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Other Forms of Muscular Dystrophy

by Michael Rubin, MDCM

Emery-Dreifuss dystrophy

This disorder can be inherited as an autosomal dominant, autosomal recessive (the rarest), or X-linked recessive disorder. The overall incidence is unknown. Females can be carriers, but only males are affected clinically by X-linked inheritance. Genes associated with Emery-Dreifuss dystrophy encode for the nuclear membrane proteins lamin A/C (autosomal) and emerin (X-linked).

Symptoms and Signs

Muscle weakness and wasting can begin any time before age 20 and commonly affect the biceps and triceps and, less often, distal leg muscles. Early contractures are characteristic. The heart is frequently involved, with atrial paralysis, conduction abnormalities (atrioventricular block), cardiomyopathy, and a high likelihood of sudden death.


Diagnosis

Diagnosis is indicated by clinical findings, age at onset, and family history. The diagnosis is supported by mildly increased serum CK levels and myopathic features on electromyography and muscle biopsy and is confirmed by DNA testing.


Treatment

Treatment involves therapy to prevent contractures. Cardiac pacemakers are sometimes lifesaving in patients with abnormal conduction.


Myotonic dystrophy

Myotonic dystrophy, the most common form of muscular dystrophy among whites, affects about 1/8000 in the general population. Inheritance is autosomal dominant with variable penetrance. Two genetic loci—DM 1 and DM 2—cause the abnormality.

Congenital myotonic dystrophy

Affected mothers and, rarely, fathers with DM 1 mutations may have offspring with a severe form of myotonia referred to as congenital myotonic dystrophy. This form is characterized by severe hypotonia (floppy infant), feeding and respiratory difficulties, skeletal deformities, facial weakness, and delayed psychomotor development. Up to 40% of infants do not survive, usually because of respiratory failure and perhaps cardiomyopathy. Up to 60% of survivors have intellectual disability.


Symptoms and Signs

Symptoms and signs of myotonic dystrophy begin during adolescence or young adulthood and include myotonia (delayed relaxation after muscle contraction), weakness and wasting of distal limb muscles (especially in the hand) and facial muscles (ptosis is especially common), and cardiomyopathy. Intellectual disability, cataracts, and endocrine disorders can also occur.

Death is most commonly due to respiratory and cardiac disease, and patients who develop cardiac arrhythmias and severe muscle weakness at a younger age are at increased risk of premature death. Mean age at death is 54 yr.


Diagnosis

Diagnosis is indicated by characteristic clinical findings, age at onset, and family history and is confirmed by DNA testing.


Treatment

Myotonia may respond to membrane-stabilizing drugs (eg, mexiletine, procainamide, quinidine, phenytoin, carbamazepine). Of these, mexiletine has been shown to significantly reduce myotonia in nondystrophic myotonia and is thus the first-line drug for myotonic dystrophy patients who have functionally limiting myotonia. Because mexiletine can rarely precipitate arrhythmias in patients with underlying ventricular arrhythmias, the drug is contraindicated in patients with 2nd- or 3rd-degree atrioventricular block; consultation with a cardiologist is recommended before initiating mexiletine therapy, particularly in those with an abnormal ECG. However, it is weakness, for which no treatment is available, and not myotonia that usually disables the patient; braces for footdrop are usually required as the disease progresses.


Limb-girdle dystrophy

Limb-girdle dystrophy at last count has 21 known subtypes, 15 autosomal recessive and 6 autosomal dominant. The overall incidence is unknown. Males and females are affected equally. Insights from molecular biology have redefined the way these disorders are classified. Autosomal dominant forms are classified as LGMD 1A, -1B, -1C, and so on, and recessive forms are classified as LGMD 2A, -2B, -2C, and so on. Several chromosomal loci have been identified for autosomal dominant (5q [no known gene product]) and recessive (2q, 4q [beta-sarcoglycan], 13q [gamma-sarcoglycan], 15q [calpain, a Ca-activated protease], and 17q [alpha-sarcoglycan or adhalin]) forms. Structural (eg, dystrophin-associated glycoproteins) or nonstructural (eg, proteases) proteins can be affected.

Symptoms and Signs

Patients typically present with slowly progressive, symmetric, proximal muscle weakness with or without facial involvement and diminished or absent tendon reflexes. The pelvic or the shoulder girdle muscles can be affected first. Onset of symptoms for autosomal dominant types ranges from early childhood to adulthood. Onset of symptoms for autosomal recessive types tends to be during childhood, and these types primarily have a pelvic-girdle distribution.


Diagnosis

Diagnosis is indicated by characteristic clinical findings, age at onset, and family history and requires muscle histology, immunocytochemistry, Western blot analysis, and genetic testing for specific proteins.


Treatment

Treatment focuses on maintaining function and preventing contractures. Guidelines recently issued by the American Academy of Neurology recommend that newly diagnosed LGMD patients at high risk of cardiac complications be referred for cardiac evaluation, even in the absence of cardiac symptoms. Those at high risk of respiratory failure should undergo pulmonary function testing. All LGMD patients should ideally be referred to a multi-specialty clinic with expertise in neuromuscular disorders. There is currently no role for gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone other than in a research study.


Facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHMD) is an autosomal dominant disorder. In about 98% of patients, FSHMD is caused by a deletion on the long arm of chromosome 4, at the 4q35 locus. In about 10 to 33% of patients, the mutation is de novo (sporadic) rather than inherited. FSHMD is the third most common muscular dystrophy after Duchenne dystrophy and myotonic dystrophy and affects 1/20,000 whites.

Symptoms and Signs

FSHMD is characterized by weakness of the facial muscles and shoulder girdle. Symptoms may develop in early childhood and are usually noticeable in the teenage years; 95% of cases manifest by age 20. Initial symptoms are slowly progressive and may include difficulty whistling, closing the eyes, and raising the arms (due to weakness of the scapular stabilizer muscles). Patients eventually notice a change in facial expression.

The course is variable. Many patients do not become disabled and have a normal life expectancy. Other patients are confined to a wheelchair in adulthood. An infantile variety, characterized by facial, shoulder, and hip-girdle weakness, is rapidly progressive, and disability is always severe. Nonmuscular symptoms frequently associated with this disorder include sensorineural hearing loss and retinal vascular abnormalities.


Diagnosis

Diagnosis is indicated by characteristic clinical findings, age at onset, and family history and is confirmed by DNA testing.


Treatment

There is no treatment for the weakness, but physical therapy may help maintain function. Monitoring for retinal vascular abnormalities is essential to prevent blindness.


Congenital muscular dystrophy

Congenital muscular dystrophy is not a single disorder but instead refers to muscular dystrophy evident at birth, occurring from any of several rare forms of muscular dystrophy. All such dystrophies are genetically recessive and result from mutations in a variety of different genes including those that encode for structural proteins of the basal membrane or the extracellular matrix of skeletal muscle fibers. The diagnosis is suspected in any floppy neonate but must be distinguished from a congenital myopathy (see Congenital Myopathies) by muscle biopsy.

Treatment consists of supportive care including physical therapy, which may help preserve function.

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