Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A

TLDR

Hypokalaemic periodic paralysis is an autosomal dominant muscle disorder marked by episodic weakness and low potassium, most commonly caused by CACNL1A3 mutations but also occasionally by SCN4A mutations. The study screened 58 independent hypoPP index cases for CACNL1A3 and SCN4A mutations to determine their relative frequency and to delineate the associated clinical and pathological features. Mutations were identified in 45 of 58 patients—40 in CACNL1A3 and five in SCN4A, including one novel variant—showing that SCN4A‑associated families have complete penetrance, early onset, severe acetazolamide‑induced attacks, and tubular‑aggregate myopathy, whereas CACNL1A3 cases display vacuolar pathology, highlighting the clinical utility of molecular diagnosis and providing new insights into hypoPP mechanisms.

Abstract

Hypokalaemic periodic paralysis (hypoPP) is an autosomal dominant muscle disorder characterized by episodic attacks of muscle weakness associated with a decrease in blood potassium levels. Mutations in the gene encoding the skeletal muscle voltage-gated calcium channel α-1 subunit (CACNL1A3) account for the majority of cases. Recently, mutations in the gene coding for the skeletal muscle voltage-gated sodium channel α subunit (SCN4A) have been reported in a small number of hypoPP families. In order to determine the relative frequency of the CANCL1A3 and SCN4A mutations in a large population of hypoPP patients, and to specify the clinical and pathological features associated with each of them, we searched for mutations in 58 independent hypoPP index cases. We detected the causative mutation in 45 cases: 40 were linked to the CACNL1A3 gene and five to the SCN4A gene. One mutation has not been described before. Some remarkable clinical features were observed in a large hypoPP family carrying an SCN4A mutation: a complete penetrance in men and women, an early age at onset, postcritic myalgias and an increased number and severity of attacks induced by acetazolamide. A muscle biopsy, performed in two members of this family, revealed a peculiar myopathy characterized by tubular aggregates. In contrast, vacuoles were predominant in muscles from hypoPP patients carrying CACNL1A3 mutations. Our findings point to the usefulness of a molecular characterization of hypoPP patients in clinical practice. They also provide new clues for understanding the mechanisms behind functional and structural alterations of the skeletal muscle in hypoPP.