Congenital Myasthenic Syndromes

Very few areas of medical genetics have been so profoundly impacted by the advent of next- generation sequencing (NGS) as the field of congenital myasthenic syndromes (CMS). This is due to the formidable genetic heterogeneity of CMS, a dearth of diagnostic clinical clues of CMS types, and the imperative need to establish an accurate molecular diagnosis of CMS type before any medication is started. A molecular diagnosis of CMS is fundamental not only to provide an appropriate therapy, but more importantly, to avoid potential deleterious treatments. Thus, NGS has transformed the tedious and expensive task of searching for causative mutations in an ever-expanding list of genes linked to CMS into an effective, and relatively inexpensive process that can rapidly identify the variant of CMS in question. One of the consequences of this transformation is a paradigm shift in the clinical practice of CMS that no longer requires, with rare exceptions, the use of special muscle biopsies that enable the analysis of the function and ultrastructure of the neuromuscular junction to determine the type of CMS. Another technological advance of recent years is CRISPR/Cas9, which allows genome editing at the zygotic stage, thus greatly simplifying the generation of mouse models carrying the same human CMS mutations in orthologous mouse genes. This permits an in-depth analysis of the pathogenesis and treatments of CMS caused by specific gene mutations. In terms of therapy, in addition to the classical pharmacologic treatments of CMS, including pyridostigmine sulfate, albuterol and 3,4 diaminopyridine, AAV-based gene therapies are now at the preclinical stage for several types of CMS. In this brief review, CMS are classified in six major groups: (1). presynaptic CMS, (2) synaptic CMS, (3) postsynaptic CMS; 4. CMS affecting the agrin-signal transduction pathway, (5) CMS linked to disorders of glycosylation, and (6) CMS associated with abnormalities of the cytoskeleton.