Basic Science Clinical

Vascular Headache Epilepsy Immunology Movement Neuromuscular Dementia Other Topics Neurosurgery

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

🚩 Don’t Miss — Test-Day Priorities

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

🔍 Buzzwords & Pathognomonic FindingsClinical / 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

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; adult-onset (4th–6th decade), Ashkenazi Jewish predilection	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 (increased delivery of blood glucose and free fatty acids to working muscle — alternative fuel sources bypass the blocked glycogenolysis)
Myoglobinuria: Dark urine after intense exertion; risk of acute renal failure
CK: Elevated at baseline; massively elevated after exercise
Forearm exercise test (non-ischemic protocol preferred): 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), avalglucosidase alfa (Nexviazyme — preferred for late-onset, FDA 2021), or cipaglucosidase alfa + miglustat (Pombiliti + Opfolda, FDA 2023); 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)

Myoadenylate Deaminase Deficiency (AMPD1)

Gene: AMPD1 — autosomal recessive; the most common inherited muscle enzyme defect (but most carriers/homozygotes are asymptomatic)
Presentation: Exercise-induced myalgia and cramps; often asymptomatic (incidental biopsy finding)
Forearm exercise test: Normal lactate rise but ABSENT ammonia rise — the mirror image of McArdle (which has absent lactate + normal ammonia)
Diagnosis: Absent AMPD staining on biopsy; AMPD1 gene testing
Treatment: Supportive; ribose supplementation has been tried with variable results

💎 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 m.3243A>G (MT-TL1, tRNA^Leu)	Maternal	Stroke-like episodes (non-vascular territory), seizures, lactic acidosis, short stature, diabetes, sensorineural hearing loss	Stroke-like episodes before age 40; parieto-occipital and temporal cortex predilection; cortical lesions that do NOT respect vascular territories
MERRF	mtDNA A8344G (tRNA^Lys)	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)
KSS & cerebral folate deficiency: impaired choroid plexus 5-MTHF transport → low CSF 5-methyltetrahydrofolate. Folinic acid (leucovorin) supplementation is standard adjunct to pacemaker placement — can improve neurologic symptoms.
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, mixed metabolic/respiratory acidosis (rising EtCO₂ from hypermetabolic CO₂ production; lactic acidosis from anaerobic metabolism), 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 (up to 10 mg/kg cumulative; higher doses if refractory); 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 — strong association); King-Denborough syndrome; RYR1-related multi-minicore disease (SEPN1-related multi-minicore is NOT MH-associated); exertional heat stroke / exertional rhabdomyolysis 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; autonomic instability

💎 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

Congenital Myopathies with Channel/MH Associations

Central Core Disease

Gene: RYR1 — autosomal dominant (same gene as MH)
Presentation: Congenital myopathy with proximal weakness; congenital hip dislocation, scoliosis, foot deformities; delayed motor milestones
Biopsy: Central cores on NADH-TR stain — central pale zone within fibers lacking mitochondria and oxidative enzymes (also COX- and SDH-negative cores)
Strong MH association — treat as MH-susceptible; avoid volatile anesthetics and succinylcholine for any procedure
CK normal to mildly elevated; non-progressive or slowly progressive course

Tubular Aggregate Myopathy (STIM1/ORAI1)

Genes: STIM1, ORAI1 (AD) — mutations affecting store-operated Ca²⁺ entry (SOCE)
Presentation: Proximal weakness, exercise-induced myalgia, cramps; some present with Stormorken syndrome (myopathy + miosis + thrombocytopenia)
Biopsy: Tubular aggregates (parallel arrays of membranous tubules derived from sarcoplasmic reticulum) on EM; basophilic on H&E; SDH-positive, NADH-positive aggregates
Note: Tubular aggregates are a non-specific biopsy finding — can also appear in chronic periodic paralysis (HypoKPP/HyperKPP), aging muscle, alcoholic myopathy, and drug-induced myopathies; primary tubular aggregate myopathy is the STIM1/ORAI1-driven entity

💎 Board Pearl

Central cores on NADH-TR + congenital proximal weakness + RYR1 = central core disease → MH-susceptible (no succinylcholine, no volatile anesthetics)
Tubular aggregates on biopsy: Non-specific — consider chronic PP, aging, alcohol, drugs first; primary tubular aggregate myopathy = STIM1/ORAI1 (store-operated Ca²⁺ entry defect)

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)

🔒

Continue reading — sign in

The full note has more clinical pearls, tables, and board-focused tips. Free account, no fee.