Myotonic Dystrophy and Other Myotonic Disorders (Continued)

DM2 is caused by an expanded cytosine-cytosine-thymine-guanine (CCTG) tetranucleotide repeat expansion located in intron1 of the zinc-finger protein 9 gene (ZNF9 gene) on chromosome 3q21.3. On normal alleles, there are 11 to 26 tetranucleotide repeats; on pathogenic alleles, the number of repeats ranges from 75 to more than 11,000, with a mean of 5000 repeats.

In contrast to DM1, there is no correlation in DM2 between CCTG repeat size and age of onset of weakness or disease severity.

In both DM1 and DM2, the respective disparate gene is transcribed into ribonucleic acid (RNA) but is not translated. The mutant RNAs accumulate in the nucleus and alter RNA binding protein activity, which, in turn, results in abnormal function of several genes, including the skeletal muscle chloride channel, the insulin receptor, and cardiac troponin T.

Management of DM is best carried out in a multidisciplinary neuromuscular clinic. Cardiac follow-up with yearly electrocardiograms (ECGs) is highly recommended because there is a significant risk of sudden death from cardiac dysrhythmias. A trial of medication (mexiletine) may be warranted to ease problematic clinical myotonia. Physical therapy and use of orthoses for the distal leg weakness leading to partial footdrop may be indicated and very helpful to optimize motor function.

Three other conditions are characterized by clinical myotonia; these include the sodium channelopathies (hyperkalemic periodic paralysis) causing myotonia without weakness until the fifth decade; paramyotonia congenita, where myotonia worsens paradoxically with activity (especially in cold environments); and the chloride channelopathy, myotonia congenita.

Myotonia congenita (MC) typically becomes symptomatic in infancy or early childhood. The incidence is 2 per l00, 000. The most common form is autosomal dominant (Thomsen disease), characterized by generalized painless myotonia and a complete absence of the extramuscular systemic features characteristic of DM1 and DM2. Affected infants may develop lid myotonia with crying and do not immediately reopen their eyes. With the exception of slowness initiating movement, that is, a tendency to fall when first standing or suddenly trying to run, these patients demonstrate relatively little functional impairment. They also complain of stiffness relieved by exercise. Their muscles need to be “warmed up”: muscles stiff from myotonia are unable to exert normal power but after use are essentially normal in strength. Clinically, the muscles are enlarged to a pseudoherculean appearance, often leading athletic coaches to encourage participation in school sports, something their dysfunctional muscles cannot support.

The less common autosomal recessive form (Becker type) also typically has significant muscle hypertrophy. It may be associated with slowly progressive weakness and greater functional impairment than the more common Thomsen variant. Both have a similar mutation in the muscle chloride channel gene (CLCN1) on chromosome 7q25.

Schwartz-Jampel syndrome is not a channelopathy and, strictly speaking, is not a myotonic disorder, but it enters into the differential diagnosis of stiffness in a child. It is a rare autosomal recessive condition that consists of blepharophimosis, low-set ears, and micrognathia. Affected children are of normal intelligence, short stature with multiple joint contractures, and scoliosis. There is continuous muscle stiffness, and percussion and grip myotonia are severe. The electromyograph (EMG) reveals complex repetitive discharges and not myotonia per se.

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