Phenotypic variability in myotonia congenita

Abstract

Myotonia congenita is a hereditary chloride channel disorder characterized by delayed relaxation of skeletal muscle (myotonia). It is caused by mutations in the skeletal muscle chloride channel gene CLCN1 on chromosome 7. The phenotypic spectrum of myotonia congenita ranges from mild myotonia disclosed only by clinical examination to severe and disabling myotonia with transient weakness and myopathy. The most severe phenotypes are seen in patients with two mutated alleles. Heterozygotes are often asymptomatic but for some mutations heterozygosity is sufficient to cause pronounced myotonia, although without weakness and myopathy. Thus, the phenotype depends on the mutation type to some extent, but this does not explain the fact that severity varies greatly between heterozygous family members and may even vary with time in the individual patient. In this review, existing knowledge about phenotypic variability is summarized, and the possible contributing factors are discussed.

The Nondystrophic Myotonias

“…This warm-up effect is transient and diminishes after a few minutes of inactivity. 17 Emotional surprises, or cold temperatures, may transiently worsen stiffness, but unlike the case with paramyotonia congenita, true weakness is conspicuously absent after cold exposure. 14 The incidence of Thomsen's disease is approximately 2 out of 50,000.…”

“…10 In contrast to most of the sodium channel myotonias, potassium ingestion does not worsen the clinical symptoms of myotonia congenita; pregnancy can both worsen and initiate symptoms. 16,17 On physical examination, true muscle hypertrophy occurs in the upper extremities, lower extremities, and facial muscles (given the nearly perpetual state of muscle contraction at these regions) in 1/3 of male patients and 1/10 of female patients. 16,18 These frequent muscle contractions often cause myotonia congenita patients to be quite strong and athletic appearing, with above-average muscle mass.…”

“…Becker's disease was named in honor of the researcher who first described it, in the 1970s. 14,17 Classically, it produces localized muscle hypertrophy, electrical myotonia, and clinical myotonia, with occasional associated persistent weakness. Compared with Thomsen's myotonia congenita, Becker's disease is more common, more insidious, and has initial symptoms that occur later in childhood.…”

“…7 In contrast to Thomsen's disease, the long exercise test in Becker's myotonia may demonstrate a small decrement after exercise with complete recovery after 3 min. 16,17 On short exercise testing, Becker's patients typically experience a large decline in CMAP amplitude, a quick 2-min recovery, and a persistent decline in amplitude on subsequent trials. 16 Laboratory tests show a trend towards a more pronounced elevation in CPK than in Thomsen's disease; potassium levels can be normal, low, or elevated.…”

“…Eighty mutations have been detailed in a recent article on phenotypic variability in myotonia congenita. 17 One hypothesis for the fact that mutations at the same gene locus can cause both the autosomal recessive and the dominant disorders proposes that, in Becker's myotonia congenita, the chloride channel homodimer loses functionality through a mutation of both monomers, whereas in the dominant forms of the disease the mutant gene product interacts with the normal monomer to produce dysfunction. 15 Another theory suggests that dominant mutations affect the common outflow chloride channel (slow flow channel), whereas recessive mutations involve two faster flow entry gates.…”