Muscle Dystrophy
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MD is painless & affects skeletal or voluntary muscles WITHOUT involvement of the nervous system.
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Muscle Dystrophy
- 2. IINNTTRROODDUUCCTTIIOO NN DYSTROPHY: •abnormal growth MUSCULAR DYSTROPHY: A group of hereditary disorders characterized by: •a primary myopathy •has a genetic basis •has a progressive course •has degeneration & death of muscle fibers stage MD is painless & affects skeletal or voluntary muscles WITHOUT involvement of the nervous system.
- 3. Duchenne MD Becker MD Emery-Dreifuss MD Myotonic dystrophy Limb-girdle MD Facioscapulohumeral MD Congenital MD Oculopharyngeal MD Distal MD
- 4. Most common form 1:3600 liveboy infant boys Affects MAINLY boys Symptoms usually start between ages 2-6 YEARS OLD
- 5. X-linked recessive inheritance, 30% patients have new mutation DYSTROPHIN: 427-kd cytoskeletal protein encoded by the gene at Xp21.2 locus Molecular defects in the dystrophinopathies: intragenic deletions, duplications, or point mutations Most mutations are due to deletion of exons 46-51 Defect causes alteration of the translational reading frame of mRNA
- 6. DYSTROPHIN
- 7. absence of dystrophin membrane defect Increased calcium influx Increased intracellular calcium Increases proteases Increases phospholipases Increases endonucleases Increases ATPase Reduces oxidative phosphorylation Cell death
- 8. Cell death Gradually lost of muscles Progressive weakness Lost of muscle is replaced by fat & fibrous tissue Fibrous tissue causes contractures and stiffness hypertrophy
- 9. Motor functions problem -poor head control -hip girdle weakness -lordotic posture
- 10. Motor functions problem -poor head control -hip girdle weakness -lordotic posture -Gowers sign Lordotic posture
- 11. Motor functions problem -poor head control -hip girdle weakness -lordotic posture -Gowers sign -Trendelenburg sign TrenGdoewleenrsb usrigg nsign
- 12. Restrictive ambulation without orthopedic intervention: -confined to wheelchair by 7 y.o -walk with difficulty up to 10 y.o with orthopedic intervention: -most are able to walk up to 12 y.o Respiratory muscle weakness -ineffective cough -frequent pulmonary infections -decreasing respiratory reserve
- 13. Pharyngeal muscle weakness -aspiration -nasal regurgitation -airy / nasal voice quality Muscle hypertrophy & muscle wasting -calves+++, thigh –-- -tongue++ -muscle of the forearm+
- 14. Scoliosis Contractures
- 15. Cardiomyopathy -persistent tachycardia -myocardiac failure Smooth muscle dysfunction -GIT is the most common CNS manifestations -intellectual impairment -mentally retarded -epilepsy
- 16. Facial muscle weakness GIT and GUT symptoms -incontinence
- 17. Duchenne MD usually preserves: -distal muscle functions -extraocular muscles -voluntary sphincter muscles -deep tendon reflexes ankle reflex > knee reflex brachioradialis reflex > biceps / triceps brachii reflexes
- 19. Positive clinical features INCREASED serum CK NORMAL serum CK Blood polymerase chain reaction (PCR) Muscle biopsy MUSCULAR DYSTROPHY WITH family history WITHOUT family history Western blot Immunohisto-chemical method or
- 20. PARAMETERS LABORATORY FINDINGS Serum CK (N: < 160 IU/L) •Consistently elevated in Duchenne MD, even in presymptomatic and at birth stage •Usually: 15 000-35 000 IU/L •At terminal stage: will be lower than a few years earlier Aldolase •Less specific •Increased Aspartate aminotransferase •Less specific •Increased Echocardiography (ECG) •Essential •Should be repeated periodically Electromyography (EMG) •Less specific •Result: -no denervation -motor & sensory nerve conduction velocities are normal
- 21. PARAMETERS LABORATORY FINDINGS Polymerase Chain Reaction (PCR) •Can identify 98% of deletions but cannot detect duplications •About 1/3 of boys with Duchenne or Becker MD have a false-normal PCR Immuno histochemistry of muscle •Diagnostic and prognostic factor •Myopathic changes: 1. endomysial CT proliferation 2. scattered degenerating & regenerating myofibers 3. foci of mononuclear inflammatory cell infiltration 4. architectural changes of functioning fibers 5. dense fibers 1. endomysial CT proliferation 2. scattered degenerating & regenerating myofibers 3. foci of mononuclear inflammatory cell infiltration 4. architectural changes of functioning fibers 5. dense fibers
- 22. PARAMETERS LABORATORY FINDINGS Western blot analysis •More accurate than immunohistochemistry test •Result: DMD: <3% of normal BMD: -80% patient: 80-90% of normal -5%: normal size but reduced quantity -5% : abnormally large protein
- 23. Permanent disability Mental impairment Pneumonia or other respiratory infections Respiratory failure Cardiomyopathy
- 24. Most patients do not survive beyond their teens or early adulthood. Death occurs usually at about 18-20 y.o Mostly due to respiratory failure in sleep, intractable heart failure, pneumonia, or occasionally aspiration and airway obstruction
- 25. There is NEITHER a medical cure NOR a method of slowing its progression Much can be done to TREAT COMPLICATIONS and to IMPROVE THE QUALITY OF LIFE of affected children
- 26. Preservation of GOOD NUTRITION state -adequate calcium intake DIETary restrictions -to avoid obesity Take a good HEALTH CARE -avoid contact respiratory or contagious illness patient -promptly treat respiratory infections -immunization
- 27. PHYSIOTHERAPY -delays contractures DRUGS -glucocorticoids FOLLOW-UP 6 monthly to observe progression of: - weakness in skeletal muscle - drug side effects - development of deformities - cardiac status
- 28. CARRIER DETECTION in female relatives at risk PRENATAL DIAGNOSIS for new mutation in the embryo
- 29. Becker muscular dystrophy has the same fundamental disease as Duchenne MD (DMD) EETTIIOOLLOOGGYY Genetic defect is same as DMD; involving dystrophin gene at locus Xp21.2 Mutations preserve the reading frame and still permit translation of coding sequences but produce semifunctional dystrophin
- 30. Clinically it follows a milder and more protracted course. Weakness usually start later than DMD Boys usually remain ambulatory until late adolescence or early adult life Calf pseudohypertrophy, cardiomyopathy, elevated serum CK level are similar with DMD Learning disabilities are less frequent
- 31. Death often occurs in the mid to late 20s Fewer than half of the patients are still alive by age 40 y.o However, these survivors are severely disabled
- 32. Etiology: •X-linked recessive(Xq28) •Autosomal dominance (1q) Clinical manifestations: •Onset: 5-15 y.o +contractures of elbow & knee +scapulohumeroperoneal muscle wasting +normal intellectual function +severe cardiomyopathy ˚ hypertrophy of muscles ˚ facial weakness ˚ myotonia •Laboratory findings: •Serum CK : mildly elevated •Muscle biopsy •Prognosis •Slow progression •Most survive to late adult Managements: •Supportive treatments •Special attention to cardiac conduction defects
- 33. Etiology •Autosomal dominance Clinical manifestation •Appear normal at birth / hypotonia / facial wasting •Onset at 5 y.o +: -facial weakness -wasting: distal muscles, dorsal forearm, anterior compartment muscle of LL, sternocleidomastoid, tongue, proximal muscle -scapular winging -Gowers sign -speech: poorly articulated -smooth muscle weakness -cardiac: heart block & arrythmia -endocrine abnormalities -immunologic deficiency -eye: cataracts, ophthalmoplegia -CNS: intellectual impairment
- 34. MMyyoottoonniicc MMDD ((ccoonntt……)) Laboratory findings •Serum CK: Normal / mildly elevated •DNA analysis: abnormal gene •Muscle biopsy Managements •Treat complications •Physiotherapy & orthopedic treatment •Drugs for myotonia
- 35. Etiology •Autosomal recessive •Autosomal dominance Clinical manifestations: •Onset before middle or late childhood •Affect muscles of hip & shoulder girdle +hypertrophy of the calves & ankle +lordotic posture +weakness of flexors & extensors +diminished tendon stretch reflexes +cardiac involvement Laboratory findings: •Serum CK: elevated •EMG & muscle biopsy: evidence of muscular dystrophy, but less specific •ECG: normal Prognosis: •Rate of progression varies •Usually confined to wheelchair by 30 y.o
- 36. Etiology: •Autosomal dominance Clinical manifestations: •Onset before middle or late childhood •Affect muscles of facial & shoulder girdle +facial and shoulder girdle muscles weakness +pharyngeal & tongue weakness +hearing loss & retinal vasculopathy +scapular winging +Gowers sign +Trendelenburg sign Laboratory findings: •Serum CK: greatly elevated •EMG: nonspecific myopathic muscle potential Prognosis: •Mild diseasew that leads to minimal disability
- 37. Arthrogryposis Etiology •Autosomal recessive -Ullrich type: defect in ≥1 of collagen VI genes -Fukuyama type: defect at 8q31-33 locus Clinical manifestations +: -arthrogryposis -hypotonia -thin muscle mass -hypoactive/absent tendon stretch reflexes -cardiomegaly & brain malformation (Fukuyama) -accompanied by other neurologic disease (exc Fukuyama) -microcephaly & mental retardation Laboratory findings •Serum CK: moderately elevated •EMG: nonspecific myopathic features •Cardiac assessment •Brain imaging study •Muscle biopsy: essential for diagnosis -IHC study: absent of merosin protein Managements •Supportive therapy
- 39. Nelson Textbook of Pediatric (18th edition) by M. Kliegman, E. Behrman, B. Jenson & F. Stanton Duchenne Muscular Dystrophy (3rd edition) by A. Emery & F. Muntoni