainic acid and glutamate) and reduced expression on the cell surface in favor of pathogenicity by a loss-of-function mechanism.ConclusionsTaken together, our results suggest that apart from known GRIA3-related disorders, an undescribed mutation-specific singular movement disorder does exist. We thus advocate considering GRIA3 mutations in the differential diagnosis of hyperekplexia and generalized chorea with myoclonus. © 2020 International Parkinson and Movement Disorder Society.
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Project description: Not available
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