Transcript Diseases of Muscle

Inherited
Diseases of
Muscle:
Histologic
Features
David Lacomis, MD
Classification of Myopathies
ACQUIRED
Inflammatory Myopathies
INHERITED
Dystrophies
Polymositis (PM)
Dystrophinopathies
Dermatomyositis (DM)
Limb-Girdle
Inclusion body myositis (IBM)
Myotonic
Granulomatous myositis
Facioscapulohumeral (FSHD)
Infectious myositis
Oculopharyngeal (OPD)
Toxic
Endocrine
Distal
Congenital
Metabolic
Mitochondrial
Glycogen & lipid storage
Frozen Section from a Patient with
Duchenne Muscular Dystrophy
Group of basophilic regenerating fibers
 Opaque or hyaline fibers
 Increase in endomysial connective tissue
Normal Immunohistochemical Stain for Dystrophin
Subsarcolemmal staining
Duchenne Muscular Dystrophy
Absent staining for dystrophin
Becker Muscular Dystrophy
Reduced but present staining
split fiber
(non-specific chronic change)
Female Carrier of Duchenne Muscular Dystrophy
A mosaic staining pattern
Female Carrier of Duchenne Muscular Dystrophy
A mosaic staining pattern
Mutations in “Limb-Girdle” & Other Dystrophies
INHERITANCE
GENETIC
ABNORMALITY
DISORDER
X-linked
Dystrophin
Emerin
Duchenne, Becker MD
Emery-Dreifuss MD
AD
Myotilin
Lamin A/C
Caveolin – 3
PABP2
-crystallin/Desmin
Limb-Girdle MD (LGMD 1A)
LGMD 1B
LGMD 1C
Oculopharyngeal
Myofibrillar Myopathy
AR
Calpain – 3
Dysferlin
g Sarcoglycan
a Sarcoglycan
 Sarcoglycan
Δ Sarcoglycan
Telethonin
LGMD 2A
LGMD 2B
LGMD 2C
LGMD 2D
LGMD 2E
LGMD 2F
LGMD 2G
LGMD 2H
LGMD 2I
Fukuitin-rel prot
Locations of Affected Proteins
in Muscular Dystrophies
Extracellular Matrix
Laminin-2

g 
sarcoglycans

Dystroglycan
complex
Sarcolemma
Lamin A/C
(emerin)
Caveolin 3
Dysferlin
Dystrophin
nucleus
Actin
Emery-Dreifuss Muscular Dystrophy
Gomori trichrome-stained frozen section
Necrotic fiber
 Variation in fiber size with many hypertrophic fibers
 Increase in endomysial connective tissue
 Nonspecific so-called dystrophic changes seen in
many of the muscular dystrophies.
 Can also be seen in any chronic myopathic disorder.
 This disorder is due to loss of the protein emerin.
Myotonic Dystrophy
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Chronic changes
Marked excess in internalized nuclei
Variation in fiber sizes
Nuclear clumps (not shown)
H & E, paraffin
The excess of internalized nuclei can lead to nuclear chains.
Myotonic Dystrophy
NADH-reacted section
Ring fibers in which myofilaments are
organized in different directions
Fascioscapulohumeral Dystrophy (FSHD)
 The majority of dystrophies do not have a
specific histopathologic appearance.
 Clinical features are also very important.
 For example, winging of the scapula is
characteristic of FSHD.
FSH Dystrophy
 Variable non-specific changes
 Range from scattered atrophy to “dystrophic” features.
 Inflammation can be present.
 Basophilic subsarcolemmal structures are
sarcoplasmic masses.
 Sometimes occur in chronic myopathies such
as FSH and myotonic dystrophy.
Sarcoplasmic Masses
Stained darkly with NADH reaction
Oculopharyngeal Muscular Dystrophy (OPD)
 Variation in muscle fiber size with atrophic angulated fibers
 Sometimes contain rimmed vacuoles
Higher power view of Gomori trichrome-stained section
 Angulated fibers
 Fiber containing a large rimmed vacuole
Oculopharyngeal Dystrophy
Gomori trichrome
 Ragged red fibers are sometimes seen.
 Characteristic of proliferation of abnormal mitochondria.
Intranuclear Filamentous Inclusions
 May be identified by electron microscopy in OPD
Congenital Myopathies: Central Core Myopathy
NADH
 Central areas of absent staining in the dark type I fibers
 Mitochondria absent
Congenital Myopathies: Central Core Myopathy
NADH
 The core consists of disorganized myofibrils
and the area is devoid of mitochondria.
Congenital Fiber Type Disproportion
H&E
 Bimodal size population
Congenital Fiber Type Disproportion
ATPase pH 4.3
 Smaller fibers are type I
 More numerous
 Stain lightly
 Larger or normal fibers are type II
Nemaline Myopathy
 Eosinophilic inclusions present
Nemaline Myopathy
Gomori trichrome
 Eosinophilic inclusions stain darkly
Nemaline Myopathy
Electron microscopy
 Named for thread-like appearance
 Inclusions extend from Z-band to Z-band
Muscle Biopsy from an Infant
 Internalized nuclei predominant
 Consistent with centronuclear myopathy
 Can be seen in other disorders such as
myotonic dystrophy with congenital onset
Muscle Biopsy from an Infant:
Centronuclear Myopathy
 Central position of the nucleus resembling an
embryonic myotube
Metabolic: Inherited – Mitochondrial
MELAS Syndrome
 Ragged red fiber present
MELAS Syndrome
Succinic dehydrogenase reaction
 SDH-rich fibers are seen with mitochondrial proliferation
“Ragged-red” Fibers
H&E
SDH-rich Fibers
Cox Normal Fibers
Many COX-negative Fibers
 COX-negative fibers are usually seen with mtDNA mutations.
Mitochondrial Disorders
Electron Microscopy
 Aggregates of mitochondria containing
paracrystalline inclusions are frequent.
 Non-specific
Mitochondrial Disorders
Electron Microscopy
Higher power view of paracrystalline inclusion
Oil-red-O stain
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Increased lipid storage
Seen in carnitine deficiency states (primary or secondary)
Sometimes as a consequence of certain toxins
Focal increases can be non-specific
Lipid Storage Myopathy
Electron microscopy
Glycogen Storage Myopathies
 Some glycogen storage myopathies, such as
myophosphorylase deficiency (McArdle’s Disease),
cause subsarcolemmal blebs.
 PAS-positive due to the presence of glycogen.
McArdles Disease:
Phosphorylase Reaction
Normal Control
Disease (Absent)
McArdle’s Disease
Electron Microscopy
Subsarcolemmal collection of
glycogen is shown.
Acid Maltase Deficiency
Acid phosphatase
Vacuolar myopathy noted.
 Due to the intralysosomal activity of this enzyme
 Prominent staining with acid phosphatase in vacuoles
Normal Glycogen
PAS stain (control)
Increased
Glycogen
 Acid maltase deficiency
 Increased glycogen (diffusely and in vacuoles)
 Glycogen is digested by diastase in
most glycogen storage diseases.
Aggregates of Glycogen
within Autophagic Vacuoles
(Acid Maltase Deficiency)
Electron microscopy
Miscellaneous Disorder
 Tubular aggregates occur in an inherited myopathy, nonspecifically, and in some patients with myalgias.
Miscellaneous Disorder
Bright red with Gomori trichrome
Miscellaneous Disorder
Stain darkly with NADH, no staining with SDH
Tubular
Aggregates
Via Electron
Microscopy