Muscular dystrophy (wecompress.com)_watermark.pdf

Muscular dystrophy types and explanations

1. MUSCULAR
DYSTROPHY
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2. •Definition :A muscle disease histologically
characterised by muscle fibre necrosis, regeneration
and an increase in fibrosis and adipose tissue.
•In majority of cases , The pathology lies in :
Dystrophin associated protein complex -sarcolemmal
proteins linking the extracellular matrix to the cytoskeleton.
considerable clinical and pathological overlap between
disorders.
•Diseases are often now referred to on the basis of the
protein defect, such as dystrophinopathy,
sarcoglycanopathy.
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4. Autosomal
dominant
X-linked
Autosomal
recessive
•LGMD 1
•AD EDMD
•FSHD
•OPMD
•Myotonicdystrophy
•LGMD 2
•Congenital MD
•Dystrophinopathies
(DMD, BMD)
•X-linked EDMD
Classification of muscular dystrophies
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5. Distribution of
muscle weakness
(a)DMD / BMD
(b)EDMD
(c)LGMD
(d)FSHD
(e)Distal
(f)OPMD
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6. Dystrophinopathi
es
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7. Clinicalform Weakness Age of loss of
ambulation
Duchennemuscular
dystrophy (DMD)
Severe < 12 years
Becker muscular
dystrophy (BMD)
Milder > 16 years
distinction between DMD and BMD is a clinical one and is based on the degree of
weakness and the age at which ambulation is lost.
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8. Clinical features
•Delayed motor milestones
•Progressive proximalweakness (LL>UL)
•Difficulty rising from floor and going up stairs
•Loss of ambulation
•Cramps (BMD)
•Lumbar lordosis; waddling gait
•Resp. failure by late teenage (DMD)
•Cardiomyopathy (DMD >> BMD)
•Impaired IQ (DMD)
•CK ↑↑(10–50 times normal), elevated at birth
-Level of CK does not correlate with clinical severity
Valley sign
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10. Histopathology
•Wide variation in fibre size
•Most fibres rounded
•Necrosis, myophagocytosis–often segmental
•Endomysial& perimysialfibrosis
•Hypercontractedfibres
•Internal nuclei with splits
•Fibre typing indistinct
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11. Regenerating fibres
Myophagocytosis
MGT
NADH
ATPase 9.4
Whorled fibres
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12. IHC
•Mutations affect the amount of protein formed
•DMD → reading frame is disrupted → complete loss of
dystrophin
•BMD → reading frame is maintained → ↓/uneven
expression of dystrophin
•↓labelling of dystrophinassociated proteins
(dystroglycans, syntrophins)
•↑expression of utrophin
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13. Female carriers
•Usually asymptomatic; rarely manifest (weakness /
cramps / calf muscle enlargement)
-Random inactivation of one X chromosome
(Lyon hypothesis)
-Chromosomal (X:autosome) translocation
affecting dystrophin locus →DMD???
•CK –N/↑
•IHC -fibres / parts of fibres lack dystrophin(mosaic
pattern)
•Susceptible to cardiomyopathy
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14. Limb girdle muscular
dystrophy
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15. Clinical features
•Difficulty in running,
climbing stairs
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16. LGMD 2A
LGMD 2B
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18. Dominant forms
LGMD Defective protein
1A Myotilin
1B LaminA/C
1C Caveolin3
1D DNAJB6
1E Desmin
1F Transportin3
1G HNRPDL
1H ?
1I Calpain3
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19. Recessive forms
LGMD Defective
protein
2A Calpain3
2B Dysferlin
2C γ-Sarcoglycan
2D α-Sarcoglycan
2E β-Sarcoglycan
2F δ-Sarcoglycan
2G Telethonin
2H TRIM 32
2IFukutin-related
protein
LGMD Defective
protein
2J Titin
2K POMT 1
2LAnoctamin5
2M Fukutin
2N POMT 2
2O POMGnT1
2PDystroglycan
2Q Plectin
LGMDDefective
protein
2R Desmin
2STRAPPC11
2T GMPPB
2U ISPD
2V GAA
2W PINCH 2
2X BVES
2YTOR1AIP1
2ZPOGLUT1
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20. Histopathology
•Good fibre type differentiation
•Extensive fibre splitting
•Excessive internal nuclei
•Regenerating fibres / phagocytosis less than DMD
•Inflammation –LGMD 2B
•Rimmed vacuoles in some forms (1A,2G),
clinicopathologically overlapping with myofibrilar
myopathy
•LGMD 2B –sarcolemmalexpression ofMHC I.
•Eosinophils in LGMD 2A.
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21. Moth-eaten fibres
Lobulated fibresNADH
NADH
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22. Proposed new classification
Bethlemmyopathy
dominant
Collagen6 LGMD D5 collagen 6-
related
LGMD Defective proteinProposed nomenclature
1A Myotilin Myofibrillarmyopathy
1B LaminA/C EDMD
1C Caveolin3 Rippling muscle disease
1D DNAJB6 LGMD D1DNAJB6-related
1E Desmin Myofibrillarmyopathy
1F Transportin3 LGMDD2TNP03-related
1G HNRPDL LGMD D3HNRPDL-related
1H ? -
1I Calpain3 LGMD D4 Calpain3-related
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23. LGMD Defective protein Proposed nomenclature
2A Calpain3 LGMD R1 Calpain3-related
2B Dysferlin LGMD R2 Dysferlin-related
2C γ-Sarcoglycan LGMD R3
2D α-Sarcoglycan LGMD R4
2E β-Sarcoglycan LGMD R5
2F δ-Sarcoglycan LGMD R6
2G Telethonin LGMD R7
2H TRIM 32 LGMD R8
2I Fukutin-related protein LGMD R9
2J Titin LGMD R10
2K POMT 1 LGMD R11
2L Anoctamin5 LGMD R12
2M Fukutin LGMD R13
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24. LGMD Defective protein Proposed nomenclature
2N POMT 2 LGMD R14
2O POMGnT1 LGMD R15
2P Dystroglycan LGMD R16
2Q Plectin LGMD R17
2R Desmin Myofibrillarmyopathy
2S TRAPPC11 LGMD R18
2T GMPPB LGMD R19
2U ISPD LGMD R20
2V GAA Pompedisease
2W PINCH 2 PINCH 2related myopathy
2X BVES BVES related myopathy
2Y TOR1AIP1 TOR1AIP1 related myopathy
2Z POGLUT1 LGMD R21
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25. Defective protein Proposed
nomenclature
Bethlemmyopathy
recessive
Collagen6 LGMD R22 collagen 6-
related
Lamininα2-related
muscular dystrophy
Lamininα2 LGMD R23 Lamininα2
-related
POMGNT2-related
muscular dystrophy
POMGNT2 LGMD R24 POMGNT2-
related
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26. Congenital Muscular
dystrophy
•Autosomal recessive
•Infants with weakness and hypotoniafrom birth or
within the first few months of life (Floppy infant)
•Contractures
•Delayed motor milestones
•Progression variable
•Degree of pathology does not represent severity of
the disease
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27. Congenital MD
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28. Merosindeficient Congenital MD
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29. ‘Merosin-deficient’ CMD / MDC1A
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30. Clinical features
•Presents at / soon after birth
•Weakness –axial + limbs (proximal > distal)
Can not walk unaided; able to sit
Feeding difficulties
Failure to thrive
•Progressive respiratory insufficiency →resp. failure
•Contractures
•Brain MRI -WM changes by 6 months (IQ normal)
•Epilepsy
•Spinal rigidity and scoliosis
•↑↑ serum CK
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31. Histopathology
•Dystrophic features -variable
•Sometimes, grouped atrophic fibres (mimics SMA)
Immunohistochemistry
•Laminin2 (merosin) –essential
•Lamininα5 is overexpressed on mature fibres
•Prenatal diagnosis → studies of expression of laminin
α2 in chorionic villus samples
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32. Ullrich Congenital MD
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33. Clinical features
•Dislocation of hips and patella
•Scoliosis / kyphosis
•Delayed / no ambulation
•Hyperkeratosis, keloid; velvety skin on hands and feet
•Progressive respiratory insufficiency →resp. failure
•CK normal or mildly elevated
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34. Bethlemmyopathy
•Milder phenotype of UllrichCMD
•AD; rarely AR
•Clinical overlap with EDMD
•Life expectancy normal
•CK normal or mildly elevated
•Some cases with intermediate severity b/w UCMD and BM
→ develop resp. insufficiency
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36. •CMDs associated with hypoglycosylationof α-dystroglycan
MDDGA–Congenital forms + brain and eye involvement
MDDGB –Congenital forms ±mental retardation
MDDGC–Limb-girdle phenotype ±mental retardation
Dystroglycanopathies
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37. Congenital MD
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38. Muscle-Eye-Brain
Disease (MEB)
•Neonatal presentation
•Mild to severe
•Type II lissencephaly
•Cerebellar cysts
•Fattening of brainstem
•Severe mental retardation,
epilepsy
•Severe myopia, glaucoma,
retinal dysplasia
•↑ CK
Walker–Warburg
Syndrome (WWS)
•Most severe form of CMD
•Very severe muscle weakness
at birth
•Type II lissencephaly
•Cerebellar cysts, brain stem
hypoplasia, hydrocephalus
•Severe microphthalmia,
cataracts, glaucoma,
hypoplasticoptic nerve
•↑↑ CK
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40. •Defects in nuclear envelope proteins
•Autosomal forms are more common and more severe
•Sometimes digenic(mutations affecting both lamin
A/C and emerin) –in atypical / severe phenotype
Inheritance Gene Protein
X-linked recessiveSTA Emerin
Autosomal
dominant
LMNA LaminA/C
SYNE1
SYNE2
Nesprin1
Nesprin2
TMEM43 LUMA
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41. Clinical features
•Weakness / wasting –
humeroperonealin X-linked EDMD
scapulohumeroperonealin AD EDMD
•Loss of ambulation in 1
st
decade (AD)
•Cardiac conduction defects (arrhythmia / heart block)
•CK –normal / mildly elevated
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42. Facioscapulohumeral
muscular dystrophy
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43. FSHD
•AD
•Common form of MD
•Onset –usually before 20 years
Infantile cases (onset before 10 yrs)
•Anticipation(earlier onset in successive generations)
•Severity may relate to size of the deletion of the
fragment
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44. Pathogenesis
•Deletionof copies of a DNA repeat fragment (D4Z4)
in subtelomericregion of chromosome 4q
•Altered expression of genes within D4Z4 (e.g. DUX4)
•FSHD1 (95%)–contraction of 4q fragment
•FSHD2(5%) –no contraction; hypomethylationat
D4Z4 locus
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45. Clinical features
•Facial and shoulder girdle weakness
inability to close eyes / whistle
difficulty in raising the arms
•Often asymmetrical
•Variable progression
•Weakness of abdominal muscles in later stages →
protruding abdomen
•Hearing loss
•Retinal vasculopathy
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46. 20 yrmale
Popeye sign
Polyhillsign
Beevorssign
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47. Histopathology
•Changes often focal and inconspicuous
•Scattered small angulated fibres (may be the only
abnormality)
•Often type 2 fibre predominance
•Inflammatory response common
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48. Oculopharyngeal
muscular dystrophy
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49. OPMD
•Usually AD; rarely AR
•Late onset (40-60 yrs)
•Slowly progressive
•Ptosis–early feature
usually bilateral, asymmetrical and progressive
•Progressive dysphagia
•Weakness of muscles of face, eyes and limbs
•CK is mildly elevated
•PABPN1 gene mutation Pgpathtutorial Dr.Abhishek

50. OPMD CPEO
Astrologist’s posture
OPMD
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51. Histopathology
•Marked hypertrophy of type 2 fibres
•Increased fibroadiposetissue deposition
•Usually no necrosis / inflammation
•Mitochondrial abnormality –
lobulated fibres
few ragged-red fibres
COX deficient fibres
•Rimmed vacuoles in many fibres
more common in type 1 fibres
often contain acid phosphatasePgpathtutorial Dr.Abhishek

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53. Myotonic
dystrophy
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54. •Nucleotide repeat disorders
•Two forms –
1.DM1 (Steinert’sdisease) –congenital & adult forms
2.DM2 (Proximal myotonicmyopathy / PROMM)
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56. ‘Hatchet face’
Clinical features
•Myotonia
•Weakness + wasting
-distal limbs, face, neck, diaphragm (DM1)
-proximal limbs (DM2)
•Ptosis (DM1)
•Frontal balding (DM1)
•Cataract
•Insulin resistance
•Cardiac conduction defects
•Gonadal atrophy
•CK –mild-moderately elevated
•Congenital DM1 –arthrogryposis, tent shaped mouth
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57. Histopathology
•↑ internalised nuclei
•Ring fibres
•Fibre splitting DM1>>DM2
•Sarcoplasmic masses
•Type 1 fibre atrophy + type 2
hypertrophy (DM1)
•Congenital DM1 –large central
nuclei
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