[Compound heterozygous mutations in the muscle chloride channel gene (CLCN1) in a Japanese family with Thomsen's disease].

Autosomal-dominant type of myotonia (Thomsen's disease) and autosomal-recessive one (Becker's disease) are caused by mutations in the skeletal muscle voltage-gated chloride channel gene (CLCN1). Clinical manifestation of the diseases ranges from minimum to severely disabling myotonia. We report a Japanese family with Thomsen's disease, featuring an index female young patient who possesses two dominantly-inherited mutated CLCN1 alleles. She showed severe myotonic symptoms from 18 months of age, associated with moderate muscle hypertrophy. Her mother had mild myotonic signs without muscle hypertrophy. Her father was quite normal by both clinical and electromyographic examinations. With genomic DNA extracted from blood leukocytes, all 23 exons of the CLCN1 gene were analyzed by direct sequencing of PCR products. The analysis revealed compound heterozygous mutations of T539A and M560T in the index patient, a heterozygous mutation of T539A in her mother, and a heterozygous mutation of M560T in her father. Since both mutations were previously described in families of Thomsen's disease, her father was regarded as a non-symptomatic carrier. The family reveals that compound heterozygosity of two dominantly inheritable disease mutations exacerbates the myotonia, suggesting the dosage effect of CLCN1 mutation responsible for myotonia congenita of Thomsen type.