Emery-Dreifuss muscular dystrophy (EMD) is a genetically heterogeneous disorder caused by mutations http://ebooksmedicine.net affecting structural proteins found in the nucleus. An X-linked form results from mutations in the gene encoding the protein emerin, whereas an autosomal dominant form is caused by mutations in the gene encoding lamin A/C. It is hypothesized that defects in these proteins compromise the structural integrity of the nucleus in cells that are subjected to repetitive mechanical stress (e.g., cardiac and skeletal muscle). These proteins may also regulate chromatin structure and thereby affect gene expression patterns. The clinical picture is characterized by progressive muscle weakness and wasting, contractures of the elbows and ankles, and cardiac disease. The cardiac involvement is severe, being associated with cardiomyopathy and arrhythmias that lead to sudden death in up to 40% of patients.
• Facioscapulohumeral dystrophy is an autosomal dominant form of muscular dystrophy that is caused by complex genetic changes that allow expression of the transcription factor DUX4 that is normally repressed in mature tissues. It is thought that the disease is caused by over expression of DUX4 target genes, many of which are involved in the normal function of skeletal muscles. Most patients become symptomatic by the age of 20 years, usually owing to weakness in the facial muscles and the shoulder. Patients also exhibit weakness in the lower trunk and the dorsiflexors of the foot. Most affected persons have a normal life expectancy.
Channelopathies, Metabolic Myopathies, and Mitochondrial Myopathies
Other important inherited disorders of skeletal muscle are the result of defects in ion channels (channelopathies), metabolism, and mitochondrial function.
• Ion channel myopathies are a group of familial disorders caused by inherited defects in ion channels that are characterized by myotonia, relapsing episodes of hypotonic paralysis associated with abnormal serum potassium levels, or both. Hyperkalemic periodic paralysis results from mutations in the gene encoding the skeletal muscle sodium channel SCN4A, which regulates sodium entry during contraction. Malignant hyperthermia is a rare syndrome characterized by tachycardia, tachypnea, muscle spasms, and hyperpyrexia. It is triggered when patients carrying mutations in the ryanodine receptor RYR1, a calcium efflux channel, receive halogenated anesthetic agents or succinylcholine during surgery. On exposure to anesthetic, the mutated receptor leads to increased efflux of calcium from the sarcoplasmic reticulum, producing tetany and excessive heat production. There is some evidence that people carrying RYR1 mutations also are unusually susceptible to exertional hyperthermia (heat stroke).
• Myopathies due to inborn errors of metabolism include disorders of glycogen synthesis and degradation (Chapter 7) and lipid handling. The latter include disorders of the carnitine transport system and deficiencies of the mitochondrial dehydrogenase enzyme system, both of which can lead to accumulation of lipid in myocytes (lipid myopathies). These storage disorders may manifest as systemic disease or as a muscle-specific phenotype. Some are associated with muscle damage and weakness. Others manifest with recurring episodes of exerciseor fasting-induced muscle damage, which if severe may lead to necrosis of myoctyes (rhabdomyolysis), myoglobulinuria and acute renal failure.