What are congenital myasthenic syndromes?

Congenital myasthenic syndromes result from gene mutations affecting the neuromuscular junction structure and function. Unlike autoimmune myasthenia gravis, the immune system is not involved and there is no association with antibodies to the acetylcholine receptor (AChR) or muscle specific kinase. Although all congenital myasthenic syndromes share the feature of fatiguable muscle weakness, they are discrete syndromes each with their own, often distinct, phenotype. Significant advances in the last 20 years, mainly in molecular genetics, have enabled identification of at least 15 genes implicated in congenital myasthenic syndromes (table 1). About 80%–90% of patients with congenital myasthenia in the UK now have a confirmed genetic diagnosis. Thus, there are likely to be many unidentified associated genes.

The delineation of these different genetic syndromes has enabled the development of a range of effective symptomatic treatments. The choice of treatment is governed by the underlying pathogenic mechanism. Importantly, the treatments routinely used for some subtypes can cause significant deterioration in others. In addition, a range of conditions can mimic congenital myasthenic syndromes and these too require different therapy. Therefore, a definitive genetic diagnosis is important and guides treatment, prognosis and genetic counselling.

Most patients with congenital myasthenia present with symptoms at birth or early infancy, although in some subtypes, particularly those predominantly affecting proximal muscles such as downstream of kinase-7 (DOK7), onset is typically in childhood with walking difficulties. Patients with the slow channel syndrome may have symptom onset well into their second or third decades. While many patients are now identified …