Tsujino et al. (2003) studied a patient with a myasthenic syndrome associated with fatigable generalized weakness and recurrent attacks of respiratory and bulbar paralysis since birth. The fatigable weakness involved lid-elevator, external ocular, facial, limb, and truncal muscles, ... Tsujino et al. (2003) studied a patient with a myasthenic syndrome associated with fatigable generalized weakness and recurrent attacks of respiratory and bulbar paralysis since birth. The fatigable weakness involved lid-elevator, external ocular, facial, limb, and truncal muscles, and the decremental response of the compound muscle action potential (CMAP) on repetitive stimulation was consistent with a myasthenic phenotype. The patient's apneic attacks and the requirement for a conditioning train of stimuli at 10 Hz to elicit a decremental response at 2-Hz stimulation closely simulated features of familial infantile myasthenia gravis (254210), which is caused by mutation in the CHAT gene (118490). 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. The phenotype differed from that of periodic paralysis associated with previously identified mutations of SCN4A: the onset was neonatal, the disorder was normokalemic, the attacks selectively involved bulbar and respiratory muscles, physiologic rates of stimulation decremented the CMAP abnormally, and the muscle fiber membrane potential was normal when action potential generation failed, whereas periodic paralysis stemming from mutation in SCN4A presents later in life, the attacks typically spare cranial, bulbar, and respiratory muscles, the serum potassium level increases or declines during attacks in most cases, mild exercise for brief periods does not decrement the CMAP, and the resting membrane potential of the muscle fiber is decreased when action potential generation fails.
Tsujino et al. (2003) detected compound heterozygosity for 2 mutations in the SCN4A gene involving conserved residues not present in 400 normal alleles: a ser246-to-leu (S246L) change in the S4/S5 cytoplasmic linker in domain I, and a val1442-to-glu ... Tsujino et al. (2003) detected compound heterozygosity for 2 mutations in the SCN4A gene involving conserved residues not present in 400 normal alleles: a ser246-to-leu (S246L) change in the S4/S5 cytoplasmic linker in domain I, and a val1442-to-glu (V1442E) change in the S3/S4 extracellular linker in domain IV. 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.