G.P.102 SCN4A mutations in Finland

Mutations in SCN4A gene are associated in several dominant myotonic disorders including potassium-aggravated myotonia, paramyotonia congenita, hyper- and hypokalemic periodic paralysis, myasthenic syndrome and acetazolamide-responsive myotonia congenita. Over 50 mutations have been identified all over the gene with some accumulation of mutations at the end of the protein. We have identified three different dominant mutations in Finnish patients: A1156T, V1293I and a novel R1460Q. These mutations are associated with different symptoms which can vary in patients even with the same mutation. Symptoms in patients with A1156T (n=9) vary from clinical myotonia to only stiffness and myalgia with increased insertional activity in EMG. Patients carrying V1293I mutation (four patients in one family) have symptoms of paramyotonia congenita without paralysis. In one family five patients have been identified with R1460Q mutation which has not been reported previously. Two of them also carry a heterozygous CLCN1 R894X mutation. The patients with only the SCN4A mutation have paramyotonia or cold-induced myotonia in addition to periodic paralyses and one is almost asymptomatic. The two double-mutants have myasthenia and myotonia among other myalgic-stiffness symptoms. The novel R1460Q mutation is obviously pathogenic, because it resides in a highly conserved region of transmembrane segment S4 of domain IV. S4 is a voltage censor and has positively charged amino acids at every third position. The change of a positively charged arginine into an uncharged glutamine disrupts the pattern of positively charged amino acids and is thus very likely harmful for the protein function. The mutations in SCN4A cause variable phenotypes and combinations with other gene mutations, such as CLCN1, can modify the clinical outcome and complicate the diagnosis. The combination of SCN4A R1460Q and CLCN1 R894X seems to cause a distinct phenotype involving myasthenia.