RESUMO
BACKGROUND: In clinical practice, myoclonus in childhood-onset neurogenetic disorders frequently remains unrecognized, because it is often overshadowed by other neurological features. Since treatment can lead to significant functional improvement, accurate phenotyping is essential. To demonstrate the importance of early identification and treatment, we report on four patients with various childhood-onset neurogenetic disorders suffering from myoclonus. METHODS: We evaluated four patients with established childhood-onset neurogenetic disorders and involuntary jerky movements, who visited our young-onset movement disorder outpatient clinic. RESULTS: We present the clinical data of four patients (aged 8-21 years) with childhood-onset neurogenetic disorders, including ataxia-telangiectasia, Coffin-Lowry syndrome and epileptic encephalopathy due to SCN1A mutations. All four suffered from jerky movements that hampered normal daily activities and that had gone unrecognized for several years. The presence of multifocal myoclonus was confirmed by polymyography. In all patients, treatment resulted in marked improvement of both myoclonus and overall functioning. CONCLUSION: These cases highlight the relevance of actively searching for myoclonus in childhood-onset neurogenetic disorders, even when a molecular diagnosis has already been established. To further improve the awareness and recognition of myoclonus in children, we provide a list of childhood-onset neurogenetic disorders with myoclonus as important associated feature.
Assuntos
Mioclonia/etiologia , Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/genética , Anticonvulsivantes/uso terapêutico , Ataxia Telangiectasia/etiologia , Ataxia Telangiectasia/genética , Encefalopatias/complicações , Encefalopatias/genética , Criança , Síndrome de Coffin-Lowry/etiologia , Síndrome de Coffin-Lowry/genética , Diagnóstico Precoce , Eletromiografia , Epilepsias Mioclônicas/genética , Epilepsia/etiologia , Epilepsia/genética , Feminino , Humanos , Masculino , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/genética , Mioclonia/tratamento farmacológico , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Doenças do Sistema Nervoso/tratamento farmacológico , Adulto JovemRESUMO
Coffin-Lowry Syndrome (CLS) is an X-linked genetic disorder associated with cognitive and behavioural impairments. CLS patients present with loss-of-function mutations in the RPS6KA3 gene encoding the mitogen-activated protein kinase (MAPK)-activated kinase p90 ribosomal S6 kinase 2 (Rsk2). Although Rsk2 is expressed in the embryonic brain, its function remains largely uncharacterized. To this end, we isolated murine cortical precursors at embryonic day 12 (E12), a timepoint when neuronal differentiation is initiated, and knocked-down Rsk2 expression levels using shRNA. We performed similar experiments in vivo using in utero electroporations to express shRNA against Rsk2. Rsk2 knockdown resulted in a significant decrease in neurogenesis and an increase in the proportion of proliferating Pax6-positive radial precursor cells, indicating that Rsk2 is essential for cortical radial precursors to differentiate into neurons. In contrast, reducing Rsk2 levels in vitro or in vivo had no effect on the generation of astrocytes. Thus, Rsk2 loss-of-function, as seen in CLS, perturbs the differentiation of neural precursors into neurons, and maintains them instead as proliferating radial precursor cells, a defect that may underlie the cognitive dysfunction seen in CLS.
