gms | German Medical Science

Introduction: The congenital myasthenic syndromes (CMS) are a diverse group of disorders which arise from mutations affecting crucial proteins at the neuromuscular junction (NMJ). A precise molecular classification of CMS subtype is of the utmost importance in order to allow administration of effective treatment, however several pitfalls and challenges in diagnosis exist.

Objectives: To improve recognition and management of CMS and highlight recently characterised clinical and pathological features of these treatable disorders.

Materials & Methods: Gene discovery at the John Walton Muscular Dystrophy Research Centre in Newcastle, UK aims to identify new causative CMS genes in genetically undiagnosed families, and explore the effects of these mutations in animal models. In addition, our clinical service for CMS patients has highlighted the variability of clinical phenotype and treatment response in these patients.

Results: In recent years the discovery of CMS related genes has accelerated and to date over 20 genes have been implicated (Figure 1 [Fig. 1]), with our laboratory being involved in the discovery of 13 genes. In parallel to gene discovery, the functional effects of novel genes have been characterised in zebrafish and mouse models, revealing new roles for NMJ proteins. Recently identified mutations in genes encoding enzymes involved in glycosylation has led to a new entity of CMS with a limb-girdle pattern of weakness and tubular aggregates on muscle biopsy. In addition, novel pre-synaptic mutations have highlighted the overlap between CMS and motor neuropathies. Whilst classically a generic diagnosis of CMS is suggested on the basis of early onset fatigable weakness with ocular and bulbar involvement, many CMS subtypes exhibit less typical clinical features and may easily be overlooked. A candidate gene may be indicated by certain clinical, histopathological and neurophysiological findings, and the current diagnostic and treatment strategies are summarised.

Conclusion: Although CMS are the rarest of the myasthenic disorders, they have nevertheless shown the greatest clinical and pathological diversity, and the study of CMS has expanded our knowledge both of how NMJ dysfunction can present clinically and pathologically and of the role of previously uncharacterised proteins at the NMJ.