Congenital myasthenic syndromes (designated as CMS throughout this entry) are characterized by fatigable weakness of skeletal muscle (e.g., ocular, bulbar, limb muscles) with onset at or shortly after birth or in early childhood; rarely, symptoms may not manifest until later in childhood. Cardiac and smooth muscle are not involved. Severity and course of disease are highly variable, ranging from minor symptoms to progressive disabling weakness. In some subtypes of CMS, myasthenic symptoms may be mild, but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may be precipitated by fever, infections, or excitement. Major findings of the neonatal onset subtype include: feeding difficulties; poor suck and cry; choking spells; eyelid ptosis; facial, bulbar, and generalized weakness. In addition arthrogryposis multiplex congenital may be present; respiratory insufficiency with sudden apnea and cyanosis may occur. Later childhood onset subtypes show abnormal muscle fatigability with difficulty in activities such as running or climbing stairs; motor milestones may be delayed; fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness are common presentations.
The diagnosis of CMS is based on clinical findings, a decremental EMG response of the compound muscle action potential (CMAP) on low-frequency (2-3 Hz) stimulation, absence of anti-acetylcholine receptor (AChR) and anti-MuSK antibodies in the serum, and lack of improvement of clinical symptoms with immunosuppressive therapy. Mutations in one of multiple genes encoding proteins expressed at the neuromuscular junction are currently known to be associated with subtypes of CMS, including the genes encoding different subunits of the acetylcholine receptor: CHRNE (epsilonAChR subunit) . CHRNA1 (alphaAChR subunit). CHRNB1 (betaAChR subunit). CHRND (deltaAChR-subunit). AGRN encoding agrin. CHAT encoding choline O-acetyltransferase. COLQ encoding acetylcholinesterase collagenic tail peptide. DOK7 encoding protein Dok-7 . GFPT1 encoding glucosamine--fructose-6-phosphate aminotransferase 1 . MUSK encoding muscle, skeletal receptor tyrosine protein kinase . RAPSN encoding rapsyn (43-kd receptor-associated protein of the synapse). SCN4A encoding the sodium channel protein type 4 subunit alpha. Clinical molecular genetic testing is available for all of these genes.
Congenital myasthenic syndromes are inherited in an autosomal recessive, or, less frequently, autosomal dominant manner. In autosomal recessive CMS (AR-CMS), the parents of an affected child are obligate heterozygotes and therefore carry one mutant allele. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. In autosomal dominant CMS (AD-CMS), some individuals have an affected parent while others have a de novo mutation. The proportion of cases caused by de novo mutations is unknown. Each child of an individual with AD-CMS has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk is possible in a clinical laboratory for most subtypes of CMS if the disease-causing mutations in a family are known; prenatal testing for the remaining subtypes may be available through laboratories offering custom prenatal testing.