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Dysferlin Deficiency (LGMD 2B)

Differential diagnosis
Immune features

LGMD 2B: Myopathy

H&E stain
Myopathy: General Features
  Varied Degrees of replacement of perimysium by fat
  Fiber sizes: Varied
  Endomysial connective tissue: Increased
  Perimysial connective tissue: Replaced by fat

H&E stain

Myopathy: Varied Degrees & Patterns of Pathology in same muscle

Myopathy, Mildly active
  Varied fiber size
  Immature fibers scattered

VvG stain
Severe pathology
  Pyknotic nuclear clumps
  Replacement of muscle by fat

VvG stain

Necrotic Muscle fibers: Scattered

H&E stain

Active Myopathy

H&E stain
Myopathic features
  Necrosis (Pale fibers)
  Regeneration (Basophilic, smaller fibers)
  Fiber size: Varied

Necrotic muscle fibers

Necrotic muscle fiber replaced by phagocytic cells

Congo red stain

Necrotic & Regenerating muscle fibers

Acid phosphatase stain

Irregular internal architecture

NADH stain

Alkaline phosphatase stain
Immature smaller muscle fibers
  Alkaline phosphatase positive cytoplasm (Above)
  Type 2C fibers (Intermediate staining; Below)

ATPase pH 4.3 stain

ATPase pH 9.4 stain
Type 2 muscle fiber predominance
  Most fibers are dark stained with ATPase pH 9.4

Dysferlinopathy: Immune features

C5b-9 stain
C5b-9 Complement deposits
  Muscle fiber surface membranes: Irregular, Punctate
  Muscle fiber cytoplasm: Necrotic fiber

C5b-9 stain

Inflammation, Lymphocytic: Found in some biopsies

May reflect superimposed immune disorder
Perimysial inflammation
  Cells in connective tissue between fascicles
Perivascular inflammation
  Cells around intermediate-sized vessels

  Muscle fibers
    Sizes: Varied
    Internal nuclei
  Endomysial connective tissue: Increased

H&E stain

Chronic Pathology

H&E stain
Small muscle fibers
  Often in Myopathic Groups
Larger muscle fibers
  Often hypertrophic
  Occasionally necrotic

NADH stain

Muscle fiber internal architecture
  Coarse staining in scattered muscle fibers
  Necrotic fiber shows only pale staining
  Pyknotic nuclear clumps: Very small, dark-stained muscle fibers

H&E stain

Varied muscle fiber size
  Pyknotic nuclear clumps: Some muscle fibers are very atrophic and composed mainly of nuclei

Late Pathology

H&E stain
Size changes
  Small muscle fibers: Rounded; Often in Myopathic Groups
  Larger muscle fibers: Often very hypertrophic
Muscle fiber splitting
Endomysial connective tissue: Increased

H&E stain
Pyknotic nuclear clumps

Amyloid (LGMD 2B): Commonly in vessel walls

Red-Green birefringent amyloid in vessel walls

Amyloid is occasionally deposited on a muscle fiber surface (Left & Below)

Congo red stain

Congo red stain

Dysferlin staining of muscle fibers

Normal: Dysferlin on surface of muscle fibers LGMD 2B:
  Absent dysferlin on muscle fiber surface

Dysferlin mutations: Ultrastructure

From: C Angelini
Sarcolemma: Focal lesion Sarcolemma: Focal projections

Subsarcolemmal region: Vacuoles Subsarcolemmal region: Disrupted internal architecture

VvG stain
Perimysial vessels: Fibrils in vessel walls are pale

VvG stain

Dysferlinopathy: Muscle Image

From: C Angelini
Leg: Involvement of posterior-medial gastrocnemius

Thigh: Involvement of posterior muscles

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