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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
    Myalgia + Rhabdo: MLIP; 6p12
    MYH1
    OBSCN
    Other
  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
  Muscular dystrophies
  MYHM (Horse): MYH1
  Myoadenylate deaminase deficiency
  Native American Myopathy: Stac3; 12q13
  Other familial
  Sickle cell anemia


MYOGLOBINURIA: General features 12


MYOGLOBINURIA: Specific causes

Malignant Hyperthermia Glycogen metabolic disorders Fatty acid oxidation & Lipid metabolism Myoglobinuria: Mitochondrial disorders Familial: Other disorders with occasional myoglobinuria Drugs & Toxins Systemic
Hypokalemic myopathy & Rhabdomyolysis Muscle Trauma Ischemia (Hypoxia) Infections Immune myopathy

Muscle: Exercise related genetics & pathology 31



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



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


Monensin-Induced Rhabdomyolysis 11


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
      • 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 &amp; 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
      • 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)

Rhabdomyolysis (Myoglobinuria), Child-onset, Recurrent 24

  Lipin-1 (LPIN1) ; Chromosome 2p25.1; Recessive

Myopathy with Myalgia, Rhabdomyolysis & baseline high Serum CK 42

  Muscular Lamin A/C Interacting Protein (MLIP, c6orf142) ; Chromosome 6p12.1; Recessive

Myopathy, Congenital, Bailey-Bloch (MYPBB) 25

  SH3 and cysteine-rich domain-containing protein 3 (STAC3) ; Chromosome 12q13.3; Recessive

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

  Transport and Golgi organization protein 2 homolog (TANGO2; C22orf25) ; Chromosome 22q11.21; Recessive

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

  Transport (Trafficking) protein particle complex 2-like (TRAPPC2L) ; Chromosome 16q24.3; Recessive

Neuroleptic Malignant Syndrome (NMS)


Serotonin syndrome


Haff disease


Mushroom intoxication


Pentaborane


e-Amino Caproic Acid (Amicar)


Lipid lowering agent myopathies 4

Fibrates
General syndromes
Myotoxins
Statins

Cocaine 3


Propofol


Proton pump inhibitors (PPI) 19


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

  Myosin Heavy Chain I (MYH1; Myosin 2X) ; Chromosome 17p13.1; Dominant

Rhabdomyolysis, Recurrent 46

  Obscurin (OBSCN) ; Chromosome 1q42.13; Recessive

Exertional Heat Stroke


Idiopathic Recurrent Myoglobinuria


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

BIOLOGIC TOXINS: SNAKE & OTHER

Acetylcholine receptor (AChR) binding
Myotoxic
Phospholipase A2 proteins

Myotoxic peptides Myotoxic phospholipase A2 proteins: 2 groups Acetylcholine receptor (AChR) binding compounds: Toxins & Venom polypeptides
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References

1. Muscle Nerve 2000;23:4-17
2. Am J Med 2000;108:577-580
3.Heart & Lung 1997;26:466-485
4. Drug Safety 2000;22:441-457, Curr Opin Lipidol 2002;13:637-644, Ann Pharmacother 2002;36:1957-1960
5. Am J Hum Genet 2001;69:
6. Epidemiology 2001;12:565-569
7. NEJM 2001;345:798-802
8. Muscle Nerve 1996;19:790-792
9. Ann Pharmacother 2001;35:1096-1107, Current Opinion in Neurology 2005;18:494–496, Curr Opin Neurol 2009;22: Online August
10. Am J Med Genet 1998;78:254-259
11. American J Kidney Disease 2001;38:1108-1112
12. Muscle Nerve 2002;25:332-347
13. Molecular Genetics and Metabolism 2002;77:21–30, J Clin Invest 2007;117:587–589
14. Clin Pharmacol Ther 2002;72:461-464
15. Clin Invest Med 2001;24:2258–2272, Curr Opin Rheumatology 2002;14:643–647
16. Transplantation 2002;74:1200-1201
17. Southern Med J 2003;96:318-320
18. Current Opinion in Pediatrics 2004;16:206–210, Int J Med Sci 2019;16:1504-1509
19. Eur J Clin Pharmacol. 2006;62:473-479
20. Am J Hum Genet 2006;79:1125-1129
21. J Clin Invest 2007;117:765–772
22. Brain 2007 Apr 5
23. Mitochondrion 2007 Mar 27, Neuromuscul Disord 2011; Jun 30, Curr Opin Neurol 2011;24:449-456, Dev Disabil Res Rev 2010;16:183-188
24. American Journal of Human Genetics 2008;83: Online September
25. Neurology 2008;71: Online October, Nat Commun 2013;4:1952, Hum Mutat 2018 Aug 31
26. American Journal of Human Genetics 2009; Online April
27. QJM 2009 Jul 24
28. Neurosci Lett 2009;456:69-73
29. Brain 2010; Online September
30. Neuromuscular Disorders 2011; Online Sept
31. J Clin Neuromuscul Dis 2012;13:122-136
32. Exp Physiol 2014 May 30
33. BMC Genet 2014;15:58
34. Am J Human Genetics 2016; Online January, Arch Pediatr 2021;28:80-86
35. Gene Tests 2017
36. Alcohol Res 2017;38:207-217
37. J Clin Med 2019 Sep 2;8(9)
38. Am J Med Genet A 2020 Aug 17
39. Sports Health 2021;13:198-202
40. Phys Sportsmed 2017;45:391–398, Open Access J Sports Med 2019;10:71–79
41. Toxins (Basel) 2018;10:182, Toxicon 2021;192:46-56
42. Brain 2021 Sep 28, Brain 2022 Aug 2
43. J Vet Intern Med 2018;32:1718–1725
44. Am J Med Genet A 2021;185:2131-2135
45. Br J Pharmacol 2022 Jun 15
46. Brain 2021 Dec 27

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