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10 notes available
1 Last Minute Review 2 Polyneuropathies 3 Mononeuropathies & Plexopathies 4 Motor Neuron Disease 5 Myasthenia Gravis & NMJ Disorders 6 Inflammatory Myopathies 7 Muscular Dystrophies 8 Channelopathies & Metabolic Myopathies 9 Neuromuscular Emergencies 10 EMG/NCS Patterns
Clinical › Neuromuscular

Channelopathies & Metabolic Myopathies

Channelopathies & Metabolic Myopathies

What You'll Learn

  • Periodic paralysis: HypoKPP (CACNA1S/SCN4A, carb triggers, low K+) vs HyperKPP (SCN4A, fasting/cold triggers, high K+, myotonia) vs Andersen-Tawil (KCNJ2, cardiac arrhythmias + dysmorphic features)
  • Myotonia congenita vs paramyotonia: Myotonia congenita (CLCN1) has warm-up phenomenon; paramyotonia congenita (SCN4A) has paradoxical myotonia (worsens with use) + cold sensitivity
  • McArdle disease (GSD V): Myophosphorylase deficiency → exercise intolerance + second-wind phenomenon + no lactate rise on forearm exercise test
  • Pompe disease (GSD II): Acid maltase deficiency; late-onset = proximal weakness + diaphragm weakness out of proportion to limbs; treatable with ERT (alglucosidase alfa)
  • CPT II deficiency: Most common lipid myopathy; recurrent rhabdomyolysis triggered by prolonged exercise, fasting, cold; normal CK between attacks
  • Mitochondrial myopathies: Maternal inheritance (mtDNA); ragged red fibers on biopsy; MELAS (stroke-like), MERRF (myoclonus), CPEO/KSS (ophthalmoplegia ± cardiac)
  • Malignant hyperthermia: RYR1 mutations + volatile anesthetics/succinylcholine → rigidity + hyperthermia + rhabdomyolysis; treat with DANTROLENE
  • Exercise-induced symptoms DDx: McArdle = early fatigue + second wind; CPT II = prolonged exercise + rhabdomyolysis; mitochondrial = progressive fatigue + lactic acidosis
HighYield Pearls
  • HypoKPP genetics: CACNA1S is the most common gene (AD); SCN4A second; attacks triggered by carbohydrate load, rest after heavy exercise, cold; K+ <3.5 during attack; treat with oral KCl + acetazolamide prophylaxis + low-carb diet
  • HyperKPP: SCN4A AD; triggers are fasting, cold, rest after exercise, K+ ingestion; K+ high or normal; tell patient to keep moving after exercise; dichlorphenamide first-line (some respond to acetazolamide)
  • Paramyotonia congenita: SCN4A AD — PARADOXICAL myotonia (worsens with repeated movement, opposite of myotonia congenita) + cold-induced stiffness/weakness
  • Andersen-Tawil (KCNJ2 AD): triad of periodic paralysis + cardiac arrhythmia (long QT, bidirectional VT, torsades) + dysmorphic features (low-set ears, hypertelorism, micrognathia, clinodactyly); cardiac monitoring mandatory; dichlorphenamide
  • Myotonia congenita: Becker AR (CLCN1) more common & more severe; Thomsen AD (CLCN1) milder; stiffness improves with repeated movement = warm-up phenomenon; treat with mexiletine
  • Thyrotoxic periodic paralysis: Asian male with thyrotoxicosis + hypokalemia + paralysis; treat the thyroid + KCl — do not miss TSH on every new HypoKPP presentation
  • McArdle (GSD V, PYGM, AR): exercise intolerance + second wind (rest 8–10 min then resume) + cramps + myoglobinuria; ischemic forearm test → NO lactate rise; biopsy → subsarcolemmal glycogen + absent phosphorylase
  • Pompe (GSD II, GAA acid α-glucosidase): late-onset = limb-girdle weakness + diaphragm/paraspinal weakness with FVC drop >30% upright→supine; biopsy → PAS+ vacuoles; alglucosidase alfa (Lumizyme) or avalglucosidase (Nexviazyme, 2021) ERT
  • CPT-II deficiency: most common adult fatty-acid oxidation defect; recurrent myoglobinuria with prolonged exercise / fasting / cold / infection; no second wind; CK normal between attacks; high-carb low-fat diet + frequent meals
  • Mitochondrial PEO/CPEO: slowly progressive bilateral ptosis + ophthalmoparesis WITHOUT diplopia; biopsy → ragged red fibers, COX-negative fibers; mostly sporadic single mtDNA deletion (common 4977 bp)
  • Malignant hyperthermia (RYR1/CACNA1S): triggered by volatile anesthetics + succinylcholine; tachycardia + hyperthermia + rigidity + rhabdo + hyperkalemia; DANTROLENE + cold IVF; ask family anesthesia history before any case
🔍 Quick ReferenceClinical / trigger · EMG / labs / biopsy · Genetics / treatment
Clinical / trigger
  • Paralysis after a high-carb meal or rest following heavy exercise → Hypokalemic periodic paralysis (CACNA1S)
  • Weakness after fasting / cold / rest after exercise with myotonia between attacks → Hyperkalemic periodic paralysis (SCN4A)
  • Stiffness worsens the more you use the muscle, especially in cold → Paramyotonia congenita (paradoxical myotonia, SCN4A)
  • Stiffness on first movement that loosens with repeated effort (“warm-up”) → Myotonia congenita (CLCN1 — Becker AR / Thomsen AD)
  • Periodic paralysis + long QT / bidirectional VT + low-set ears, hypertelorism, clinodactyly → Andersen-Tawil syndrome (KCNJ2)
  • Asian man with thyrotoxicosis + sudden weakness + low K+ → Thyrotoxic periodic paralysis
  • Cramps and dark urine early in exercise, then symptoms ease after rest (“second wind”) → McArdle disease (GSD V)
  • Prolonged exercise, fasting, or cold → recurrent myoglobinuria with normal baseline CK → CPT-II deficiency
  • Slowly progressive bilateral ptosis and ophthalmoparesis without diplopia → Chronic progressive external ophthalmoplegia (CPEO)
  • Anesthesia induction → jaw rigidity, hyperthermia, rising end-tidal CO2, rhabdo → Malignant hyperthermia (RYR1)
EMG / labs / biopsy
  • Ischemic forearm test with NO rise in lactate (normal ammonia rise) → McArdle disease
  • PAS-positive vacuoles in muscle fibers, diaphragm/paraspinal weakness, upright→supine FVC drop >30% → Pompe disease (GSD II)
  • Ragged red fibers (Gomori trichrome) + COX-negative fibers → Mitochondrial myopathy / CPEO
  • Myotonic discharges on EMG with warm-up phenomenon clinically → Myotonia congenita (CLCN1)
  • Myotonia that worsens with cold and repeated contraction on EMG → Paramyotonia congenita (SCN4A)
  • Subsarcolemmal glycogen deposits, absent myophosphorylase stain → McArdle disease (PYGM)
  • U waves and flat T on ECG during attack → HypoKPP attack
  • Peaked T waves on ECG during attack → HyperKPP attack
Genetics / treatment pearls
  • CACNA1S or SCN4A, AD, acetazolamide prophylaxis + low-carb diet → Hypokalemic periodic paralysis
  • SCN4A AD, dichlorphenamide, “keep moving after exercise” → Hyperkalemic periodic paralysis
  • KCNJ2 AD — cardiac monitoring is mandatory → Andersen-Tawil syndrome
  • CLCN1 — Becker recessive (severe) vs Thomsen dominant (mild), treat with mexiletine → Myotonia congenita
  • PYGM AR (GSD V) → McArdle disease
  • GAA AR (GSD II), ERT with alglucosidase alfa (Lumizyme) or avalglucosidase (Nexviazyme, 2021) → Pompe disease
  • AGL (debrancher, GSD III) and PFKM (Tarui, GSD VII) → Other glycogen storage myopathies
  • RYR1 / CACNA1S — volatile anesthetics & succinylcholine trigger; treat with DANTROLENE + cold IVF → Malignant hyperthermia
  • Single large mtDNA deletion (often 4977 bp), sporadic → CPEO / Kearns-Sayre
  • Anti-HMGCR antibodies, weakness persists after statin withdrawal → Statin-associated IMNM (see Inflammatory Myopathies)
Periodic Paralysis

Comparison of Periodic Paralysis Syndromes

Feature Hypokalemic PP Hyperkalemic PP Andersen-Tawil (ATS1)
Gene CACNA1S (most common) or SCN4A SCN4A KCNJ2 (Kir2.1 potassium channel)
Inheritance AD AD AD
K+ during attack Low (<3.5 mEq/L) High-normal or elevated (often ≥4.5 mEq/L; may be normal between attack peak) Variable (high, low, or normal)
Attack triggers Carbohydrate-rich meals, rest after exercise, insulin, stress, cold Rest after exercise, fasting, cold, K+ ingestion Same as hypo/hyperKPP; variable
Attack duration Hours to days Minutes to hours (shorter) Variable
Myotonia No Yes (often between attacks; lid lag, grip myotonia) No
Unique features Attacks begin in adolescence; may develop fixed proximal myopathy over time Onset earlier (first decade); overlap with paramyotonia congenita Triad: periodic paralysis + cardiac arrhythmias + dysmorphic features
Cardiac EKG changes from hypokalemia (U waves, flat T) EKG changes from hyperkalemia (peaked T) Prolonged QT/QU, U waves, bidirectional VT
Dysmorphic features No No Yes: low-set ears, hypertelorism, clinodactyly, micrognathia, short stature, scoliosis
Acute treatment Oral/IV K+ replacement Carbohydrate/glucose to drive K+ intracellularly; inhaled β-agonist; IV glucose/insulin Based on K+ level during attack
Prevention Acetazolamide; K+-sparing diuretics; avoid carbs/triggers Acetazolamide; thiazide diuretics; avoid fasting/cold Acetazolamide; flecainide (for arrhythmia); avoid QT-prolonging drugs

Thyrotoxic Periodic Paralysis

  • Acquired form — resembles hypoKPP but occurs in setting of hyperthyroidism
  • Most common in Asian males (20–40 years)
  • K+ low during attacks; triggered by carbs, exercise, stress
  • Treatment: Treat the underlying thyroid disease → attacks resolve; K+ replacement for acute episodes; β-blockers while awaiting thyroid control
  • Must check TSH in any young man presenting with hypokalemic paralysis

Secondary Periodic Paralysis

  • Hypokalemia from any cause (renal tubular acidosis, diuretics, GI losses, hyperaldosteronism) can mimic hypoKPP
  • Hyperkalemia from any cause (renal failure, K+-sparing diuretics, Addison disease) can mimic hyperKPP
  • Key distinction: Primary PP → K+ normalizes between attacks; secondary → persistent K+ abnormality from underlying cause

Normokalemic Periodic Paralysis

  • Now considered a phenotypic variant of HyperKPP (SCN4A)
  • Serum K+ may not rise during attacks but responds to the same triggers and treatments as HyperKPP (rest after exercise, K+ ingestion, cold; acetazolamide for prevention)
  • Not a separate genetic entity — reclassified under the HyperKPP spectrum
💎 Board Pearl
  • Periodic paralysis + cardiac arrhythmias + dysmorphic facies = Andersen-Tawil syndrome (KCNJ2) — the triad is pathognomonic
  • Myotonia between attacks = hyperKPP (hypoKPP does NOT have myotonia)
  • Asian male + hypokalemic paralysis → check TSH before diagnosing primary hypoKPP
  • Acetazolamide prevents attacks in both hypo- and hyperKPP — the carbonic anhydrase inhibitor is the go-to preventive agent
🔒

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