Targeted Treatments for Myasthenia Gravis in Children and Adolescents.

Myasthenia gravis (MG) is an antibody-mediated disorder of the neuromuscular junction affecting children and adults. MG is a treatable condition with most patients requiring immunosuppression for disease control and/or remission. Juvenile myasthenia gravis (JMG) is rare in comparison with adult-onset MG but given the same underlying pathophysiology, treatment strategies are similar to those in adults. Until recently, there were only a few randomised controlled trials (RCTs) for MG treatments in adults and none in children, and management strategies were primarily based on expert consensus. In addition, treatment options for refractory MG cases have been severely limited, resulting in poor long-term quality of life in such patients due to the significant disease burden. Recently, there have been several RCTs focussing on novel therapeutic strategies with potentially promising outcomes, suggesting a change in MG management over the coming years and access to more effective and faster-acting drugs for MG patients. This paper will review current and new MG treatments including efgartigimod, eculizumab, rozanolixizumab, ravulizumab, and zilucoplan, with a focus on juvenile myasthenia gravis.

ε-Sarcoglycan: Unraveling the Myoclonus-Dystonia Gene.

Myoclonus-dystonia (MD) is a rare childhood-onset movement disorder, with an estimated prevalence of about 2 per 1,000,.000 in Europe, characterized by myoclonic jerks in combination with focal or segmental dystonia. Pathogenic variants in the gene encoding ε-sarcoglycan (SGCE), a maternally imprinted gene, are the most frequent genetic cause of MD. To date, the exact role of ε-sarcoglycan and the pathogenic mechanisms that lead to MD are still unknown. However, there are more than 40 reported isoforms of human ε-sarcoglycan, pointing to a complex biology of this protein. Additionally, some of these are brain-specific isoforms, which may suggest an important role within the central nervous system. In the present review, we aim to provide an overview of the current state of knowledge of ε-sarcoglycan. We will focus on the genetic landscape of SGCE and the presence and plausible role of ε-sarcoglycan in the brain. Finally, we discuss the importance of the brain-specific isoforms and hypothesize that SGCE may play essential roles in normal synaptic functioning and their alteration will be strongly related to MD.

Delineating the motor phenotype of SGCE-myoclonus dystonia syndrome.

OBJECTIVE: To perform phenotype and genotype characterization in myoclonus-dystonia patients and to validate clinical rating tools. METHOD: Two movement disorders experts rated patients with the Burke-Fahn-Marsden and Unified-Myoclonus rating scales using a video-recording protocol. Clinimetric analysis was performed. SGCE mutations were screened by Sanger sequencing and multiplex ligation-dependent probe amplification. RESULTS: 48 patients were included and 43/48 rated. Mean age at assessment was 12.9±10.5 years (range 3-51) and 88% were ≤18 years of age. Myoclonus was a universal sign with a rostro-caudal severity-gradient. Myoclonus increased in severity and spread to lower limbs during action tests. Stimulus-evoked myoclonus was observed in 86.8% cases. Dystonia was common but mild. It had a focal distribution and was action-induced, causing writer's cramp (69%) and gait dystonia (34%). The severity of both myoclonus and dystonia had a strong impact on hand writing and walking difficulties. The Unified Myoclonus Rating scale showed the best clinimetric properties for the questionnaire, action myoclonus and functional subscales, and exceeded the Burke-Fahn-Marsden scale in its utility in assessing functional impairment in MDS patients. Twenty-one different SGCE mutations were identified in 45/48 patients, eleven being novel (most prevalent p. Val187*, founder mutation in Canary Islands). CONCLUSION: This study quantifies the severity of the motor phenotype in SGCE-myoclonus dystonia syndrome, with a special focus on children, and identifies disabilities in gross and fine motor tasks that are essential for childhood development. Our results contribute to the knowledge of SGCE-related MDS in the early stage of evolution, where disease-modifying therapies could be initiated in order to prevent long-term social and physical burdens.