dystrophy肌营养不良症课件

What disease did the child suffer from? Muscular Dystrophies 肌营养不良症 Department of Neurology Xuanwu Hospital You Should Know: 1. the inheritance pattern, pathogenesis, and clinical features of Duchenne/Becker muscular dystrophy 2. how to diagnose a patient with Duchenne muscular dystrophy 3. the category of muscular dystrophies Definition of Muscular Dystrophies qThe muscular dystrophies are progressive hereditary degenerative diseases of skeletal muscles.(遗传性骨骼肌变性疾病 ） qMany are now known to be secondary to abnormalities to one of the structural muscle proteins.（肌肉蛋白的异常） Clinical Features of MDs v Muscular weakness and atrophy v Intact sensibility v Heredofamilial incidence Muscular Dystrophies: Category of Molecular Genetics Classification of MDs Pseudohypertrophic muscular dystrophies Dystrophin-deficient dystrophy - Dystrophinopathies（Duchenne and Becker) Limb girdle muscular dystrophy (LGMD) Facioscapulohumeral muscular dystrophy(FSHD) Oculopharyngeal muscular dystrophy (OPMD) Distal muscular dystrophy Emery-Dreifuss muscular dystrophy Congenital muscular dystrophy Different distribution of muscle weakness and atrophy 1. Duchenne /Becker 2. Emery-Dreifuss 3. Limb-girdle 4. Fascioscapulohumeral 5. Distal 6. Oculopharyngeal The Inheritance Pattern of Muscular Dystrophies Sex-linked MDs Duchenne （杜兴型） Becker（贝克型） Emery-Dreifuss Autosomal dominant MDs Fascioscapulohumeral （面肩肱型） Limb-girdle(肢带型） Distal （远端型） Ocular （眼型） Oculopharyngeal（眼咽型） Autosomal recessive MD -limb-girdle form Pseudohypertrophic Muscular Dystrophies Dystrophin-deficient dystrophies DystrophinopathiesDystrophinopathies Duchenne and Becker G.B.A Duchenne a French neurologist 1868 Etiology and Pathogenesis Mutations of dystrophin gene A largest gene Located on the short arm of the X chromosome (Xp21) Approximately 3 million base pairs in length Encoding 79 exons Loss of dystrophin protein(抗肌萎缩蛋白） A 427kd protein Localized to the sarcolemma（肌膜） present in skeletal, cardiac muscle, cerebral cortex, etc Dystrophin Gene and Protein Function of Dystrophin v Dystrophin is a component of the plasmamembrane cytoskeleton （细胞骨架 ） v It forms the structural basis for mechanical stabilization of sarcolemma during contraction and relaxation of muscle fibers Genetics of DMD DMD is the most common and severe MD X-linked recessive inheritance 2/3 of the cases are familial, i.e. there are pedigrees suggesting that the mother is a carrier, i.e. other affected male sons exist 1/3 of the cases are sporadic, i.e. they appear to be due to new mutations affects about 1/3500 live birth males X-linked Inheritance Clinical Presentation of DMD Onset at 3-5 years of age in one of 3 ways: 1. With delay in motor milestones (delayed walking by 3-6 months) - most common 2. Elevated serum levels of creatine kinase, ALT, AST . 3. Malignant hyperthermia after exposure to halothane anesthesia The first symptoms are usually difficulty with running, jumping, and climbing stairs Progressive Symmetric Weakness and Atrophy of Skeletal Muscles Proximal distal Earlier: muscle of the pelvic girdle, lumbosacral spine, and shoulders Later: spread to the muscles of legs and forearms, neck flexors, etc Muscle Hypertrophy Especially calf Most commonly due to muscle fibrosis (psudohypertrophy) 假性肥大 Gait Abnormality lclassically is a waddling, wide- based gait with hyperlordosis（ 脊柱过度前突） of the lumbar spine , and heel cord contractures occur, producing “tip toe” walking (鸭步） lFrequent falls without tripping or stumbling occur The Gower Sign Having problems getting up from the sitting or supine position, (in arising from a supine on the floor, first turn their face to the floor, then, spread their legs, and use their hands to climb up their thighs to an upright position) . The Gower Sign Muscle Weakness Progresses Relentlessly The ability to ambulate（行走能力） is lost usually around 7-13 years of age then boys take the wheel chair or are confined to the bed Death usually occurs by age 15-25 years : attributed to respiratory insufficiency (90%) or cardiac insufficiency (10%) Other Organs Involvement Musculoskeletal Contractures Scoliosis（脊柱侧突） Respiratory and accessory muscle weakness Dilated cardiomyopathy（扩张性心肌病） Mental retardation Laboratory Serum Muscle Enzymes(a marker of muscle breakdown) CK: Very high: 50-100 times the normal value AST , ALT, LDH - May be high Electromyography: Myopathic changes Muscle biopsy : classic muscular dystrophic changes Dystrophin immunostaining Western blot Gene testing Pathology of DMD Variable fiber size: atrophy and hypertrophy Muscle fiber degeneration Dystrophin has reduced abundance but normal size. Lane 2: BMD; Dystrophin has reduced size and abundance. Lane 3: normal; Dystrophin has normal size and amount. Lane 4: DMD; Almost no protein is present. Lane 5: outlier; Dystrophin has severely reduced abundance Diagnosis XR inheritance pattern( positive family history) Typical clinical presentation Serum muscle enzymes: CK, LDH, AST, ALT Electromyography: Myopathic Muscle biopsy Classical histopathology Dystrophin staining Gene testing: PCR or point mutation screening Differential Diagnosis1 vSpinal muscular atrophy Weakness of the proximal m. (Pelvic and shoulder girdle) Fasciculation, muscle wasting Muscle enzymes: normal EMG: neurogenic changes Muscle biopsy: group atrophy Differential Diagnosis2 vChronical polymyositis No family history Muscle biopsy: inflammatory changes Curable Treatments No specific treatment. Temporary stabilization with treatment of steroids -Prednisone The quality of life of patients with dystrophy can be much improved by a positive attitude to management which includes respiratory care, physiotherapy, and the surgical correction of contractures , electric wheel chairs Future Treatments Cell therapy -the use of bone marrow cells - The use of muscle-derived stem cells Gene therapy Still in pre-clinical (animal) trials and thus have a long way to go before they can be implemented as a cure for DMD. Prevention of Diseases vGenetic counseling vCarrier detection vPrenatal diagnosis Becker Muscular Dystrophy Occurs in 1 out of 30,000 live male births Clinical picture similar to that of DMD Generally is milder than DMD, and onset of symptoms usually occurs later(between 5- 15years) Less severe muscle weakness Continue to be ambulatory after age 15-20 years Usually survive beyond the age of 30 years Becker Muscular Dystrophy Other unusual presentations : Myoglobinuria（肌红蛋白尿） with persistent elevation of CK between myoglobinuric attacks Muscle cramping and myalgias with exercise （运动后肌痉挛和肌痛） CK is not as high as that of DMD Dystrophin staining: reduced staining/ patchy distribution(BMD) Facioscapulohumeral muscular dystrophy -Etiology Autosomal dominant disorder Gene located at chromosome 4q Occurs equally in male and female Begins in late childhood or adolescence FSHD-Clinical Features1 Weakness in a striking distribution of the face, upper arms, shoulders Winging of the scapulae （翼状肩胛） Difficulty raising arms above the head Unable to whistle or suck through a straw May not be able to close eyes completely Poorly developed chest muscles give the appearance of pectus excavatum（胸肌萎陷 ） FSHD-Clinical Features2 vProgresses to involve the forearms, pelvic girdle, peroneal muscles vSymptoms can be extremely variable FSHD- Other Features Hearing loss Retinopathy Calf pseudohypertrophy FSHD- Laboratory lSerum CK are usually normal, though may be elevated up to 5 times normal lMuscle biopsy may reveal minimal myopathic changes or severe dystrophic changes, lEMG: myopathic findings FSHD- Diagnosis lPositive family history lClinical presentation lDNA analysis FSHD 假肥大型肌营养不良症 l分为Duchenne和Becke