InheritedInheritedDiseases of Diseases of

Muscle:Muscle:

Histologic FeaturesHistologic Features

David Lacomis, MDDavid Lacomis, MD

Classification of MyopathiesClassification of Myopathies

ACQUIREDACQUIRED INHERITEDINHERITED

Inflammatory MyopathiesInflammatory Myopathies DystrophiesDystrophiesPolymositis (PM)Polymositis (PM) DystrophinopathiesDystrophinopathiesDermatomyositis (DM)Dermatomyositis (DM) Limb-GirdleLimb-GirdleInclusion body myositis (IBM)Inclusion body myositis (IBM) MyotonicMyotonicGranulomatous myositisGranulomatous myositis Facioscapulohumeral (FSHD)Facioscapulohumeral (FSHD)

Infectious myositisInfectious myositis Oculopharyngeal (OPD)Oculopharyngeal (OPD)

ToxicToxic DistalDistal

EndocrineEndocrine CongenitalCongenital

MetabolicMetabolicMitochondrialMitochondrialGlycogen & lipid storageGlycogen & lipid storage

Opaque or hyaline fibersOpaque or hyaline fibers

Increase in endomysial connective tissueIncrease in endomysial connective tissue

Frozen Section from a Patient withFrozen Section from a Patient withDuchenne Muscular DystrophyDuchenne Muscular Dystrophy

Group of basophilic regenerating fibers

Normal Immunohistochemical Stain for DystrophinNormal Immunohistochemical Stain for DystrophinSubsarcolemmal stainingSubsarcolemmal staining

Duchenne Muscular DystrophyDuchenne Muscular Dystrophy Absent staining for dystrophin Absent staining for dystrophin

split fiber(non-specific chronic change)

Becker Muscular DystrophyBecker Muscular Dystrophy Reduced but present staining Reduced but present staining

Female Carrier of Duchenne Muscular Female Carrier of Duchenne Muscular DystrophyDystrophy

A mosaic staining pattern A mosaic staining pattern

Female Carrier of Duchenne Muscular Dystrophy

A mosaic staining pattern

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

Sarcoglycan

a Sarcoglycan

Sarcoglycan

Δ Sarcoglycan

Telethonin

Fukuitin-rel prot

LGMD 2A

LGMD 2B

LGMD 2C

LGMD 2D

LGMD 2E

LGMD 2F

LGMD 2G

LGMD 2H

LGMD 2I

Mutations in “Limb-Girdle” & Other Mutations in “Limb-Girdle” & Other DystrophiesDystrophies

Sarcolemma

nucleus

Lamin A/C(emerin)

sarcoglycans

Dystroglycancomplex

Laminin-2

Extracellular Matrix

Dysferlin

Caveolin 3

Actin

Dystrophin

Locations of Affected ProteinsLocations of Affected Proteinsin Muscular Dystrophiesin Muscular Dystrophies

Emery-Dreifuss Muscular DystrophyEmery-Dreifuss Muscular DystrophyGomori trichrome-stained frozen section Gomori trichrome-stained frozen section

Necrotic fiberNecrotic fiber

Variation in fiber size with many hypertrophic fibersVariation in fiber size with many hypertrophic fibers Increase in endomysial connective tissueIncrease in endomysial connective tissue Nonspecific so-called dystrophic changes seen in many Nonspecific so-called dystrophic changes seen in many

of the muscular dystrophies.of the muscular dystrophies. Can also be seen in any chronic myopathic disorder.Can also be seen in any chronic myopathic disorder. This disorder is due to loss of the protein emerin.This disorder is due to loss of the protein emerin.

Myotonic DystrophyMyotonic Dystrophy

Chronic changesChronic changes Marked excess in internalized nucleiMarked excess in internalized nuclei Variation in fiber sizesVariation in fiber sizes Nuclear clumps (not shown)Nuclear clumps (not shown)

H & E, paraffinH & E, paraffin

The excess of internalized nuclei can lead to nuclear chains.The excess of internalized nuclei can lead to nuclear chains.

Myotonic DystrophyMyotonic DystrophyNADH-reacted sectionNADH-reacted section

Ring fibers in which myofilaments are Ring fibers in which myofilaments are organized in different directionsorganized in different directions

Fascioscapulohumeral Dystrophy (FSHD)Fascioscapulohumeral Dystrophy (FSHD)

The majority of dystrophies do not have a The majority of dystrophies do not have a specific histopathologic appearance.specific histopathologic appearance.

Clinical features are also very important.Clinical features are also very important. For example, winging of the scapula is For example, winging of the scapula is

characteristic of FSHD.characteristic of FSHD.

FSH DystrophyFSH Dystrophy

Variable non-specific changesVariable non-specific changes Range from scattered atrophy to “dystrophic” features.Range from scattered atrophy to “dystrophic” features. Inflammation can be present.Inflammation can be present.

Basophilic subsarcolemmal structures are Basophilic subsarcolemmal structures are sarcoplasmic masses.sarcoplasmic masses.

Sometimes occur in chronic myopathies such as Sometimes occur in chronic myopathies such as FSH and myotonic dystrophy.FSH and myotonic dystrophy.

Sarcoplasmic MassesSarcoplasmic MassesStained darkly with NADH reactionStained darkly with NADH reaction

Oculopharyngeal Muscular Dystrophy (OPD)Oculopharyngeal Muscular Dystrophy (OPD)

Variation in muscle fiber size with atrophic angulated fibersVariation in muscle fiber size with atrophic angulated fibers Sometimes contain rimmed vacuolesSometimes contain rimmed vacuoles

Higher power view of Gomori trichrome-stained sectionHigher power view of Gomori trichrome-stained section

Angulated fibersAngulated fibers Fiber containing a large rimmed vacuoleFiber containing a large rimmed vacuole

Oculopharyngeal DystrophyOculopharyngeal DystrophyGomori trichromeGomori trichrome

Ragged red fibers are sometimes seen.Ragged red fibers are sometimes seen. Characteristic of proliferation of abnormal mitochondria.Characteristic of proliferation of abnormal mitochondria.

May be identified by electron microscopy in OPDMay be identified by electron microscopy in OPD

Intranuclear Filamentous Intranuclear Filamentous InclusionsInclusions

Central areas of absent staining in the dark type I fibersCentral areas of absent staining in the dark type I fibers Mitochondria absentMitochondria absent

Congenital Myopathies: Central Core MyopathyCongenital Myopathies: Central Core MyopathyNADHNADH

Congenital Myopathies: Central Core MyopathyCongenital Myopathies: Central Core MyopathyNADHNADH

The core consists of disorganized myofibrils and The core consists of disorganized myofibrils and the area is devoid of mitochondria.the area is devoid of mitochondria.

Congenital Fiber Type DisproportionCongenital Fiber Type DisproportionH&EH&E

Bimodal size populationBimodal size population

Smaller fibers are type ISmaller fibers are type I More numerousMore numerous Stain lightlyStain lightly

Larger or normal fibers are type IILarger or normal fibers are type II

Congenital Fiber Type DisproportionCongenital Fiber Type DisproportionATPase pH 4.3ATPase pH 4.3

Eosinophilic inclusions presentEosinophilic inclusions present

Nemaline MyopathyNemaline Myopathy

Eosinophilic inclusions stain darklyEosinophilic inclusions stain darkly

Nemaline MyopathyNemaline MyopathyGomori trichromeGomori trichrome

Named for thread-like appearanceNamed for thread-like appearance Inclusions extend from Z-band to Z-bandInclusions extend from Z-band to Z-band

Nemaline MyopathyNemaline MyopathyElectron microscopyElectron microscopy

Muscle Biopsy from an InfantMuscle Biopsy from an Infant

Internalized nuclei predominantInternalized nuclei predominant Consistent with centronuclear myopathyConsistent with centronuclear myopathy Can be seen in other disorders such as myotonic Can be seen in other disorders such as myotonic

dystrophy with congenital onsetdystrophy with congenital onset

Muscle Biopsy from an Infant:Muscle Biopsy from an Infant:Centronuclear MyopathyCentronuclear Myopathy

Central position of the nucleus resembling an embryonic Central position of the nucleus resembling an embryonic myotubemyotube

Metabolic: Inherited – MitochondrialMetabolic: Inherited – MitochondrialMELAS SyndromeMELAS Syndrome

Ragged red fiber presentRagged red fiber present

SDH-rich fibers are seen with mitochondrial proliferationSDH-rich fibers are seen with mitochondrial proliferation

MELAS SyndromeMELAS SyndromeSuccinic dehydrogenase reactionSuccinic dehydrogenase reaction

“Ragged-red” Fibers H&E

SDH-rich Fibers

Cox Normal Fibers

Many COX-negative Fibers

COX-negative fibers are usually seen with mtDNA mutations.COX-negative fibers are usually seen with mtDNA mutations.

Aggregates of mitochondria containing Aggregates of mitochondria containing paracrystalline inclusions are frequent.paracrystalline inclusions are frequent.

Non-specificNon-specific

Mitochondrial DisordersMitochondrial DisordersElectron MicroscopyElectron Microscopy

Mitochondrial DisordersMitochondrial DisordersElectron MicroscopyElectron Microscopy

Higher power view of paracrystalline inclusion

Increased lipid storageIncreased lipid storage Seen in carnitine deficiency states (primary or secondary)Seen in carnitine deficiency states (primary or secondary) Sometimes as a consequence of certain toxinsSometimes as a consequence of certain toxins Focal increases can be non-specificFocal increases can be non-specific

Oil-red-O stain

Lipid Storage MyopathyLipid Storage MyopathyElectron microscopyElectron microscopy

Some glycogen storage myopathies, such as Some glycogen storage myopathies, such as myophosphorylase deficiency (McArdle’s Disease), myophosphorylase deficiency (McArdle’s Disease), cause subsarcolemmal blebs.cause subsarcolemmal blebs.

PAS-positive due to the presence of glycogen.PAS-positive due to the presence of glycogen.

Glycogen Storage MyopathiesGlycogen Storage Myopathies

McArdles Disease:McArdles Disease:Phosphorylase ReactionPhosphorylase Reaction

Normal Control Disease (Absent)

Subsarcolemmal collection of Subsarcolemmal collection of glycogen is shown.glycogen is shown.

McArdle’s DiseaseMcArdle’s DiseaseElectron MicroscopyElectron Microscopy

Acid Maltase DeficiencyAcid Maltase DeficiencyAcid phosphataseAcid phosphatase

Due to the intralysosomal activity of this enzymeDue to the intralysosomal activity of this enzyme Prominent staining with acid phosphatase in vacuolesProminent staining with acid phosphatase in vacuoles

Vacuolar myopathy noted.Vacuolar myopathy noted.

Normal GlycogenNormal GlycogenPAS stain (control)PAS stain (control)

Increased Increased GlycogenGlycogen

Acid maltase deficiency Increased glycogen (diffusely and in vacuoles)

Glycogen is digested by diastase in most glycogen storage diseases.

Aggregates of GlycogenAggregates of Glycogenwithin Autophagic Vacuoleswithin Autophagic Vacuoles(Acid Maltase Deficiency)(Acid Maltase Deficiency)

Electron microscopyElectron microscopy

Tubular aggregates occur in an inherited myopathy, non-Tubular aggregates occur in an inherited myopathy, non-specifically, and in some patients with myalgias.specifically, and in some patients with myalgias.

Miscellaneous DisorderMiscellaneous Disorder

Miscellaneous DisorderMiscellaneous Disorder

Bright red with Gomori trichrome

Stain darkly with NADH, no staining with SDH

Miscellaneous DisorderMiscellaneous Disorder

Tubular Aggregates Via Electron Microscopy