• Definition: heterogeneous group of inherited progressive myopathies. Typically each has a specific phenotypic pattern, specific mendellian inheritance pattern, and known gene defect.
• Clinical C: inherited, proximal muscle involvement, normal reflex sensation, mental impairment, cardiomegaly and conduction defect
• Lab: Ý CK, Ý urine creatine, myopathic biopsy
• Classifications:
• X-Linked: Duchenne, Becker (both Xp21), Emery-Dreifus
• Autosomal-Dominant: Myotonic, Facioscapulohumeral, Distal, Oculopharyngeal, , Limb girdle (type1)
• Autosomal-Recessive: Limb Girdle (type2), congenital

 Duchenne Muscular Dystrophy (DMD) – X-linked (Xp21) – most common

• Etiology: mutation (frameshift or point) in the gene that encodes an actin binding protein Dystrophin – results in an unstable Dystrophin that is non-functioning
• Dystrophin: a flexible elongated protein that binds actin and b -dystroglycan (DG) – a glycoprotein complex that spans the sarcollema. DG binds to laminin in the muscle cell basement membrane. Recall that actin along with myosin comprise the myofiber (multinucleated single cell of the muscle) which is surrounded by a sarcollema. A bundle of these surrounded by a membrane comprise the skeletal muscle. Therefore dystrophin provides a link between the contractile cytoskeleton (myofibril) and the cell membrane. A regular rib-like arrangement of dystrophin encircle the muscle fiber conveying strength and flexibility to the cell membrane
• Pathogenesis: When dystrophin is deficient, the sarcollema, the contractile elements (actin and myosin), and the cell membrane are no longer functioning in conjunction with each other Þ loss of elasticity. Contractions allows the sarcollema to become susceptible to stress-induced fracture because the elements are no longer sliding smoothly over each other. Tiny breaks develop in the membrane, permitting influx of calcium ions that trigger segmental hypercontraction and activates proteases leading to muscle fiber necrosis
• REVIEW: Defect in dystrophin gene Þ production of non-functional dystrophin Þ failure of dystrophin to associate with DG complex Þ membrane dysfunction Þ necrosis of muscle fibers Þ proliferation of fibroblasts Þ inhibition of: revascularization, reinnervation, normal metabolism.
• Clinical Course: - weak on toes, frequent falls, hesitant when ascending steps
• Occurs only in males. Onset early in life before age 6. Most common childhood myopathy. VERY rapid progression.
• Pseudohypertrophy of muscles – especially gastrocnemius. – because of extensor muscles typically weaker than flexors.
• Muscles affected in symmetrical fashion
• Pelvic girdle and trunk – results in abnormal posture (lordosis) and walking
• shoulder girdle
• distal muscles (hands, wrist)
• Cardiac muscle involvement: tachycardia, EKG abnormalities
• Upper Respiratory Infection – VERY dangerous – may be fatal due to weakness of respiratory muscles. Respiratory complications usual cause of death.
• Treatment: Physical therapy (stretching, walking), bracing, surgery (Harrington/Luke rods for scoliosis of the spine), respiratory treatment
• Histology: Evidence of destruction - Ca+Ý Þ hypercontraction Þ rips muscle apart – results in ghost fibers
• Evidence of regeneration – protein synthesis (basophilia)

Becker’s Muscular Dystrophy (BMD) – less severe and common form of DMD

• Etiology: Same genetic defect site as DMD Þ Xp21 – Dystrophin
• Pathogenesis: Difference in disease explained by frameshift hypothesis. In DMD, a point mutation alters the reading frame resulting in a premature stop codon Þ defective dystrophin. In BMD, a frameshift mutation allows preservation of the reading frame Þ semifunctional shorter dystrophin. Therefore still some functioning dystrophin in BMD.
• Clinical Course: more delayed than DMD and progression is slower.

Limb-Girdle Muscular Dystrophy – the "exclusionary" dystrophy.

Facioscaphulohumeral (FSH) Muscular Dystrophy – autosomal dominant – 4q

 Myotonic Dystrophy – autosomal dominant – chromosome 19q (CTG)