Channelopathies & Metabolic Myopathies
Channelopathies & Metabolic Myopathies
What Do You Need to Know?
- 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
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 or normal (≥5.0 mEq/L) | 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 | 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
💎 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
Non-Dystrophic Myotonias
Myotonia Congenita (Chloride Channelopathy)
| Feature | Thomsen Disease (AD) | Becker Disease (AR) |
|---|---|---|
| Gene | CLCN1 | CLCN1 |
| Severity | Milder | More severe |
| Onset | Early childhood | Later childhood/adolescence |
| Transient weakness | Rare | Yes — episodes of weakness after prolonged rest |
| Muscle hypertrophy | Present (“Herculean” appearance) | Present (more prominent) |
| Warm-up phenomenon | Yes — stiffness improves with repeated movement | Yes |
| Systemic features | None | None |
- Grip myotonia: Difficulty releasing handshake; improves with repetition (warm-up)
- Percussion myotonia: Tap thenar eminence → sustained contraction
- No systemic features (no cataracts, no cardiac, no endocrine — unlike myotonic dystrophy)
- Treatment: Mexiletine (sodium channel blocker) is first-line for symptomatic myotonia
Paramyotonia Congenita
- Gene: SCN4A (sodium channel) — AD
- Paradoxical myotonia: Stiffness worsens with repeated activity (opposite of warm-up phenomenon in myotonia congenita)
- Cold-induced: Stiffness and weakness dramatically worsen in cold environments
- Face and hands most commonly affected
- Overlap with hyperKPP: Same gene (SCN4A); some patients have both phenotypes
- Treatment: Mexiletine; avoid cold exposure
Sodium Channel Myotonias
- Gene: SCN4A — potassium-aggravated myotonia
- Spectrum includes: myotonia fluctuans, myotonia permanens, acetazolamide-responsive myotonia
- K+ ingestion worsens myotonia (but does NOT cause paralysis)
- Treatment: Mexiletine; acetazolamide for some subtypes
Myotonia Congenita vs Paramyotonia vs Myotonic Dystrophy
| Feature | Myotonia Congenita | Paramyotonia Congenita | Myotonic Dystrophy (DM1) |
|---|---|---|---|
| Gene/Channel | CLCN1 (chloride) | SCN4A (sodium) | DMPK (CTG repeat) |
| Warm-up phenomenon | Yes | No (paradoxical — worsens) | Variable |
| Cold sensitivity | Mild or none | Marked | Minimal |
| Weakness | No fixed weakness | Episodic (cold-induced) | Progressive distal weakness |
| Muscle bulk | Hypertrophy | Normal or hypertrophy | Atrophy (temporal wasting, distal) |
| Systemic features | None | None | Many: cataracts, cardiac conduction, endocrine, GI, cognitive |
| Prognosis | Normal lifespan | Normal lifespan | Reduced lifespan (cardiac/respiratory) |
EMG in Myotonic Disorders
- Myotonic discharges: Waxing and waning amplitude/frequency — “dive bomber” sound on audio
- Present in ALL myotonic disorders (channelopathies + myotonic dystrophy)
- Myotonic discharges ≠ clinical myotonia — EMG myotonia can exist without visible grip myotonia
- Electrical myotonia without clinical myotonia: Consider acid maltase deficiency (Pompe), hypothyroid myopathy
💎 Board Pearl
- Warm-up phenomenon = myotonia congenita (CLCN1); paradoxical myotonia (worsens with use) = paramyotonia congenita (SCN4A)
- Myotonia + NO systemic features = channelopathy; myotonia + cataracts + cardiac + endocrine = myotonic dystrophy (DM1)
- Muscle hypertrophy + myotonia + no weakness = myotonia congenita; muscle atrophy + myotonia + progressive weakness = DM1
- Mexiletine is first-line for symptomatic myotonia in both channelopathies and myotonic dystrophy
Glycogen Storage Myopathies
Overview of Glycogen Storage Diseases Affecting Muscle
| Disease | GSD Type | Enzyme Deficiency | Inheritance | Key Features | Diagnosis |
|---|---|---|---|---|---|
| McArdle | GSD V | Myophosphorylase | AR | Exercise intolerance, myoglobinuria, second-wind phenomenon | Forearm exercise test (no lactate rise); absent myophosphorylase on biopsy; PYGM gene |
| Pompe | GSD II | Acid α-glucosidase (GAA) | AR | Infantile: floppy + cardiomegaly; Late-onset: proximal weakness + diaphragm weakness | GAA enzyme activity (blood); GAA gene; biopsy: vacuolar myopathy with glycogen |
| Tarui | GSD VII | Phosphofructokinase (PFK) | AR | Similar to McArdle + hemolytic anemia; no second-wind; worsens with glucose | Forearm exercise test; absent PFK on biopsy; PFKM gene |
| Cori/Forbes | GSD III | Debranching enzyme | AR | Hepatomegaly in childhood; adult-onset distal myopathy; cardiomyopathy possible | Enzyme assay; AGL gene |
| Branching enzyme | GSD IV | Branching enzyme | AR | Adult polyglucosan body disease (APBD): spastic paraparesis + neuropathy + neurogenic bladder | Polyglucosan bodies on nerve/muscle biopsy; GBE1 gene |
McArdle Disease (GSD V) — High Yield
- Exercise intolerance: Myalgia, fatigue, and cramps within minutes of vigorous exercise
- Second-wind phenomenon: Brief rest → able to resume exercise with less pain (switch from glycolysis to fatty acid oxidation)
- Myoglobinuria: Dark urine after intense exertion; risk of acute renal failure
- CK: Elevated at baseline; massively elevated after exercise
- Forearm exercise test: No rise in venous lactate (blocked glycolysis) with normal ammonia rise (purine nucleotide cycle intact)
- Biopsy: Subsarcolemmal glycogen accumulation; absent myophosphorylase staining
- Treatment: Aerobic conditioning; pre-exercise carbohydrate (sucrose) ingestion; avoid intense anaerobic exertion
Pompe Disease (GSD II) — High Yield
- Infantile-onset: Severe — hypotonia (“floppy baby”), hypertrophic cardiomegaly, macroglossia, hepatomegaly; fatal by age 1–2 without treatment
- Late-onset (juvenile/adult): Proximal limb-girdle weakness + respiratory failure out of proportion to limb weakness — the hallmark clue
- Diaphragm weakness: Orthopnea, morning headaches, daytime somnolence; FVC drops >10% supine vs sitting
- CK: Mildly elevated (2–10×)
- EMG: Myotonic discharges (especially paraspinal muscles) WITHOUT clinical myotonia
- Diagnosis: Dried blood spot GAA enzyme activity (screening); lymphocyte/fibroblast enzyme assay (confirmatory); GAA gene sequencing
- Treatment: Enzyme replacement therapy — alglucosidase alfa (Myozyme/Lumizyme); early treatment improves outcomes; respiratory support
Tarui Disease (GSD VII)
- Similar to McArdle but NO second-wind phenomenon
- Hemolytic anemia: PFK also expressed in RBCs → compensated hemolysis (reticulocytosis, indirect hyperbilirubinemia)
- Glucose paradoxically worsens symptoms (glucose inhibits fatty acid oxidation, the only remaining energy source)
- Forearm exercise test: No lactate rise (same as McArdle)
💎 Board Pearl
- Exercise intolerance + second-wind phenomenon + no lactate rise on forearm test = McArdle disease
- Proximal weakness + diaphragmatic weakness out of proportion to limbs + myotonic discharges on EMG = late-onset Pompe — check GAA enzyme
- McArdle-like symptoms + hemolytic anemia = Tarui disease (PFK deficiency)
- Forearm exercise test: No lactate rise + normal ammonia = glycolytic defect (McArdle or Tarui); no lactate rise + no ammonia rise = poor effort (malingering)
- Pompe is the only treatable glycogen storage myopathy (ERT with alglucosidase alfa)
Lipid Myopathies
Overview of Fatty Acid Oxidation Defects
| Disease | Enzyme/Transporter | Inheritance | Key Features | Diagnosis |
|---|---|---|---|---|
| CPT II deficiency | Carnitine palmitoyltransferase II | AR | Most common lipid myopathy; recurrent rhabdomyolysis; triggered by prolonged exercise, fasting, cold, illness; CK normal between attacks | Elevated long-chain acylcarnitines; CPT2 gene; enzyme assay in fibroblasts |
| VLCAD deficiency | Very long-chain acyl-CoA dehydrogenase | AR | Similar to CPT II; can also cause cardiomyopathy and hypoketotic hypoglycemia | Acylcarnitine profile; ACADVL gene |
| Primary carnitine deficiency | OCTN2 carnitine transporter | AR | Systemic carnitine depletion; cardiomyopathy (dilated); proximal weakness; hepatic encephalopathy | Very low plasma carnitine; SLC22A5 gene |
| MADD (glutaric aciduria type II) | Multiple acyl-CoA dehydrogenases (ETF/ETFDH) | AR | Proximal myopathy + lipid storage; responds to riboflavin (“riboflavin-responsive myopathy”) | Elevated multiple acylcarnitines + organic acids; ETFDH gene |
| Neutral lipid storage disease | ATGL (Chanarin-Dorfman) or PNPLA2 | AR | Lipid droplets in muscle + other tissues; ichthyosis (Chanarin-Dorfman); Jordan anomaly (lipid vacuoles in neutrophils) | Lipid droplets on muscle biopsy (oil red O stain); Jordan anomaly on blood smear |
CPT II Deficiency — High Yield
- Most common inherited cause of recurrent rhabdomyolysis in young adults
- Triggers: Prolonged exercise (NOT brief intense exercise like McArdle), fasting, cold, febrile illness, general anesthesia
- Presentation: Myalgia → dark urine (myoglobinuria) → massively elevated CK (>10,000)
- Between attacks: CK normal, strength normal, exam normal
- NO second-wind phenomenon (distinguishes from McArdle)
- Acylcarnitine profile: Elevated C16, C18 long-chain species
- Treatment: Avoid triggers; frequent carbohydrate-rich meals; medium-chain triglyceride (MCT) oil supplementation; avoid fasting; aggressive hydration during rhabdomyolysis
Primary Carnitine Deficiency
- Plasma carnitine levels <5% of normal (free carnitine <5 μmol/L)
- Cardiomyopathy is the most life-threatening manifestation — dilated cardiomyopathy in childhood
- Responds dramatically to oral L-carnitine supplementation — lifelong therapy required
- Newborn screening programs now detect this via acylcarnitine profile (low free carnitine)
Riboflavin-Responsive Myopathy (MADD/ETF Deficiency)
- Late-onset MADD presents as proximal myopathy with lipid storage
- Dramatic response to riboflavin (vitamin B2) supplementation — strength may normalize
- Consider in any patient with lipid storage myopathy + proximal weakness + elevated acylcarnitines
- ETFDH mutations most common in late-onset form
💎 Board Pearl
- Recurrent rhabdomyolysis + prolonged exercise/fasting trigger + normal CK between attacks = CPT II deficiency
- CPT II vs McArdle: CPT II = prolonged exercise + no second wind; McArdle = brief intense exercise + second wind
- Lipid myopathy + responds to riboflavin = MADD (ETF/ETFDH deficiency) — always try riboflavin in lipid storage myopathy
- Very low plasma carnitine + cardiomyopathy = primary carnitine deficiency — treatable with L-carnitine (one of the few curable myopathies)
Mitochondrial Myopathies
Key Mitochondrial Syndromes
| Syndrome | Mutation | Inheritance | Key Clinical Features | Distinguishing Features |
|---|---|---|---|---|
| MELAS | mtDNA A3243G (tRNALeu) | Maternal | Stroke-like episodes (non-vascular territory), seizures, lactic acidosis, short stature, diabetes, sensorineural hearing loss | Stroke-like episodes before age 40; occipital/parietal predilection; cortical lesions that do NOT respect vascular territories |
| MERRF | mtDNA A8344G (tRNALys) | Maternal | Myoclonus epilepsy, ataxia, myopathy, lipomas | Myoclonus + epilepsy + ataxia + ragged red fibers |
| CPEO | Single large mtDNA deletion (sporadic) or nuclear genes (POLG, TWNK, RRM2B) | Sporadic or AD/AR | Progressive external ophthalmoplegia + ptosis; proximal myopathy | Bilateral symmetric ptosis + ophthalmoplegia without diplopia (insidious onset) |
| KSS | Single large mtDNA deletion | Sporadic | CPEO + onset <20 years + cardiac conduction defects + pigmentary retinopathy + elevated CSF protein + cerebellar ataxia | Must monitor for cardiac block (may need pacemaker); CSF protein >100 mg/dL |
| MNGIE | TYMP (thymidine phosphorylase) | Autosomal recessive | GI dysmotility (pseudo-obstruction, gastroparesis), cachexia, leukoencephalopathy, peripheral neuropathy, ptosis/ophthalmoplegia | Severe GI symptoms + wasting + leukoencephalopathy; the only AR mitochondrial syndrome commonly tested |
| NARP | mtDNA T8993G (ATPase 6) | Maternal | Neuropathy, ataxia, retinitis pigmentosa | >90% heteroplasmy → Leigh syndrome (infantile); 70–90% → NARP phenotype |
| LHON | mtDNA point mutations (11778, 3460, 14484) | Maternal | Acute/subacute bilateral painless visual loss; central scotoma; optic atrophy | Young males (incomplete penetrance); 14484 mutation has best prognosis; idebenone may help |
Muscle Biopsy in Mitochondrial Disease
| Stain/Finding | Description | Significance |
|---|---|---|
| Ragged red fibers (RRF) | Modified Gomori trichrome → red-staining subsarcolemmal mitochondrial aggregates | Hallmark of mitochondrial myopathy; accumulation of abnormal mitochondria |
| COX-negative fibers | Cytochrome c oxidase (complex IV) staining absent in some fibers | Indicates mtDNA mutations affecting respiratory chain; mosaic pattern |
| SDH-positive (“ragged blue”) fibers | Succinate dehydrogenase (complex II) staining intensely positive | SDH is entirely nuclear-encoded → spared in mtDNA mutations; increased as compensatory mitochondrial proliferation |
| Combined COX-negative/SDH-positive | Fibers lacking COX but strongly SDH-positive | Most specific finding for mtDNA-related mitochondrial disease |
General Principles
- Maternal inheritance for mtDNA mutations (MELAS, MERRF, LHON, NARP); nuclear gene mutations are AD or AR (POLG, TYMP, TWNK)
- Heteroplasmy: Proportion of mutant vs wild-type mtDNA determines phenotype severity; threshold effect (~60–90% mutant load needed for symptoms)
- Lactate/pyruvate ratio elevated (impaired oxidative phosphorylation → anaerobic glycolysis)
- Multi-organ involvement: Brain, muscle, heart, endocrine, GI, eyes, ears — any tissue with high metabolic demand
- Treatment: Largely supportive; CoQ10, L-carnitine, B vitamins; avoid valproate in POLG mutations (risk of fatal hepatotoxicity); manage complications (pacemaker for KSS, seizure control for MELAS)
💎 Board Pearl
- Stroke-like episodes in a young patient + lactic acidosis + seizures = MELAS (A3243G)
- Myoclonus epilepsy + ataxia + ragged red fibers = MERRF (A8344G)
- CPEO + cardiac conduction defect + retinopathy + onset <20 = KSS — must monitor ECG (risk of complete heart block)
- GI dysmotility + cachexia + leukoencephalopathy = MNGIE — autosomal recessive (TYMP), NOT maternal
- Ragged red fibers + COX-negative fibers on biopsy = mitochondrial disease
- POLG mutations + valproate = fatal hepatotoxicity — always test POLG before starting valproate in epilepsy with mitochondrial features
Malignant Hyperthermia
Overview
| Feature | Details |
|---|---|
| Gene | RYR1 (ryanodine receptor, most common ~70%) or CACNA1S; AD with variable penetrance |
| Triggers | Succinylcholine (depolarizing NMJ blocker) + volatile anesthetics (halothane, sevoflurane, isoflurane, desflurane) |
| Pathophysiology | Uncontrolled Ca2+ release from sarcoplasmic reticulum → sustained muscle contraction → hypermetabolism |
| Earliest sign | Masseter rigidity (jaw stiffness after succinylcholine) — may be the first clue |
| Clinical features | Rapidly rising temperature, generalized rigidity, metabolic acidosis (rising EtCO2), hyperkalemia, rhabdomyolysis, DIC, arrhythmias |
| CK | Massively elevated (often >20,000); peaks 12–24 hours after onset |
| Treatment | DANTROLENE (ryanodine receptor antagonist) — 2.5 mg/kg IV, repeat q5–10 min until response; stop triggering agents; active cooling; treat hyperkalemia; IV fluids |
| Diagnostic test | Caffeine-halothane contracture test (CHCT) = gold standard (in vitro muscle biopsy test); genetic testing (RYR1 sequencing) |
| Associated conditions | Central core disease (RYR1); King-Denborough syndrome; multiminicore disease; exertional heat stroke susceptibility |
Safe vs Unsafe Anesthetic Agents
| Safe | Unsafe (Triggers) |
|---|---|
| Propofol, barbiturates, etomidate | Succinylcholine |
| Nitrous oxide | Halothane |
| Non-depolarizing NMJ blockers (vecuronium, rocuronium) | Sevoflurane |
| Opioids, benzodiazepines | Isoflurane |
| Local anesthetics (lidocaine, bupivacaine) | Desflurane |
| Ketamine | Enflurane |
Neuroleptic Malignant Syndrome (NMS) vs Malignant Hyperthermia
| Feature | Malignant Hyperthermia | NMS |
|---|---|---|
| Trigger | Volatile anesthetics / succinylcholine | Dopamine blockers (antipsychotics, metoclopramide) |
| Onset | Minutes to hours (intraoperative) | Days to weeks |
| Genetic basis | RYR1 / CACNA1S | None (idiosyncratic) |
| Treatment | Dantrolene | Dantrolene + bromocriptine; stop offending agent |
| Key lab | CK >20,000; acidosis; hyperkalemia | CK elevated; leukocytosis; elevated CK |
💎 Board Pearl
- Intraoperative rigidity + rising temperature + rising EtCO2 + metabolic acidosis = malignant hyperthermia → give DANTROLENE immediately
- Masseter rigidity after succinylcholine = possible early MH — cancel procedure and monitor
- Central core disease (RYR1) = MH susceptibility — always use MH-safe anesthesia in these patients
- Caffeine-halothane contracture test = gold standard for MH susceptibility testing (requires fresh muscle biopsy)
- Dantrolene works by blocking RYR1 — it is the ONLY specific treatment for MH; must be immediately available in all ORs
Exercise-Induced Muscle Symptoms — DDx Comparison
McArdle vs CPT II vs Mitochondrial Myopathy
| Feature | McArdle (GSD V) | CPT II Deficiency | Mitochondrial Myopathy |
|---|---|---|---|
| Defect | Glycogenolysis (myophosphorylase) | Fatty acid transport into mitochondria | Oxidative phosphorylation (respiratory chain) |
| Symptom trigger | Brief intense exercise (sprinting, lifting) | Prolonged exercise, fasting, cold, illness | Sustained aerobic exercise |
| Onset of symptoms | Within first minutes | After 30+ minutes of exertion | Progressive with exertion |
| Second-wind phenomenon | Yes (classic) | No | No |
| Myoglobinuria/Rhabdomyolysis | Yes (50%) | Yes (frequent, severe) | Rare |
| CK between attacks | Elevated (baseline) | Normal | Normal to mildly elevated |
| Fixed weakness | Late (after years of disease) | No (normal between attacks) | Yes (progressive) |
| Lactate | No rise with exercise (forearm test) | Normal rise with exercise | Excessive rise with exercise |
| Biopsy | Glycogen accumulation; absent myophosphorylase | Lipid droplets (between attacks may be normal) | Ragged red fibers; COX-negative fibers |
| Treatment | Aerobic training; pre-exercise sucrose | Avoid triggers; frequent carb meals; MCT oil | CoQ10; supportive; manage complications |
🎯 Clinical Pearl
- Timing of symptoms is the key distinguishing feature: Early (minutes) = glycogen defect; late (prolonged exertion) = lipid defect; progressive/sustained = mitochondrial
- Second wind is pathognomonic for McArdle disease — no other condition produces this phenomenon
- Normal CK between attacks with recurrent rhabdomyolysis strongly favors CPT II over McArdle (McArdle CK stays elevated at baseline)
- If a patient has exercise intolerance + lactic acidosis + multisystem involvement → think mitochondrial disease first
Quick-Reference: Metabolic Myopathy by Energy Substrate
| Energy Pathway | Disorders | Key Clue |
|---|---|---|
| Glycogen metabolism | McArdle, Pompe, Tarui, Cori, GSD IV | Exercise intolerance (early fatigue); forearm exercise test abnormal; glycogen on biopsy |
| Lipid metabolism | CPT II, VLCAD, carnitine deficiency, MADD | Prolonged exercise/fasting triggers; rhabdomyolysis; acylcarnitine profile abnormal; lipid on biopsy |
| Mitochondrial (oxidative phosphorylation) | MELAS, MERRF, CPEO, KSS, MNGIE | Multisystem involvement; lactic acidosis; ragged red fibers; maternal inheritance (usually) |
💎 Board Pearl
- Three metabolic myopathy categories = three fuel sources: glycogen (immediate/anaerobic), lipid (sustained/aerobic), mitochondrial (oxidative phosphorylation) — each has distinct timing and triggers
- Forearm exercise test: No lactate + normal ammonia = glycolytic block; excessive lactate = mitochondrial; normal lactate and ammonia = lipid defect or normal
- Treatable metabolic myopathies to remember: Pompe (ERT), primary carnitine deficiency (L-carnitine), MADD (riboflavin), McArdle (aerobic training + sucrose)