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DISORDERS OF SKELETAL MUSCLE

Mechanisms of Impaired Movement. Central nervous systemPeripheral nervous systemImpaired neuromuscular transmissionAbnormalities of the muscle membraneAbnormalities of myocyte structureDefective energy metabolismExtrinsic attack on the muscle . Mechanisms of Impaired Movement. Impaired neurom

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DISORDERS OF SKELETAL MUSCLE

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    1. DISORDERS OF SKELETAL MUSCLE http://www.emedicine.com/neuro/TOPIC230.HTM Dr. Roberta Seidman

    2. Mechanisms of Impaired Movement Central nervous system Peripheral nervous system Impaired neuromuscular transmission Abnormalities of the muscle membrane Abnormalities of myocyte structure Defective energy metabolism Extrinsic attack on the muscle

    3. Mechanisms of Impaired Movement Impaired neuromuscular transmission Myasthenia gravis Eaton-Lambert Syndrome Abnormalities of sarcolemmal channels Periodic paralyses Abnormalities of the muscle membrane structure Muscular dystrophies Abnormalities of myocyte structure Nemaline myopathy Tubular aggregate myopathy Defective energy metabolism Glycogen storage diseases Mitochondrial myopathies Extrinsic attack on the muscle Idiopathic inflammatory myopathies

    4. GENERAL CLINICAL FEATURES OF MYOPATHY Subacute or chronic Weakness, proximal Myalgia Fatigability

    5. Weakness

    6. Clinical presentation of myopathy by age The fetus- Decreased movement in utero The newborn- Floppy infant The infant to toddler- Delay in acquisition of milestones The young child Does not keep up with peers Observe at play

    7. The floppy infant

    8. Grading of strength Medical Research Council (MRC) Scale 1 Muscle contracts but the joint does not move Joint moves with gravity eliminated Joint moves against gravity Joint moves against gravity and some resistance (4+ or 4- ) 5 Full strength (for that individual)

    9. Evaluation of patient with suspected myopathy Creatine Kinase (CK) Aldolase Electrodiagnostic studies Nerve conduction Electromyogram Endocrine serological studies Genetic tests Muscle biopsy

    10. Preparation for the Muscle Biopsy Clinical history is important Moderately involved muscle should be biopsied

    13. TECHNICAL CONSIDERATIONS Fresh specimen for histochemistry and immunofluorescence Fixed specimen for routine microscopy and possible electron microscopy Possible additional fresh specimen for special biochemical analysis

    17. MYOFIBER TYPES

    18. Normal muscle, H&E

    19. NADH-tetrazolium reductase

    20. NADH-tr

    21. Myosin ATPase pH 10.5

    22. Myofiber types by immunohistochemistry

    23. Trichrome

    24. PAS (glycogen)

    25. Fat (Sudan black)

    27. Dropped in cold fixative

    28. Stuck to dry ice

    31. Myofiber types

    32. Minced muscle

    33. Mechanisms of Impaired Movement Central nervous system Peripheral nervous system Impaired neuromuscular transmission Abnormalities of the muscle membrane Abnormalities of myocyte structure Defective energy metabolism Extrinsic attack on the muscle

    34. THE MUSCLE BIOPSY IN NEUROPATHY Angulated atrophic fibers Group atrophy Fiber-type grouping Target fibers

    35. Innervation determines myofiber type

    39. Fiber-type grouping = reinnervation pattern

    40. Fiber-type grouping = reinnervation pattern

    41. Target fibers

    42. CHARACTERISTICS OF MYOPATHY Necrosis Regeneration Rounded atrophic fibers Fiber hypertrophy and splitting Myophagocytosis Greater than 3% internal nuclei Fibrosis Specific inclusions / cellular alterations

    43. Myofiber necrosis

    44. Regenerating fibers

    46. Muscular Dystrophy From Molecules to Cure

    47. Mechanisms of Impaired Movement Central nervous system Peripheral nervous system Impaired neuromuscular transmission Abnormalities of the muscle membrane Abnormalities of myocyte structure Defective energy metabolism Extrinsic attack on the muscle

    48. The Faces of Muscular Dystrophy

    49. Muscular Dystrophies (the old classification) X-linked recessive Duchenne Muscular Dystrophy Becker Muscular Dystrophy Emery-Dreifuss Muscular Dystrophy Autosomal Dominant Fascioscapulohumeral Oculopharyngeal Autosomal recessive Limb Girdle Congenital

    50. Clinical features The most severe and most common muscular dystrophy 1/3500 live male births X-linked Presents at age 3, death by third decade Mental retardation fairly common Less severe and less common than DMD 1/8th as common X-linked Presentation usually later in childhood Mental retardation uncommon

    51. Gowers sign

    58. Opaque fibers = hypercontracted

    59. BB Multiple x-linked disorders Visible deletion in X-chromosome The DNA that was absent was cloned

    60. DNA missing from BB was cloned Probes were made from subclones Run against DNA from 57 boys with DMD One of these was absent from 5 Eventually, the gene that this probe comes from was cloned

    61. Portions of the cDNA from the mouse DMD gene were inserted into plasmids and cloned Transcription and translation produced a fusion protein Antibodies were raised to this protein The antibodies identified a protein in skeletal muscle samples in control patients but not DMD patients

    63. Dystrophin is absent in DMD Dystrophin is abnormal and/or reduced in quantity in BMD

    64. Normal control immunohistochemistry for dystrophin

    65. Immunohistochemistry for dystrophin in Duchenne Muscular Dystrophy

    66. Dystrophinopathies Duchenne Muscular Dystrophy Becker Muscular Dystrophy Manifesting carriers Other muscular dystrophies

    67. 25 year old man presented with progressive myopathy in early childhood

    71. DYS 1 (dystrophin mid-rod) antibody

    72. DYS 3 antibody (N-terminal)

    75. Case 50 yo woman 1 years of progressive musculoskeletal pain- shoulder girdles, back, hip CK 350- 1800 Exam- Mild (4+/5) weakness of deltoids and iliopsoas muscles Treated for an inflammatory disorder Adult daughter has LGMD

    81. Diagnosis Manifesting carrier of dystrophin mutation X-linked disorder, variable manifestations are due to random inactivation of X-chromosome In her case, enough of her myofibers contain the X-chromosomes with the dystrophin mutation to cause symptoms

    83. Other Muscular Dystrophies Sarcoglycanopathies Dystroglycanopathies Congenital muscular dystrophy with Laminin-2a deficiency Many others

    84. The Limb Girdle Muscular Dystrophies

    85. 4 month old baby boy Difficult delivery Low Apgars Floppy at birth Severe weakness Minimal joint contractures EMG abnormal

    86. Muscle biopsy in a floppy infant

    88. IHC a-sarcoglycan

    89. IHC laminin 2a

    90. Laminin -2a deficient Congenital MD

    91. Treatment of Muscular Dystrophy Steroids Potential treatments: Upregulation of Utrophin Myoblast Transfer Gene Therapy Stem Cell Transplant

    92. Booster genes and other therapies to help muscle to cope with primary defect (ideas for those who want to develop therapies) promote basement membrane formation promote cell adhesion and muscle stability prevent muscle necrosis prevent inflammation promote regeneration and reduce fibrosis

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