Myopathies

Muscle disorders may be genetically determined or may result from autoimmune disorders, systemic diseases or the effects of  a  variety  of  exogenous  toxins.  They  can  be  classified  in terms of causative genetic mutations, by specific protein deficiencies, on the basis of histopathological changes, by pathogenic mechanisms, and by clinical phenotype. Molecular classifications change as knowledge increases, so a clinicopathological classification remains satisfactory for practical purposes. Only the most common of the very large number of muscle diseases are discussed in this contribution. Genetically determined myopathies There are four main groups of genetic myopathies. Muscular dystrophies are generally characterized by fiber necrosis and replacement of muscle by fat and fibrous connective tissue. However, some diseases classified as ‘dystrophies’ show less conspicuous pathology and in some there is evidence of muscle fiber degeneration by apoptosis (programmed cell death). Different types of muscular dystrophy can sometimes be recognized by clinical features (e.g. muscle hypertrophy, contractures,  evidence  of  cardiac  involvement)  and  by  the pattern of involvement of muscle groups. Three main patterns are evident – axial and limb girdle weakness, non-limb girdle weakness pattern with prominent involvement of cranial musculature, and distal weakness. Congenital  myopathies  are  classified  by  specific  histopathological and ultrastructural features. Myotonias and periodic paralyses are associated with dis- orders of muscle ion channels (muscle channelopathies). Genetically  determined  metabolic  myopathies  include disorders of glycogen and lipid metabolism, malignant hyperthermia and the mitochondrial cytopathies.

Muscular  dystrophies
Muscular dystrophies with predominantly axial and limb girdle weakness.
 Patients with Duchenne and Becker dystrophies typically (but not invariably) have muscle hypertrophy, particularly of the calves;  limb  girdle  dystrophies  usually  feature  prominent scapular winging, whereas in Emery–Dreifuss dystrophy and Bethlem myopathies, muscle contractures are a prominent feature, as is the case in some congenital dystrophies.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD):
DMD is an X-linked disease that nearly always affects only males. The incidence is about 1/3500 live male births. It is diagnosable at birth, but the diagnosis is seldom made until age 3–6 years or later, by which time a carrier mother may already have conceived another affected child. The condition causes delay in motor milestones. Muscle involvement is typically selective, affecting the girdles, axial muscles and proximal limbs, particularly the legs; this results in problems rising from the floor (Gowers’ manoeuvre) and the development of excessive lumbar lordosis. The calf muscles typically become enlarged (sometime termed ‘pseudohypertrophy’, though true fiber enlargement occurs in addition to accumulation of fat  and  fibrous  tissue).  The  ability  to  walk  is  lost  by  about 12 years of age and death from respiratory or cardiac failure usually occurs in the 20s or early 30s. Some degree of mental retardation occurs in about one-third of patients. BMD has a much more variable clinical picture and can present from childhood to early adult life. Lifespan may be normal. The pattern of muscle involvement is similar to that of DMD but weakness is less severe, patients often remaining ambulant into their 20s. Exertional myalgia is a common presenting symptom. Calf muscle enlargement is typical and often striking. DMD and BMD are forms of dystrophinopathy. Dystrophin, a component of the cytoskeleton lying beneath the muscle fiber sarcolemma, is one of the largest proteins in the body, encoded by a gene of over 2 million base-pairs at Xp21.2. Dystrophin deficiency results in loss of structural integrity of the muscle surface membrane. Mutations of the gene may be ‘out of frame’ resulting in complete absence of dystrophin, causing DMD, or ‘in frame’, producing partial dystrophin deficiency characteristic of BMD. However, phenotypic expression of dystrophinopathies is wide and can also include limb-girdle syndrome, isolated quadriceps weakness, isolated exertional myalgia, isolated cardiomyopathy and asymptomatic ‘hyperCKaemia’. The diagnosis of dystrophinopathy may be suggested by the history and physical signs, with very high serum creatine kinase (CK), and  can  usually  be  confirmed  by  standard  DNA  analyses, which detect the common dystrophin gene deletions in 70% of patients. Point mutations are more difficult to detect, however, and most patients require muscle biopsy.

Management
Treatment with prednisone, 0.75–1.5 mg/day, has been shown to improve the natural history of DMD for up to 2 years. However, there are problems with long-term corticosteroid  use.  Gene  therapy,  using  myoblasts  and  other  cells transfected with the dystrophin mini-gene, can restore muscle dystrophin, but clinical trials have been disappointing. There is interest in the possibility of up-regulating the expression of the dystrophin analogue utrophin. Otherwise, physical therapy and the use of orthoses and surgical correction of spinal and other deformities remain the mainstays of treatment.