12.6. Ryanodine-Receptor/Calcium Channel Disease
Central Core Disease
- Genetics:
- Clinical presentation:
- Onset in infancy
- Hypotonia
- Congential hip dislocation
- Spares extraocular muscles, face and swallowing
- Weakness slowly progressive into adulthood
- Some children are severely affected and develop kyphoscoliosis
- Patients at risk for malignant hyperthermia
- Pathology
- Cores of degenerating myofibrils at the center of Type I fibers
Malignant Hyperthermia
- Genetics: mutations of several genes: usually AD
- RYRI gene nystagmus (malignant hyperthermia I; MHI):
- Chromosome 19q 13.1
- Most common genetic mutation
- MH2
- MH3:
- Chromosome 7q 21-q22
- α2/8 subunit of L-Type dihydropteridine (DHP) receptor
- MH4
- MH5:
- Chromosome 1q31-q32
- Mutation of the α, subunit of the DHP calcium channel c-receptor (CACNL-1A3)
- MH6
Mechanism of Attacks
- Increased release of calcium causes severe prolonged muscle contraction
- RYRI receptor is activated at lower than normal calcium concentration; located in the sarcoplasmic reticulum (SR)
- Succinylcholine increases membrane depolarization
- DHP-receptor is located in the T-tubule system and is the voltage sensor for the RYRI receptor
- Opening of DHP receptor causes the RYRI channel to release calcium
- Ether and halothane trigger the process in susceptible individuals
- Prevalence:
- Occur in one of every 50,000 adults undergoing anesthesia
- Clinical presentation:
- Muscle spasm
- Often masseter muscle rigidity and spasms occur initially and is noted by the anesthetist; increase of end-tidal CO2
- Generalized rigidity
- Rapid rise in temperature greater than 105° Fahrenheit
- Usually temperature falls during anesthesia
- Hypermetabolism:
- Increased oxygen consumption
- Acidosis; respiratory or metabolic
- Hypoxemia; increased end-tidal CO2 greater than 60
- Cardiac arrhythmia; tachycardia
- Muscle necrosis:
- Elevated CK; greater than 10,000 units/liter
- Potassium increases
- Lactic acidosis
- Myoglobinuria greater than 60 μg/liter:
- If unrecognized may lead to renal failure
- Serum myoglobin greater than 170 μg/liter
- Labile blood pressure
- Mottled cyanotic hot sweating skin
- Attacks may be triggered by exercise and stress; rare attacks may be observed 24 hours after surgery; this includes minimally invasive procedures in susceptible patients
- Diseases associated with a MH-like syndrome:
- Congential myopathies:
- Central core disease (calcium release mechanism)
- Multicore disease
- Evans myopathy
- King–Denborough Syndrome
- Muscular dystrophies:
- Dystrophinopathy
- Myotomic dystrophies
- Periodic paralysis
- Metabolic myopathies:
- Phosphorylase deficiency
- Carnitine palmityl transferase deficiency
- Miscellaneous diseases:
- Hyper CK-emia
- Brodie's disease
- Myotonia congenita
Differential Diagnosis of Malignant Hyperthermia
The differential diagnosis is clear in susceptible individuals who have a full blown syndrome during anesthesia. Several similar appearing attacks during anesthesia occur in some myopathies due to increased muscle membrane depolarization, but not calcium release mechanisms. These myopathies are noted above. Central core disease is allelic to MH and the attacks are similar. Exercise and stress may induce MH with consequent myoglobinuria. The cramps are more severe, exercise tolerance is more limited in the metabolic myopathies where this occurs. Hyperthermia is not seen with the metabolic myopathies. Anesthetic clearance should include a family history of unexplained death during minimally invasive procedures (or unexplained problems with minor surgery), a history of congenital myopathy or unexplained CK-emia.
- Diagnosis:
- Established by the caffeine or halothane induced contracture test of biopsied muscle
- Possible triggering agents include:
- Catecholamines
- Ketamine
- Phenothiazines
- MAO inhibitors
- Triggering Agents in Susceptible Patients
- Depolarizing blockers:
- Succinylcholine
- Decamethonium
- Suxamethonium
- Inhalational anesthetics:
- Enflurane
- Halothane
- Desflurane
- Sevoflurane
- Isoflurane
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