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INTRODUCTION

Myopathies are disorders of the skeletal muscle due to a structural or metabolic abnormality of the muscle cells resulting in muscle weakness and dysfunction. They can be due to hereditary or acquired causes. This chapter will focus specifically on inherited forms of myopathies. Inherited myopathies relate to specific genetic defects affecting 1 of many areas involved in the integrity of the muscle. These include genes related to proteins of ion channels (eg, sodium channels), sarcolemma membrane (eg, dystrophin), sarcomere (eg, actin or myosin), or nuclear membrane (eg, emerin). In addition, some inherited myopathies are caused by impaired muscle metabolism of carbohydrates, lipid, or the mitochondrial electron transport chain. Myopathies are named based on the classical description (eg, Duchenne and Becker muscular dystrophy), their phenotype to include the distribution of weakness (eg, limb-girdle muscular dystrophy or facioscapulohumeral dystrophy), or the specific underlying genetic defect (eg, laminopathy secondary to LMNA mutations). This latter descriptor has some particular relevance as newer genetic methods have expanded the previously narrow spectrum of phenotypes associated with a particular gene.

MUSCULAR DYSTROPHY

The use of the term muscular dystrophy generally implies an inherited myopathy in which there is progressive degeneration and necrosis of muscle cells (Fig. 563-1). Muscular dystrophies may present at birth as congenital muscular dystrophies (CMDs), such as merosin deficiency CMD, or later in childhood, such as Duchenne muscular dystrophy (DMD). The age of onset, the distribution of weakness, and associated clinical features allow for a preliminary differential diagnosis to be constructed.

Figure 563-1

Muscle biopsy shows marked fiber size variability, necrosis, as well as (a) fibrosis, (b) fat accumulation, (c) split fiber, (d) hypercontracted fiber, and (e) inflammatory cells.

DYSTROPHINOPATHIES

Dystrophinopathies include a severe form of disease known as DMD and a milder form, called Becker muscular dystrophy (BMD). Both are inherited as X-linked progressive muscle diseases resulting from a defect in the dystrophin gene (DMD) resulting in a complete (DMD) or partial (BMD) deficiency of the dystrophin structural protein.

DUCHENNE MUSCULAR DYSTROPHY

DMD is the most common hereditary childhood muscular dystrophy, with an estimated incidence of 1 in 3500 boys. Out-of-frame exon deletions, duplications, or nonsense mutations in the DMD gene on Xp21.2 will result in complete absence of the dystrophin protein, leading to degeneration of muscle fibers. Although most boys with DMD inherit the abnormal gene from their mother, 30% may develop the diseases as the result of a spontaneous mutation of the dystrophin gene.

CLINICAL MANIFESTATIONS

Signs and symptoms of muscle weakness start before 5 years of age to include occasional delayed walking followed by more obvious signs of a waddling gait with difficulty in running and getting up from the floor or climbing stairs. The ...

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