Congenital myopathies Notes

NOTES NOTES CONGENITAL MYOPATHIES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Inherited, progressive myopathic disorders caused by genetic dystrophin gene mutation (dystrophinopathies) ▪ Duchenne and Becker’s muscular dystrophy (most common types) ▫ X-linked recessive inheritance pattern ▪ Dystrophin protein ▫ Normally links intracellular actin, dystrophin-associated protein complex to extracellular matrix to stabilize sarcolemma ▪ Genetic defect → misshapen/absent dystrophin protein → weak sarcolemma, cell damage → creatine kinase escapes from/calcium enters damaged cell → cell death → muscle degeneration → progressive weakness ▪ Motor development milestone delays (e.g. walking) ▪ Progressive limb, girdle weakness ▪ Gowers’ sign ▫ Weak hips, upper legs → using arms to help stand ▪ Waddling gait ▪ Musculoskeletal abnormalities (e.g. calf pseudohypertrophy, scoliosis, contracture) ▪ Progressive mobility impairment DIAGNOSIS ▪ See individual myopathies TREATMENT ▪ See individual myopathies BECKER'S MUSCULAR DYSTROPHY osms.it/beckers-dystrophy PATHOLOGY & CAUSES ▪ Caused by misshapen dystrophin gene due to missense mutation ▫ See mnemonic: BMD COMPLICATIONS ▪ Rapidly progressive heart failure, arrhythmia 544 OSMOSIS.ORG MNEMONIC: BMD Cause of Becker’s Muscular Dystrophy Badly Made Dystrophin (truncated protein)

Chapter 69 Congenital Myopathies TREATMENT SIGNS & SYMPTOMS ▪ Milder form, later onset than Duchenne muscular dystrophy ▪ Symptoms appear 10–20 years old ▪ Intellectual disability, contractures not as common/severe as Duchenne muscular dystrophy ▪ Cardiac fibrosis may be predominant presentation feature ▫ Starting with right ventricular involvement, left ventricular dysfunction later ▪ No cure MEDICATIONS ▪ Glucocorticoids to slow muscle degeneration OTHER INTERVENTIONS ▪ Vitamin D, calcium supplements support bone health ▪ Physical therapy, conditioning ▪ Complication management DIAGNOSIS LAB RESULTS ▪ ↑ serum creatine kinase ▪ Mutations in dystrophin by DNA test/ Western blot ▪ Muscle biopsy ▫ Stain for dystrophin DUCHENNE MUSCULAR DYSTROPHY osms.it/duchenne_muscular_dystrophy PATHOLOGY & CAUSES ▪ Caused by absent dystrophin gene due to nonsense/frameshift mutation ▫ See mnemonic: DMD MNEMONIC: DMD Cause of Duchenne Muscular Dystrophy Doesn’t Make Dystrophin COMPLICATIONS ▪ Wheelchair needed for mobility → scoliosis ▫ Scoliosis → poor pulmonary function ▪ Weak diaphragm → respiratory failure (may develop) ▪ Fibrosis progression in dilated cardiomyopathy → mitral regurgitation (may develop) ▪ Dilated cardiomyopathy (late stages) → heart failure, arrhythmias (may develop) ▪ Falling → arm, leg fractures ▫ Vertebral compression fractures with glucocorticoid therapy ▪ Respiratory insufficiency/cardiomyopathy → death (late teens, early twenties) OSMOSIS.ORG 545

SIGNS & SYMPTOMS ▪ More severe dystrophinopathy form ▪ Symptoms appear by five years old; weakness usually occurs 2–3 years old ▪ Walking begins later in childhood; may have slow, ungainly run; difficulty jumping, walking up steps ▪ Proximal-limb muscle weakness before distal, lower extremities before upper ▪ Gowers’ sign ▪ Waddling gait, calf pseudohypertrophy ▪ Decreased mobility ▫ May lead to independent ambulation impairment, wheelchair-use by 12 years old (usually) ▪ Primary dilated cardiomyopathy, conduction abnormalities Figure 69.1 A muscle biopsy from an individual in the later stages of Duchenne muscular dystrophy. The myocyte hypertrophy is even more pronounced and there is marked fatty replacement of the muscle. TREATMENT ▪ No cure MEDICATIONS ▪ Glucocorticoids to slow muscle degeneration OTHER INTERVENTIONS ▪ Vitamin D, calcium supplements support bone health ▪ Physical therapy, conditioning ▪ Complication management Figure 69.2 A muscle biopsy from an individual in the early stages of Duchenne muscular dystrophy. There is variation in myocyte size with small atrophic myocytes juxtaposed with large, rounded hypertrophic myocytes. There is intervening fibrosis. DIAGNOSIS LAB RESULTS ▪ ↑ serum creatine kinase ▪ Mutations in dystrophin by DNA test/ Western blot ▪ Muscle biopsy ▫ Stain for dystrophin 546 OSMOSIS.ORG Figure 69.3 A histological section of muscle showing complete fibrofatty replacement in end stage Duchenne muscular dystrophy.