Dear Insurance Company Representative:
With this letter, the Malignant Hyperthermia Association of the United States (MHAUS) would like to take the opportunity to provide some background information about malignant hyperthermia (MH) and genetic testing for MH susceptibility. As background,MHAUS is a non-profit organization committed to reducing the morbidity and mortality from MH by improving medical care for those susceptible to MH; providing support and information for patients; and improving the scientific understanding of MH. Established in 1981, our organization has become the key resource for clinical advice and educational materials concerning the diagnosis and treatment of MH in the United States.
What is MH and how can it be prevented?
MH is the genetic predisposition to a life-threatening syndrome triggered by commonly used anesthetic drugs. The clinical symptoms of MH such as hypermetabolism, muscle rigidity and damage, high temperature, and disturbances in cardiac rhythm may progress to serious complications such as kidney damage, blood coagulation problems, and cardiac arrest. If MH is not recognized and treated rapidly, it is likely to be fatal.
Health care professionals must be well-prepared to diagnose and treat patients who are experiencing this potentially life-threatening disorder. In addition, an integral part of MH preparedness involves taking steps to prevent its occurrence at the outset. The best way to prevent an MH episode is to identify individuals who are MH-susceptible (MHS) and develop alternate treatment plans for them, devoid of the use of MH triggering agents.
How are MHS individuals identified?
Susceptibility to MH is not readily apparent from a patient’s physical appearance nor is it detectable on physical examination. The majority of MHS individuals live a normal life unless exposed to triggering agents.
An individual may be identified as MHS if he/she has experienced a clinical MH episode. In addition, MH is inherited as an autosomal dominant trait which gives a 50% chance for each child of an MHS parent to be affected. As such, family members of an MHS individual are considered MHS until confirmatory diagnostic testing can be performed.
Up until 2005 the only available test for susceptibility involved a muscle biopsy done in an operating room, testing muscle for its physiologic response to a variety of pharmaceutical agents such as caffeine and halothane (i.e., the caffeine-halothane contracture test, or CHCT). This test, while extremely sensitive and specific, is invasive and requires specialized equipment available in a limited number of centers. Genetic (DNA) testing is an acceptable alternative to the contracture test in certain families.
When may genetic testing be useful and thus recommended?
Genetic testing is useful where there is a high level of suspicion that the patient is at risk for an MH episode based on clinical history or results of the contracture test or genetic test (of a family member). This determination is made through evaluation of the medical and anesthetic histories of the patient (and his/her family) by a physician or genetic counselor. Of note, MHAUS has access to many MH experts willing to review medical/anesthetic histories with the patient and/or their physician, in order to assist them, if desired, in making an informed decision prior to proceeding with genetic testing.
Genetic testing is also useful to confirm the diagnosis of MH susceptibility subsequent to a suspected clinical MH episode. Genetic testing is of value even though a patient may have experienced a clinical episode of MH because once a causal mutation is found in a patient, other family members can be screened more easily and less expensively.
Thus, genetic testing may be recommended in the following situations:
- The patient has experienced an almost certain clinical episode of MH as determined by someone expert in diagnosing MH, or the patient has a positive CHCT.
- The patient has an MHS relative who experienced an almost certainclinical episode as determined by someone expert in diagnosing MH, or the MHS relative has a positive CHCT.
- The patient has an MHS relative with a known causal mutation.
Of note, genetic testing may be recommended in special situations where the patient either refuses to undergo a CHCT or where the patient is not eligible for a CHCT. Such situations may include cases where the patient does not meet the age or weight requirements of the biopsy center; or after death.
How is genetic testing for MH susceptibility done?
Genetic testing for MH susceptibility is available in two CLIA-certified clinical laboratories in the United States. The test involves sequencing the skeletal muscle ryanodine receptor gene (RYR1). This gene is considered the primary genetic locus associated with MH susceptibility; that is, nearly all known mutations causal for MH susceptibility have been found in RYR1.
For the genetic test to be performed, one must first isolate DNA from the patient’s blood, muscle, or other tissue sample. The patient’s DNA is then analyzed for the presence of RYR1 variants, and specifically, for mutations causal for MH susceptibility.
RYR1sequencing is usually performed in a step-wise manner, examining the ‘hot spots’ where mutations are most frequent first, then proceeding to other parts of the gene if no variants are found. A partial sequencing approach may also be chosen to target a known causal mutation previously identified in the family.
What is the likelihood that genetic testing will be useful for a patient?
The likelihood that genetic testing will be useful (i.e., yield a finding of interest) for a patient depends upon the assessment of his/her risk for an MH episode, as well as the method of sequencing chosen. For example, in one study of individuals with positive CHCTs where RYR1 sequencing was limited to ‘hot spot’ regions, 25% of the individuals were found to harbor causative mutations. However, in other studies of CHCT positive individuals where RYR1 was fully sequenced, gene findings (variants of unknown significance [VUS] and causative mutations) were reported in up to 70% of the individuals.
In up to 70% of those who are MHS, one or more DNA variants are detected. However, there are over 300 RYR1 variants that we know of, and not all result in a disease or disorder. It has been clearly determined that 30 are definitely causal for MH; the significance of the other RYR1 variants is under investigation.
Of note, if genetic testing yields no finding of interest, MH susceptibility cannot be ruled out. A CHCT test (described in detail in a separate MHAUS reference document) would then be required to confirm a patient’s status with regard to MH susceptibility.
What are the benefits of genetic testing?
Once a causative mutation or VUS is found, family members can be tested for that specific causative mutation or VUS; if a known causative mutation is found, the individual is considered MHS and a muscle biopsy can be avoided. This reduces the cost of testing significantly. In addition, the patient who is diagnosed as MHS now has proof that the wrong type of medication can kill him/her. If this patient should need to undergo surgery, his/her family and doctors will be aware of his/her true medical condition and a possible death or a long expensive stay in the hospital or ICU can be averted.
Finally, prevention is better than a cure. Once armed with the knowledge resultant from this test, a patient can choose to pursue risk evaluation of his/her present or future children.
Patient Counseling and Consent for Genetic Testing:
MHAUS strongly recommends that, prior to ordering and performing genetic testing, the following topics be discussed during the informed consent process:
- The benefits and potential risks of genetic testing;
- Cost of genetic testing;
- Possible need for CHCT testing;
- Possible testing of other family members;
- Risks of MH during surgery or without anesthetics;
- Clinical implications for future anesthetics in MH positive individuals.
In addition, MHAUS recommends that the results of genetic testing be explained to the patient by a genetic counselor or other appropriate health care professional.
All patients who had a positive genetic test will be advised to wear a medical identification tag and to advise other family members that they too may be at risk and should be evaluated.
Finally, if approved by the patient, the test results will be shared with the North American Malignant Hyperthermia Registry, a subsidiary of MHAUS. The Registry is essentially a database of information about MH episodes, providing a clinical correlation between clinical history, genetic, and biopsy test results (if available).The Registry provides a place where patients/families and their health care professionals can retrieve valuable medication information, communicate and store important medical histories relating to the risk for MH.
For further information regarding malignant hyperthermia and bibliographic information concerning genetic testing, please feel free to contact us at 607-674-7901.
Sincerely,
Henry Rosenberg, MD
MHAUS President
