Myotonic Muscular Dystrophy

Myotonic muscular dystrophy (MMD) is one of the most common inherited human myopathies, affecting 1 in 8,000 to 18,000 people. It shows autosomal dominant inheritance with high penetrance. The hallmark of the disease is muscle stiffness (myotonia), which results from repetitive bursts of electrical activity in the muscle, and can be observed in the electromyogram. Muscle wasting and weakness also occur. In addition, patients may experience oph-thalamic (cataracts, ptosis), endocrine, cardiac, and mental problems. When the gene is inherited from the female parent, the condition may present in childhood, but more usually it becomes clinically overt between the ages of 20 and 50. Patients usually present with weakness of the hands and difficulty in walking.

Genetic mapping localised the MMD gene to chromosome 19q13.3. Subsequently, it was shown that the disease is produced by an expanded CTG repeat in the 3'-untranslated region of a gene that encodes a protein with homology to protein kinases (Fu et al., 1992). The length of the CTG expansions increases in successive generations and is associated with increasing disease severity. The role of the DM protein kinase in MMD remains unclear. Its function has not been established, and mice in which the gene encoding this protein has been 'knocked out' do not develop the disease (Jansen et al., 1996). The presence of the CTG repeat expansion also affects the expression of a flanking gene known as DMAHP, which contains a homeodomain sequence. Because homeodomains are implicated in the binding of proteins to DNA, the DMAHP protein may be involved in regulating the expression of other genes, one or more of which may be involved in the pathology of MMD.

There is accumulating evidence that SK3 channels may play a role in MMD. As described earlier, this channel is apamin sensitive. Apamin binding is not detectable in normal human skeletal muscle, but is markedly increased in muscle biopsies from MMD patients (Renaud et al., 1986), suggesting that the amount of SK3 protein may be increased. Apamin decreases myotonic activity when injected into the muscle of MMD patients (Behrens et al., 1994), consistent with the idea that overexpression of SK3 may contribute to the MMD phenotype. Why an increase in SK3 channel density should cause myotonia is still far from clear. One possible explanation, however, is that it results in an increased K+ current and thus in an enhanced accumulation of K+ ions in the T-tubules of skeletal muscle. This would tend to depolarize the muscle fibre and lead to the repetitive muscle activity that characterises the disease. Indeed, muscle biopsies have shown that the resting potential of myotonic muscle is more depolarized than normal muscle. Muscle atrophy in MMD might be a consequence of the enhanced Ca2+ entry produced by myotonia and depolarization; several of the ion channel diseases described in this book which cause myotonia (or depolarizing muscle block) are associated with increased Ca2+ influx and muscle damage.

To date, it remains unclear whether the increase in SK3 expression is the cause or consequence of the muscle dystrophy. Because apamin binding is induced following denervation (Schmid-Antomarchi et al., 1985), the high level of apamin binding in MD muscle may simply reflect a secondary increase in SK3 resulting from muscle degeneration.

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