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

Hypokalaemic periodic paralysis (hypoPP) is an autosomal dominant muscle di sorder characterized by episodic attacks of muscle weakness associated with a decrease in blood potassium levels. Mutations in the gene encoding the s keletal muscle voltage-gated calcium channel alpha -1 subunit (CACNL1A3) ac count for the majority of cases. Recently, mutations in the gene coding for the skeletal muscle voltage-gated sodium channel a subunit (SCN4A) have be en reported in a small number of hypoPP families. In order to determine the relative frequency of the CANCL1A3 and SCN4A mutations in a large populati on of hypoPP patients, and to specify the clinical and pathological feature s associated with each of them, we searched for mutations in 58 independent hypoPP index cases. We detected the causative mutation in 45 cases: 40 wer e 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 increas ed number and severity of attacks induced by acetazolamide. A muscle biopsy , performed in two members of this family, revealed a peculiar myopathy cha racterized by tubular aggregates. In contrast, vacuoles were predominant in muscles from hypoPP patients carrying CACNL1A3 mutations. Our findings poi nt to the usefulness of a molecular characterization of hypoPP patients in clinical practice, They also provide new clues for understanding the mechan isms behind functional and structural alterations of the skeletal muscle in hypoPP.