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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 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 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