• NEUROMUSCULAR
• MYASTHENIA

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by mutations in genes that encode proteins essential for neuromuscular transmission.1 2 These are distinct from the autoimmune conditions myasthenia gravis and Lambert–Eaton myasthenic syndrome, which are associated with pathogenic autoantibodies.

To date, over 35 genes have been implicated.3 4 The advent of next-generation sequencing has led to the identification of new genetic causes for CMS that include either mutations in proteins directly involved in neuromuscular transmission and neuromuscular junction structure or modification of proteins such as in the N-linked glycosylation pathway. Although N-linked glycosylation is ubiquitous in eukaryotic cells, neuromuscular junction function appears sensitive to deficits in the early steps of this pathway. Moreover, next-generation sequencing has facilitated the identification of variants in several large CMS genes, such as AGRN, LRP4 and MUSK, for which screening of individual exons is laborious.

All patients with CMS have fatiguable weakness, but the phenotypes vary in their onset age, pattern of weakness, severity, progression over time and response to therapy.2 Added to this, the array of implicated genes, the growing number of causative mutants and overlapping features with other diseases can make the diagnosis challenging, as evidenced by the case described by McLean et al in this edition of Practical Neurology.5

CMS are rare; the detected prevalence of genetically confirmed cases in the UK in a 2013 study was approximately 9.2 cases per million.4 However, this study predated the widespread adoption of next-generation sequencing, so it is likely an underestimate. To help understanding, the syndromes are usually classified based upon the localisation of the offending protein at the neuromuscular junction: presynaptic, synaptic basal lamina associated, postsynaptic or ubiquitously expressed (figure 1).6