Myopathies — Overview & Classification

Key Clinical Features

• Proximal, symmetric limb weakness — difficulty rising from a chair, climbing stairs, raising arms overhead (waddling gait, Gowers' sign)
• Preserved deep tendon reflexes (vs. neuropathy)
• No sensory loss (sensory loss points to peripheral neuropathy or CNS lesion)
• No fasciculations (which suggest motor neuron disease)

Classification

1. Muscular Dystrophies

• Duchenne (DMD) / Becker (BMD) — X-linked; dystrophin gene mutations; childhood onset; pseudohypertrophy of calves; DMD is severe/progressive, BMD is milder
• Emery-Dreifuss (EDMD) — X-linked or AD/AR; early contractures (elbow, Achilles), cardiac involvement (arrhythmias) obligatory
• Limb-Girdle Muscular Dystrophies (LGMD) — Autosomal dominant or recessive; affect pelvic and shoulder girdle; genetically heterogeneous (sarcoglycanopathies, calpainopathy, dysferlinopathy, etc.)
• Facioscapulohumeral (FSHD) — AD; facial, scapular, and humeral weakness; often asymmetric
• Oculopharyngeal — AD; ptosis and dysphagia in mid-adulthood

2. Myotonic Myopathies

• Myotonic Dystrophy Type 1 (DM1) — DMPK gene (CTG repeat); distal > proximal weakness; multisystem (cataracts, arrhythmia, endocrine, cognitive)
• Myotonic Dystrophy Type 2 (DM2) — CNBP gene; proximal > distal
• Myotonia Congenita — CLCN1 (chloride channel); myotonia without significant weakness; muscle hypertrophy
• Paramyotonia Congenita — SCN4A (sodium channel); paradoxical worsening with repeated activity; cold-triggered

3. Inflammatory Myopathies (Idiopathic)

4. Metabolic Myopathies

• Glycogen storage diseases — McArdle disease (myophosphorylase deficiency): exercise intolerance, cramps, "second wind" phenomenon; forearm exercise test shows no lactate rise
• Lipid disorders — CPT2 (carnitine palmitoyltransferase 2) deficiency: prolonged low-intensity exercise triggers rhabdomyolysis; fasting/cold are triggers
• Mitochondrial myopathies — Maternal inheritance (mtDNA mutations); chronic progressive external ophthalmoplegia (CPEO), MELAS, MERRF, Kearns-Sayre syndrome; ragged red fibers on Gomori trichrome stain

5. Congenital Myopathies

6. Channelopathies / Ion Channel Disorders

• Periodic paralyses — Hypokalemic (CACNA1S/SCN4A) or hyperkalemic (SCN4A); episodic flaccid weakness related to K⁺ shifts
• Malignant Hyperthermia — RYR1 mutations; life-threatening hyperthermia + rigidity triggered by volatile anesthetics/succinylcholine

7. Endocrine & Toxic Myopathies

• Endocrine: Hypothyroid (elevated CK, stiffness), hyperthyroid, Cushing's syndrome (steroid myopathy — type II fiber atrophy, normal CK)
• Toxic: Statins (spectrum from myalgia → rhabdomyolysis), glucocorticoids, zidovudine (mitochondrial), alcohol, colchicine, hydroxychloroquine

8. Critical Illness Myopathy

• Occurs in ICU patients (sepsis, steroids, non-depolarizing neuromuscular blockade)
• Includes: cachectic myopathy (type II atrophy, normal CK/EMG), acute necrotizing ICU myopathy (panfascicular necrosis), thick-filament myopathy (myosin loss; associated with steroids + NMBAs)

Diagnostic Approach

Key Points to Remember

• Most myopathies → proximal > distal weakness, reflexes preserved, no sensory loss
• Elevated CK points to muscle disease, but can be normal in steroid myopathy and some endocrine causes
• Aldolase can be elevated in perimysial/fascial inflammation (DM) even when CK is normal
• GGT elevation (not elevated in muscle) distinguishes liver from muscle as the source of elevated transaminases
• Myotonia = prolonged post-contraction relaxation; key in channelopathies and myotonic dystrophies

Pathophysiology of Myopathies — Overview by Category

1. Muscular Dystrophies — Structural Membrane Failure

The Dystrophin-Glycoprotein Complex (DGC)

• Dystroglycans (α and β) — form the direct bridge between dystrophin and laminin
• Sarcoglycans (α, β, γ, δ) — associated transmembrane proteins that stabilize the complex
• Dystrobrevin / Syntrophins — intracellular scaffold proteins
• nNOS (neuronal nitric oxide synthase) — anchored to the complex via syntrophins; involved in vasodilatation during exercise
• Caveolin — associated with the complex

Duchenne / Becker MD (Dystrophinopathies)

• Gene: DMD on X chromosome (2.3 Mb, 79 exons — one of the largest human genes)
• DMD: Frameshift or deletion → complete absence of dystrophin
• BMD: In-frame deletions → truncated but partially functional dystrophin

1. Loss of dystrophin → DGC destabilized → sarcolemma mechanically fragile
2. During contraction, micro-tears develop in the sarcolemma
3. Uncontrolled Ca²⁺ influx through membrane defects
4. Ca²⁺ activates proteases (calpains) and mitochondrial apoptotic pathways → myofiber necrosis
5. Repeated cycles of necrosis exceed regenerative capacity (satellite cells)
6. Progressive replacement by collagen and fat (fatty replacement / endomysial fibrosis)
7. Loss of nNOS anchoring → impaired exercise-induced vasodilation → relative ischemia

• Early: Fiber size variation, segmental necrosis, basophilic regenerating fibers, mild fibrosis
• Late: Marked atrophy + hypertrophy of remaining fibers, extensive fatty infiltration, loss of fascicular architecture
• Pseudohypertrophy of calf muscles = infiltration by fat + connective tissue, not true hypertrophy

Limb-Girdle MD (LGMDs)

• Mutations in sarcoglycans (α, β, γ, δ) — autosomal recessive forms (LGMD2C–F)
• Mutations in caveolin-3 — autosomal dominant form (LGMD1C)
• Mutations in calpain-3 (LGMD2A), dysferlin (LGMD2B) — affect membrane repair
• Common endpoint: DGC instability → same cycle of membrane damage → Ca²⁺ influx → necrosis

Emery-Dreifuss MD

• Mutations in emerin (X-linked) or lamins A/C (AD/AR) — nuclear envelope proteins
• Pathophysiology: nuclear envelope disruption → impaired mechanotransduction and nuclear integrity → muscle and cardiac muscle damage
• Distinctive early contractures (Achilles, elbow, posterior neck) and obligatory cardiac conduction defects/arrhythmias

2. Myotonic Dystrophies — RNA Toxic Gain-of-Function

• DM1 (DMPK gene, chr 19): CTG trinucleotide repeat expansion → transcribed but not translated → toxic CUG-repeat RNA accumulates in the nucleus → sequesters RNA-binding proteins (MBNL1/MBNL2) → widespread alternative splicing dysregulation of many downstream transcripts (including the chloride channel ClC-1, insulin receptor, cardiac troponin T)
• DM2 (CNBP gene, chr 3): CCTG repeat expansion → similar RNA toxicity mechanism
• Myotonia results from abnormal splicing of the CLCN1 transcript → reduced chloride channel conductance → prolonged sarcolemmal depolarization after each action potential → delayed relaxation

Channelopathies (Non-dystrophic)

• Myotonia Congenita: Loss-of-function mutations in CLCN1 (chloride channel) → same mechanism as above — reduced Cl⁻ conductance → prolonged depolarization → myotonia (without weakness)
• Paramyotonia Congenita / Hyperkalemic Periodic Paralysis: Gain-of-function mutations in SCN4A (sodium channel) → impaired channel inactivation → sustained depolarization → at mild levels produces myotonia; at severe levels produces depolarization block → flaccid paralysis
• Hypokalemic Periodic Paralysis: Mutations in CACNA1S (Ca²⁺ channel, type 1) or SCN4A → gating pore currents allowing cation leak → K⁺ shifts into cells with carbohydrate load or rest after exercise → sarcolemmal hyperpolarization → failure to generate action potentials → paralysis

3. Inflammatory Myopathies — Immune-Mediated Injury

Dermatomyositis (DM)

• Humoral / vasculopathic mechanism: Autoantibodies activate complement → C5b–9 membrane attack complex deposits on capillary endothelium → microangiopathy → dropout of intramuscular capillaries → ischemia and perifascicular microinfarcts
• Prominent type I interferon (IFN) signaling pathway activation: IFN-induced protein MxA overexpressed in muscle and endothelial cells; tubuloreticular inclusions in capillary endothelium are ultrastructural hallmarks of IFN activation
• Perifascicular atrophy — fibers at the periphery of fascicles are most ischemic and atrophy preferentially
• Myositis-specific antibodies (anti-TIF1-γ, anti-Mi-2, anti-MDA5, anti-NXP-2) associate with distinct pathologic and clinical subsets

Polymyositis / Immune-Mediated Necrotizing Myopathy (IMNM)

• Cell-mediated (CD8+ T cell) mechanism: CD8+ cytotoxic T cells invade and destroy MHC class I–expressing myofibers directly
• MHC class I is normally absent from muscle; its upregulation under inflammatory stress marks fibers for immune attack
• IMNM: Anti-SRP or anti-HMGCR antibodies → complement-mediated or antibody-dependent necrotizing injury → prominent fiber necrosis with minimal inflammatory infiltrate; statin exposure can expose HMGCR as an antigen

Inclusion Body Myositis (IBM)

• Dual pathology — both inflammatory and degenerative:
  • Endomysial CD8+ T cell infiltrates invading MHC I–expressing fibers (immune component)
  • Rimmed vacuoles containing aggregates of misfolded proteins: β-amyloid, TDP-43, ubiquitin, p62 — proteins shared with neurodegenerative diseases
  • Filamentous inclusions on electron microscopy
  • Protein homeostasis failure (impaired autophagy/ubiquitin-proteasome system) → toxic protein aggregation within myofibers
• Whether inflammation is primary or secondary to degeneration is unresolved; the end result is endomysial fibrosis and fatty replacement in a characteristic topographic pattern (finger flexors, quadriceps)

4. Metabolic Myopathies — Energy Supply Failure

Glycogen Storage Diseases (Glycogenoses)

• McArdle Disease (GSD type V): Myophosphorylase (PYGM) deficiency → glycogen cannot be broken down to glucose-1-phosphate during exercise → ATP deficit under high-demand conditions → muscle cramps, contracture, rhabdomyolysis
  • "Second wind" phenomenon: After 8–10 min of aerobic exercise, free fatty acid and hepatic glucose delivery compensates, relieving symptoms
  • Forearm ischemic exercise test: Lactate fails to rise (blocked glycolysis) but ammonia rises normally
• Pompe disease (GSD type II): Acid maltase (α-glucosidase) deficiency → lysosomal glycogen accumulation → lysosomal rupture → myofiber destruction; also progressive respiratory muscle failure

Lipid Metabolism Disorders

• CPT2 Deficiency: Carnitine palmitoyltransferase II deficiency → long-chain fatty acids cannot enter the mitochondrial matrix → fatty acid oxidation blocked during prolonged low-intensity exercise, fasting, or cold exposure → ATP depletion → rhabdomyolysis and myoglobinuria
• Carnitine deficiency: Impaired fatty acid transport → lipid vacuoles accumulate in myofibers

Mitochondrial Myopathies

• Mutations in mitochondrial DNA (mtDNA) or nuclear genes encoding mitochondrial proteins → defects in the electron transport chain (ETC) complexes → impaired oxidative phosphorylation → failure of aerobic ATP generation
• Heteroplasmy: mtDNA exists in multiple copies per cell; disease manifests when mutant mtDNA exceeds a threshold (threshold effect)
• Energy failure preferentially affects high-demand tissues: muscle, brain, heart, retina
• Ragged red fibers (RRF) on Gomori trichrome stain: Subsarcolemmal and intermyofibrillar accumulation of abnormal mitochondria (mitochondrial proliferation as a compensatory response to energy failure)
• Classic syndromes: MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes), MERRF (myoclonic epilepsy with RRF), Kearns-Sayre (CPEO, pigmentary retinopathy, heart block — large mtDNA deletion)

5. Congenital Myopathies — Sarcomere Structural Defects

6. Toxic Myopathies — Direct or Immune-Mediated Fiber Damage

• Statins: Inhibit HMG-CoA reductase → reduced mevalonate → depleted geranylgeranyl pyrophosphate (required for Rho GTPase prenylation and mitochondrial CoQ synthesis) → impaired mitochondrial function and membrane integrity → myofiber necrosis; in genetically predisposed individuals, can trigger IMNM via anti-HMGCR antibody generation
• Glucocorticoids: Activate proteolytic pathways (ubiquitin-proteasome, calpains) preferentially in type II (fast-twitch) fibers → selective type II atrophy; CK is typically normal (no necrosis)
• Zidovudine (AZT): Inhibits mitochondrial DNA polymerase γ → mtDNA depletion → mitochondrial dysfunction → morphologic features resembling mitochondrial myopathy (ragged red fibers)
• Alcohol: Direct membrane toxicity + mitochondrial dysfunction + hypokalemia and hypophosphatemia → acute or chronic myopathy/rhabdomyolysis

Unifying Pathologic Themes