Phenotypic heterogeneity in skeletal muscle sodium channelopathies: A case report and literature review
A 14-year-old Asian boy presented to pediatric neurology with 4-year history of episodes of muscle stiffness and weakness in lower limbs, occurring following sitting (resting) for nearly 1 h after exercise. The muscle stiffness episode would improve following shaking of legs (“warm-up effect”). There was no history of difficulty in climbing stairs or running.\nHe was born at term vaginally to unrelated parents. There was no history of decreased fetal movements or polyhydramnios. He did not require active resuscitation at birth and weighed 3.4 kg. There was no history of feeding or breathing difficulties in the neonatal period, and his weaning period was uneventful. He had normal developmental milestones.\nFamily history was remarkable for his father having episodes of muscle stiffness; however, no specific diagnosis was assigned.\nPhysical examination did not reveal dysmorphism or neurocutaneous stigmata. His growth parameters were within normal limits. Gait was normal and Gower sign was negative. There was no evidence of calf muscle hypertrophy or limb weakness (proximal or distal). Tone, power, and deep tendon reflexes were normal in all the four limbs. Creatine kinase (CK) was elevated at 1024 IU/L (25-200). Electromyography (EMG) revealed myopathic changes []. There was evidence of muscle membrane irritability with myotonia, which was highly suggestive of a myotonic disorder. As a result, it was decided to arrange for short exercise testing as part of the myotonia protocol. At room temperature there was mild post-exercise potentiation for about half a minute, followed by recovery toward normal. Cold exposure produced reduction in muscle action potential amplitude to about 50% accompanied by severe clinical weakness. It also exposed a post-exercise drop in amplitude with slight recovery, and a subsequent progressive further decrease in the action potential with serial exercises [], which was consistent with features of paramyotonia congenita (PC) (Fournier pattern I). At this point the history and EMG suggested a myotonic disorder, and consequently the long exercise tests were not carried out. Molecular genetic testing was negative for myotonic dystrophy and MC (CLCN1). Further testing detected a heterozygous pathogenic mutation c. 2111C > T; p.Thr704Met in the coding regions (c. 2020-2376) and (c. 4571-4838) of sodium channel type IV α subunit (SCN4A).