Abstract
Myotonia congenita (MC) is a skeletal muscle channelopathy characterized by inability of the muscle to relax following voluntary contraction. Worldwide population prevalence in humans is 1∶100,000. Studies in mice, dogs, humans and goats confirmed myotonia associated with functional defects in chloride channels and mutations in a skeletal muscle chloride channel (CLCN1). CLCN1 encodes for the most abundant chloride channel in the skeletal muscle cell membrane. Five random bred cats from Winnipeg, Canada with MC were examined. All cats had a protruding tongue, limited range of jaw motion and drooling with prominent neck and proximal limb musculature. All cats had blepharospasm upon palpebral reflex testing and a short-strided gait. Electromyograms demonstrated myotonic discharges at a mean frequency of 300 Hz resembling the sound of a ‘swarm of bees’. Muscle histopathology showed hypertrophy of all fiber types. Direct sequencing of CLCN1 revealed a mutation disrupting a donor splice site downstream of exon 16 in only the affected cats. In vitro translation of the mutated protein predicted a premature truncation and partial lack of the highly conserved CBS1 (cystathionine β-synthase) domain critical for ion transport activity and one dimerization domain pivotal in channel formation. Genetic screening of the Winnipeg random bred population of the cats' origin identified carriers of the mutation. A genetic test for population screening is now available and carrier cats from the feral population can be identified.
Highlights
Myotonia is defined as delayed relaxation of voluntarily or reflexively contracted muscle [1] and is due to repetitively firing muscle action potentials after a single stimulus
Individuals affected with various forms of myotonia typically describe a painless, muscle stiffness that remits with several repetitions of the same movement; the so-called ‘warm-up’ phenomenon [2,3]
If symptoms worsen with repeated exercise, paradoxical myotonia is more appropriate, which is usually due to mutant sarcolemmal Na+ channels [4]
Summary
Myotonia is defined as delayed relaxation of voluntarily or reflexively contracted muscle [1] and is due to repetitively firing muscle action potentials after a single stimulus. Individuals affected with various forms of myotonia typically describe a painless, muscle stiffness that remits with several repetitions of the same movement; the so-called ‘warm-up’ phenomenon [2,3]. Myotonia congenita (MC) is characterized by mutations within CLCN1, a gene [5] encoding the skeletal muscle voltage-gated chloride channel ClC-1. This chloride channel is responsible for up to 80% of the resting sarcolemmal conductance [4,6,7] and belongs to the ClC family of anion channels (ClC-0, ClC-1, ClC-2 and ClC-Ka/Kb) and anion/proton antiporters (ClC-3–ClC-7) [8]. CLCN1 functions as a homodimer with four proposed sites of dimerization [12,14]
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