7.3 Muscle, NMJ & Peripheral Nerve Disorders

Skeletal Muscle Excitation–Contraction Coupling

A motor neuron action potential invades the presynaptic terminal, opens voltage-gated Ca²⁺ channels (P/Q-type VGCC), and triggers acetylcholine (ACh) vesicle release into the synaptic cleft. ACh binds nicotinic ACh receptors on the motor end plate, opening cation channels → end-plate potential → muscle action potential if threshold is reached. The muscle AP propagates along the sarcolemma and into T-tubules. Voltage-sensing dihydropyridine receptors (DHPR) in the T-tubule mechanically couple to ryanodine receptors (RyR1) on the sarcoplasmic reticulum, releasing stored Ca²⁺ into the cytosol.

Cytosolic Ca²⁺ binds troponin C, moving tropomyosin and exposing myosin-binding sites on actin. Cross-bridge cycling (ATP-dependent) shortens sarcomeres (sliding filament). Relaxation requires Ca²⁺ reuptake into the SR via SERCA, plus ACh hydrolysis by acetylcholinesterase in the cleft so the end plate can repolarize. Anything that reduces ACh release (LEMS, botulinum), blocks AChR (curare-like agents, MG antibodies), or prevents ACh breakdown (organophosphates) alters the safety factor of neuromuscular transmission.

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Type I vs Type II Muscle Fibers

Type I (slow-twitch, oxidative): abundant mitochondria and myoglobin, rich capillary supply, fatigue-resistant—posture and endurance. Type II (fast-twitch): faster myosin ATPase; IIA has mixed oxidative-glycolytic capacity; IIX/IIB more glycolytic, powerful, fatigable—sprint/power tasks. Motor units are fiber-type homogeneous and recruited orderly (size principle: smaller slow units first). Denervation, training, and hormones remodel fiber properties; boards mainly require matching fiber type to metabolic profile and fatigue resistance.

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Duchenne and Becker Muscular Dystrophy

Dystrophin links the intracellular actin cytoskeleton to the transmembrane dystrophin-associated glycoprotein complex and extracellular matrix—stabilizing the sarcolemma during contraction. DMD gene on Xp21; X-linked inheritance.

Duchenne muscular dystrophy (DMD): usually frameshift/nonsense mutations → essentially absent dystrophin. Onset in early childhood: proximal weakness, Gowers sign, calf pseudohypertrophy (fat/fibrosis), elevated CK, wheelchair dependence in teens historically without modern care, cardiomyopathy and respiratory failure drive mortality. Female carriers may have mild weakness or elevated CK and cardiac risk.

Becker muscular dystrophy (BMD): typically in-frame mutations → reduced/truncated but partially functional dystrophin. Later onset, milder course, ambulatory longer; cardiomyopathy still important.

Both are dystrophinopathies; mutation reading-frame logic is the high-yield mechanistic discriminator.

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Myotonic Dystrophy

Myotonic dystrophy type 1 (DM1): autosomal dominant CTG trinucleotide repeat expansion in DMPK (anticipation). Clinical: distal weakness, myotonia (delayed relaxation—grip myotonia, percussion myotonia), temporal wasting, cataracts, cardiac conduction block, hypogonadism, insulin resistance, frontal balding teaching habitus. Congenital DM1 with severe hypotonia can occur with large maternal expansions. Type 2 (DM2, CCTG in CNBP) is milder/proximal-predominant—DM1 remains the classic board package.

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Inflammatory Myopathies: Lab and Pattern Anchors

Revisited briefly from the rheumatology section with muscle-centric labs: polymyositis and dermatomyositis elevate CK (and aldolase, AST/ALT from muscle, LDH). ANA may be positive; anti-Jo-1 flags antisynthetase syndrome with ILD. Biopsy patterns (endomysial CD8 vs perimysial/complement capillary injury) separate PM vs DM. Inclusion body myositis (older adults, finger flexors/quadriceps, poor treatment response, rimmed vacuoles) is a common contrast case. Endocrine/toxic myopathies (hypothyroid, glucocorticoid, statin) enter the differential of proximal weakness with variable CK.

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Myasthenia Gravis vs Lambert–Eaton

Myasthenia gravis (MG): autoimmune antibodies against postsynaptic nicotinic AChR (most common) or MuSK/LRP4 in subsets. Fewer functional receptors → smaller end-plate potentials → fatigable weakness. Pattern: ocular (ptosis, diplopia) often early; bulbar (dysarthria, dysphagia); limb fatigability; worse with repetition, better with rest. Thymoma/thymic hyperplasia associations are classic. Crisis can cause respiratory failure. Conceptual pharmacology: acetylcholinesterase inhibitors increase cleft ACh; crisis management distinguishes cholinergic vs myasthenic crisis clinically.

Lambert–Eaton myasthenic syndrome (LEMS): antibodies against presynaptic P/Q-type VGCC → impaired ACh release. Weakness often proximal legs; autonomic features (dry mouth); reflexes diminished but may improve after brief exercise; strength may improve temporarily with repeated use (facilitation)—opposite of MG fatigability teaching. Strong association with small cell lung cancer (paraneoplastic). Incremental response on high-rate repetitive nerve stimulation is the electrophysiologic teaching point (vs decremental in MG).

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NMJ Toxins and Drugs: Botulinum, Curare, Organophosphates

Botulinum toxin cleaves SNARE proteins (serotype-specific targets such as SNAP-25 or synaptobrevin) → blocks ACh vesicle fusion → flaccid paralysis; also reduces autonomic cholinergic transmission (dry mouth, ileus themes). Used therapeutically in focal dystonia and cosmesis—mechanism remains SNARE cleavage.

Curare / nondepolarizing neuromuscular blockers (e.g., d-tubocurarine conceptual class) competitively antagonize nicotinic AChR → flaccid paralysis; overcome by increasing ACh (AChE inhibitors) in anesthesia teaching.

Depolarizing blocker succinylcholine activates then desensitizes AChR (phase concepts); contraindicated in certain hyperkalemia risk states—boards touch malignant hyperthermia risk with volatile anesthetics/succinylcholine in susceptible patients (RyR1).

Organophosphate / nerve gas AChE inhibition: excess ACh at muscarinic and nicotinic synapses → DUMBBELS/SLUDGE muscarinic picture plus fasciculations, weakness, and CNS effects. Treatment concepts: atropine (muscarinic), pralidoxime (regenerate AChE if timely), supportive care. Contrast with botulinum (too little ACh release) versus organophosphate (too much ACh signaling).

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Demyelinating vs Axonal Neuropathy

Peripheral nerve disease localizes to axon, myelin, neuron cell body (neuronopathy), or vasa nervorum.

Demyelinating neuropathies: myelin injury slows conduction velocity, prolongs distal latencies, and may cause conduction block. Weakness and early areflexia are common; sensory large-fiber involvement causes paresthesias and proprioceptive loss. Examples: Guillain–Barré syndrome (AIDP form), CIDP, some hereditary demyelinating neuropathies (CMT1).

Axonal neuropathies: axon loss reduces amplitude of action potentials with relatively preserved velocities until severe dropout. Length-dependent “stocking-glove” sensory patterns dominate many toxic-metabolic axonopathies (diabetes, alcohol, B12 deficiency—though B12 can be mixed). Wallerian degeneration distal to injury is the prototype axonal response.

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Guillain–Barré vs CIDP

Guillain–Barré syndrome (GBS): acute monophasic polyradiculoneuropathy, often post-infection (Campylobacter jejuni with molecular mimicry to gangliosides in AMAN/AMSAN variants; AIDP is demyelinating). Rapidly progressive ascending weakness, areflexia, cytoalbuminologic dissociation (high CSF protein, few cells), risk of respiratory failure and autonomic instability. IVIG/plasma exchange conceptual therapies; avoid equating with simple “peripheral neuropathy” without the acute areflexic pattern.

CIDP (chronic inflammatory demyelinating polyneuropathy): related immune-mediated demyelination but chronic (progression >8 weeks teaching threshold) or relapsing course; responds more often to corticosteroids (unlike typical GBS). Think of CIDP as the chronic cousin of AIDP.

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Nerve Injury Classification Basics

Seddon/Sunderland teaching grades:

1. Neurapraxia: focal demyelination/conduction block without axonal interruption; good recovery weeks–months.
2. Axonotmesis: axon disrupted, connective tissue frameworks (endoneurium ± perineurium) partly preserved; Wallerian degeneration distal; regeneration ~1 mm/day if scaffolding intact.
3. Neurotmesis: full transection of axon and nerve sheaths; spontaneous recovery poor without surgical repair.

Clinically, closed stretch injuries may be neurapraxia/axonotmesis; open lacerations risk neurotmesis. Tinel sign and advancing sensory march can track regenerating axons.

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Clinical Integration for NBME Vignettes

Map fatigable ocular-bulbar weakness to MG; proximal legs + dry mouth + cancer smoking history to LEMS; toddler Gowers + huge CK + X-linked family pattern to Duchenne; grip myotonia + cataracts + conduction block to myotonic dystrophy; post-diarrheal ascending areflexic paralysis to GBS; chronic demyelinating polyneuropathy to CIDP; hot swollen joint still belongs to the prior section—but toxin questions sit at the NMJ table (botulinum vs organophosphate opposite ACh tone). Fiber type and EC coupling supply the physiology base that makes each lesion’s weak link predictable.