Muscular Dystrophy : Duchenne and Becker's

1. Neuromuscular Disorders – Duchenne and Becker’s Muscular Dystrophy Download more documents and slide shows on The Medical Post [ www.themedicalpost.net ] Dr. Kalpana Malla MD Pediatrics Manipal Teaching Hospital

2. Neuromuscular disorders Consists of - Motor neuron in brain stem - Ventral horn of spinal cord - Its axon with other axon forms peripheral nerve - Neuromuscular junction - All muscle fibers innervated by single motor neuron

3. May be Genetic Congenital Acquired Acute Chronic Progressive Static

4. Myopathy Proximal distribution of weakness and muscle wasting except- myotonic muscular dystrophy Slow progression Tendon reflexes – preserved Sensation – intact

5. Neuropathy Distal distribution (except- juvenile spinal muscular atrophy Acute onset Tendon reflexes – lost Sensory abnormalities –neuropathy

6. Classification 1. Muscular dystrophies: -X-linked recessive - Duchenne / becker Limb –girdle MD - Cong muscular dystrophies - Facioscapulohumeral - Oculopharyngeal - Myotonic dystrophy - Scapuloperoneal dystrophy

7. Classification 2.Disorder of neuromuscular junction - Myesthenia gravis 3.Myotonic syndromes 4. Myopathies a ) Congenital myopathies b ) Endocrine - Hypothyroidism - Hyperparathyroidism

8. Classification b ) Endocrine - Steroid-induced - Hyperaldosteronism C ) Metabolic – K-related periodic paralysis - Mitochondrial disorders

9. Classification 5. Inflammatory myopathies (myasthitis): A. Idiopathic – Juvenile dermatomyositis - polymyositis B. Infectious – viral, parasitic, bacterial, fungal 6. Floppy infant syndrome

10. Evaluation Clinical – Muscle – bulk, tone ,power, Head lag See involvement of face, tongue, palate ,extra- ocular muscles Fasciculations – sign of denervation

11. Evaluation Undescended testes, funnel shaped thorax -congenital NMD Generalized hypotonia, delayed motor development

12. Laboratory findings Serum enzymes – CPK Nerve conduction velocity- motor & sensory conduction measured electrophysiologically Electromyelography - records maximum voluntary contraction of muscle

13. Laboratory findings Muscle biopsy – most important, specific and diagnostic (Vastus lateralis) Nerve biopsy (sural nerve) ECG-cardiac evaluation in myopathies

14. Duchenne muscular dystrophy

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16. What is Duchenne Muscular Dystrophy? The disease characterized by: - Early onset often before school age - Progressive muscular deterioration and death by 14 - 18 years of age - Defect on a large gene on X chromosome 17

17. Duchenne Muscular Dystrophy Commonest muscular dystrophy Incidence- 1/3600 male birth Inheritance – X- linked recessive 30% - new mutations sporadic 18

18. FACTS The abnormal gene is on the X chromosome at the Xp21 locus Becker muscular dystrophy is the same fundamental disease as Duchenne dystrophy, with a genetic defect at the same locus, but clinically it follows a milder and more protracted course

19. X-Linked recessive Features- 1.Only males are affected. All his daughters will be carriers as they receive abnormal X from father 2. Will not manifest in females- 50% sons affected 50% daughters will be carriers when the mother is a carrier 20

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22. X-Linked recessive 3.Normal sons do not transmit disease 4.Pattern of inheritance is oblique as only males on the maternal side are affected 5.Females may be affected when affected male marries a carrier female/or when only one X chromosome is present 23

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24. X-Linked recessive 6. Fresh mutations are known 7. Carriers may have biochemical abnormalities 25

25. A muscular dystrophy is distinguished from all other neuromuscular diseases by four obligatory criteria: (1) It is a primary myopathy (2) It has a genetic basis (3) The course is progressive (4) Degeneration and death of muscle fibers occur at some stage in the disease

26. DMD - Muscle wasting In DMD - attachment of muscle fibers to their surrounding endomysium (extracellular matrix) becomes weakened due to mutations in the dystrophin gene. The absence of dystrophin leads to increased death and destruction In turn, scar tissue (a mix of collagen and blood vessels) replaces the muscle fibers, and it can gradually contract leading to increased muscle rigidity

27. Clinical features Asymptomatic at birth - Early gross motor skills ( rolling over, sitting, standing) may be normal or mildly delayed Poor head control in infancy may be the first sign of weakness Walking achieved at the normal age - but hip girdle weakness may be seen in subtle form as early as the 2nd year - waddling gait

28. Clinical features Weakness starts in pelvic girdle- Extensor muscles of back affected – lordosis to stabilize spine by bony opposition Toddlers may assume a lordotic posture when standing to compensate for gluteal weakness. Cannot bend forward without falling

29. Presents – 2- 4 yrs Frequently falls, has difficulty getting up, climbing stairs or getting in and out of a car An early Gower’s sign is often evident by age 3 yr and is fully expressed by age 5 or 6 yr

30. Gets up climbing up his legs- Gower’s sign

31. Enlargement of the calves ( pseudohypertrophy ) and wasting of thigh muscles is a classic feature. Next most common site of muscular hypertrophy - tongue, forearm.

32. Pseudohypertrophy also seen - triceps, quadriceps Pseuhypertrophy of muscle fibers - infiltration of muscle by fat, and proliferation of collagen. Fasciculations of the tongue do not occur.

33. Pseudohypertrophy seen in supra, infraspinatus , deltoids – Valley sign 34

34. Clinical features Hypertrophy of calf muscles with tightening of tendo achillis-toe walking By 8 yrs –walking becomes difficult Knee jerks disappear early but ankle jerk may be preserved Positive valley sign

35. Clinical features cont. By 12 yrs – wheel chair bound – Loss of lordosis - lose stabilization of spine ↓ Tendency to tilt to one side ↓ Develop– Scoliosis ↓ Bunching of ribs leads to E. reflux with acute esophagitis, hematemesis, aspiration pneumonitis 36

36. Clinical features cont. Intellectual impairment in all 20- 30% - IQ < 70 Cardiac muscle may be affected – Cardiomyopathy Die by 18 yrs – respiratory failure, pneumonia, aspiration, heart failure 37

37. Clinical features By 12 yrs –wheel chair bound – loss of lordosis lose stabilization of spine – tendency to tilt to one side - develop –scoliosis-bunching of ribs leads to E. reflux with acute esophagitis, hematemesis, aspiration pneumonitis Contractures most often involve the ankles, knees, hips, and elbows. Scoliosis is common.

38. The function of distal muscles is usually well preserved - child can continue using eating utensils, a pencil, and a computer keyboard. Respiratory muscle involvement - weak and ineffective cough, frequent pulmonary infections Pharyngeal weakness - episodes of aspiration, nasal regurgitation of liquids, and an airy or nasal voice quality Extraocular muscles - well preserved

39. Death occurs usually at about 18 yr of age. The causes of death are respiratory failure in sleep, intractable heart failure, pneumonia, or occasionally aspiration and airway obstruction

40. Laboratory findings Serum creatinine phosphokinase (CPK)  even in presymptomatic stages, including at birth > 10,000 units ( range 15,000 – 35,000 IU/L) Normal level < 160 IU/L - In severe cases, maybe lower Other lysosomal enzymes of muscles: Aldolase, Aspartate aminotransferase – increased (less specific) 42

41. EMG Electromyography (EMG) shows characteristic myopathic features but is not specific for Duchenne muscular dystrophy Nerve conduction velocity- normal, No evidence of denervation

42. Diagnostic (Vastus lateralis/ Gastrocnemius) Myopathic changes – endomysial connective tissue proliferation Scattered degenerating and regenerating myofibers Foci of mononuclear inflammatory cell infiltrates Muscle biopsy –

43. Muscle biopsy 45

44. Others Cardiac evaluation CXR ECG ECHO Molecular genetic diagnosis – Immunohistochemical staining of section of muscle biopsy or by DNA analysis from peripheral blood -- absent dystrophin 46

45. Molecular genetic diagnosis - demonstrating deficient or defective dystrophin by immunohistochemical staining of sections of muscle biopsy

46. Treatment No medical cure or a method of slowing its progression. To improve mobility: Physical therapy Surgery on tight joints Prednisone Non-steroidal medications Wheelchair

47. Management Multidisciplinary approach: Exercise – physical exercise, physiotherapy Dietary – prevent obesity Orthopedic Psychological Education Genetic counselling 49

48. Physiotherapy delays but does not always prevent contractures.

49. Preservation of a good nutritional state Adequate calcium intake - to minimize osteoporosis sedentary children burn fewer calories than active children and depression is an additional factor – these children tend to eat excessively and gain weight – Obesity makes a patient with myopathy even less functional

50. Management Pharmacological-treat complication Suggestion – To reduuce rate of deterioration cyclical ( 10 days /month)-catabolic steroid –prednisolone low dose -decreases the rate of apoptosis and may decelerate the myofiber necrosis Cyclosporin – under study

51. Some approaches Experimental approach – Myoblast transfer therapy Unproven approach – I/M injection of recombinant dystrophin gene " minigenes, " which carry instructions for a slightly smaller version of dystrophin 53

52. Advances in Gene Therapy Researchers - created the so-called gutted virus, a virus that has its own genes removed so that it is carrying only the dystrophin gene

53. To improve breathing: Pulmonary infections should be promptly treated. O 2 therapy Ventilator Scoliosis surgery Tracheotomy

54. Cardiac decompensation often responds well to digoxin, at least in early stages. Immunizations for influenza virus and routine vaccinations are indicated.

55. GENETIC COUNCELLING Prenatal diagnosis for women having risk pregnancies - with a family history of muscular dystrophy. Identification of dystrophin gene exon deletions in a male fetus - Couples may elect to terminate the pregnancy if the fetus is affected. Carrier status may be determined in the mother and siblings of the proband.

56. Becker muscular dystrophy This Ds was first described by Becker and Klener in 1955 X-linked recessive Late onset – ambulatory till late adolescence Calf pseudohypertrophy, cardiomyopathy, increased CPK are similar to DMD Learning disabilities are less Death – in late 20s but severely disabled; fewer than half of patients are still alive by age 40 yr

57. Dermatomyositis Pathognomonic feature - Gottron's papules overlying the dorsal interphalangeal joints.

58. Gottron's sign: Erythematous or violaceous atrophic macules and plaques overlying the dorsal interphalangeal joints and sparing the interphalangeal spaces

59. Heliotrope Characteristic finding a violaceous eruption with periorbital edema .

60. Shawl sign. Poikilodermatous macules appear in a "shawl" distribution over the shoulder, arms and upper back

61. Mechanic's hand. Fissured, scaly, hyperkeratotic and hyperpigmented hands are suggestive of manual labor

62. Thank you Download more documents and slide shows on The Medical Post [ www.themedicalpost.net ]