Clinical, electrophysiological, and molecular genetic studies in a new family with paramyotonia congenita

Objectives-To characterise the clinical and electrophysiological features a nd to determine the molecular genetic basis of pure paramyotonia congenita in a previously unreported large Irish kindred. Methods-Clinical and neurophysiological examination was performed on three of the five affected family members. Five unaffected and three affected mem bers of the family were available for genetic testing. Direct sequence anal ysis of the SCN4A gene on chromosome 17q, was performed on the proband's DN A. Restriction fragment length polymorphism (RFLP) analysis was used to scr een other family members and control chromosomes for the SCN4A mutation ide ntified. Results-Each affected member had clinical and examination features consiste nt with pure paramyotonia congenita. Electrophysiological studies disclosed a 78% drop in compound muscle action potential (CMAP) amplitude on cooling to 20 degrees C. DNA sequence analysis identified a heterozygous point mut ation G4367A in exon 24 of the SCN4A gene which segregated with paramyotoni a and was absent in 200 control chromosomes. The mutation is predicted to r esult in a radical amino acid substitution at a highly conserved position w ithin the voltage sensing fourth transmembrane segment of the fourth repeat ed domain of the sodium channel. Conclusions-The G4367A mutation is likely to be pathogenic and it associate s with a pure paramyotonia phenotype. In keeping with other paramyotonia mu tations in this region of the skeletal muscle sodium channel, it is predict ed that this mutation will impair voltage sensing or sodium channel fast in activation in a temperature dependent fashion. This study provides further evidence that exon 24 in SCN4A is a hot spot for paramyotonia mutations and this has implications for a DNA based diagnostic service.