It is a hereditary disease which triggers muscle contractions and an accelerated rise in body temperature.
Malignant hyperthermia (MH) is a dominant hereditary disorder of skeletal muscle that predisposes people susceptible to a potentially fatal adverse reaction (fulminating event of MH) after exposure to potent volatile anesthetics (halothane, isoflurane, sevoflurane, desflurane, etc.). ) and relaxant succinylcholine.
Anesthetic drugs trigger an uncontrolled release of calcium (Ca2 +) from the sarcoplasmic reticulum (SR) through the ryanodine receptor (RYR1) and cause a rapid and sustained increase in myoplasmic Ca2 +.
The high intracellular Ca2 + activates the Ca2 + pumps in the SR and the sarcolemma to re-take calcium in SR or to transport it to the extracellular space, respectively.
The energy cost to recover cellular control of Ca2 + causes the need for ATP, which in turn produces heat. The integrity of the muscle membrane is compromised, leading to hyperkalemia and rhabdomyolysis .
If not treated in a timely manner, withdrawing the anesthetic and administering dantrolene, the mortality can be greater than 70%. In some individuals, fulminant episodes of HM can be induced by stress, exercise and high environmental temperatures in the absence of anesthetics.
Signs and symptoms
A fulminating episode of Malignant Hyperthermia is characterized by hypermetabolism that produces heat (hyperthermia), increased oxygen consumption and carbon dioxide production, together with hyperkalemia and acidosis with hyperlacaectemia.
Skeletal muscle rigidity may be localized in the masseter or generalized muscle.
Muscle damage is reflected in increases in serum creatine kinase, potassium, calcium and phosphate. Rhabdomyolysis with myoglobinuria and myoglobinemia often occurs.
The time of onset after the induction of general anesthesia can vary from minutes to hours, and patients may have had previous exposure without incident to anesthetics.
The HM phenotype is inherited as an autosomal dominant trait with incomplete penetrance and variable expression. Dominant genetic disorders occur when only a single copy of an abnormal gene is needed to cause a particular disease.
The abnormal gene may be inherited from either parent or may be the result of a new mutation (gene change) in the affected individual. The risk of transmitting the abnormal gene of the affected parent to the offspring is 50% for each pregnancy. The risk is the same for men and women.
Molecular genetics studies in humans have established the rianaxin receptor-type calcium channel (RYR1) gene on the chromosome 19 (19q13.1) as the primary locus for malignant hyperthermia.
Several studies in different populations reported that mutations in the RYR1 gene represent approximately 50% of cases of MH, while 1% of cases of MH have been linked to the CACNA1S gene located on chromosome 1 (1q32) ( which encodes the a1 subunit of the voltage-dependent dihydropyridine receptor (DHPR)).
The incidence of MH during general anesthesia is estimated at 1 / 4,200 (suspicion of Malignant Hyperthermia) at 1 / 250,000 (fulminant HM). Published reports probably underestimate the actual incidence due to the difficulty of defining mild MH events.
In the last decade, two independent studies have estimated the incidence of RYR1 variants in the general population as 1 in 2,000 to 1 in 3,000 people. More recent studies suggest that the frequency of RYR1 variants may be greater than that.
The demographic data on the distribution by age and sex of the patients referred for the tests indicate that 68% are men and 32% are women. Acute MH is distributed throughout the world and affects all ethnic groups, with an average age of 21-23 years.
HM has been associated with other myopathies such as central core disease (CCD), multimineral disease (MMD) and nemaline rod myopathy, as well as stress rhabdomyolysis (ER). by its acronym in English) and heat illness of effort.
An increasing number of congenital myopathies have been associated with highly penetrating dominant and recessive mutations in the RYR1 gene.
Congenital myopathies are a clinically and genetically heterogeneous group of inherited muscular disorders characterized by the onset of childhood, muscle weakness and histopathological features that include: central nuclei, nemaline bodiesand central nuclei.
Recent studies suggest that in> 50% of patients with congenital myopathies had RYR1 mutations. These myopathies include nemaline myopathy, disproportion of the congenital fiber type, and central myopathy comprising central core disease and multiminorrea disease.
While congenital myopathies are recessive disorders, most patients with central core disease carry dominant mutations in the RYR1 gene.
Many people with MH are not affected. Therefore, it is difficult to identify these people before they are given general anesthesia. The family history of the disorder is important, as is the history of any metabolic adverse reaction to anesthesia.
The definitive diagnosis of susceptibility to MH is made by the in vitro contracture test performed on the muscle of the leg undergoing biopsy. These tests are based on the differential contractile response of normal muscle and HM to halothane and caffeine.
In North America, it is the test for halothane contracture of caffeine (CHCT), and in Europe it is the in vitro contracture test (IVCT for its acronym in English). Both tests are invasive, require a muscle biopsy and can only be performed in specialized centers for the diagnosis of Malignant Hyperthermia.
The successful treatment of an episode of Malignant Hyperthermia involves the rapid cessation of the triggering agent for anesthesia, cooling and the administration of dantrolene intravenously.
Dantrolene inhibits the calcium release channel in skeletal muscle without affecting neuromuscular transmission and is effective both for prophylaxis and for the treatment of fulminating MH.
The recommended initial dose is 2.4 mg / kg intravenously, with additional increments as needed for an acute episode.
Synonym of Malignant Hyperthermia