Overview of Muscular Dystrophies
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An overview of genetic disorders in muscular dystrophies.
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Overview of Muscular Dystrophies
- 2. An 7 year old boy is presented to you for difficulty in walking and muscle weakness with difficulty in climbing stairs, running and particularly in vigorous physical activities, he also had decreased strength and endurance.
- 3. An 7 year old boy is presented to you for difficulty in walking and muscle weakness with difficulty in climbing stairs, running and particularly in vigorous physical activities, he also had decreased strength and endurance. Lets call him Ricky.
- 4. What to do?
- 6. The first thing you notice while observing is that Ricky has waddling gait when walking.
- 7. The first thing you notice while observing is that Ricky has waddling gait when walking.
- 8. In examination you notice that Ricky has considerably enlarged calf muscles.
- 9. During physical examination, Ricky has difficulty going up the examination table and makes strange manoeuvres to get up.
- 11. What was that?
- 12. Gowers' sign is a medical sign that indicates weakness of the proximal muscles. The sign describes a patient that has to use their hands and arms to "walk" up their own body from a squatting position due to lack of hip and thigh muscle strength.
- 13. What now?
- 14. Family History
- 15. Family History His parents did not have consanguineous marriage. One brother and two sisters were all healthy. No other family members were similarly affected.
- 17. Blood testing
- 18. ? Boy Serum Levels Normal Range Levels Creatine Kinase (CK) 7476 U/L 55 to 300 U/L Aldolase 24 U/L 1.0 to 7.5 U/L
- 19. Creatine Kinase (CK) — 37x ↑ Boy Serum Levels Normal Range Levels Creatine Kinase (CK) 7476 U/L 55 to 300 U/L Aldolase 24 U/L 1.0 to 7.5 U/L Aldolase — 8x ↑
- 20. Findings strongly suggest some kind of myopathy. Creatine Kinase (CK) — 37x ↑ Aldolase — 8x ↑
- 21. Creatine Kinase (CK) — 37x ↑ Aldolase — 8x ↑ Findings strongly suggest some kind of myopathy. But which myopathy?
- 22. Hopefully, we are in genetics class…
- 23. Hopefully, we are in genetics class…
- 24. Hopefully, we are in genetics class… We consider two myopathies:
- 25. Hopefully, we are in genetics class… Becker Muscular Dystrophy Duchenne Muscular Dystrophy We consider two myopathies:
- 27. Becker Muscular Dystrophy Duchenne Muscular Dystrophy But you don’t remember much about those.
- 29. Becker Muscular Dystrophy Duchenne Muscular Dystrophy progressive muscle weakness (atrophy) skeletal muscles and heart (cardiac) muscle occur almost exclusively in males
- 30. occur almost exclusively in males
- 31. occur almost exclusively in males + genetics class
- 32. occur almost exclusively in males + genetics class sex-linked
- 33. occur almost exclusively in males + genetics class sex-linked X or Y ?
- 34. occur almost exclusively in males + genetics class + father is not affected sex-linked
- 36. occur almost exclusively in males + genetics class + father is not affected sex-linked x-linked
- 37. occur almost exclusively in males + genetics class + father is not affected sex-linked x-linked DOMINANT or RECESSIVE ?
- 38. occur almost exclusively in males + genetics class + father is not affected sex-linked x-linked family genogram +
- 40. occur almost exclusively in males + genetics class + father is not affected sex-linked x-linked family genogram +
- 41. occur almost exclusively in males + genetics class + father is not affected sex-linked x-linked family genogram + for sake of probabilities +
- 42. occur almost exclusively in males + genetics class + father is not affected sex-linked x-linked family genogram + for sake of probabilities +recessive
- 43. occur almost exclusively in males + genetics class + father is not affected sex-linked x-linked family genogram + for sake of probabilities +recessive x-linked recessive disorder
- 44. Becker Muscular Dystrophy Duchenne Muscular Dystrophy both are x-linked recessive disorders
- 45. Becker Muscular Dystrophy Duchenne Muscular Dystrophy both are x-linked recessive disorders both result from mutation in the same gene (dystrophin gene, on locus Xq21)
- 46. Becker Muscular Dystrophy Duchenne Muscular Dystrophy both are x-linked recessive disorders How to distinguish? both result from mutation in the same gene (dystrophin gene, on locus Xq21)
- 49. Becker Muscular Dystrophy Duchenne Muscular Dystrophy missense mutation nonsense mutation frameshift mutation
- 50. Becker Muscular Dystrophy Duchenne Muscular Dystrophy miss-shapen dystrophin missense mutation nonsense mutation frameshift mutation
- 51. Becker Muscular Dystrophy Duchenne Muscular Dystrophy no dystrophinmiss-shapen dystrophin missense mutation nonsense mutation frameshift mutation
- 52. Becker Muscular Dystrophy Duchenne Muscular Dystrophy no dystrophinmiss-shapen dystrophin missense mutation nonsense mutation frameshift mutation symptoms age 5symptoms age 10 to 20 ‘mild’ ‘severe’
- 53. Muscle Biopsy
- 55. Ricky Control
- 56. Ricky Control staining of dystrophin is present but reduced
- 57. Ricky Control Could be both!
- 58. Ricky Control Could be both! the pathologist says…
- 59. So, what now?
- 61. looking for mutations DNA test
- 62. looking for mutations DNA test Western blot
- 63. Diagnosis:
- 65. But wait!
- 71. If it’s a boy: If it’s a girl: What’s the probability of being healthy?
- 72. If it’s a boy: If it’s a girl: What’s the probability of being healthy? 50% 100%
- 73. What’s the probability of both twins being healthy?
- 76. Duchenne Muscular Dystrophy fatigue frequent falls
- 77. Duchenne Muscular Dystrophy fatigue frequent falls muscle fiber deformities
- 78. Duchenne Muscular Dystrophy fatigue frequent falls progressive difficulty with motor skills muscle fiber deformities
- 79. Duchenne Muscular Dystrophy fatigue frequent falls muscle contracturesprogressive difficulty with motor skills muscle fiber deformities
- 80. Duchenne Muscular Dystrophy fatigue frequent falls muscle contracturesprogressive difficulty with motor skills muscle fiber deformities skeletal deformities (like scoliosis)
- 81. Duchenne Muscular Dystrophy fatigue frequent falls muscle contracturesprogressive difficulty with motor skills muscle fiber deformities higher risk of neurobehavioral disorders (like ADHD) skeletal deformities (like scoliosis)
- 82. Duchenne Muscular Dystrophy fatigue frequent falls muscle contracturesprogressive difficulty with motor skills muscle fiber deformities higher risk of neurobehavioral disorders (like ADHD) skeletal deformities (like scoliosis) cardiomyopathy
- 83. Duchenne Muscular Dystrophy fatigue frequent falls muscle contracturesprogressive difficulty with motor skills muscle fiber deformities higher risk of neurobehavioral disorders (like ADHD) skeletal deformities (like scoliosis) cardiomyopathy arrhythmia
- 84. Duchenne Muscular Dystrophy fatigue frequent falls muscle contracturesprogressive difficulty with motor skills muscle fiber deformities higher risk of neurobehavioral disorders (like ADHD) skeletal deformities (like scoliosis) cardiomyopathy arrhythmia respiratory disorders (like pneumonia)
- 85. no treatment
- 86. no treatment
- 87. controlling the symptoms to maximize the quality of life no treatment
- 88. controlling the symptoms to maximize the quality of life no treatment life expectancy is estimated to be around 25
- 90. Back to Square 1
- 92. A 4 month-old girl was referred to the service because of seizures and was observed to have abnormal skin findings.
- 93. A 4 month-old girl was referred to the service because of seizures and was observed to have abnormal skin findings. Lets call her Nicole.
- 94. What to do?
- 95. On physical examination Nicole shows diffuse blisters on the surface of the skin of her arms and legs.
- 96. On physical examination Nicole shows diffuse blisters on the surface of the skin of her arms and legs.
- 97. What do we have?
- 98. 4 month-old girl diffuse blisters on arms and legs history of seizures What do we have?
- 99. 4 month-old girl diffuse blisters on arms and legs history of seizures What do we have? neurological problems?
- 100. What to do?
- 101. What to do?
- 102. What to do?
- 103. What to do? ophthalmoscopy is your friend
- 105. scattered intra-retinal haemorrhages and abnormal arborisation of the peripheral vessels
- 106. white intra-retinal lesion on the macula and a haemorrhage above the fovea scattered intra-retinal haemorrhages and abnormal arborisation of the peripheral vessels
- 107. these findings are compatible with the history of seizures
- 108. these findings are compatible with the history of seizures What now?
- 109. Family History
- 110. What can you get from it? Family History
- 113. all generations affected affected father pass too all daughters
- 114. all generations affected affected father pass too all daughters x-linked dominant disorder
- 115. What do we know so far?
- 116. x-linked dominant disorder What do we know so far?
- 117. x-linked dominant disorder What do we know so far? diffuse skin blisters on arms and legs
- 118. x-linked dominant disorder What do we know so far? diffuse skin blisters on arms and legs neurological symptoms
- 119. x-linked dominant disorder What do we know so far? diffuse skin blisters on arms and legs neurological symptoms 4 month-old girl
- 120. x-linked dominant disorder What do we know so far? diffuse skin blisters on arms and legs neurological symptoms 4 month-old girl A - rett syndrome B - alport syndrome C - bloch–sulzberger syndrome D - x-linked hypophosphatemia E - lesh-nyhan syndrome
- 121. x-linked dominant disorder What do we know so far? diffuse skin blisters on arms and legs neurological symptoms 4 month-old girl A - rett syndrome B - alport syndrome C - bloch–sulzberger syndrome D - x-linked hypophosphatemia E - lesh-nyhan syndrome
- 122. x-linked dominant disorder What do we know so far? diffuse skin blisters on arms and legs neurological symptoms 4 month-old girl A - rett syndrome B - alport syndrome C - bloch–sulzberger syndrome D - x-linked hypophosphatemia E - lesh-nyhan syndrome
- 124. Bloch–Sulzberger Syndrome Incontinentia Pigmenti x-linked dominant disorder
- 125. Bloch–Sulzberger Syndrome Incontinentia Pigmenti x-linked dominant disorder locus Xq28 mutation in NEMO (IKBKG) gene (NF-κB protein)
- 126. Bloch–Sulzberger Syndrome Incontinentia Pigmenti x-linked dominant disorder 1 - blistering locus Xq28 mutation in NEMO (IKBKG) gene (NF-κB protein)
- 127. Bloch–Sulzberger Syndrome Incontinentia Pigmenti x-linked dominant disorder 1 - blistering locus Xq28 mutation in NEMO (IKBKG) gene (NF-κB protein)
- 128. Bloch–Sulzberger Syndrome Incontinentia Pigmenti x-linked dominant disorder 1 - blistering 2- wart-like rash locus Xq28 mutation in NEMO (IKBKG) gene (NF-κB protein)
- 129. Bloch–Sulzberger Syndrome Incontinentia Pigmenti x-linked dominant disorder 1 - blistering 2- wart-like rash locus Xq28 mutation in NEMO (IKBKG) gene (NF-κB protein)
- 130. Bloch–Sulzberger Syndrome Incontinentia Pigmenti x-linked dominant disorder 1 - blistering 2- wart-like rash 3 - swirling macular hyperpigmentation locus Xq28 mutation in NEMO (IKBKG) gene (NF-κB protein)
- 131. Bloch–Sulzberger Syndrome Incontinentia Pigmenti x-linked dominant disorder 1 - blistering 2- wart-like rash 3 - swirling macular hyperpigmentation locus Xq28 mutation in NEMO (IKBKG) gene (NF-κB protein)
- 132. Bloch–Sulzberger Syndrome Incontinentia Pigmenti x-linked dominant disorder mutation in NEMO (IKBKG) gene (NF-κB protein) 1 - blistering 2- wart-like rash 3 - swirling macular hyperpigmentation 4 - linear hypopigmentation locus Xq28
- 133. Bloch–Sulzberger Syndrome Incontinentia Pigmenti x-linked dominant disorder 1 - blistering 2- wart-like rash 3 - swirling macular hyperpigmentation 4 - linear hypopigmentation locus Xq28 mutation in NEMO (IKBKG) gene (NF-κB protein)
- 135. Bloch–Sulzberger Syndrome Incontinentia Pigmenti abnormal tooth shape
- 136. Bloch–Sulzberger Syndrome Incontinentia Pigmenti abnormal tooth shape alopecia
- 137. Bloch–Sulzberger Syndrome Incontinentia Pigmenti abnormal tooth shape alopecia neurological problems
- 138. Bloch–Sulzberger Syndrome Incontinentia Pigmenti abnormal tooth shape alopecia neurological problems slow motor development
- 139. Bloch–Sulzberger Syndrome Incontinentia Pigmenti abnormal tooth shape alopecia neurological problems slow motor development mental retardation
- 140. Bloch–Sulzberger Syndrome Incontinentia Pigmenti abnormal tooth shape alopecia neurological problems cerebral atrophy slow motor development mental retardation
- 141. Bloch–Sulzberger Syndrome Incontinentia Pigmenti abnormal tooth shape alopecia neurological problems cerebral atrophy slow motor development muscle weakness mental retardation
- 142. Bloch–Sulzberger Syndrome Incontinentia Pigmenti abnormal tooth shape alopecia neurological problems cerebral atrophy slow motor development muscle weakness mental retardation seizures
- 143. Bloch–Sulzberger Syndrome Incontinentia Pigmenti abnormal tooth shape alopecia neurological problems cerebral atrophy slow motor development muscle weakness mental retardation seizures ophthalmological problems
- 144. Bloch–Sulzberger Syndrome Incontinentia Pigmenti abnormal tooth shape alopecia neurological problems cerebral atrophy slow motor development muscle weakness mental retardation seizures ophthalmological problems crossed eyes
- 145. Bloch–Sulzberger Syndrome Incontinentia Pigmenti abnormal tooth shape alopecia neurological problems cerebral atrophy slow motor development muscle weakness mental retardation seizures ophthalmological problems cataracts crossed eyes
- 146. Bloch–Sulzberger Syndrome Incontinentia Pigmenti abnormal tooth shape alopecia neurological problems cerebral atrophy slow motor development muscle weakness mental retardation seizures ophthalmological problems cataracts crossed eyes severe visual loss
- 147. Diagnosis
- 148. Diagnosis mostly by clinical findings
- 149. Diagnosis mostly by clinical findings molecular genetic testing of the NEMO gene
- 150. Treatment
- 151. Treatment
- 154. off-topic
- 161. the end