A Paramyotonia Congenita Family with an R1448H Mutation in SCN4A

Paramyotonia congenita (PC) is a type of Na channelopathy caused by mutations in the Na voltage-gated channel alpha subunit 4 (SCN4A) gene on chromosome 17q23, which encodes voltage-gated Na channels (Nav1.4) in skeletal muscles and is inherited in an autosomal dominant pattern [1,2]. These channels are integral membrane proteins that exist in most excitable cells. They are mainly responsible for rapid membrane depolarization, which is the initial phase of the action potential. Rapid inactivation after an action potential prevents repetitive excitation and maintains normal physiological excitability of skeletal muscles. Abnormal activity of human skeletal muscle due to a dysfunctional Na channel α-subunit with an SCN4A mutation causes excessive excitability and leads to the activation or inactivation of the channel. Clinical phenotypes associated with SCN4A mutations include PC, type 2 hyperkalemic periodic paralysis (PP), type 2 hypokalemic PP, congenital myasthenic syndrome-16, and acetazolamide-responsive myotonia congenita [1]. Furthermore, PC is characterized by muscular myotonia without weakness, and it mainly affects the muscles of the neck, face, and upper limbs. PC typically occurs in infancy or childhood and is triggered by exposure to cold or physical activity [3]. In this paper, we report the case of a male adolescent and his three-generation family with PC caused by an SCN4A mutation. This case was reviewed and approved by the Institutional Review Board of Pusan National University Hospital (IRB No. 2205-013-114). Informed consent was obtained from all parents. Patients’ medical records and other data were anonymized to ensure confidentiality. The proband was a 14-year-old boy with a 2-year history of episodic muscular stiffness and weakness. The patient often experienced weakness and stiffness in the lower and upper extremities. During exercise, the lower extremities were affected more than the upper extremities; however, symptoms were also observed in the hands, arms, and face. During the asymptomatic period, the patient exercised normally. However, once symptoms developed, the patient was unable to move. When exposed to cold environments, such as when washing the face or during cold weather, symptoms were aggravated in the exposed body parts. The patient was born at a gestational age of 40 weeks via normal vaginal delivery, weighing 3,400 g. He showed normal development and growth. The mother of the patient also had stiffening and muscle weakness in the upper extremities, face,