genetic diseases

I.Randi Malignant Hyperthermia

Generality

Malignant hyperthermia is a severe reaction that usually occurs following the administration of some drugs used in general anesthesia.

More in detail, malignant hyperthermia represents a particular pathological condition, potentially lethal, which occurs in genetically predisposed individuals following the intake of certain anesthetic drugs and / or muscle relaxants. Fortunately, despite its severity, it is a rather rare pathology.

Unfortunately, there is no specific cure for malignant hyperthermia, but the speed of intervention is fundamental for the protection of the patient.

What is that

What is Malignant Hyperthermia?

Malignant hyperthermia is a pathological condition due to a genetic defect transmitted from parents to children.

More precisely, malignant hyperthermia is a disease with autosomal dominant inheritance . This means that - to be sick - it is sufficient that there is the presence of only one mutant allele in the pair of homologous chromosomes, since - being an autosomal dominant transmission disease - this will always prevail over the healthy allele (not mutated).

Malignant hyperthermia, however, has a particular characteristic, ie it occurs only if the patient is exposed to certain drugs or, more rarely, if subjected to considerable physical stress. Not surprisingly, this pathological condition is also defined as a " drug-genetic syndrome ".

Curiosity

Malignant hyperthermia is a genetic disease that not only affects humans, but can also occur in some animal species, such as dogs, horses and some pig breeds.

Incidence

Incidence of Malignant Hyperthermia in the Population

Malignant hyperthermia can affect any genetically predisposed individual, regardless of gender or age. In detail, it has been estimated that the syndrome occurs once every 15, 000 anesthesia performed on infant patients and once every 50, 000 anesthesia performed in adult patients.

Symptoms

Symptoms and Clinical Manifestations of Malignant Hyperthermia

The symptoms that characterize the onset of malignant hyperthermia consist of:

  • Abnormal and sudden increase in body temperature which can reach 45 ° C;
  • Increased levels of carbon dioxide in the blood (hypercapnia);
  • Increased potassium in the bloodstream (hyperkalemia);
  • Decreased oxygen available in the blood (hypoxemia);
  • Decreased blood calcium levels (hypocalcemia);
  • Tachycardia;
  • tachypnea;
  • Respiratory and metabolic acidosis;
  • Muscle stiffness accompanied by pain;
  • Muscle spasms;
  • Destruction of muscle fibers (rhabdomyolysis);
  • Dark urine.

If not promptly diagnosed and, consequently, not promptly treated, malignant hyperthermia can lead to even more severe conditions, such as kidney failure, cerebral ischemia, respiratory failure, cardiac arrest and, in the most serious cases, death.

Generally, the symptomatology appears within an hour of contact with the drug or drugs used during general anesthesia, but in some cases the syndrome can occur even after 12 hours.

To learn more: Malignant Hyperthermia Symptoms »

Causes

As mentioned, malignant hyperthermia is a drug-genetic syndrome. This means that the disease manifests itself in genetically predisposed individuals (ie who have a well-defined genetic mutation), but only after contact with certain types of anesthetic and muscle relaxant drugs. Therefore, the causes that lead to the appearance of malignant hyperthermia are essentially two:

  • Genetic mutations;
  • Intake of drugs used in general anesthesia.

These causes are closely connected to each other, in the absence of one of them, malignant hyperthermia should not manifest itself except in extremely rare situations, as will be seen in this chapter.

Genetic mutations that cause malignant hyperthermia

Malignant hyperthermia is mainly caused by a genetic mutation located on chromosome 19, at the level of the gene that codes for the receptor for ryanodine 1 ( gene RYR1 ). This receptor is a particular type of calcium channel found mainly on skeletal muscles, whose job is to release calcium ions from calcium-like seals located in muscle cells in response to certain signals . The release of calcium ions means that there is an increase in the levels of this ion within the muscle fibers which results in an inevitable contraction of the same.

However, the genetic mutation of the RYR1 gene does not seem to be the only responsible for this syndrome. In fact, some cases of malignant hyperthermia have been associated with a mutation of the CACNA1S gene, located on chromosome 1 and coding for one of the subunits forming the L-type calcium channels present on the skeletal musculature. In this regard, it is interesting to note how these channels are able, in a certain sense, to interact with the receptor for rianodine 1. In fact, following their opening, we are witnessing the activation of the aforementioned receptor, which results in the leakage of calcium from calciosomes.

Despite this, the mutation of the CACNA1S gene has been identified only on a few occasions, while in the vast majority of cases, the mutation that leads to the appearance of malignant hyperthermia is that of the RYR1 gene.

Nevertheless, it is necessary to point out that numerous variants of the aforementioned mutation have been identified that can favor the onset of the syndrome and therefore determine what is defined as a susceptibility to malignant hyperthermia .

Drugs that cause Malignant Hyperthermia

As repeatedly stated, malignant hyperthermia occurs after the administration of some types of drugs used in general anesthesia. More precisely, this syndrome is triggered by the intake of:

  • Halogenated general anesthetics, such as halothane, sevoflurane, desflurane, isoflurane and enflurane;
  • Succinylcholine (a depolarizing muscle relaxant also known as sussametonio or suxametonio);
  • Decamethonium (another muscle relaxant blocker of the neuromuscular junction).

Due to the genetic mutations mentioned above, following the intake of some of the aforementioned drugs, there is an uncontrolled increase in calcium levels within the skeletal muscle cells, resulting in hypermetabolism and the appearance of the symptoms that characterize the malignant hyperthermia.

Local anesthetics (eg lidocaine, mepivacaine, etc.), nitrous oxide (or dinitrogen oxide) and muscle relaxants such as pancuronium, cisatracurium, atracurium, mivacurium, vecuronium and rocuronium are considered safe and not able to give rise to malignant hyperthermia.

Other factors that can induce malignant hyperthermia

In the presence of some of the genetic mutations mentioned above, taking the drugs used in general anesthesia does not seem to be the only factor capable of triggering malignant hyperthermia. In fact, cases have been reported in which the syndrome has manifested itself also following significant physical stresses secondary to excessive physical activity, heat, or stroke. However, these particular cases are extremely rare and most of the genetically predisposed individuals manifest malignant hyperthermia only after taking the drugs described above.

Diagnosis

How is malignant hyperthermia diagnosed?

Unfortunately, it is not always easy to diagnose malignant hyperthermia before it can manifest itself. In most cases, in fact, one realizes the disease only when it occurs in the middle - or immediately after - a surgical operation conducted under general anesthesia.

At the moment, the safest test to make a diagnosis of susceptibility to malignant hyperthermia before surgery involves performing a muscle biopsy . The skeletal muscle tissue taken from the patient is then exposed in vitro to the action of halothane and caffeine in order to assess its contractility. Generally, the test is considered positive if one or both substances are able to induce the contractility of muscle tissue.

The test is not overly invasive, but it is still a biopsy which, as such, must be performed by medical personnel specialized in the operating room.

Clinical Signs of Possible Susceptibility to Malignant Hyperthermia

Genetically predisposed patients who do not come into contact with general halogenated anesthetics, succinylcholine and decamethonium, theoretically, should not show malignant hyperthermia and should therefore lead a normal life, without experiencing any particular symptoms.

However, there are some clinical signs that may indicate a possible susceptibility to malignant hyperthermia and that should, therefore, prompt the doctor to investigate further if the patient presents them. Going into more detail, these signs consist of:

  • Poor resistance to prolonged muscular effort (that is, the patient becomes very tired);
  • Presence of pain and / or muscle cramps;
  • Elevated levels of creatine kinase (CK) in the blood (this condition is significant for the susceptibility to malignant hyperthermia if it is possible to exclude that the alteration of CK levels is not caused by high muscular stress, it is not caused by a heart attack and it is not caused by taking drugs that can known to induce an increase in CK blood values).

Please note

The presence of one or more of the above conditions does not necessarily mean that the patient has the genetic mutation that leads to the onset of malignant hyperthermia; but without thorough investigation it is not possible to exclude this possibility. For this reason, if you suffer from any of these conditions, before undergoing any surgery under general anesthesia, you should inform your doctor and anesthesiologist.

Malignant Hyperthermia Related Diseases

Malignant hyperthermia is closely related to some congenital diseases that affect skeletal muscles, such as congenital central core myopathy and multi-minicore disease.

Central core congenital myopathy (or CCD, from the English Central Core Disease) is closely related to the drug-genetic syndrome in question because it is caused by mutations in the RYR1 gene (the same implicated in the susceptibility to malignant hyperthermia). Not surprisingly, most patients with this disease are also susceptible to malignant hyperthermia.

The multi-minicore disease (or MmD, from the English Multi-minicore Disease) is a hereditary neuromuscular pathology caused by genetic mutations that are also localized at the level of the RYR1 gene. In fact, even in this case, patients suffering from this disease are more likely to develop episodes of malignant hyperthermia following contact with drugs used in general anesthesia.

When to Perform Muscle Biopsy?

Generally, if a patient manifests any of the above mentioned clinical signs and / or if he suffers from one of the aforementioned diseases, it would be appropriate to resort to performing a muscle biopsy, all the more so if there is a family history of malignant hyperthermia and / or if the patient has CCD or MmD.

Genetic tests

As mentioned, the susceptibility to malignant hyperthermia can be caused by genetic mutations of various types (different variants) which, sometimes, can also involve genes different from RYR1. Unfortunately, the genetic tests currently available for the diagnosis of susceptibility to the syndrome do not seem to be able to identify with absolute certainty all the potential mutations causing susceptibility to malignant hyperthermia.

Care and Treatment

Is there a cure for malignant hyperthermia?

Unfortunately - since it is a disease caused, at least in part, by a genetic mutation - a real cure for malignant hyperthermia does not exist. In fact, at the moment, it is not possible to intervene on the genetic mutations that give rise to the disorder. It is, however, possible to act on the cause triggering the crisis, or the administration of anesthetic drugs or muscle relaxants used during general anesthesia.

Treatment of Malignant Hyperthermia Crisis

The treatment of an acute episode of malignant hyperthermia consists in immediately interrupting the administration of the drug that triggered the syndrome and in the immediate intravenous administration of dantrolene sodium (Dantrium®). This last active ingredient has specific indications for the treatment of fulminant hypermetabolism of skeletal muscle typical of malignant hyperthermia crisis. Naturally, the patient will also undergo all the appropriate supportive therapies (for example, 100% oxygen supply) to control the symptoms induced by the syndrome in order to restore normal physiological conditions.

The success of the treatment of malignant hyperthermia depends on the speed of intervention; in fact, if not promptly treated, this syndrome can prove fatal for the patient.