Myoglobinuria; Rhabdomyolysis

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MYOGLOBINURIA - RHABDOMYOLYSIS

Myoglobinuria
Malignant hyperthermia
General features
Pathology
Pathophysiology
Specific causes

Myoglobinuria: Acquired causes
Muscle activity
Overactivity
Exercise
Drugs
Idiopathic recurrent
Infections
Ischemia (Hypoxia)
Compartment syndromes
Mitochondrial
Neuroleptic malignant syndrome
Other: Occasional myoglobinuria
Polymyositis: Anti-MAS syndrome
Serotonin syndrome
Snake venoms
Systemic
Hypokalemia
Thyroid: Hyper or Hypo
Toxins
Trauma

Myoglobinuria: Familial causes
Acyl-CoA Dehydrogenase (VLCAD)
Carnitine Palmitoyltransferase II (CPT2)
Central core
Childhood/Juvenile
Recurrent: LPIN1; 2p25
DNMT3A
COL4A1: HANAC
MYH1
OBSCN
Other
COL4A2
Glycogen metabolism disorders
Hypokalemia
Gitelman syndrome (SLC12A3)
Periodic paralysis
King-Denborough syndrome
Malignant hyperthermia (MHS) loci
MHS1: Ryanodine Receptor; 19q13
MHS2: Na⁺ channel (SCNA4); 17q11
MHS3: Ca⁺⁺ channel (CACNL2A); 7q21
MHS4: 3q13
MHS5: Ca⁺⁺ channel (CACNA1S); 1q32
MHS6: 5p
CPT2: 1p32
Marinesco-Sjögren: SIL1
Mitochondrial
MMCKR
1: MLIP; 6p12
2: DTNA; 18q12
Muscular dystrophies
MYHM (Horse): MYH1
Myoadenylate deaminase deficiency
Native American Myopathy: Stac3; 12q13
Other familial
Sickle cell anemia

MYOGLOBINURIA: General features ¹²

History: Early descriptions of rhabdomyolysis
- Old Testament
  - Jews after eating quail during exodus from Egypt
  - Hemlock herbs consumed by birds during migration across Mediterranean Sea
- Napoleon's army
  - Limb gangrene from rhabdomyolysis in carbon monoxide victims
Definition & General features
- Acute syndrome due to extensive injury of skeletal muscle
- Muscle fiber pathology
  - Necrosis or permeabilization of sarcolemma
  - Release of muscle proteins into circulation
- Serum CK: > 10,000, Usually > 30,000
- Most common causes: Exercise, Drugs & Alcohol
Clinical patterns: Distinctive features
- More likely hereditary etiology
  - Rhabdomyolysis on minimal exertion or fasting
  - Family history
  - Multiple episodes
- Childhood onset (≤ 6 years)
  - Common: Lipin-1
  - Other
- Muscular dystrophy
  - Exercise-induced myalgia
  - Fixed weakness
  - Muscle hypertrophy
  - Resting CK: High
- Glycogen metabolism
  - Disease onset: Child or Adult
  - Episode onset: Within minutes of exercise & with isometric contraction
  - ‘Second wind’ phenomenon
- Aldolase A
  - Childhood onset: 1st episode ≤ 1 year
  - Episode onset: Fever
  - Hemolysis: Some patients
- Fatty acid oxidation
  - Symptoms occur after prolonged exercise, infections, fasting, stress or cold
  - Dicarboxylic aciduria
- Lipin-1
  - Repeated rhabdomyolysis
  - Childhood onset: 1st episode ≤ 6 years
  - Fasting
- RYR1
  - Onset: Exercise in heat & humidity
  - Age: > 6 years
  - Anesthetic (Succinylcholine) association
- Statins
  - Myotonic discharges during rhabdomyolysis
  - Abnormal metabolic degradation
- Mitochondrial
  - Lactate: High at rest or with mild exercise
Mechanisms of muscle injury
- Rise in free intracellular calcium: Due to
  - Damage to muscle sarcolemma
  - Failure of energy supply within muscle cell
- Activation of calcium-dependent neutral proteases & phospholipases
  - Destroys myofibrillar, cytoskeletal, and membrane proteins
  - Lysosomal digestion of muscle fiber contents ensues
Typical clinical features
- Muscle
  - Weakness: Proximal > Distal
  - Discomfort: Pain; Tenderness
  - Swelling
  - May be asymptomatic
- Renal: More severe cases
  - Dysfunction
  - Urine: Pigmenturia; "Tea-colored"
- General
  - Fever
  - Leukocytosis
  - Cardiomyopathy
  - Encephalopathy
Common causes
- Adults: Non-recurrent myoglobinuria
  - Alcohol & Drug abuse
  - Muscle Compression or Trauma
    - Acute
    - Falls
    - Prolonged immobility
  - Seizures
  - Multiple contributing factors
- Children: Non-recurrent myoglobinuria
  - Trauma
  - Nonketotic hyperosmolar coma
  - Infections: Common cause in children
    - Viral: Myositis (Influenza B); Influenza; CMV; EBV; Group A beta hemolytic streptococci
    - HIV: Acute retroviral syndrome
    - Bacterial: Legionella; Salmonella
    - Malaria
  - Dystonia
  - Malignant hyperthermia
- Recurrent myoglobinuria: Metabolic & Hereditary disorders
  - Most common
    - 1st decade: Lipin-1
    - Myophosphorylase
    - CPT II
    - Idiopathic
Predisposing & Precipitating factors
- Exercise: Progressive exercise produces Fatigue & Myalgia
- Fasting
- Hypokalemia
- High ambient temperatures
- Infections
- Increased age: Falls
- Toxins & Drugs
- Genetic
Time course
- Early: Pigment in urine may occur immediately or with delay up to 24 hours
- Late: Severe rhabdomyolysis may be followed by fibrosis & contractures
Complications
- Compartment syndrome
  - Muscles in closed space swell & become ischemic
  - May require fasciotomy
- Renal failure
  - Risk factors with exertional rhabdomyolysis ⁵⁶
    - NSAIDs
    - Dehydration
  - Acute tubular necrosis: Due to
    - Ferrihemate toxicity: Dissociates from globulin below pH 5.6
    - Tubular obstruction: Precipitation of myoglobin casts
    - Alterations in glomerular filtration rate
    - Myoglobin toxicity: Treatment is Volume expansion
      - Mannitol or Normal saline: Maintain urine output at 200 to 300 ml/hr
    - Hypotension
    - Crystal formation: Alkalinize urine with Na bicarbonate
    - Protease release from muscle: Avoid nephrotoxic agents
- Hyperkalemia
  - Due to: Muscle breakdown; Renal failure
  - Treatment: Calcium gluconate; Diuresis
- Hypocalcemia: Due to binding by damaged muscle & hyperphosphatemia
- Hypercalcemia
  - Due to: Release from muscle; Reduced renal excretion
  - Treatment: Diuresis
- Hyperphosphatemia & Tissue calcification
  - Due to: Release of organic & inorganic phosphates from muscle
  - Treatment: Diuresis
- Disseminated intravascular coagulopathy
Laboratory
- Urine dip stick (benzidine)
  - Positive: Myoglobin; Hemoglobin; Hematuria
  - Negative: Porphyria
- Myoglobin
  - Urine
    - Precedes rise in CK
    - Visible pigmentation with level > 1 g/L
    - Testing: Radioimmunoassay; Use urine fresh & neutralized
    - Urinalysis pattern: Albumin & Heme with Few RBCs
  - Serum
    - Normal levels: 3 to 80 μg/L
    - Rhabdomyolysis: High
- Serum CK
  - Very high: > 20,000; Up to hundreds of thousands
  - Half life: 1 to 3 days
- Serum lactate
  - Glycogenoses: No rise with exercise
  - Mitochondrial disorders: Rise with minimal exercise
- Serum carnitine: Low in β-oxidation disorders, especially during attack
- Acylcarnitine profile
- Muscle biopsy: Useful for diagnosis in some hereditary disorders
  - Pathology: Scattered muscle fiber necrosis & degeneration
  - Metabolic analysis: Perform at least 1 month after episode
    - Biopsies performed near time of rhabdomyolysis will give spurious biochemical results
  - Suggestive changes
    - Lipid storage
    - Tubular aggregates: PGAM2
    - Cores: RYR1
    - Chronic myopathy
      - ANO5
      - Dysferlin
      - Dystrophin
      - FKTN
      - FKRP
- MRI with gadolinium enhancement: Increased signal; T₂ > T₁
Treatment
- Maintain airway & circulation
- Prevent acute tubular necrosis
  - Normal saline IV: 10 to 15 mL/kg; Continue if adequate urine output
  - Isotonic Sodium bicarbonate
  - Mannitol: 0.3 to .05 g/kg IV; Monitor K⁺
  - Furosemide: 40 to 80 mg IV initially; Up to 200 mg total
- Treat other complications
  - Hyperkalemia
  - Disseminated intravascular coagulation
- Treat specific underlying condition: Diet; Ribose; Riboflavin; Carnitine

MYOGLOBINURIA: Specific causes

Malignant Hyperthermia

Malignant Hyperthermia - Central Core Disease (MHS 1)
● Ryanodine Receptor (RYR1) ; Chromosome 19q13; Dominant
King-Denborough Syndrome
● Ryanodine Receptor (RYR1) ; Chromosome 19q13; Dominant
MHS2
● SCN4A ; Chromosome 17q11.2-q24; Dominant
- Same Sodium channel gene as in hyperkalemic periodic paralysis
MHS3
● Calcium channel, Skeletal muscle, Voltage-dependent, L-type, α-2 peptide (CACNL2A) ; Chromosome 7q21-q22; Dominant
MHS4
● Chromosome 3q13.1; Dominant (MHS 4)
- Epidemiology: Single German family
MHS5
● L-type Calcium Channel, α1_S subunit (Dihydropyridine Receptor; CACNA1S) ; Chromosome 1q32; Dominant
MHS6
● Chromosome 5p; Dominant
- Epidemiology: Single Belgian family
Other Malignant Hyperthermia loci
● Carnitine Palmitoyltransferase II; Chromosome 1p32; Dominant
● Autosomal Dominant
Malignant hyperthermia susceptibility

Glycogen metabolic disorders

Myophosphorylase - McArdle's
● Chromosome 11q13.1; Recessive
- Muscle pain after short intense exercise
- Persistent proximal weakness in teens & 20's
Phosphofructokinase
● PFK-M; Chromosome 12q13.11; Recessive
- Muscle cramps & Myoglobinuria after vigorous exercise; Second wind
- Late-onset with fixed myopathy in some patients
- Fatal infantile cases reported
Other glycogenoses

Fatty acid oxidation & Lipid metabolism

Carnitine Palmitoyltransferase II
● Chromosome 1p32; Recessive
- Myoglobinuria after moderate sustained exercise
Acyl-CoA Dehydrogenase deficiencies
AMACR
Electron transfer flavoprotein (ETF) disorders
- ETFA
- ETFDH
Ketoacyl CoA thiolase deficiency
Lipin-1: Myoglobinuria in childhood
Trifunctional enzyme deficiency

Myoglobinuria: Mitochondrial disorders

Mitochondrial myopathies: mtDNA
- Cytochrome c Oxidase (COX) deficiency
  - Cytochrome c Oxidase, Subunit I (MTCO1)
  - Cytochrome c Oxidase, Subunit II (MTCO2)
  - Cytochrome c Oxidase, Subunit III (MTCO3)
- Cytochrome b deficiency (Complex III)
- Point mutations
  - tRNA Leucine (A3243G)
  - tRNA Ile (A4281G; G4298A)
    - Trigger: Intense exercise
    - Muscle with many COX negative fibers
    - Mitochondrial oxidative enzymes: Normal activity
  - tRNA Phenylalanine (A606G)
    - A606G mutation: Not pathogenic; Actual mutation in COX II
    - Muscle with many COX negative fibers
Mitochondrial myopathies, Recessive
- Coenzyme Q₁₀ deficiency
- Krebs cycle
  - Succinic Dehydrogenase + Aconitase
  - Lipoamide dehydrogenase
- Mitochondrial DNA deletions: Multiple
  - DGUOK: 2p13
- Iron-Sulfur complex disorders
  - FDX2 (FDX1L)
  - ISCU
- TANGO2
- Long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD; Trifunctional protein)
  - HADHA
  - HADHB
- MTDPS17: MRM2

Familial: Other disorders with occasional myoglobinuria

Brody myopathy
Cylindrical spiral (Myofilamentous) myopathy
Familial Recurrent Rhabdomyolysis
Fingerprint body disease
G6PD deficiency
Hypokalemic periodic paralysis
Marinesco-Sjögren
Muscular Dystrophy
- General
  - Resting CK: High
  - Often no specific trigger
- Duchenne & Becker
- Miyoshi myopathy (Dysferlin; LGMD 2B): Occasional
- Sarcoglycanopathies (α, β, γ)
- LGMD 1C
- LGMD 2A
- LGMD 2I: Frequent presentation
- LGMD 2L
- LGMD 2T
Myoadenylate deaminase deficiency
Myotonias
Multicore disease
Native American Myopathy: Stac3
PCH2: TSEN54
Schwartz-Jampel
Sickle cell anemia: Myonecrosis; Sterile abscesses

Drugs & Toxins

Toxins
- Intravenous
  - Cocaine: Ischemia due to vasoconstriction
  - Heroin
- Ingestion
  - Haff disease: Fish ingestion (US - Buffalo fish; Northern Europe - burbot)
  - Mushrooms: Amanita phalloides; Tricholoma equestre (T. flavovirens)
  - Small birds that have previously eaten water hemlock (Conium maculatum)
  - Ethanol
  - Monensin
  - Chromium picolinate
  - Kidney beans
  - Peanut oil
  - Methylenedioxypyrovalerone (MDPV)
  - Mephedrone
  - Phencyclidine
- Venoms
  - Snake
    - Cobra; Coral; Viper; Rattlesnake
    - Toxin action: Muscle membrane damage
  - Insect
    - Hornet
    - Redback spider
    - Wasp
    - African bee
  - Blowpipe dart poison
- Environmental exposure
  - Chlorophenoxy insecticides
  - Pentaborane
  - Toluene: Membrane damage
Medications: Direct effects on muscle
- Amiodarone
- Arsenic trioxide
- Emetine
- e-Amino Caproic Acid (Amicar)
- Lipid lowering agents
  - Clofibrate
  - Statins
    - Lovastatin; Simvastatin; Pravastatin; Fluvastatin; Atorvastatin; Cervistatin
    - Especially with concurrent: Cyclosporine A, Danazol, Erythromycin, Gemfibrozil, Niacin...
- Isoniazid
- Lamotrigine
- Neuroleptic/Antipsychotic: Neuroleptic Malignant syndrome
- Nicotinic acid
- Pentamidine
- Propofol
- Proton pump inhibitors
- Ritodrine: May be more common in patients with DM1
- SSRI ⁵¹: Irinotican; Escitalopram
- Temazepam (Intra-arterial; Gel form): Rhabdomyolysis due to local limb ischemia
- Trabectedin
- Valproate: Patients with CPT2 deficiency
- Vasopressin: Ischemia
- Zidovudine
  - Pathology: Ragged red muscle fibers
Drugs & toxins producing muscle overactivity
- Amphetamines
- Hemlock
- Loxapine
- LSD
- Mercuric chloride
- Phencyclidine
  - Pathology: Myofibrillar architectural changes
- Strychnine
- Tetanus
- Terbutaline
- Also see
  - Neuroleptic Malignant Syndrome (NMS)
  - Serotonin syndrome

Other drugs & toxins associated with rhabdomyolysis ¹⁸

Acetaminophen
Amoxapine
Anticholinergics
Azathioprine
Azithromycin
Baclofen
Barbiturates
Benzodiazepines
Butyrophenones
Caffeine
Carbon Monoxide
Cefachlor
Cefdinir
Cefditoren
Chloral hydrate
Chlorpromazine

Ciproflaxzcin
Colchicine
Corticosteroids (Myosin loss)
Daptomycin
Diphenhydramine
Doxylamine
Ephedra
Fenfluramine
Glutethimide
Hydroxyzine
Ketamine
Linezolid
Lysergic acid diethylamide
Meropenem
Methanol
Minocycline

Morphine
Phencyclidine
Phenothiazines
Phentermine Phenytoin
Pipoeracillin-Tazobactam
Proton pump inhibitors
Quinolones
Salicylate
Serotonin antagonists
Succinylcholine
Sunitinib Sympathomimetics
Theophylline
Trimethoprim-sulfamethoxazole
Vasopressin
Vincristine

Systemic

Electrolyte changes
- Hypokalemia
- Hypophosphatemia
- Hypocalcemia
- Hyper-/Hyponatremia
Endocrinopathies
- Adrenal insufficiency
- Thyroid: Hyper; Hypo
- Hyperaldosteronism
- Diabetic ketoacidosis
- Hyperosmolar state

Hypokalemic myopathy & Rhabdomyolysis

Causes
- Pharmacologic
  - Diuretics & Laxatives: Thiazides
  - Amphotericin (Renal tubular acidosis)
  - Lithium
  - Gossypol
  - Licorice
  - Methylxanthines: Caffeine; Theophylline
  - Laxative abuse
- Toxic
  - Aldosterone-like: Licorice (Glycyrrhizic acid); Carbenoxolone (Glycyrrhetinic acid)
  - Barium
  - Ethanol
  - Cottonseed oil (with low dietary K⁺)
  - Volatile substances: Toluene
- Thyroid hormone
Hypokalemia: Clinical syndromes
- Painless proximal weakness
- Periodic paralysis
- Hypokalemia: Myoglobinuria
Treatment
- Potassium: Up to 20 mEq per hour i.v.
- Removal of underlying cause of hypokalemia

Muscle Trauma

Acute (minutes): Crush
Chronic (hours): Due to sedation
- Alcohol
- Opiates
- Sedatives
Overactivity
- Exercise: Military training; Bodybuilding
- Drugs
- Hyperthermia
- Seizures
Compartment syndromes
Temperature
- Heat stroke (Hyperthermia): Often with exertion
- Malignant hyperthermia
- Neuroleptic Malignant syndrome
- Burns
- Hypothermia

Ischemia (Hypoxia)

Vascular occlusion
Hemangioma steal syndrome: Focal exertional rhabdomyolysis ²
Sickle cell trait
Cocaine
Calciphylaxis
Compartment syndrome
CO exposure
Cyanide

Infections

General
- Rhabdomyolysis is uncommon in most infections
- Minor syndromes
  - Some case reports may define rhabdomyolysis as a rise in serum CK of only 5-fold
Specific infections associated with rhabdomyolysis or moderate rise in CK
- Viral: Influenza A & B; Coxsackie; Herpes; Adenovirus; HIV-1; Dengue
- Bacterial: Streptococci; Salmonella; Staphylococci; Typhoid; Legionella; Clostridia; E. coli
- Rickettsia: Mediterranian tick typhus; Scrub typhus
- Tick-bourne: Ehrlichia, Anaplasma, Babesiosis, Lyme, Rocky Mountain spotted fever
- Hyperthermia related

Immune myopathy

Polymyositis: Anti-MAS syndrome
Polymyositis: Occasional
Dermatomyositis: Occasional

Rhabdomyolysis, Exercise-related: Associations ³¹

Epidemiology
- Young males
- African-Americans, non-Hispanic
- Hospital visits/Year: 0.66 per 100,000 population
- Course: Usually non-recurrent
Genetics: Exercise/Heat tolerance & Exercise performance
- Angiotensin 1-converting enzyme (ACE)
  - ACE functions: Kininase II–type enzyme, influences bradykinin degradation
  - Increased heat tolerance
  - Insertion/deletion intron 16 alleles (rs1799752): I (Longer); D (Shorter; Higher ACE activity)
    - Phosphorylase deficiency, Severe phenotype: More D alleles
    - Normals
      - I alleles
        
        More efficient response to muscle training
        
        More common: Endurance athletes
      - D alleles
        
        More common in athletes engaged in intense, short-duration sports
        
        Possible coronary artery disease risk
- Angiotensin II type 2 receptor (AGTR2) ³²
  - Polymorphism: rs11091046
  - C allele: More type 1 muscle fibers, endurance athletes & aerobic performance
  - A allele: More type 2 muscle fibers, power-oriented athletes
- α-actinin-3 (ACTN3): Endurance athletes (Arg577Ter)
- Myosin light chain kinase (MLCK): Exaggerated CK postexercise (C49T & C37885A)
- Creatine kinase, muscle (CK-MM): Maximal oxygen uptake with exercise (NcoI/ RFLP)
- AMPD1: C34T gene polymorphism ³³
  - TT genotype: 2.4% in controls; 0% in athletes
  - CC genotype: 70% controls; 86% Sprint/power-orientated athletes; Anaerobic performance
- Higher CK post-exercise
  - Heat shock protein A1B (HSPA1B): +190 G/C & +1267 A/G
  - Interleukin-6 (IL-6): IL6-174C allele
- Sickle cell trait ⁵⁵
  - Incident increased: Frequency; Exertional collapse; Death
  - No relation to complicatons or outcome
  - p.C477R (rs115958260) variant in SLC44A3
Strenuous exercise: Effects
- Muscle pathology: Scattered necrotic muscle fibers
- Serum CK
  - Baseline
    - Males > Females
    - African-American, non-Hispanic > White
  - Post exercise
    - May rise by 10x to 20x
    - More with short maximal, than with prolonged sub-maximal exercise
    - No systemic damage with CK < 20,000
Rhabdomyolysis, Exertional: More common with
- Baseline: Low fitness levels
- Exercise patterns
  - Early introduction of repetitive eccentric exercises (squats, pushups, sit-ups)
  - Persistent exertion after normal fatigue
  - Strenuous physical activity: Duration & Frequency
- Associated factors
  - Environment: Hot temperature
  - Renal disease: More common with CK > 15,000
  - Military training: Recruits, young ⁵⁴
- Competitive animals: Race horses; Sled dogs
Also see: Sports disorders

Malignant Hyperthermia Syndromes (MHS) ¹

General features
Pathophysiology

Hypokalemic periodic paralysis
MHS loci
MHS1: Ryanodine Receptor; 19q13
MHS2: Na⁺ channel (SCNA4); 17q11
MHS3: Ca⁺⁺ channel (CACNL2A); 7q21
MHS4: 3q13
MHS5: Ca⁺⁺ channel (CACNA1S); 1q32
MHS6: 5p
CPT2: 1p32
King-Denborough: RYR1; 19q13
Native American Myopathy: Stac3; 12q13
Occasional MH

Malignant hyperthermia: General features
- Genetics
  - Inheritance: Commonly autosomal dominant
  - Most common gene: Ryr1 mutations
- Epidemiology
  - Species affected: Humans; Pigs; Turkeys; Cats; Dogs; Horses
  - Frequency with triggering anesthetics: Children 1:15,000; Adults 1:62,000
  - World-wide occurrence: All racial groups
  - Age
    - Most common: Children & Young adults; Mean age = 18 years
    - Rare: Infants
    - Reduced frequency: After 50 years of age
  - Male:Female = 2:1
  - Prior history
    - May have prior exposure to triggering anesthetic without developing MH
    - Most patients asymptomatic before developing MH syndrome
    - High serum CK: Not sensitive or specific as screening test
- Triggers
  - Full episodes: General anaesthesia
    - Associated agents
      - Inhalational agents (potent); Halothane; Sevoflurane; Desflurane
      - Muscle relaxant: Succinylcholine
      - Not Xenon
    - More common after several exposures than with first
  - Milder MH: Exercise in hot conditions; Neuroleptic drugs; Alcohol; Infections
  - Safe agents
    - Barbiturates
    - Epinephrine/Norepinephrine
    - Etomidate
    - Ketamine
    - Local anesthetics
    - Narcotics
    - Nitrous oxide
    - Nondepolarizing muscle relaxants
- Clinical features
  - Onset
    - Time: During anesthetic to 24 hours after
    - Sudden rise in end tidal CO₂ or core temperature
    - Trismus
  - Skeletal muscle
    - Rigidity
    - Weakness
    - Rhabdomyolysis
  - Autonomic: Sympathetic hyperactivity
    - Hyperventilation (Tachypnea)
    - Tachycardia, Sinus
    - Hemodynamic instability
    - Hyperhidrosis
  - General
    - Fever: May have delayed onset
    - Cyanosis
  - Late features
    - Edema: Muscle; Brain
    - Cardiac arrest
    - Renal failure
    - Disseminated intravascular coagulation
  - Poor prognosis
    - Fulmanent onset
    - Late diagnosis
- Laboratory
  - Hypermetabolism
    - Increased oxygen consumption
    - Rising CO₂
  - Respiratory (Lactic) acidosis: Arterial pH < 7.25
  - Disseminated intravascular coagulation: With high core temperatures
- Diagnostic tests
  - Halothane contracture test
    - Muscle exposed to 3% halothane
    - Positive contracture response: > 0.7 grams
    - Requires fresh muscle
  - Caffeine contracture
    - Muscle exposed to increasing caffeine concentrations from 0.5 mM to 32 mM
    - Positive contracture response: > 0.7 grams at caffeine < 2 mM
    - Requires fresh muscle
  - Testing locations
- Drug Treatment: Dantrolene
  - Initial doses: 2.5 mg/kg q 10 to 15 minutes
  - Total dose: 10 mg/kg
  - Later doses: 1 mg/kg every ~6 hours
  - Avoid, if possible: During obstetric labor & delivery
  - Also useful for other hyperthermia
    - Neuroleptic malignant syndrome
    - MDMA (3,4-Methylenedioxymethamphetamine) toxicity
    - Juvenile diabetes, New onset
- Other treatments
  - Stop triggering agent
  - Cooling
  - Manage arrhythmias & hyperkalemia
- External link: UCLA
Malignant hyperthermia: Pathophysiology
- General cascade of events
  - Increased cytosolic Ca⁺⁺
  - Muscle hyperactivity & hypermetabolism
  - Rhabdomyolysis & Fever
- Pathophysiology of malignant hyperthermia (Postulated)
  - Increased tendency for calcium release from sarcoplasminc reticulum (SR)
    - Probably produced by defective ryanodine receptor
    - Dantrolene prevents or inhibits this tendency
  - Triggering agent produces rapid abnormal increase in cytoplasmic calcium
  - Muscle ATP is depleted by activity of
    - Muscle contractile apparatus
    - SR calcium reuptake pump
  - Aerobic metabolism increases to replace ATP
    - Heat & CO2 produced as a byproduct
  - Calcium accumulates in mitochondria: Failure of aerobic metabolism
  - Anaerobic metabolism increases
    - Lactic acidosis
- Pathogenic mechanisms & related symptoms
  - Elevated myoplasmic Ca⁺⁺
    - Muscle spasms: Masseter; Generalized
    - Heat production
    - Hypermetabolism
    - Rhabdomyolysis
  - Rhabdomyolysis
    - Muscle pain
    - Myoglobinuria: May cause Renal failure
    - Cardiac arrhythmia
    - Serum: Increased Creatine kinase (CK) & K⁺
  - Hypermetabolism
    - Tachycardia
    - Acidosis
    - ATP depletion
    - Hypoxemia
    - Heat production
- Compensatory mechanisms
  - Heat loss
  - Sympathetic hyperactivity: Increased circulating catecholamines
  - Increased cardiac output
  - Increased ventilation
MHS1: Malignant Hyperthermia - Central Core Disease
● Ryanodine Receptor (RYR1) ; Chromosome 19q13; Dominant
- Genetics
  - Ryanodine receptor 1 mutations producing + in vitro contracture test
    - > 50 Missense mutations
    - No splice or stop mutations
    - Patient frequency: RYR mutations found in
      - 50% of MH families
      - 20% of all MH patients
    - Mutation locations
      - 50% between exons 39 to 46
      - Leu13Arg: Ryr1 hypersensitivity
    - Mutation types
      - Missense: Most
      - Deletion, In-frame
      - Deletion of Glu2347
        
        Large evoked contraction tension by electrical stumulus in absence of drugs ⁵
  - Allelic disorders
    - Central core disease
    - King-Denborough
    - Porcine malignant hyperthermia
      - Recessive Arg615Cys mutation (Same as human Arg614Cys)
      - 4% to 9% of human MH also at this locus
  - Correlations of mutations with in vitro contracture test
    - Strong: Caffeine threshold & tension values
    - None: Halothane threshold and tension values
- Clinical features
  - High fever
  - Muscle rigidity: All pigs; 75% of humans
    - Isolated trismus: May be early sign
  - Cardiovascular: Tachycardia; Dysrhythmias; Hypotension
  - Laboratory
    - Increased pCO2
    - High lactate & acidosis: pH may be < 7
    - CK
      - During episode: Very high (up to 100,000)
      - Elevation correlates
        
        Best with rhabdomyolysis
        Less well with fever & acidosis
      - Resting CK: Mild elevation
  - Triggering agents
    - Halothane (volatile anesthetics)
    - Succinylcholine & carbachol (depolarizing agents)
  - Diagnosis
    - Gene testing
    - Caffeine contracture test (only on fresh muscle)
  - Treatment
    - Dantrolene: 2 mg/kg i.v. q 5 minutes to a total of 10 mg/kg
    - Hyperventilation; Sodium bicarbonate; Cooling
    - Discontinue anesthesia
    - Maintain urine output: 2 ml/kg/hr
    - Avoid calcium, Calcium antagonists, beta blockers
- External link: Gasnet
Other Malignant Hyperthermia loci
- General
  - MHS2
    ● Chromosome 17q11.2-q24; Dominant
    - Same Sodium channel gene (SCN4A) as in hyperkalemic periodic paralysis
  - MHS3
    ● Chromosome 7q21-q22; Dominant
    - Calcium channel, Skeletal muscle, Voltage-dependent, L-type, α-2 peptide (CACNL2A)
  - MHS4
    ● Chromosome 3q13.1; Dominant
  - MHS5
    ● Chromosome 1q32; Dominant
    - L-type Calcium Channel, α1 subunit (Dihydropyridine Receptor)
    - Same gene as Hypokalemic periodic paralysis
    - Different gene location: Arg1086His
      - Mutation in cytoplasmic loop betweeen S3 and S4
      - ? Region that interacts with ryanodyne receptor
  - MHS6
    ● Chromosome 5p; Dominant
  - MHS Other
    ● Autosomal Dominant
- King-Denborough Syndrome
  ● Autosomal Dominant
- Other: Occasional familial MH

King-Denborough Syndrome

● Ryanodine Receptor

; Chromosome 19q13.1; Dominant
● ? Other; Autosomal Dominant, or Sporadic

Nosology (Other names)
- King syndrome ¹⁰
Epidemiology
- Male preponderance (4:1)
Genetics
- Ryr1 mutations: Missense; Lys33Glu, Thr2206Arg,
  Arg2452Trp, Arg2508Cys, Ser2776Phe
- Allelic disorders: Central core +
Clinical
- Age of ascertainment: 2 to 14 years
- Malignant hyperthermia (94%)
  - Triggered by heat or anesthesia
- Weakness (90%)
  - Proximal
  - Symmetric
  - Mild
  - Delayed motor development
  - Scapular winging
  - Myopathy often not present in other family members
- Tendon reflexes: Often reduced
- Skeletal abnormalities: Noonan syndrome-like
  - Short stature (90%): < 5th percentile
  - Chest: Pectus carinatum/excavatum
  - Spinal curvature
    - Onset: 1st decade
    - Kyphosis, Scoliosis or Lumbar Lordosis
  - Dislocating shoulders
  - Vertebral fusion
  - Pes cavus
  - Contractures
- Faces
  - Dysmorphic: Malar hypoplasia
  - Low-set ears
  - Micrognathia
  - Eyes: Ptosis; Strabismus
- Cryptorchidism
- Intelligence: Usually normal (80%)
- Not present: Congenital heart disease
Laboratory
- Serum CK: High (63%) or High normal at rest
- EMG: Myopathic
- Muscle: Non-specific
  - Myopathic, mild
  - Fiber type disorders: Some patients
    - Type 1 predominance
    - Few Type 2A muscle fibers
  - Cores: Some patients
Differential diagnosis

From: A Connolly MD

Ethanol-Induced Myopathies

Myopathy syndromes ³⁶
- ? Association with malnutrition
- Acute necrotizing myopathy
  - Epidemiology & History
    - History of
      - Chronic alcohol intake; Binge drinking
      - Prior pain & swelling of muscles
      - Food deprivation or Fasting
      - Onset associations: Heavy alcohol intake; Acute withdrawal; Seizure
    - Predominantly males
  - Clinical
    - Myalgias
    - Cramps
    - Weakness
      - Proximal
      - May be localized to quadriceps or gastrocnemius
    - Duration: 1/2 to 6 months
  - Laboratory
    - Associated metabolic disorders: Low K⁺; Low PO₄
    - Serum CK: High
    - Urine: Myoglobinuria
    - Muscle Pathology
      - Scattered necrotic or regenerating muscle fibers
      - Monophasic damage
- Hypokalemia: Painless acute weakness
- Chronic myopathy
  - Epidemiology
    - More with higher cumulative lifetime consumption of alcohol (>10 kg of pure alcohol/kg body weight)
  - Clinical
    - Onset age: 40 to 60 years
    - Muscle size: Wasting
    - Weakmess: Proximal
    - Associated disorders
      - Liver cirrhosis
      - Cardiomyopathy
      - Episodes of acute alcoholic skeletal myopathy
      - Nutritional deficiencies
  - Muscle pathology
    - Type II atrophy
    - Moth-eaten muscle fibers
- ± Associated cardiomyopathy
  - Cobalt intoxication in beer drinkers
  - Beriberi heart disease
  - Chronic alcoholic
    - Males < 50 years
    - Long history of alcohol intake
    - Congestive heart failure
    - Prognosis: 40% mortality over 3 years%
- Anti-MAS antibody associated myositis
Pathology
- Muscle fiber necrosis & regeneration: Segmental
- Tubular aggregates
- Separation of myofibrils
Also see: Alcoholic neuropathy

Monensin-Induced Rhabdomyolysis ¹¹

Drug Properties
- Sodium-selective carboxylic ionophore antibiotic
- Facilitates the transmembrane exchange of sodium for other protons
- Sodium: Increased intracellular concentration.
- Used by
  - Poultry and pig producers: Anticoccidial action
  - Cattlemen: Changes rumen microbial population, increasing feed efficiency
Toxicity
- Overdose
  - Human: 500 mg
  - Animals: 2 to 25 mg/kg
- Epidemiology
  - Common in animals
  - Human: 1 case reported
- Clinical Syndrome
  - Onset: 6 hours; Nausea
  - Myalgias
  - Weakness
  - Myoglobinuria
  - Renal failure
  - Cardiac failure
- Laboratory
  - Serum CK: Very high
  - Pathology
    - Skeletal & cardiac muscle fiber necrosis
    - Swelling of mitochondria & Sarcoplasmic reticulum
  - Lactate production: Increased
  - Hyperkalemia: Late

Coenzyme Q₁₀ Deficiency ²³

Coenzyme Q₁₀ ¹³
- General properties
  - Forms: Reduced (Ubiquinol) & Oxidized (Ubiquinone)
  - Locations
    - All human tissues
    - Highest levels: Heart, Kidney & Liver
  - Cellular location: Mitochondria; Many other organelles
  - Synthesis: ≥ 10 genes required
- Functions
  - Distributes electrons between
    - Dehydrogenases, and
    - Cytochrome segments of respiratory chain
  - Transports electrons
    - From: Complexes I & II; Electron transfer flavoproteins (ETF)
    - To: Complex III in respiratory chain
  - Allows proton extruded from mitochondrial matrix to intermembrane space
  - Can act as
    - Pro-oxidant, or
    - Anti-oxidant: Both lipoproteins & Cell membranes
  - Role in pyrimidine biosynthesis: Connects energy production with
    - Cell cycle
    - DNA replication & repair
  - Apoptosis modulation: Via regulation of transition pore
  - Body temperature: Acts on uncoupling proteins
- Large excess compared to other components of respiratory chain
  - Kinetically compartmentalized pool
  - Redox status regulates activity of dehydrogenases
- Coenzyme Q₁₀ deficiency disorders ³⁵
  - Inheritance: Usually Recessive or Sporadic
  - Biochemistry
    - 1° syndromes: Genes related to ubiquinone biosynthesis
    - 2° syndromes: Genes not directly related to ubiquinone biosynthesis
  - Screening for deficiency
    - Gold standard: Measurement in muscle biopsy (HPLC)
    - Measure in all patients with suspected mitochondrial disease
    - Especially recommended with
      - SDH+ (Ragged red) muscle fibers
      - Lipid increased
      - Type 2C muscle fibers: Increased numbers
        
        Infants (< 1 year)
        
        Morphologically normal muscle
      - Reduced activities of: Complexes I+III or II+III
    - Deficiency may occur with normal muscle histology
  - Clinical syndromes: Heterogeneous
    - Infantile & Childhood
      - Encephalopathy: COQ2; PDSS2
      - Encephaloneuropathy + Multisystem disorder: PDSS1
      - Encephaloneuropathy + Multisystem disorder: COQ7
      - Lactic acidosis + CNS, Cardiac & Renal disorders: COQ9
      - Encephalocardiopathy: COQ4
      - Leigh syndrome: PDSS2
      - Multiple acyl CoA dehydrogenation deficiency (MADD)
      - Encephalomyopathy: SLC25A26
      - Intellectual disability: ADCK4 (COQ8B)
    - Ataxia: Most frequent presentation of Coenzyme Q₁₀ deficiency
      - Ataxia: Aprataxin (APTX) (2°)
      - Ataxia + CoQ₁₀ deficiency, Adult onset: ? Genetic etiology
      - Ataxia + CoQ₁₀ deficiency: ANO10
      - Ataxia + Hypogonadism
      - Ataxia: CABC1 (COQ8; ADCK3)
      - Ataxia + Dystonia: COX20 (FAM36A)
      - Ataxia +: COQ5
    - Myopathy
      - Myopathy: ETFDH (2°)
      - Statin toxicity
      - Lipid myopathy & Liver dysfunction with CoQ Deficiency: ADCK2
      - Myopathy, Myoglobinuria & CNS: CABC1 (COQ8; ADCK3)
      - Rhabdomyolysis: CABC1 (COQ8A; ADCK3)
    - Cardiofaciocutaneous syndrome 1 (CFC1) : BRAF (2°)
    - Steroid-resistant nephrotic syndrome (+/- Sensorineural hearing loss)
      - Nephrotic syndrome, type 9 : ADCK4 (COQ8B)
      - COQ2
      - COQ6
      - PDSS2
    - Secondary Coenzyme Q₁₀ deficiencies
      - Mitochondrial encephalopathies: Mostly due to mtDNA mutations
      - MELAS: Coenzyme Q₁₀ levels 40% to 60% of control levels
      - Myopathy: ETFDH
      - Ataxia: Aprataxin (APTX)
      - Cardiofaciocutaneous syndrome : BRAF
    - Responsive to treatment
      - COQ2
      - PDSS2
      - COQ6
      - COQ9: Partial
      - 8A: Occasional patient
      - ADCK4 (COQ8B)
  - Treatments
    - Riboflavin
    - Coenzyme Q₁₀: 5 to 50 mg/kg/day; Up to 3 grams daily
    - ACE inhibitors: With CoQ supplementation in persons with proteinuria
    - Idebenone: Not effective
    - End-stage renal disease: Kidney transplant
  - Muscle pathology

Coenzyme Q₁₀ Synthetic Pathway

COQ10 Deficiencies (COQ10D)
1: COQ2
2: PDSS1
3: PDSS2
4: COQ8A (CABC1; ADCK3)
5: COQ9
6: COQ6
7: COQ4
8: COQ7
9: COQ5
ADCK2
NPHS9: ADCK4 (COQ8B)

Lipid myopathy & Liver dysfunction with CoQ Deficiency ³⁷
● aarF domain-containing mitochondrial protein kinase 2 (ADCK2) ; Chromosome 7q32-q34; Dominant
- Epidemiology: 1 patient
- Genetics
  - Mutation: Heterozygous; c.997C>T (p.Arg333*)
  - Mother & Sister with mutation: Asymptomatic
- ADCK2 protein
  - Mitochondrial import of CoQ lipid precursors
  - Mitochondrial-associated membranes
- Clinical
  - Onset age: 30 years
  - Weakness
    - Proximal
    - Arms & Legs
    - Symmetric
    - Scapular winging
    - Respiratory
    - Dysphagia: Late in course
    - Course: Slow progression
  - Myalgias: Worse with exercise
  - Calf hypertrophy
  - CNS: Normal cognition & cerebellar function
  - Treatment: CoQ10, 75mg per day
- Laboratory
  - Serum lasctate: High
  - Muscle
    - Myopathy
    - Lipid droplets
    - Complexes I+III & II+ III reduced activities
    - Carnitine mildly reduced
  - Fibroblasts: CoQ10 levels reduced
  - EMG: Myopathic + Spontaneous activity
  - Muscle MRI
    - Abnormal: Shoulder girdle, Deltoid, Biceps, Hamstring, Calf muscles
    - Normal: Triceps
  - Liver dysfunction: Steatosis
  - Plasma short- & medium-chain acyl-carnitine species: Moderately high (MADD pattern)
  - Urine organic acids: Ethylmalonic acid high
Myopathy, Myoglobinuria + CNS disorder
- Genetics
  - CABC1 (COQ8; ADCK3) mutations in 1 family
  - Allelic disorder: SCAR9
- Clinical features
  - Onset age: Childhood
  - Exertional fatigue
  - Myoglobinuria
    - Recurrent
    - Preciptiated by fever, convulsions, mild to moderate exercise
  - Weakness
    - Proximal
    - May occur without other systemic features
  - CNS: Seizures; Cognitive impairment
- Muscle pathology
  - Ragged red fibers
  - Prominent lipid accumulation
  - Coenzyme Q₁₀ levels < 50% of normal
- Treatment: Coenzyme Q₁₀ 150 to 200 mg qd
Myopathy + (MADD) ²²
● Electron transfer flavoprotein dehydrogenase (ETFDH) ; Chromosome 4q32-qter; Recessive
- Nosology: Riboflavin-responsive Multiple Acyl CoA Dehydrogenase Deficiency (MADD)
- Epidemiology
  - Female:Male 3:1
  - 93% of MADD
  - China
    - Common in lipid storage disease
    - MADD incidence: 1:26,670
  - 1 patient originally reported as: Myopathy + Coenzyme Q₁₀ deficiency ³⁸
- Genetics
  - Mutations
    - Missense, Nonsense, Intron & Splice
    - > 300 described
  - China: Ala84Thr, Leu409Phe
  - Japan: Y507D
  - Allelic with: Glutaricaciduria, Type IIC
  - Subtype of
    - Glutaricaciduria, Type II (GAII)
    - Multiple acyl CoA dehydrogenation deficiency (MADD)
- ETFDH protein
  - Mitochondrial: Inner membrane
  - Associated with: Electron transfer flavoprotein with ETFA & ETFB in mitochondrial matrix
  - Electron transfer
    - Accepts electrons from Electron transfer flavoprotein (ETF) & Reduces ubiquinone
    - From 9 mitochondrial flavin-containing dehydrogenases to main respiratory chain
  - Lipid pathways
  - Contains: FAD & 4Fe-4S cluster
- Clinical: General syndromes
  - Neonatal
    - Type 1: Neonatal + Congenital with liver disease & Hypoglycemia
    - Type 2: Neonatal, No congenital anomalies
    - Early death common
  - Type 3: Late onset, Myopathy ± Hepatomegaly, Encephalopathy, Vomiting, Hypoglycemia
- Clinical: Myopathy ± Other features
  - Onset: Childhood to 7th decade
  - Weakness
    - Limbs: Proximal; Legs & Arms
    - Trunk & Neck (Anterior & Posterior): Some with Bent spine
    - Symmetric
    - Respiratory: With exacerbations
  - Other muscle symptoms
    - Fatigue: Exercise intolerance; Chewing
    - Cramps
    - Myalgia: Tenderness after exercise
    - Rhabdomyolysis: Some patients
  - Tendon reflexes: Reduced
  - Course
    - Sub-acute exacerbations
      - Weakness: Rapid onset ± Respiratory failure
      - Precipitated by
        
        Childhood
        
        Pregnancy
        
        Fasting
        
        Cold
        
        Infections
    - Long term: Slowly progressive weakness
  - GI
    - Vomiting: After meals rich in fat or protein
    - Diet: Prefer fruits and vegetables to meat and eggs
  - Other systemic
    - Often normal
    - Polyneuropathy: Axon loss
    - Skin rash: Ichthyotic
    - Occasional: Elevated liver enzymes
  - GA IIC features: Multisystem
    - Nausea or Vomiting: Recurrent
    - Encephalopathy, Acute
    - Movement disorders
    - Hepatomegaly
    - Pancreatitis
    - CNS: Leukodystrophy
    - Acidosis
    - Hypoglycemia
    - Carnitine deficiency
  - Treatment
    - Coenzyme Q₁₀: 150 to 500 mg per day
    - Riboflavin: 100 mg/day
      - Y507D: Frequenctly riboflavin non-responders
    - Diet: Low fat
- Laboratory
  - Serum CK
    - High: 1000 to 20,000
    - May return to normal after treatment
  - Metabolic: Hypoglycemia; Acidosis
  - Serum LDH: High ³⁰
    - Skeletal muscle-derived LDH-5 (M₄): Low
    - LDH-1 (H₄; Heart & Type I muscle fibers) > LDH-2 (H₃M₁): Predominant isoforms
  - Serum Homocysteine: May be high ⁵²
  - Muscle MRI: Early involvement of semimembranosus & semitendinosus
  - EMG: Variable
    - Myopathic, Neurogenic or Normal
    - Some patients: Irritative myopathy
  - Muscle pathology
    - Muscle fibers with mitochondrial proliferation: SDH+
    - SDH in other fibers: Reduced or Normal
    - COX: Normal or Increased
    - Lipid: Increased in Type 1 > Type 2 muscle fibers
    - Respiratory chain
      - Complexes I & II + III: Severely reduced
      - Complex IV (COX): Moderately decreased
      - Citrate synthase: High
    - Coenzyme Q₁₀ levels: Reduced
    - Tandem mass spectrometry: Multiple acyl-CoA deficiency
  - Acylcarnitine analysis: High short, medium & long chain
  - Urine organic acids: Increased dicarboxylic acids , ethylmalonic acid, 2-hydroxyglutaric acid, lactic acid & ketone bodies
  - Liver: Steatohepatitis
  - MRI
    - Subcutaneous fat: Increased
    - Visceral fat: Normal
Coenzyme Q₁₀ deficiency syndrome: Infantile-childhood encephalopathy & Nephrotic syndrome (COQ10D1)
● COQ2 ; Chromosome 4q21.23; Recessive
- Epidemiology: 6 families
- Genetics
  - COQ2 Mutations
    - Homozygous missense: Tyr279Cys
    - Truncation
    - Effect: Defect in CoQ₁₀ synthesis; Blocks ubiquinone synthesis
    - COQ2 polymorphisms may be related to: Lipid-lowering agent myopathy
  - Possible allelic disorder: Susceptibility to Multiple System Atrophy 1 (MSA1)
    - Mutation: V343A in Japanese but not in other populations
    - Odds ratio for MSA development: 1 to 2.23
- COQ2 protein
  - Mitochondrial
  - Parahydroxybenzoate-polyprenyltransferase
- Clinical: Neurological
  - Onset
    - Age: Birth to 18 months
    - Nystagmus
    - Nephrotic syndrome
  - Hypotonia
  - Weakness
  - Psychomotor delay & regression
  - Seizures
  - Tremor
  - Ataxia
  - Severe: If untreated, rapidly fatal
- Clinical: Other
  - Nephrotic syndrome: Corticosteroid-resistant
  - Hematologic: Anemia; Pancytopenia
  - Diabetes
- Laboratory
  - Serum CK: Normal
  - Serum & CSF lactate: Normal or High
  - Muscle pathology
    - SDH: Mild mitochondrial proliferation
    - Complex I + III & II + III deficient
    - Complex II + III deficiency repaired by decylubiquinone
  - Hyperglycemia
- Treatment
  - Coenzyme Q₁₀ (30 mg/kg per day po)
  - Improved CNS but not renal function
Coenzyme Q₁₀ deficiency syndrome: Encephaloneuropathy & Multisystem disorder (COQ10D2) ²¹
● PDSS1 (Decaprenyl diphosphate synthase, subunit 1) ; Chromosome 10p12.1; Recessive
- Epidemiology: 6 patients
- Genetics
  - Mutations: Missense & Stop; Val239Gly, Gln245His, Asp308Glu
  - Allelic disorder: Inherited Retinal Dystrophy (Retinitis Pigmentosa)
- Protein
  - 1st subunit of decaprenyl diphosphate synthase
  - 1st enzyme of CoQ₁₀ biosynthetic pathway
- Clinical
  - Onset: Infant or Early childhood
  - CNS
    - Deafness: Onset 1-2 years
    - Encephalopathy: Mental retardation, Mild; Developmental delay
    - Optic atrophy
  - Polyneuropathy: Tendon reflexes absent
  - Systemic
    - Obesity & Bulemia
    - Skin: Livedo reticularis; Distal phalangeal erythema
    - Cardiac: Valvulopathy; Aortic and mitral regurgitation
  - Macrocephaly
  - Course: Early death or Progressive into adulthood
- Laboratory
  - Plasma lactate: Mildly high
  - Muscle pathology: Mitochondrial aggregates; COQ10 deficiency
  - Brain MRI: White matter pathology
Coenzyme Q₁₀ deficiency syndrome: Infantile encephalomyopathy & Nephrotic syndrome (COQ10D3) ²⁰
● PDSS2 (Decaprenyl diphosphate synthase, subunit 2) ; Chromosome 6q21; Recessive
- Genetics: PDSS2 gene
- Onset
  - Age: Infancy
  - Hypotonia
  - Pneumonia
- Clinical
  - Hypotonia
  - Poor feeding
  - Episodic vomiting
  - Seizures: Focal with secondary generalization
  - Cortical blindness
  - CoQ₁₀ treatment: No benefit
- Laboratory
  - Nephrotic syndrome
  - Serum lactate: High
  - Muscle
    - Increased subsarcolemmal mitochondria
    - No COX- muscle fibers
    - Complex I activity mildly reduced: Others normal
    - Complex II + III activity: Reduced; Increased by decylubiquinone
    - CoQ₁₀ reduced
Coenzyme Q₁₀ deficiency syndrome: Lactic acidosis + CNS, Cardiac & Renal disorders (COQ10D5) ²⁶
● COQ9 ; Chromosome 16q13; Recessive
- Epidemiology: Pakistani family
- Genetics
  - Mutation: Stop
  - R244X
- COQ9 protein
  - Location: Mitochindria
  - Forms tetramer & octamer with COQ7
  - Function: Role in synthesis of Coenzyme Q10
- Clinical
  - Intrauterine: Growth retardation
  - Onset age: Congenital
  - Poor feeding
  - Hypotonia
  - Seizures
  - Developmental delay
  - Cardiac: Ventricular hypertrophy
  - Treatment with Coenzyme Q10 supplementation: No benefit
- Laboratory
  - Lactic acid: High
  - MRI: Cerebral & Cerebellar atrophy
  - Kidney: Renal tubular dysfunction
  - Muscle
    - Type IIB fiber atrophy
    - Lipid accumulation
    - Mitochondrial
      - Complexes II+III activity: Reduced
      - Complexes II & III: Normal
      - Coenzyme Q10 levels in skeletal muscle: Severely reduced
Coenzyme Q₁₀ deficiency syndrome: Encephaloneuropathy & Multisystem disorder (COQ10D8) ²¹
● COQ7 ; Chromosome 16p12.3; Recessive
- Epidemiology: > 5 patients
- Genetics
  - Mutation: Missense; Val141Glu, Ile66Asn, Tyr149Cys
  - Allelic disorders
    - Motor neuropathy, Distal
    - Hereditary Spastic Paraparesis (SPG)
- COQ7 protein
  - Di-iron oxidase
  - Penultimate step of CoQ₁₀ synthesis
  - Forms tetramer & octamer with COQ9: Coordinates synthesis steps of COQ10
  - Cellular location: Mitochondrial
- Clinical
  - Onset: Pregnancy, Born at term or Neonatal
  - Oligohydramnios
  - Fetal lung hypoplasia
  - Joints: Contractures; Displacements
  - Growth retardation
  - Motor
    - Hypotonia
    - Delayed development: No standing or walking
    - Weakness: Progressive
  - Neonatal features normalizing in 1st year (Before treatment)
    - Kidneys: Hypoplastic; Hypertension
    - Cardiac hypertrophy
    - Pulmonary: Hypertension
  - GI: Poor feeding; Gastrostomy required
  - Sensory
    - Visual dysfunction
    - Hearing impairment
  - Treatment: CoQ10 supplementation may benefit renal& myopathy
- Laboratory
  - Lactate: High in Serum & CSF
  - Fumarate & Malate: High in urine
  - Muscle
    - Fiber size: Small
    - Combined mitochondrial respiratory complex enzyme activity deficiency
    - CoQ10 levels: Low
    - Ultrastructure: Normal
  - Brain MRI: Normal
  - NCV: Polyneuropathy
    - Axon loss
    - Demyelination
- COQ7 allelic disorder: HMNR9 Motor neuropathy, Distal ⁴⁷
  - Epidemiology: 10 patients; 0.2% of hereditary neuropathies
  - Genetics
    - Inheritance: Recessive
    - Mutations: Missense (Met1Ile, Arg 54Gln, Ile66Asn, Tyr149Cys, L156Q, L156R); Splice
    - Mutation mechanisms
      - Probable haploinsufficiency
      - Higher residual activity of COQ7 than early onset disease
  - Clinical
    - Onset age: 14 mo to 2nd decade
    - Weakness
      - Distal
      - Arms & Legs
      - Proximal legs: Later in course
    - Pes cavus
    - Tendon reflexes: Normal or Brisk
    - Course: Slow progression
  - Laboratory
    - NCV: Motor axonopathy
      - CMAPs
        
        Ampludes: Small or Absent
        
        Velocities: Normal
        
        Most involved: Distal legs
      - Sensory: Normal
    - EMG: Distal denervation
    - Muscle: No distinctive changes
- COQ7 allelic disorder: Hereditary Spastic Paraparesis (SPG) + Seizures & Motor Neuropathy ⁵³
  - Epidemiology: 1 patient
  - Genetics
    - Inheritance: Recessive
    - Mutation: Homozygous; Pro108Thr
  - Clincal
    - Onset age: 11 years
    - Spastic paraparesis
      - Legs > Arms
      - Gait disorder
      - Tendon reflexes: Increased
      - Urinary incontinence
    - Weakness: Legs & Arms; Distal
    - Seizures
    - Sensation: Normal
  - Laboratory
    - NCS: CMAPs small amplitude; SNAPs normal
    - EMG: Denervation
    - MRI: Thoracic cord atrophy; Normal cerebrum
    - Nerve pathology: Axon loss, mild; Thinly myelinated axons
    - Fibroblasts: COQ7 reduced
Coenzyme Q₁₀ deficiency syndrome: Ataxia + (COQ10D9)
● Coenzyme Q5 (COQ5) ; Chromosome 12q24.31; Recessive
- Epidemiology: Iraqi-Jewish family
- Genetics
  - Mutation: Homozygous; 9590 bp duplication
- COQ5 protein
  - Location: Matrix side of mitochondrial inner membrane
  - Catalyzes C-methylation involved in biosynthesis of Coenzyme Q (Ubiquinone)
- Clinical
  - Onset age: 1st decade
  - Short stature
  - Intellectual disability: Delayed motor & cognitive milestones; Impulsivity; Attention span short
  - Ataxia: Non-progressive; Dysarthria, Tremor, Dysmetria, Gait
  - Eyes: Slow saccades; Saccadic pursuit; Apraxic gaze (AOA); Nystagmus, horizontal
  - Myoclonic jerks
  - Seizures: Generalized; Tonic-Clonic
  - Legs: Spasticity, mild
  - Treatment: CoQ10 supplementation
- Laboratory
  - Brain imaging: Cerebellar atrophy
  - Muscle biopsy: 2C fibers frequent
Coenzyme Q₁₀ deficiency syndrome: Childhood-onset cerebellar ataxia
- See: Aprataxin mutation (AOA1)
- Clinical
  - Ataxia
  - Seizures
  - Muscle weakness
  - Mental retardation
  - Pyramidal tract signs
  - Peripheral neuropathy
Also see
- Ataxia, recessive
- Mitochondrial disorders
- AOA1: Secondary CoQ₁₀ deficiency

Rhabdomyolysis (Myoglobinuria), Child-onset, Recurrent ²⁴

● Lipin-1 (LPIN1)

; Chromosome 2p25.1; Recessive

Epidemiology
- Common cause of rhabdomyolysis in children: > 35 patients; > 30 families
- 37% of rhabdomyolysis patients: Age ≤ 6 years & Serum CK > 10,000
- Ethnic origins: Many
Genetics
- LPIN1 mutations
  - Type: Often stop codons or deletion; 1 missense (Arg725His)
  - Location: Scattered throughout LPIN1 coding region
  - > 20 mutations described
  - Caucasians: Common deletion mutation; c.2295-863_2410-27del (c.2295-866_2410-30del)
- LPIN1 polymorphism associations
  - Body mass index
  - Insulin sensitivity
  - Severity of fatty liver disease in children
  - Essential hypertension
- Mouse mutations: Fatty liver dystrophy (fld)
- LPIN2 mutations
  - Chronic recurrent multifocal osteomyelitis
  - Congenital dyserythropoietic anaemia (Majeed syndrome)
LPIN1 protein
- Muscle-specific
  - Acts in exercise-induced adaptation & oxidative gene expression
- Cytoplasm
  - Lipid phosphatase: Phosphatidate phosphatase 1 (PAP1)
  - Catalyzes dephosphorylation of phosphatidic acid (phosphatidate) to diacylglycerol (DAG)
  - Triacylglycerol (TAG) synthesis pathway
  - Lipid droplet metabolism
- Nucleus
  - Transcriptional (PPARα & PGC-1α-mediated) co-activator
  - Interacts with transcription factors which regulate expression of genes involved in energy pathways
- Inflammatory inducers: May decrease lipin-1 expression
Clinical features
- Onset age
  - Most common: Young children 1 to 6 years
  - Occasional: Adults, up to 5th decade
- Attacks
  - Rhabdomyolysis: Severe
  - Triggered by
    - Febrile episodes: Most common
    - Other: Exercise, Fasting, Anesthesia, Stress
  - Reduced frequency with increasing age
  - May lead to death (30%)
- Between attacks
  - Usual: Normal strength, tendon reflexes & fat distribution
  - Myalgias: With effort
  - Older patients (30%): May have mild weakness
  - EMG: Usually normal
- LPIN1 mutations rare with
  - Myalgias without Rhabdomyolysis
  - Mild rhabdomyolysis (CK < 10,000 UI/L)
Muscle pathology
- Lipid droplets in muscle fibers: Increased in 50% to 75%
- Mitochondrial: Occasional
  - COX staining: May be diffusely reduced
  - SDH: Few fibers with increased staining
- Fiber types
  - I predominance
  - II atrophy
- Ultrastructure: Lipid droplets
- May be normal
- Phospholipids: Normal
Systemic pathology: Some rhabdomyolysis patients at autopsy with
- Cardiomyopathy
- Liver steatosis
Laboratory
- Serum CK
  - During episodes: > 10,000 (10,000 to 1,000,000)
  - Between episodes: Normal
Heterozygotes
- Symptomatic in 10% to 40%: Cramps; Myalgias, exercise induced
- 3 adults (Glu796Gly): Statin-induced myopathy
- LPIN1 common variants: Metabolic syndrome & Associated phenotypes
Mouse mutation
- fld: Fatty liver dystrophy
Differential diagnosis
- Idiopathic recurrent myoglobinuria
- Rhabdomyolysis

Myopathy with Myalgia, High CK ± Rhabdomyolysis (MMCKR1) ⁴²

● Muscular Lamin A/C Interacting Protein (MLIP, c6orf142)

; Chromosome 6p12.1; Recessive

Epidemiology: 16 patients
Genetics
- Mutations: Nonsense (Truncating); Point or Deletion
- Allelic disorder: Dilated cardiomyopathy risk
MLIP protein
- Expression: Heart; Skeletal muscle; Brain
- Interactions & Colocalization: Lamins A & C
- Functions: Myoblast differentiation
- Mlip deficient mice: Increased muscle fiber central nuclei
Clinical
- Onset age: 8 months to Adult
- Muscle discomfort
  - On exertion
  - Types: Fatigue, Pain, Ache, Cramps, Stiffness
- Weakness: 70%; Proximal
- Rhabdomyolysis: Episodes; Spontaneous, Post-exercise, Cold
- Cardiac
  - Usually normal
  - Some patients with: Cardiomyopathy; Rhythm disorders
Laboratory
- Serum CK: High at rest (297 - 8,000); Increased during episodes
- Muscle MRI: Normal or Changes in thigh sparing rectus, sartorius & gracilis
- EMG: Myopathic
- Muscle pathology
  - Necrosis & Regeneration
  - Myopathy (Mild 28%): Fiber sizes varied; Internal nuclei
  - MLIP: Staining not clearly abnormal; mRNA reduced

CMYO13: Myopathy, Congenital, Bailey-Bloch ²⁵

● SH3 and cysteine-rich domain-containing protein 3 (STAC3)

; Chromosome 12q13.3; Recessive

Nosology: Native American Myopathy; MYPBB; CMYP13; CMYO13
Epidemiology
- > 40 patients
- Focus: Lumbee Indians in North Carolina
- Other: Africa; Asia; South America
Genetics
- Mutation
  - Most patients: Missense; Homozygous; Trp284Ser
  - Other mutation: c.997>1G>T splice variant
- Variant syndromes: Carey-Fineman-Ziter; Möbius syndrome
Stac3 protein
- Component of excitation-contraction coupling machinery
- Expression: Skeletal muscle
- Co-localization: DHPR α-1 (CACNA1C); RYR1
- Interacts with: Ca_v1.1 II-III loop
- Trafficking of Ca_v1.1 (Pore forming subunit of DHPR) to plasma membrane
- Mutation: Abnormal EC coupling
Clinical
- Onset age: Congenital, Mild or Severe
- Congenital anomalies
  - Face
    - Telecanthus
    - Palpebral fissures: Short; Downslanting
    - Cleft palate
    - Micrognathia
    - Ears: Low set
    - Ptosis
  - Skeletal
    - Short stature
    - Foot deformities: Talipes equinus
    - Arthrogryposis: Ankle; Knee; Elbow; Finger
    - Kyphoscoliosis: Progressive
    - Palate: High arched
- Muscle
  - Early: Hypotonia; Poor feeding
  - Weakness: Congenital onset
    - Face: Myopathic; Ptosis
    - Arms & Legs
    - Distal legs: Spared
    - Respiratory: With increasing age
  - Malignant Hyperthermia
    - Provoked by anesthesia
    - Atypical: Normal myoglobin, Potassium, Serum CK
    - Treatment: Dantrolene
  - Wasting
- Tendon reflexes: Reduced
- Other
  - Cryptorchidism 50%
  - Hearing loss
- CNS: Intelligence usually normal
- Course: Mortality 36% by age 18
Laboratory
- Serum CK: Normal
- EMG: Myopathic or Normal
- NCV: Normal
- Muscle biopsy: Normal or Fiber type abnormalities
  - Muscle fiber atrophy
  - Type 1 fibers: Small; Predominant
  - Central nuclei: 1 patient
  - Lipid droplets: Increased
Differential diagnosis
- King-Denborough syndrome

Encephalocardiomyopathy with Cardiac Arrythmias, Rhabdomyolysis & Neurodegeneration (MECRCN) ³⁴

● Transport and Golgi organization protein 2 homolog (TANGO2; C22orf25)

; Chromosome 22q11.21; Recessive

Epidemiology: > 20 patients
Genetics
- Mutations: c.4delT; c.460G>A, p.Gly154Arg, Hispanic; Deletions Exons 3–9 (European) or 4-6 (Middle Eastern Arab); Other stop
- Also see: 22q11.2 deletion syndrome
TANGO2 protein
- Location: Mitochondria for some isoforms; Golgi & Cytoplasm
- Redistribution of Golgi membranes into the Endoplasmic reticulum
- Possible metabolic defect with TANGO2 deficiency
  - Impaired electron transfer from FAD-dependent dehydrogenases to mitochondrial respiratory chain or cofactor metabolism
  - Mitochondrial β-oxidation impairment
Clinical
- Onset age: 5 months to 7 years
- Course
  - Episodic
  - Trigger: Infection
  - CNS deficits with disease progression
- Rhabdomyolysis
  - Episodic
  - Weakness
  - Myalgias
- Weakness
  - Moderate to severe during episodes
  - Gait disorder
- Cardiac (60%): Tachyarrhythmias, Life threatening
- Encephalopathy: Episodic crises
- CNS: With disease progression
  - Cognitive impairment
  - Seizures (60% to 75%)
  - Pyramidal signs: Tone increased; Hyperreflexia
  - Ataxia: Some patients
  - Hearing loss
- Course
  - Early death: Some patients
  - Prognosis related to cardiac disorders
- Treatment: Avoid fasting
Laboratory
- Hypoglycemia: May be severe (18 to 21 mg/dL)
- Hyperammonemia
- Lactic acidosis
- Acylcarnitines & Dicarboxylic acids: High
- Ketonuria
- Mitochondrial fatty acid oxidation disorder
- Thyroid: TSH may be high
- Brain MRI: Global brain atrophy with disease progression
- Serum CK
  - During episodes: 8,000 to 300,000
  - Between episodes: Normal or Mildly high
- Muscle
  - Histopathology: Normal or Muscle fiber atrophy
  - mtDNA levels: Normal
  - Oxidative enzymes: No major change

Encephalomyopathy, early onset, with Rhabdomyolysis (Mild) & Neurodegeneration (PERRB)

● Transport (Trafficking) protein particle complex 2-like (TRAPPC2L)

; Chromosome 16q24.3; Recessive

Epidemiology: 2 patients, 2 families
Genetics
- Mutation: Asp37Tyr
TRAPPC2L protein
- Component of: Transport protein particle (TRAPP) complexes
- RAB11 pathway
- Interacts with: TRAPPC10
- Other TRAPPC mutations
  - LGMD R18: TRAPPC11
  - Spondyloepiphyseal dysplasia tarda: TRAPPC2
  - Neurodevelopmental disorders: TRAPPC6B, TRAPPC9; TRAPPC12
Clinical
- Onset
  - Age: < 1 year
  - Perinatal distress
  - Developmental delay
- Development: Motor delay & regression; No speech
- Microcephaly
- Tetraplegia
- Dystonia
- Epilepsy
- Vision: Central impairment
- Other: Enteropathy; Anemia
- Course: Episodic progression with febrile episodes
Laboratory
- Serum CK: High (Maximum 5,000 & 16,000) during febrile episodes
- Brain MRI: Myelination delayed; Brain atrophy
- Muscle: Fiber size varied; Lipid mildly increased

Neuroleptic Malignant Syndrome (NMS)

Drugs
- Butyrophenones; Lithium; Phenothiazines; Pimozide; Promethazine; Thioxanthines
- Dopamine agonist withdrawal
Pathophysiology
- Probably caused by heat generated by muscle rigidity & tremor
- Heat production amplified by sarcolemmal depolarization & muscle contraction
Onset
- Days to weeks after initiation of drug
- Encephalopathy
Clinical
- Muscle
  - Rigidity
  - Rhabdomyolysis
- CNS: Extrapyramidal signs; Altered consciousness; Seizures
- Other neural: Dysarthria & Dysphagia; Oculogyric crises
- Systemic: Autonomic instability
  - Hyperthermia: > 38°C
  - Cardiac: Blood pressure lability; Tachycardia
  - Incontinence
  - Tachypnea
  - Hyperhidrosis
- Disease course: Resolution in
  - 2 weeks withshort acting drugs
  - 4 weeks with depo drugs
Associations
- Often not familial
- Age: Any age; Most often young adults
- Precipitating factors
  - Psychoactive drugs
    - Within 1 week for short-acting & 4 weeks for long-acting
    - Lithium; Haloperidol; Phenothiazines; or especially combinations
    - High doses of neuroleptics
  - Cytochrome P4502D mutation (Allele CYP2D6J)
    - Homozygous
    - Poor hepatic metabolism of drugs associated with NMS
  - General: Dehydration; Exhaustion; Organic brain damage
Lab
- Serum CK
  - Transient increase in 2/3
  - Levels: Usually 2,000 to 15,000
- Leukocytosis
- Hyponatremia: Some patients
- CSF: Normal
Treatment
- Medication: Bromocriptine; Dantrolene; Amantadine
- Cooling to < 38°C
- Supportive care: Hydration; Reduce fever
- Discontinue predispoasing drugs

Serotonin syndrome

Precipitating factors
- Serotonergic agents: SSRIs (Prozac, Zoloft, Paxil, Luvox, Irinotican), Wellbutrin (Bupropion), Tryptophan
- Tricyclic antidepressants
- Often with MAO inhibitors
- Other: Amphetamines; Ecstasy; Nefazodone; Venlafaxine
Onset: Minutes to hours after increasing dosage of serotonergic agent
Clinical
- Fever
- CNS: Altered mental status; Hypomania; Seizures
- Autonomic dysfunction: Hyperhidrosis; Blood pressure lability; Tachycardia; Mydriasis; Flushing
- Movement disorders: Myoclonus; Shivering; Tremor; Rigidity
- Muscle: Rhabdomyolysis
- Hyperreflexia
- GI: Diarrhea
- Respiratory: Tachypnea; Respiratory failure
Lab
- Serum CK: May be high but lower than neuroleptic malignant syndrome
- Leukocytosis
Treatment
- Medications: Cyproheptadine; Mehtysergide
- Stop offending agent

Haff disease

Toxin
- Unknown
- Heat resistant
Epidemiology
- General
  - Trigger: Freshwater Fish or Seafood ingestion
  - Occurs in clusters
  - More common in Summer
  - Variability in individual susceptibility
- Initial description
  - Summer & Fall of 1924
  - Königsberger Haff (Shallow lagoon) shores along Baltic coast
- US
  - Buffalo fish (Ictiobus cyprinellus)
  - Fish from Mississippi river
- Northern Europe (Baltic, Russia & Scandinavia): Burbot
- China: Crayfish; Summer season
Clinical
- Onset
  - Time: 6 to 24 hours after ingestion
  - Age: Usually adults
- Pain
  - To light touch
  - Myalgia
  - Muscle allodynia
  - With respiration
  - Distribution: Trunk & Limbs
- Weakness
- Tone: Rigidity or Stiffness
- Rhabdomyolysis
- Numbness: 20% to 40%
- Systemic: Few or no renal features
- Occasional: Nausea, Vomiting, Abdominal pain, Diarrhea
- Course
  - Disease onset: Develops over 1 to 2 days
  - Disease subsidance: 2 to 3 days
  - Death: Rare; 1%
  - No recurrence
- After effects
  - Fatigue
  - Pruritis
- Treatment
  - Supportive
  - Fluids
Laboratory
- Serum CK
  - Range: 200 to 40,000
  - Peak at: 1 to 2 days
  - Normalization: 5 to 6 days
- Myoglobin peak: 1st 12 hours
- Myoglobinuria: Some patients
Similar syndrome: Crayfish (Boiled)-related myositis

Mushroom intoxication

Amanita phalloides ⁸
- Toxins
  - Amanitin (Amatoxin) : Cyclopeptide; Inhibits mRNA transcription
  - Phallolysin: Binds actin & Suppresses functions of cytoskeleton
  - Toxophallin : L-amino acid oxidase; Caspase-independent pathway of apoptosis induction
- Clinical features
  - Hepatic failure
  - Encephalopathy
  - Myopathy
- External link
Tricholoma equestre ⁷ (Tricholoma flavovirens)
- Onset
  - After ingestion at several consecutive meals
  - Myalgias & Fatigue: 1 to 3 days after ingestion
- Clinical features
  - Rhabdomyolysis: 1 week after ingestion
  - Other signs
    - Nausea
    - Facial erythema
    - Profuse sweating
    - Myocarditis
  - Course
    - Early: Progressive myalgias
    - Late: Resolution over ~ 2 weeks
- Laboratory
  - EMG: Complex & Myotonic activity; No fibrillations
  - Serum CK: Very high
  - Hyperthermia
  - Muscle biopsy: "Nibbled" myofibrils; Edema
- External link
Russula subnigricans
- Toxin: Cycloprop-2-ene carboxylic acid
  - Mechanism of muscle damage: ?
- Clinical
  - Rhabdomyolysis
    - Stiff shoulders
    - Backache
    - CK: Very high
    - Urine: Myoglobin
  - Onset
    - Nausea & Diarrhea
    - 30 min after ingestion
  - Speech impairment
  - Convulsions
  - Pupil contractions
Clitocybe acromelalga & C. amoenolens
- Toxin: Acromelic acid (ACRO) ²⁸
  - A isoform (ACROA) most potent
  - Kainate analogue
  - Stimulates unmyelinated mechanosensitive afferent axons in skeletal muscle
  - Produces selective damage of inhibitory spinal cord interneurons
  - Effect blocked by
    - N-methyl D-aspartate (NMDA) receptor antagonists
    - Joro spider toxin (Ca⁺⁺-permeable AMPA receptor antagonist)
- Clinical
  - Onset: Days after ingestion
  - Allodynia: Strong & Long-lasting; Tactile
  - Burning pain, Redness & Swelling: Periphery of the body
  - Symptoms similar to erythromelalgia
  - Course: Resolution over weeks

Pentaborane

Uses: Rocket fuels; Semiconductors; Catalysts
Exposure: Inhalation; Ingestion; Skin
Clinical: High dose
- Cardiac: Depression; Hypotension; Bradycardia
- Metabolic acidosis
- Muscle: Rhabdomyolysis; High CK; Myoglobinuria
- Neurologic: Encephalopathy
Laboratory
- EEG: Slowing; Seizures
- CT: Cerebral edema followed by brain atrophy
Treatment: ? Catecholamines; Pyridoxine
Prognosis: High mortality; Residual cognitive defects

e-Amino Caproic Acid (Amicar)

Use: Inhibits fibrinolysis
Onset of myopathy
- Up to several weeks afer treatment with high dose (30 g/day)
- Tenderness & weakness in proximal muscles
Clinical syndrome
- Necrotizing myopathy: Weakness & Muscle tenderness
- Rhabdomyolysis
Symptoms improve after discontinuation of treatment
Mechanisms of disease
- ? Production of carnitine deficiency: Competes with lysine for carnitine synthesis
- Ischemia

Lipid lowering agent myopathies ⁴

Fibrates
General syndromes
Myotoxins
Statins

General clinical syndromes
- Frequency of myopathy: 1 to 6 in 10,000
- Risk factors
  - Epidemiology
    - Gender: Female
    - Age: > 70 years
    - Body mass: Low
  - Diseases
    - Renal: Creatinine clearance < 30 mL per minute per 1.73 M²
    - Liver
    - Diabetes
    - Hypothyroidism
    - Debilitated status
    - ? Mitochondrial disease ¹⁷
  - Associations
    - Exercise
    - Surgery or Trauma
  - Concurrent
    - Medications & Dietary factors
    - Excessive alcohol intake
    - Other substance abuse
  - Statin
    - Dose: > 50% Maximal recommended dosage
    - Drug property
      - Lipophilicity
      - Serum protein binding: Low
  - Gene polymorphisms
    - CoQ2
    - SLCO1B1
    - ATP2B1
    - DMPK
    - Transporters: ABCG2 & ABCB1
    - Metabolic enzymes: CYP2C8 & UGT1A3
- Clinical features
  - Onset
    - Usual: 2 to 3 months after starting lipid-lowering drug
    - Range: 2 days to 2 years
    - Myalgias
    - ? Serum CK elevation before symptoms
  - Myalgias
    - Type of discomfort: Pain; Cramp sensation; Muscle tenderness
    - Pain: Present at rest; Increased with exercise
    - May occur with normal CK
    - Progress to myoglobinuria unless drug stopped
  - Weakness
  - Myoglobinuria
  - Recovery: Days to months after stopping drug
- Laboratory
  - Serum CK
    - Myopathy: High; < 1% of patients taking statins
    - Myalgias only: May be normal
  - Pathology: Scattered necrotic muscle fibers
Fibric acid derivatives (Fibrates)
- Specific drugs: Clofibrate; Bezafibrate; Ciprofibrate; Clofibrate; Gemfibrozil
- Primary metabolism: Renal
- Epidemiology
  - Frequency: 6 cases per 10,000 patients
  - Relative risk of myopathy in fibrate users vs controls: 42x ⁶
- Increased risk
  - Renal failure
  - Nephrotic syndrome
  - Drugs, concurrent: Probenecid; Furosemide; Statins
- Onset: After 2 to 3 months of treatment
- ± Associated cardiomyopathy
- Biochemistry
  - Reduced Fatty acid & Branched chain amino acid oxidation
  - Reduced Carnitine palmitoyl transferase activity

HMG-CoA Reductase Inhibitors (Statins) ⁹

Drugs: All statins associated with myopathic disorders
- Lovastatin; Simvastatin; Pravastatin; Fluvastatin; Atorvastatin; Cervistatin
- Relative risks: Increased incidence of myopathy when
  - Compared to controls ⁶: 8x
  - Statin relations
    - Higher doses used
    - Statins with longer half life
    - Relative toxicity: Atorvastatin > Pravastatin = Simvastatin = Lovastatin > Fluvastatin
      - Correlates with drug half-life
  - Statins are given with drugs that inhibit metabolism in liver
    - Gemfibrozil, Niacin, Cyclosporine; Azoles; Diltiazem; Erythromycin; Colchicine
  - Organ failure: Hepatobiliary dysfunction; Renal failure
  - Cytochrome P450 polymorphisms with reduced activity: Except pravastatin & rosuvastatin
  - SLCO1B1
    - Encodes organic anion-transporting polypeptide, OATP1B1
    - Regulates hepatic uptake of statins
    - Odds ratio for simvastatin myopathy with non-coding CC SNP polymorphism: 16.9x greater
  - Hypothyroidism
Toxins: Red yeast rice (Monascus purpureus) ¹⁶
- Contains monacolin K (identical to active product in lovostatin)
- Fermented food product in China: Variable content of monacolin K
- High CK (asymptomatic) developed in transplant patient also taking cyclosporine

Pharmacology

General features
- Primary metabolism: Hepatic
- HMG-CoA Reductase enzyme
  - Catalyzes formation of Mevalonic acid from HMG-CoA
  - Also plays role in synthesis of Ubiquinone & Isoprenylated proteins
- Statin toxicity
  - Direct effects on muscle metabolism
  - RYR1 activation ⁴⁵
    - No relation to HMG-CoA reductase activity
    - Most potent statin for RYR1 activation: Cerivastatin
  - ? Association with coenzyme Q10 deficiency ¹⁵
  - Increased likelihood of effects: Inhibition of statin metabolism by interactions with other drugs
Statin Interactions
- Statin myopathy syndromes more common with associated interacting medications
- Mechanism of interaction: Often related to inhibition of statin metabolism
  - Most statins lipid soluble
    - Degradation: Hepatic & enteric systems
      - Most statins: Degradative enzyme is CYP3A4
      - Fluvastatin: Degradative enzyme is CYP2C9; Fewer drug interactions
    - Common drug interaction mechanism: Inhibit degradation of most statins by inhibition of CYP3A4
  - Exception: Pravastatin
    - Water soluble
    - Renal excretion
    - Fewer reports of interactions with Cyclosporin A

Statins: Metabolic interactions with other drugs

Metabolic enzyme
(Catabolic)

Statins

Drugs inducing
enzyme

Drugs inhibiting
enzyme

CYP3A4

Atorvastatin
Lovastatin
Simvastatin
Cerivastatin

Phenytoin
Barbiturates
Carbamazepine
Rifampin
Dexamethasone
Cyclophosphamide
Troglitazone
St John's wort

Antifungal
Ketoconazole
Itraconazole
Fluconazole
Antibiotic
Erythromycin
Clarithromycin
Azithromycin
Fusidic acid
Tricyclic antidepressants
Calcium channel blockers
Diltiazem
Verapamil
Mibefradil

Other
Amiodarone
Bezafibrate
Chlorzoxazone
Cholestyramine
Colchicine
Corticosteroids
Cyclosporin A
Danazol
Dicumarol
Digoxin
Fluoxetine
Fluvoxamine
Gemfibrozil
Grapefruit juice
Midazolam
Nefazodone
Niacin
Protease inhibitors
Sertraline
Tacrolimus
Tamoxifen
Venlaflaxine

CYP2C9

Fluvastatin
Rosuvastatin

Rifampin
Phenobarbital
Phenytoin
Troglitazone

Ketoconazole
Fluconazole
Sulfaphenazole
Warfarin

Statins: Drug interactions associated with rhabdomyolysis
	Fibrates	Warfarin	Digoxin	Macrolide antibiotics	Niacin	Antifungals	Cyclosporin
Atorvastatin	+	+	+	+		+	+
Cerivastatin	+	+	+	+			+
Fluvastatin	+	+	+
Lovastatin	+	+	+	+	+	+	+
Pravastatin	+	+	+	+	+		+
Simvastatin	+	+	+	+	+	+	+

Possible direct mechanisms underlying myopathy production by statins
- Mevalonic acid & farnesol formation: Inhibition in skeletal muscle
  - Causes reduced levels of cholesterol precursors
  - End result: Altered cell membrane permeability
- Mitochondrial
  - Reduced levels of ubiquinone: Might cause disturbances in cell energy production
  - Reduced synthesis of Coenzyme Q10: Association with lactic acidosis ¹⁴
Inhibition of isoprenoid synthesis

Clinical myopathy syndromes
- Frequency of myopathic side effects
  - Overall frequency
    - 10% to 15%
    - Dose dependent
  - Myalgias
    - Frequency: 6% to 14%; ? Higher frequency than with placebo
    - Type of discomfort: Pain; Cramp sensation; Muscle tenderness
    - Pain: Present at rest; Increased with exercise
    - Present while taking drug & possible for several months after drug discontinuation
  - Myopathy: Frequency
    - Overall: ~1 in 10,000 patients; 0.02% to 2%
    - Monotherapy: 0.1% to 0.5%
    - ? Less common with Fluvastatin, Atorvastatin & Cervistatin
  - Rhabdomyolysis: 0.5%
- Myalgia
  - Most common syndrome
  - Distribution: Proximal or Diffuse
  - May occur with normal CK
- Myopathy
  - Weakness: Proximal > Distal, Symmetric
  - Often preceeds rhabdomyolysis
  - Rarely persists after discontinuation of drug
  - Early ultrastructural changes in lovastatin myopathy: Mitochondria & SR membranes
  - Fast twitch muscles more sensitive to lovastatin myopathy
- Rhabdomyolysis
  - Onset during drug administration: 3 Weeks to Months
  - Associated with weakness: Proximal > Distal
  - Serum CK
    - Very high
    - Rapid fall after drug discontinuation
    - Monitoring may not predict rhabdomyolysis
  - Pathology: Muscle
- Exercise intolerance
  - Frequency: Many athletes
  - May increase exercise induced muscle damage
- Myopathy with HMGCR antibody
  - Not a direct toxic effect of statins: Many patients with no history of statin use
  - Possible increased frequency of statin use in disease population
- Increased CK: Statins
  - May increase resting CK by 50%
  - Exaggerate exercise-induced CK elevations (~1.9x)
- Other features
  - Arthralgias
  - Peripheral neuropathy
  - Weakness & falling in elderly ²⁷
  - Myasthenia gravis: May occasionally cause increased weakness
Serum CK
- CK level higher in more severe disorders
- Statins may predispose to high CK after exercise
Treatment
- Stop drug in all patients with weakness
- ? Coenzyme Q10 60 mg bid x 2 months
- Treat for rhabdomyolysis
- Monitor serum CK until normalized
Animal models: Statin-Induced Muscle Necrosis
- Onset: ≥ 10 days after onset of drug exposure
- Drug dose dependent: High doses required
- Type IIB (Fast twitch) muscle fibers: Most sensitive to toxic necrosis
- Type I (Slow twitch) muscle fibers: Least sensitive to toxic necrosis
- Resting cytosolic Ca⁺⁺ concentrations
  - Increased
  - Increasing Ca⁺⁺ release from
    - Sarcoplasmic reticulum: Caffeine-stimulated
    - Mitochondria: Through permeability transition pore

Cocaine ³

Source: Leaves of coca tree, Erythroxylon coca
Toxic exposure: IV; Nasal; Oral
Clinical syndromes
- CNS
- Myopathy
- Systemic
  - Renal failure
  - Cardiac: Infarction; Dysrhythmias
  - Pulmonary edema
  - Effects on fetus: Crosses placenta

Propofol

Use
- General anesthetic
- CNS sedative: Interacts with gamma amino butyric acid aminotransferase receptors
Rhabdomyolysis
- Skeletal ± Cardiac muscle
- In children & adults
- Onset
  - After prolonged infusion: 24 to 48 hours
- Prognosis: High mortality
Produces: Metabolic acidosis; Hypoxia

Proton pump inhibitors (PPI) ¹⁹

Drugs: Omeprazole, Pantoprazole, Lansoprazole, Esomeprazole, Rabeprazole,
Use: GI ulcer, reflux & hypersecretory disorders
Usual onset of toxicity: 1 to 10 weeks after drug use onset
Clinical myopathy syndromes
- Myalgias: 3% to 10%
- Rhabdomyolysis
- Myopathy
  - Weakness
  - Serum CK: High
  - Muscle: ? Inflammation
  - Course
    - Usually improves to normal after drug withdrawal
    - May recur with reinstitution of PPIs
- Dermatomyositis: Rash + Weakness + High serum CK
- High CK without symptoms
- Drug interactions
  - Statin
  - Clarithromycin
  - Methotrexate: Myalgias
Hyperhidrosis: Omeprazole, not other PPIs
- Intermittent: Episodes persist for minutes to hours
- Diffuse
- No clear precipitating factors
- Few other autonomic symptoms or signs

Quarter Horse (QH), Myosin heavy chain Myopathy (MYHM) ⁴³

● Myosin Heavy Chain I (MYH1; Myosin 2X)

; Chromosome 17p13.1; Dominant

Epidemiology
- Heterozygotes: 7% to 24% of Quarter horses, especially reining & cow
- Other causes of rhabdomyolysis in horses
  - Hypoglycin A toxicity
  - Type 1 polysaccharide storage myopathy (PSSM1)
  - Malignant hyperthermia (MH)
Genetics
- Mutation: Missense; E321G; Homozygous or Heterozygous
- Allelic disorder: Rhabdomyolysis, human
MYH1 protein
- Myosin 2X
- Present in Type 2B (Fast; Fatiguable) human muscle fibers
Clinical
- Triggers: Respiratory pathogens; Vaccination
- Rhabdomyolysis: Non-exertional
- Myositis, Immune
Laboratory
- Muscle
  - Atrophy: After exertional rhabdomyolysis
  - IMM 2X fibers: Fewer; Glycogen lost; associated lymphocytes
- Serum CK: High
MYH1 variant: Rhabdomyolysis, humans ⁴⁴
- Epidemiology: 2 patients
- Genetics
  - Inheritance: Recessive
  - Mutation: Homozygous; lys432Thr, Val609Met
- Clinical: Rhabdomyolysis
  - Onset: 14 to 28 years
  - Episodic/Recurrent: 1 to 2 per year
  - Episodes: Pain; Cramps; Weakness
  - Precipitants: Infections; Exertion
- Laboratory
  - Serum CK: up to 200,000
  - EMG: Myopathy, irritable
  - Muscle pathology: Necrosis

Rhabdomyolysis, Recurrent (RHABDO1) ⁴⁶

● Obscurin (OBSCN)

; Chromosome 1q42.13; Recessive

Nosology: Rhabdomyolysis, susceptibility to, 1
Epidemiology: 6 patients
Genetics
- Mutations: Loss of function
- Allelic disorder: Cardiomyopathy
OBSCN protein
- SR function: Linker protein between Sarcomere & SR
- Ca⁺⁺ handling
- Sarcomere: Localises to M-band & Z-disks
- Interacts with: Titin, Myomesin, Small ankyrin 1
Clinical
- Onset age: 12 to 27 years
- Between episodes: Exercise intolerance (50%); Myalgias
- Weakness: 1 patient
- Rhabdomyolysis triggers: Exercise; Heat
- Renal failure (40%)
- Compartment syndrome (30%)
Laboratory
- Serum CK: Normal to Mildly high between episodes
- Muscle MRI: Normal
- Muscle pathology
  - Fiber sizes: Varied
  - Cores: 1 patient
  - Ultrastructure: T-tubules dilated

Rhabdomyolysis, Adult onset ⁵⁷

● Collagen IV-α2 (COL4A2)

; Chromosome 13q34; Recessive

Epidemiology: 1 patient
Genetics
- Mutation: Missense; G1383R
- Allelic disorder: Brain small vessel disease 2, Dominant
COL4A2 protein
- Vascular basement membranes with COL4A1
  - Form sheetlike basement membranes
  - Separate epithelium from connective tissue
- Collagens
Clinical
- Onset age: 35 years
- Acute onset
- Pain
- Leg swelling
Laboratory
- Serum CK: 31,000; May be high at rest
- Brain MRI: Polymicrogyria

Exertional Heat Stroke

Epidemiology
- Rare in women
- More common with type II muscle fiber predominance
Clinical syndrome
- Fever
- Encephalopathy: Delerium; Seizures; Coma
- Muscle: Rhabdomyolysis; Weakness
- Anhidrosis: Some patients
- Systemic: Hypotension; Multi-organ failure
Laboratory
- Lactic acidosis
- Hypoglycemia
- Disseminated intravascular coagulation
- Potassium: Variable; Hypokalemia promotes rhabdomyolysis
- Serum CK: Very high

Idiopathic Recurrent Myoglobinuria

Overall: Probably caused by multiple disorders
Genetics: May be Sporadic, Recesssive or Dominant
Onset triggers
- Exertion
  - More common
  - Male > Female
- Infection
  - Earlier onset
  - Male = Female
  - More frequent renal failure: Some with lipid myopathies
Laboratory
- Serum CK: High during attacks
- Muscle biopsy: Non-specific changes; Mildly abnormal to Myopathic

Compartment Syndromes

Definitions & Features

Tissue damage: Pathogenesis
- Tissue pressure > Perfusion pressure (Capillary)
- Location: Closed anatomic space
- Effects: Ischemia; Necrosis after 6 hours
Tissue damage: Clinical effects
- Functional impairment
  - Intracompartmental structures: Nerve; Muscle
  - Weakness
- Rhabdomyolysis: Renal failure
- Pain
  - Early: Out of proportion to examination
  - Induced by: Passive limb movement, Muscle stretch
  - Neural compression: Burning; Paresthesias
  - Tightness
- Swelling
Variant: Chronic exertional compartment syndrome (CECS)

General associations

Fracture: 69%; Long bones
Local injury: Trauma; Overexertion
Males: Up to 90%
Age: Mean < 35 years; Older in females
Hypotension
Bleeding disorder

Precipitating factors & Localization

Fractures & Trauma
- Distal leg: Tibial shaft (diaphysis) fracture; Trauma ³⁹
  - Most common syndrome
  - 6% of tibial shaft fractures
  - Precipitants: Sports & Traffic accidents
  - Compartments involved
    - Anterior
      - Most common location
      - Contents
        
        Muscles: Anterior tibial, Toe extensors
        
        Tibial artery
        
        Deep peroneal nerve
    - Other compartments in lower leg
      - Lateral
        
        Superficial & Deep peroneal nerves
      - Superficial posterior
        
        Gastrocnemius & Soleus
        
        Least common
      - Deep posterior
        
        Muscles: Posterior tibial, Toe flexors
        
        Peroneal artery
        
        Tibial nerve
- Distal radius: Forearm
  - Radial fracture
    - Frequency: 1%
    - More in younger patients
  - Associated with high-energy injury
Soft tissue injury
- Types
  - Trauma: High velocity; Stretch; Vigorous exercise; Crush
  - Envenomation
- Regions: Proximal arm or leg; Abdomen; Other
Vascular damage
- Penetrating injury
- Intra-arterial injection
Reduced compartment size
- Compression: Tight clothing; Casts
- Burns

Laboratory

Compartment pressure measurement: High
Serum CK: High
MRI: Increased T2 signal in muscle compartment

Treatment

Syndrome recognition: Within 6 hours
Surgery
- Fasciotomy
- Prognosis: Often good recovery
Manage rhabdomyolysis


Compartment syndrome: Deltoid muscle (MRI)

Compartment syndrome variant: Chronic exertional compartment syndrome (CECS) ⁴⁰

Nosology: Effort-related chronic compartment syndrome (ERCCS); Arm Pump
Definition: Pathologic increase in intramuscular compartment pressure with effort
Diagnosis: Needle manometry
- Pressure in muscle may remain midly high at rest
Clinical: Loocalized discomfort during exercise or effort
- Dull ache: Continuous
- Swelling
- Weakness
- Paresthesias
- Endurance capacity: Limited
- Pain course: Activity related
  - May last minutes to hours ater stopping activity
  - Recurrence of symptoms soon after resuming activity
- Sports
  - Upper limbs: Motorcyclists, Mountain biker, Race car, Wrestlers, Rowers, Weightlifters, Climbers
  - Lower limbs: Running; Marching military
- Treatments
  - Non-operative
  - Fasciotomy
Differential diagnosis
- Upper limb
  - Claudication (PAD) Tendonitis/myositis
  - Radiculopathy Peripheral nerve entrapment)
  - Tendonitis/myositis
  - Fibromyalgia
- Lower limb
  - Medial tibial stress syndrome (Shin splints)
  - Stress fracture
  - Stress fracture DVT
  - DVT
  - Radiculopathy
  - Popliteal artery-entrapment syndrome
  - Fibromyalgia

BIOLOGIC TOXINS: SNAKE & OTHER

Acetylcholine receptor (AChR) binding
Clinical syndromes
Myotoxic
Peptides
Phospholipase A₂ proteins
Venom protein classes
Three-finger
Metalloproteases
PLA₂: General
Serine protease
Secondary

Snake Venoms: Protein classes ⁴⁸

Phospholipase A₂ (PLA₂)
- Most common venom protein family: Elapids & Vipers
- Up to 90% of venom proteins in some species (Pseudechis papuanus)
- Sizes (kDa): 13 to 18.5
- Mono- or Multi-meric: Oligomers most toxic
- Toxicity
  - Some are Myotoxic
  - Poor correlation with phospholipase enzyme activity
  - No direct effect on muscle contractile apparatus
- PLA₂ activity in serum: Suggests envenomation
- May oligomerize with other venom families: β-bungarotoxin in krait venoms
Snake venom metalloprotease (SVMP)

Sizes (kDa): 20 to 100
Mono or Multi domain
Abundant in viper venoms (Bothrops)
Actions: Varied
- Hemorrhagic: Common
- Procoagulant: Echis induced consumption coagulopathy

Three-finger toxins (3FTx)
- Elapid venoms
- Sizes (kDa): 6 to 9
- Monomeric
- Up to 95% of venom proteins in some species (Micrurus tschudii, M. surinamensis)
- Non-enzymatic actions
- Sub-groups
  - α-neurotoxins
    - Post-synaptic AChR binding
      - Antagonize ligand gated channels
      - Prevent channel opening
    - Longer chain α-neurotoxins: More important in human syndromes
- Other venom targets & types
  - Muscarinic ion channels
  - Calcium channels, L-type: Calciseptines; African mamba (Dendroaspis) venoms
  - Acetylcholinesterase: Fasciculins; African mamba (Dendroaspis) venoms
  - Na_v1.4 channel: Calliotoxin; Malayan Blue Coral Snake (Calliophis bivirgata)
  - Cytotoxins (CTX; Cardiotoxins): Cobra (Naja) venom ⁴⁹
    - CTX protein properties
      - 60 to 62 AAs
      - Protein folding: Produces 3 fingers or loops
      - > 100 different sequences
      - May form complexes with other venom components: More toxicity
    - Pharmacolgical mechanisms
      - Interactions with cell membranes
        
        Involves 1 to 3 loops (fingers) in toxin molecule
        
        Recognizes phospholipid micro-domains or rafts
        
        May form pores in lipid bilayer
      - May be internalized: Localize to lysosomes & mitochondria
    - Cell effects
      - Alter cell membrane structures
      - Affect membrane-bound proteins
      - Activate apoptotic & necrotic cell death pathways
    - Tissue pathology types
      - Neuromuscular paralysis
      - Tissue necrosis
        
        Dermonecrosis: Cytotoxic 3FTx; Spitting cobras
        
        Muscle fiber necrosis & regeneration: Local toxin injection
Snake venom serine protease (SVSP)

Sizes (kDa): 26 to 250
Mono- or Multi-meric
Effects
- Procoagulants: Common
- Kininogen clevage: Release bradykinin → Hypotension

Secondary classes: Several types
- L-Amino acid oxidase (LAAO)
- Cysteine-rich secretory protein (CRiSP)
  - Cyclic nucleotide-gated (CNG) ion channel blockade: Australian elapids
- C-type lectin (CTL): Hemotoxic
- Disintegrin (DIS): Integrin receptors blockade
- Natriuretic peptide (NP): May potentiate or inhibit bradykinin
- Kunitz peptide (KUN)
  - Kv1 channel blockade: Dendroaspis polylepis
  - β-bungarotoxin: Krait (Bungarus)
- Vascular endothelial growth factor (VEGF)
- Nerve growth factor (NGF)
- Nucleotidase (NUC)
- Phosphodiesterase (PDE)
  - Hypotensive: (Crotalus spp (Rattlesnake))
- Cobra venom factor: Activates & Depletes complement
- Crotamine: Myoneurotoxin
- Waglerin: Antagonizes muscle nAChRs (Tropidolaemus)

Snake Venoms: General syndromes

Coagulopathy
Neurotoxicity
Myotoxicity
Cytotoxicity

Myotoxic peptides

Crotalus: Crotamine ; Peptide c ; Toxin III; CAM-toxin
43 to 45 amino acid peptides cross-linked by 3 disulfide bridges
No enzyme activity
Mechanisms
- Interact with Na⁺ channels in sarcolemma & T-tubules
- Increase Na⁺ flux into muscle
- ? Also disrupt membrane structure
Biologic activities on muscle after i.m. injection
1. Contracture for 1 to 3 hours
2. Vacuolation: Dilation of sarcoplasmic reticulum
3. Necrosis

Myotoxic phospholipase A₂-like proteins: 2 groups

LD₅₀ > 1 mg/kg
- Myotoxic; Produce myoglobinuria
- Toxins: Pseudechis (Mulga snakes) ; Bothrops ; Agkistrodon
- Biologic activities: Toxins on muscle fibers (After i.m. injection)
  - Lys49 myotoxin
    - Toxic region: C-terminal peptides 115-129
    - Membrane acceptor on sarcolemma: Nucleolin
    - No phospholipase activity
    - Action blocked by: Heparin
    - No effects on: Nerve; Satellite cells; Vessels
    - Also produce: Inflammatory reactions
    - Other venom toxin: Phospholipase A₂ Asp49
      - Has phospholipase hydrolysis activity
      - Synergistic with Lys49 protein
  - Membrane effects: Lysis; Focal "Delta" lesions
    - Basal lamina & satellite cells remain intact
    - May show selectivity for species & slow (oxidative) muscles
    - Hydrolytic activity of phospholipases A₂: May not be necessary for toxicity
  - Muscle fiber effects
    - Necrosis: Rapid; 1 to 3 hours
    - Phagocytosis: 1 to 2 days
    - Fiber Regeneration
      - Pure toxin: 3 to 4 weeks
      - Whole venom
        
        Muscle fiber regeneration: Poor
        
        Connective tissue: Increased
    - Damage biomarker: Serum CK
- Biologic activities: Whole snake venom ⁴¹
  - Damage to: Muscle fibers, Vessels & Connective tissue
  - Poor muscle fiber regeneration
LD₅₀ < 1 mg/kg
- Act on: Presynaptic nerve terminal & Muscle
  - Toxins: Notexin ; Crotoxin ; Taipoxin ; Mojave toxin ;
    Ceruleotoxin; Micrurus corallinus; Bungarus niger ²⁹
  - Structure: 2 peptide chains
    - Phospholipase A2 chain
    - Kunitz-type protease inhibitor chain
  - Toxin effects
    - Presynaptic motor nerve terminal: Damage
    - Muscle fibers: Necrosis
    - Post-synaptic structures at NMJ: Normal
  - Epidemiology
    - B. caeruleus & B. niger: Bites on people sleeping on floor
  - Clinical
    - Weakness
      - Onset: Hours after bite
      - Eye: Ptosis; Ophthalmoplegia
      - Respiratory
      - Dysphagia: Painful
      - Proximal
      - Myalgias
    - Myoglobinuria
- β-bungarotoxin : Selective for presynaptic nerve terminal; Not myotoxic
  - Snakes: B. multicinctus, B caeruleus
  - Toxin type: Polypeptide; Homologies with proteinase inhibitors
  - Binds to K⁺ channels by B-chain
  - Internalized
  - Effects: Triphasic via internalized A-chain (phospholipase A₂ )
    - Inhibition of ACh release: Transient
    - Facilitation of ACh release: Transient
    - Necrosis of presynaptic axon: Permanent block of ACh release

Acetylcholine receptor (AChR) binding compounds: Toxins & Venom polypeptides

Block active site of AChRs
No morphologic damage to muscle or nerve
Different avidities & binding properties

Skeletal muscle types

Target: Nicotinic AChRs containing
- α 1-subunit: Amino acids 173-204; Skeletal muscle
- α 7-subunit: Neuronal nicotinic
Permanent AChR blockade
- α-bungarotoxin
  - Snake: Bungarus multicinctus
  - Toxin: Polypeptide; 61-62 amino acids
  - Effect: Blocks ACh binding site on AChR
  - Also binds to neuronal membranes but no ACh blockade
- Lophotoxin
  - Lactone from Pacific gorgonian sea coral Lophogorgia
  - Covalently binds to AChRs
  - No toxicity in humans documented
Reversible AChR blockade
- α-cobra toxin
  - Snake: Cobra; Naja naja
  - Toxin: Polypeptide; 71-74 amino acids
  - Effect: Blocks ACh binding site on AChR
- Erabutoxin
  - Snake: Sea snake; Laticauda semifasciata
  - Binds to NMJs & neuronal AChRs containing α7-subunit
  - Clinical: Weakness of EOM, Facial & Bulbar; Generalized ± Respiratory
- Micrurus species: frontalis, lemniscatus, nigrocinctus
  - Weakness may be treated with anti-cholinesterase drugs
- Imidacloprid ⁵⁰
  - Neurotoxic insecticide
  - Neonicotinoid
    - Structural & Functional homology to nicotine
    - Interferes with synaptic transmission between neurons & at NMJ
    - Selectivity towards insect vs mammmalian nicotinic AChRs
  - Human toxicity: 1 patient reported
    - Mental status: Drowsiness; Irritability
    - EOM disorder: Ptosis, fatiguable; Limited abduction & upgaze
    - Other muscles: Normal strength
    - RNS: Decrement
    - Course: Improvement over 2 days

Neuronal types: Nicotinic AChR binding

κ-bungarotoxin & κ flavotoxin
- Toxin: Polypeptide; 66 amino acids
- Snake: Bungarus multicinctus
- Bind to AChRs containing alpha 3-subunit (especially α3-β2)
- Effect: Blocks ACh binding site on neuronal AChRs
Epibatidine
- Skin of equadoran frog: Epipedobates tricolor
- Toxin: Alkaloid; Molecular weight 210
- Binds to α3 subunit of neuronal AChR: Cholinergic agonist
- Anti-nociceptive effects
ABT-594

From Aquaviva

Epipedobates tricolor

Epibatidine

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12/17/2024