Muscle disorder and muscular dystrophy.pptx

muscular dystrophy

1. MUSCULAR DYSTROPHIES/PRINCIPLE OF MUSCLE BIOPSY Dr. MadhuSudhan Pandeya Resident Dept of Orthopaedics UCMS

2. INTRODUCTION G roup of genetically determined , progressive diseases of skeletal muscle M yopathies rather than as myositis Pathology within the muscle fibers ,but innervation and the peripheral nerves are also normal

3. HISTORY The first documentation by Meryon in 1852 , progressive atrophy and weakness of the muscles developed during childhood. In 1868 Duchenne --disease of childhood or adolescence(boys), progressive weakness of the muscles , beginning in the lower limbs. E nlargement ( pseudohypertrophy ) ; hyperplasia of interstitial connective tissue ; and an increase in fat cells.

4. In 1879 Gowers described the classic clinical sign of a patient “climbing up the legs ”. Limb-girdle, facioscapulohumeral (FSH), and myotonic dystrophies in the late 1800s

5. PATHOLOGY The pathologic changes in muscles are similar in all forms. loss of muscle fibers, by segmental necrosis and fragmentation of the fibers. Random arrangement of large and small fibers.

6. Interstitial connective tissue increased, with substantial infiltration of adipose tissue. H istopathologic findings: Fiber necrosis, splitting, phagocytosis, and fatty replacement ( DMD) fiber size variation, fibrosis, and central nucleation( later-onset dystrophies In myotonic dystrophy, rows of central nuclei and annulets.

7. EMG: NCV studies:

8. Duchenne Muscular Dystrophy most common form of muscular dystrophy, occurs in 1 in 3500 boys. X-linked recessive , in males and in females with Turner syndrome family history in 70% of patients , as a spontaneous mutation in approximately 30% of patients. delay in diagnosis may lead to further pregnancies in a carrier and the birth of affected children in an uninformed family.

9. ETIOLOGY Mutation in gene at Xp21 ,locus coding DYSTROPHIN protein Dystrophin gene mutation: Deletions ( commonest ) - usually deletions of exons 46-51 - total absence of dystrophin Duplications Point mutation

10. PATHOPHYSIOLOGY Absent/reduced dystrophin protein Sarcolemma injured under normal stress Increased calcium influx into the muscle fibre Activates proteases , phospholipases , ATPase, Endonucleases Muscle cell death Replaced by fibrosis and fat deposition Progressive muscle weakness Pseudo-hypertrophy Contractures and stiffness

11. CLINICAL FEATURES 3 and 6 years of age. Insidious onset Waddling gait to difficulty climbing stairs to marked muscle weakness and clumsiness. Toe walking during ambulation. A ny young boy with ankle equinus and a normal birth history.

12. symmetrical weakness, initially in the proximal musculature . Lower extremity involvement usually precedes upper extremity disease by 3 to 5 years. Ankle equinus -toe-walking- Knee hyperextension -augment the weak quadriceps and preventing buckling of the knee

13. PHYSICAL EXAMINATION Trendelenburg gait

14. contracture in the gastrosoleus .

15. Meryon sign Ober test Posterior tibialis muscle contracture - varus hindfoot

16. Knee and hip flexion contractures develop as ability to walk lose and use wheelchair. Scoliosis - late childhood or early adolescence. wheelchair --trunk lists to the side, and sitting without the assistance becomes progressively difficult.

17. OUR CONCERN P ulmonary insufficiency Cardiac systems - right ventricular hypertrophy, sinus tachycardia , mitral valve prolapse.

18. INVESTIGATIONS Serum Creatine phosphokinase (CPK): - muscle enzyme ( not specific to skeletal muscles) - Elevated 50 to 100 times above normal range - Elevated in early stage , declines at later stages, near normal in end stage disease ( progressive muscle loss ) - useful for carrier screening

19. Electromyography (EMG) : - not diagnostic but excludes primarily neurogenic cause - myopathic pattern (decreased amplitude, decreased duration, increased frequency) Nerve Conduction Velocity(NCV) : - usually normal in myopathy

20. Molecular Diagnosis: - diagnosis at gene level (DNA mutation analysis):PCR , DNA blot analysis - Blood or amniotic fluid sample - definitive diagnosis

21. Flowchart for diagnosis of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD)

22. MUSCLE BIOPSY Differentiates myopathy from neuropathy Distinguishes different myopathies from one another Useful for quantifying muscle dystrophin Techniques: - Open biopsy (preferred) - Needle biopsy (Bergstrom needle)

23. Imaging: - radiographs of the spine for evaluation of kyphoscoliotic deformity - chest radiographs for cardiopulmonary status - Dual energy X-ray absorptiometry (DEXA): - disuse osteopenia/osteoporosis - assessment of fracture risk X ray spine of DMD patient

24. Electrocardiogram (ECG): - sinus arrhythmias , may show deep Q waves , elevated R waves in V1 electrode Echocardiography (Echo) : - dilated cardiomyopathy in later stages Pulmonary Function Test (PFT) : - declines progressively with disease

25. Carrier detection: - important aspect of evaluation - family members must be screened ( females ) - Methods: - CPK levels -Muscle provocative test - DNA mutation analysis - Muscle biopsy

26. DIFFERENTIAL DIAGNOSIS Disease Similar traits to DMD Distinguishing traits from DMD Becker’s muscular dystrophy Calf pseudohypertrophy Elevated CPK X-linked inheritance Onset late Slower progression of weakness Cardiac involvement frequent Spinal muscular atrophy - Proximal weakness Onset earlier Absent deep tendon reflex Fasciculations CPK normal Pseudohypertrophy absent Emery- Dreifuss dystrophy - X-linked inheritance - Calf pseudohypertrophy absent CPK near normal elbow and ankle contractures develop early Limb-girdle dystrophy - Progressive muscle weakness Autosomal recessive inheritance Calf pseudohypertrophy absent CPK mildly elevated

27. MANAGEMENT General Treatment The primary goal to help the patient maintain functional ambulation as long as possible. When the patient becomes nonambulatory , directed toward treating scoliosis when it develops A ddressing the problems associated with nonambulation

28. Medical treatment: Prednisone , delay the loss of ambulation in patients for 2 to 5 years Deflazacort :prolong ambulation, decrease incidence of scoliosis(16 %vs90%) Mechanism of action : - stabilize cell membranes - decrease inflammation - inhibit myocyte cell death & decrease the secondary effects associated with cell death

29. Advantage : - preserve or improve strength - prolong ambulation - slow the progression of scoliosis - long-term maintenance of pulmonary function(FVC) Side effects: - weight gain, osteopenia, behavioral changes, cataracts, and myopathy

30. Aminoglycosides : - cases with STOP codon within dystrophin gene - allows readthrough of some STOP codons Bisphosphonates: - delays osteopenia - reduces risk of fracture

31. Gene therapy: - transplanted myoblast or direct genetic manipulation - under experiment Stem cell therapy: - under experiment

32. ORTHOPAEDICS TREATMENT 1) Ambulatory approach: - Interventions while patient still ambulating - aims to continue ambulation - basically correction of contractures 2) Rehabilitative approach: - Interventions after patient have stopped walking - aims to resume ambulation with/without braces

33. 3) Palliative approach: - Interventions after child have been long wheelchair bound - aims to comfort patient with shoe wear and wheelchair positioning and slow down the complications

34. PROGNOSIS life expectancies of 22 years without ventilator support, and 36 years with such support vital capacity falls below 1 L has been shown to predict mortality , with a 5-year survival rate of only 8 % Cardiac involvement is the cause of death in approximately 20% of males

35. Becker Muscular Dystrophy onset is later and the rate of muscle deterioration is slower D iagnosis after 7 years of age , and the patient may be able to ambulate into early adulthood X-linked recessive pattern. mutation at the Xp21 locus on the X chromosome

36. CLINICAL FEATURE Bushby and Gardner- Medwin described two groups of patients with BMD first group --younger , lose the ability to ambulate in adolescence, and have cardiac involvement. Other: an older age, milder clinical course, and patients may walk until 40 years of age . Calf pseudohypertrophy

37. ISSUE!!!!!!!!!!! Dilated cardiomyopathy Left Ventricular Ejection Fraction (LVEF) decreased by 1% point per year mitral regurgitation and heart failure Severe restrictive lung disease is a less frequent and later complication

38. TREATMENT MEDICAL TREATMENT: Prednisolone Gene therapy: under investigation

39. Ankle equinus : heel cord lengthening , posterior tibialis transfer Lower extremity bracing Spinal fusion

40. EMERY-DREIFUSS MUSCULAR DYSTROPHY X-linked recessive form of the disease STA gene located in the Xq28 region of the X chromosome E ncodes for a nuclear membrane protein called E merin

41. CLINICAL FEATURE onset at 5 to 15 years of age classic triad 1. slowly progressive muscle wasting and weakness - humeroperoneal distribution 2. cardiomyopathy - atrio -ventricular conduction defects - may cause sudden cardiac death 3. early contractures - ankle ,elbow, neck and lumbar paravertebral muscles .

42. INVESTIGATION Creatine Phosphokinase ( CPK): may be elevated EMG- myopathic pattern Muscle biopsy : - immunohistochemistry reveals normal levels of dystrophin but an absence of emerin ECG: atrial and atrioventricular rhythm disturbances

43. MANAGEMENT Physiotherapy( stretching exercises to prevent and correct contractures) Operative: - Achilles tendon lengthening and posterior ankle capsulotomy +/- anterior transfer of tibialis posterior tendon - release of elbow contractures less successful Contractures around the neck and back treated conservatively Scoliosis can occur but has a lower incidence of progression .

44. Limb-Girdle Muscular Dystrophy W eakness in the proximal muscles of the limbs. A utosomal recessive traits, autosomal dominant ,X-linked form. A utosomal recessive forms are more common (accounting for 90% of cases)

45. ETIOLOGY Type 2A LGMD is the most common form Gene for calpain 3 is located on chromosome 15 Type 2B LGMD ---mutations in the dysferlin gene on chromosome 2p13 Type 2I---mutations in fukutin -related protein , causative in congenital muscular dystrophy (CMD )

46. CLINICAL FEATURES Onset in second or third decade The age at onset of type 2A averages 14 years, manifesting muscle weakness between 6 and 18 years of age . more benign than Duchenne muscular dystrophy

47. Two major patterns of weakness are noted. pelvic-femoral type : primarily the pelvic girdle musculature(the iliopsoas , gluteus maximus , and quadriceps) Shoulder weakness, tibialis anterior before gastrosoleus . Contractures of the Achilles tendon Weakness of hip abduction and extension leading to increased lumbar lordosis

48. scapulo humeral type shoulder girdle is affected initially, with pelvic weakness occurring several years later. Initial symptoms: difficulty lifting the arms above the head, rising from the floor, or climbing stairs. Calf pseudohypertrophy usually retain the ability to walk into adulthood.

49. INVESTIGATION Serum CK levels may be normal or elevated . Myopathy is noted on EMGs, but NCV is normal M uscle biopsy: predominantly dystrophic changes; less frequently, myopathic and neurogenic changes . Inflammatory cells seen in the autosomal recessive forms .

50. I mmunoassay analysis of muscle tissue using antibodies against a panel of muscular dystrophy–associated proteins . stains for calpain are abnormal.

51. Cardiac involvement is less common Pulmonary involvement occurs but is much milder than in DMD or BMD. Cardiac and pulmonary failure is more common in type 2I, the form linked with fukutin mutations .

52. TREATMENT similar to that for Becker muscular dystrophy . Scoliosis rarely requires orthopaedic intervention Anti-gravity aerobic training may improve strength and performance in patients with limb girdle dystrophy.

53. Facioscapulohumeral Muscular Dystrophy The incidence is 1 in 20,000 live births Autosomal dominant trait Second decade of life gene located to chromosome 4q35.

54. facial weakness with an inability to whistle, purse the lips, wrinkle the brow , or blow out the cheeks trapezius , rhomboids , and levator scapulae The deltoid remains strong , but its ability to abduct the shoulder is lost.

55. winging of the scapulae, loss of forward flexion and abduction of the shoulder

56. Lower extremity involvement is uncommon . The hip girdle is affected late , and may need wheelchairs in their 30s or 40s Spinal deformity documented in up to 35% ,primary deformity being hyperlordosis . Scoliosis

57. INVESTIGATION Serum CK levels -- normal B iopsy from supraspinatus muscle specimen to confirm the diagnosis when genetic testing is equivocal

58. TREATMENT scapulothoracic stabilization Indications for fusion : intractable shoulder pain and limited shoulder abduction and flexion of more than 90 degrees , scapular winging, and shoulder discomfort improvement in abduction and increase in flexion after arthrodesis; relieve shoulder fatigue and improve cosmesis of neck and shoulder

59. CONGENITAL DYSTROPHIES Mutation with no specific mendelian inheritance pattern Includes: - nemaline dystrophy - central core myopathy - myotubular myopathy - congenital fiber disproportion - multicore and minicore disease Merosin -deficient CMD (CMD1a) is the most common form and neonatal hypotonia , delayed motor milestones, and contractures

60. Define by histological appearance No specific clinical or molecular criteria Clinical features: - weakness and contractures at birth( hip dislocation, CF) - respiratory, feeding & swallowing problems common - dysmorphism ( long face , high palate ) present - Kyphoscoliosis and chest deformities Child having Nemaline myopathy

61. Aim - To keep the patient ambulatory and prevent contractures by exercises and orthotic splinting Equinus and varus deformities of the feet may require releases if they interfere with ambulation Congenital dislocation of the hip and clubfoot deformity are treated conventionally, but recurrence is frequent.

62. MYOTONIC DYSTROPHY steadily progressive familial disease I nvolving the face, eyes, jaw, neck, and distal limb muscles is associated with myotonia Genetic basis: - Autosomal dominant inheritance ( mostly ) 1. Type I ( Steinert disease) - CTG triplet on MPK gene on chromosome 19 2. Type 2 (proximal myotonic myopathy) - Genetic locus similar CCTG expansion on chromosome 3 .

63. CLINICAL FEATURE onset : late adolescence or adulthood characteristic failure of voluntary muscles to relax immediately & persistence of contraction following voluntary movement or mechanical or electrical stimulation initially muscles of hand and feet fails to relax after contraction striking the muscle of the thenar eminence or deltoid elicits myotonia .

64. Expressionless Face and ptosis distal musculature first, with the muscles of the hand , the tibialis anterior , and the peroneals involved early Scoliosis in around 30% cases

65. Congenital myotonic dystrophy - severe muscle weakness and hypotonia - feeding difficulty and respiratory distress - severe club foot

66. INVESTIGATION Molecular diagnosis: - Polymerase chain reaction ( PCR ) Electromyography (EMG): - characteristic increase in frequency, duration and amplitude - “dive bomber” (repetitive abnormal spontaneous muscle fiber discharges with waxing and waning frequency)

67. Clubfoot: - serial casting , recurrence common - extensile release , recurrence common - triple arthrodesis required at later life Scoliosis: - posterior spinal fusion and instrumentation if progressive Note : cardiac abnormalities and decreased pulmonary function increases the risk of surgery ORTHOPAEDICS MANAGEMENT

68. PRINCIPLE OF MUSCLE BIOPSY An adequate biopsy specimen must be obtained to make a correct diagnosis. The biopsy specimen must be obtained from a muscle that is involved but still functioning—usually the deltoid, vastus lateralis , or gastrocnemius. The biopsy specimen should not be taken from the region of musculotendinous junctions. Specimens should be fixed in glutaraldehyde in preparation for electron microscopy.

69. The muscle specimen that is to be processed for light microscopy should be frozen in liquid nitrogen within a few minutes after removal An open muscle biopsy is usually performed but, in some cases, a needle biopsy in small children has proved satisfactory muscle be maintained at its normal length between clamps or sutures and specimen should not be violated by a needle electrode during an electromyogram

70. A second sample of muscle tissue should be taken at the time of biopsy and sent for dystrophin analysis ( dystrophin immunoblotting ). Regional block anesthesia can be used for the biopsy, but a general anesthetic may be necessary.

71. TAKE HOME MESSAGE Muscular dystrophy primarily involves muscles ,has genetic basis and degeneration of the muscle fibres Progressive weakness of the involved muscles is the chief symptom Gradual deformities of the limbs with difficulty in ambulation No cure to disease till date Management aims to slow the disease progression, make the patient ambulatory as long as possible and facilitate to carry out basic daily activities

72. REFERENCES: Tachdjain’s Pediatric Orthopedics 5 th Edition Campbell’s Operative Orthopedics 14 th Edition Apley’s System of Orthopedics and Trauma 10 th edition Internet sources

73. T H A N K y O U