A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-16 (CMS16) is caused by compound heterozygous or homozygous mutation in the SCN4A gene (603967) on chromosome 17q23.

Congenital myasthenic syndrome is a disorder characterized by variable degrees of muscle fatigability caused by impaired transmission of electrical signals at the neuromuscular junction (NMJ) (summary by Arnold et al., 2015).

For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).

Tsujino et al. (2003) reported a 20-year-old woman with delayed motor development and severe generalized muscle weakness. She also had recurrent attacks of respiratory and bulbar paralysis a few times a month since birth, resulting in cerebral anoxia and secondary cognitive impairment. The muscle weakness was worsened by activity. Additional features included high-arched palate, adduction deformity of the knees and ankles, and lumbar lordosis. Laboratory studies showed that she was normokalemic. There was no family history of a similar disorder. Electrophysiologic studies showed a decremental response of the compound muscle action potential (CMAP) on repetitive stimulation, consistent with a myasthenic syndrome. A study of intercostal muscle revealed no abnormality of the resting membrane potential, evoked quantal release, synaptic potentials, acetylcholine receptor channel kinetics, or endplate ultrastructure, but endplate potentials depolarizing the resting potential to -40 mV failed to elicit action potentials.

Arnold et al. (2015) reported a 57-year-old woman with lifelong episodic generalized weakness that occurred several times per week and often lasted for hours. The episodes resulted in difficulty with simple tasks and occasional need for a walker. She also had ptosis and almost complete external ophthalmoplegia. No other abnormalities were reported, and her cognition was normal. Laboratory studies showed normokalemia, and electrophysiologic studies showed a decremental CMAP response on repetitive stimulation, consistent with a defect at the neuromuscular junction. A trial of pyridostigmine was ineffective.

The findings in the patient of Tsujino et al. (2003) had therapeutic implications: after the defect in SCN4A was identified, therapy with pyridostigmine, which increases the number of acetylcholine receptors activated by each quantum, improved the patient's endurance; additional therapy with acetazolamide, which was known to mitigate periodic paralysis due to mutation in SCN4A, prevented further attacks of respiratory and bulbar weakness. Moreover, this study demonstrated that a reduced margin of safety for neuromuscular transmission may occur in the setting of a normal endplate potential.

The patient with CMS16 reported by Arnold et al. (2015) had no beneficial response to treatment with pyridostigmine.

The transmission pattern of CMS16 in the family reported by Arnold et al. (2015) was consistent with autosomal recessive inheritance.

In a 20-year-old woman with normokalemic congenital myasthenic syndrome, Tsujino et al. (2003) identified compound heterozygous variants in the SCN4A gene (V1442E, 603967.0018 and S246L, 603967.0031). The genetically engineered V1442E sodium channel expressed in cultured cells showed marked enhancement of fast inactivation close to the resting potential, and enhanced use-dependent inactivation on high-frequency stimulation. The authors concluded that S246L is likely a benign polymorphism, whereas the V1442E mutation defines a novel disease mechanism and a novel phenotype with myasthenic features. Tsujino et al. (2003) concluded that the inheritance pattern of this congenital myasthenic syndrome could not be unambiguously established. They suggested that the more severe V1442E mutation may be dominant, but it could not be proven because the mutation was observed only in combination with S246L on the other chromosome.

In a 57-year-old woman, born of consanguineous parents, with CMS16, Arnold et al. (2015) identified a homozygous missense mutation in the SCN4A gene (R1457H; 603967.0032). In vitro electrophysiologic studies showed that the mutation caused a 25-mV hyperpolarizing shift in the voltage dependence of inactivation, resulting in enhanced fast inactivation, as well as slowed recovery from fast inactivation. In addition, repetitive stimuli elicited markedly weaker current responses. These changes resulted in reduced channel availability, which could explain the patient's muscle weakness. The unaffected parents and sibs were heterozygous for the mutation.