The Differing Phenotypes of the Three Most Common Postsynaptic Congenital Myasthenic Syndromes Governed by Their Underlying Molecular Pathogenic Mechanisms

ABSTRACT

The congenital myasthenic syndromes are rare disorders of impaired signal transmission at the neuromuscular junction. Despite next generation sequencing facilitating the identification of variants in myasthenic‐associated genes, these variants are frequently of unknown significance and the clinical diagnosis can be delayed. It is mutations in the genes encoding neuromuscular junction proteins AChR, RAPSN, and DOK7 that underlie most cases. Appreciation of key phenotypic features that distinguish between AChR deficiency due to mutations in CHRNE , AChR deficiency due to mutations in RAPSN, and the “limb girdle” myasthenic syndrome due to mutations in DOK7 can facilitate early diagnosis. While severity for each of these conditions is markedly variable and thus there are exceptions to the rule, the CHRNE mutations result in stable generalized fatigable weakness with marked ophthalmoparesis, RAPSN mutations often result in respiratory crises in neonates or early childhood that tend to resolve with age, and DOK7 mutations cause a limb girdle myasthenic pattern of weakness that may present at birth or shortly after the walking motor milestone is achieved, is slowly progressive but responds well to treatment. The differences and time course for these phenotypes may be explained by the underlying molecular mechanisms. For the CHRNE mutations, patients at least partially function on the fetal form of the AChR; for RAPSN mutations, AChR clustering on the postsynaptic membrane is destabilized; and for DOK7 mutations, the stability of endplate structures is affected. Each of these disorders responds to treatments that can be life‐transforming and so early recognition is key.