Treatment of patients with dystrophinopathies is challenging. Current treatment consists primarily of supportive care. Definitive therapy requires restoration of dystrophin levels in skeletal and cardiac muscle fibers. Genetic approaches to accomplish this are being tested in clinical trials. One strategy involves the expression of anti-sense RNAs that alter RNA splicing so as to cause “skipping” of exons containing deleterious mutations, thus permitting the expression of a truncated, but partially functional, dystrophin protein. A second strategy involves the use of drugs that promote ribosomal “read-through” of stop codons, another ploy that may enable the synthesis of some functional dystrophin protein.
Other forms of muscular dystrophy share features with DMD and BMD but have distinct clinical, genetic, and pathologic features.
• Myotonic dystrophy. Myotonia, the sustained involuntary contraction of a group of muscles, is the cardinal neuromuscular symptom in myotonic dystrophy. Patients often complain of stiffness and difficulty in relaxing their grip, for example, after a handshake. Myotonic dystrophy is a nucleotide repeat expansion disease (Chapter 7) that is inherited as an autosomal dominant trait. More than 95% of patients with myotonic dystrophy have mutations in the gene that encodes the dystrophia myotonica protein kinase (DMPK). In normal subjects, this gene contains 5 to 37 CTG repeats, whereas affected patients usually carry 45 to several thousand. As with other nucleotide repeat expansion diseases, myotonic dystrophy exhibits anticipation, characterized by worsening of the disease manifestations with each passing generation because of further trinucleotide repeat expansion. The CTG repeat is located in the 3′ untranslated region of the DMPK mRNA. Experimental studies suggest that the skeletal muscle phenotype stems from a “toxic” gain-of-function caused by the triplet repeat expansion. The mutant DMPK mRNA with the resulting CUG expansions sequesters muscleblindlike proteins involved in RNA splicing. This functional depletion of proteins involved in RNA splicing disrupts normal gene expression patterns and alters the function of diseased tissues like skeletal and cardiac muscle. Myotonic dystrophy often manifests in late childhood with gait abnormalities due to weakness of foot dorsiflexors, with subsequent progression to weakness of the intrinsic muscles of the hands and wrist extensors, atrophy of the facial muscles, and ptosis. Involvement of other organ systems results in potentially fatal cardiac arrhythmias, cataracts, early frontal balding, endocrinopathies, and testicular atrophy.
Limb-girdle muscular dystrophies. These muscular dystrophies preferentially affect the proximal musculature of the trunk and limbs. Their genetic basis is heterogeneous. The growing list includes at least 7 dominant subtypes and 15 autosomal recessive subtypes. Some of the responsible mutations affect components of the dystrophin-glycoprotein complex other than dystrophin. Others affect proteins involved in vesicle transport and repair of cell membrane after injury (caveolin-3 and dysferlin), cytoskeletal proteins, or posttranslational modification of dystroglycan, a component of the dystrophin-glycoprotein complex.