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FAQs: Molecular Genetics

Intended Audience: Healthcare Professionals, Patients

The availability of molecular genetic testing for susceptibility to malignant hyperthermia (MH) represents a new era for those interested in and affected by MH. This group of FAQs provides basic information concerning genetic testing for MH.

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(1)
What is the history of molecular genetics?

PreventionGenetics LLC, a biotechnology company focused on molecular genetics (CLIA-certified), located in Marshfield, Wisconsin, began to offer in mid 2005 molecular genetic testing for the diagnosis of MH.

(2)
Will molecular genetic testing replace the caffeine halothane contracture test (CHCT) using biopsied muscle?

No. Not all MH susceptibles will, for the near future, have evidence of a DNA change. The CHCT by contrast is a very sensitive test, meaning that virtually all those with risk and susceptibility for MH will be detected by the contracture test. The genetic test will detect only about 30% of those at risk. However, the genetic test is very specific — that is, those with a positive test are virtually assured of being at risk for MH.

(3)
Why should someone have a genetic test?

If a person is known to be MH susceptible and has a DNA change (mutation) known to be causative for MH, then his or her relatives may be diagnosed as MH susceptible through the DNA test. Those in the family with this mutation are therefore MH susceptible and do not need to undergo the muscle biopsy test for confirmation. However, the absence of the mutation does not mean that the patient is not at risk for MH.

(4)
Do I need a referral for genetic testing? Who should refer me for testing?

Yes, a referral is needed. If you have had a biopsy test, the biopsy center director should refer you. However, any licensed physician or genetic counselor may make the referral.

(5)
Does a patient need to have a CHCT or special procedure to enable a genetic test?

No. All that is required is a blood sample that is sent to the diagnostic laboratory.

(6)
Who should have the genetic test?

In order to increase the sensitivity of the test, MHAUS advises that only the following individuals be considered for the test:

  1. Those who have been tested positive by the contracture test.
  2. Relatives of those who have been tested positive by the contracture test.
  3. Relatives of those with a known mutation for MH.
  4. Those who have been found to have a mutation causative for MH under a research protocol.
  5. Those who have experienced a clinical episode of MH.
(7)
How do I determine if I or a relative has a high likelihood of having experienced an MH episode?

This is a complex question that depends on the evaluation of medical records and events that transpired during or following anesthesia. If you are registered in the North American MH Registry of MHAUS database, a likelihood figure may be calculated. Please contact the Registry.

If not, you may need to release your medical information to your physician or to one of the MHAUS designated consultants to review the records (at no charge if you are a member of MHAUS). Please contact MHAUS for further details.

(8)
What is the inheritance pattern of MH? Who should be tested if I am found to have a mutation?

MH is inherited in an autosomal dominant pattern. This means that children, parents and sibs of an MH susceptible have a 50% chance of inheriting MH susceptibility. Aunts and uncles of the MH susceptible and grandchildren have a 25% chance. More distant relatives have a lesser chance. The decision to spend money to determine susceptibility is complex and individual and requires guidance by an expert in genetics and MH.

(9)
How much will genetic testing cost?

For full details, please contact the following sites: 

(10)
Are there any other laboratories in the US that perform molecular genetic testing?

No. At present, there are the two laboratories listed above.

(11)
Will insurance cover the cost of the test?

That depends on the insurance company. Many companies will have to be educated as to the nature of the MH syndrome and the validity of the test. This has not yet been done and is a major task that MHAUS will begin in the near future. Meanwhile, contact your own insurance company for details. MHAUS can provide the insurance company with references as to validity of the test.

(12)
I participated in a research protocol for the genetics of MH and was found to have a mutation. Do I need to have the test repeated?

Yes, we advise that it be repeated. Complex regulations that cover a clinical genetic test versus a research test are in force. We advise that the research findings be confirmed in the laboratory certified by the College of American Pathologists and certified under the CLIA act. MHAUS may be able to cover the costs of such clinical confirmation if the research protocol was conducted in the United States. Unfortunately, MHAUS does not have the resources to cover the costs for confirmation of tests done outside the United States. Please contact us for further details.

(13)
Should I have genetic counseling done prior to or following genetic testing?

We strongly advise such counseling to help interpret the results of the test and evaluate family members for testing.

(14)
If I have a test, what result will my doctor receive?

The result will indicate one of the following:

  1. No DNA variation found
  2. Mutation associated with MH and or Central Core Disease found
  3. DNA variation found of uncertain significance.
(15)
Will the test increase in accuracy over time?

Undoubtedly it will. Not all mutations associated with MH susceptibility have been found, and many DNA variations with uncertain significance will be investigated as to whether they are causal for MH.

(16)
What will happen to the specimen following the test?

With your permission, the residual DNA will be stored for further investigation. The sample may be stored either in an anonymized manner (no identifiers attached) or, with your permission, with your name attached.

(17)
Where can I read more about the molecular genetics of MH and options for testing?

There are many Web sites that address the issues of molecular genetic testing. We suggest GeneTests and search for the information on MH. Also, the MHAUS Web site slide show (Home page) contains information on genetics of MH. A variety of other sources are available. Please contact MHAUS for further recommendations.

(18)
What is Central Core Disease (CCD) and how is it related to MH?

Central Core Disease is an inherited disorder with varied manifestations. Some are weak from birth on, others only later in life. The inheritance may be autosomal dominant or recessive, depending on the family. The genetic variation that underlies the disorder is also found on the same gene (RYR-1 gene) that is responsible for MH. It has been known for a long time that patients with this disorder are also at risk for MH and should be treated as MH-susceptible. The signs and symptoms of CCD are variable but mostly are characterized by weakness. A muscle biopsy is needed to confirm the diagnosis. Genetic diagnosis of CCD is developing very rapidly.

See Also:  Central Core Disease

(19)
When can we expect that the genetic test will find all those who are at risk for malignant hyperthermia?

A very difficult question. First, the investigators have to find all the mutations and DNA changes that predispose to MH. This is a laborious process since there are several genes that predispose to MH, although changes in the ryanodine receptor gene probably underlie about 70% of cases. Another gene identified as predisposing to MH is the DHPR gene, also related to muscle function. In addition, there are probably over 60 mutations in the RYR-1 gene that are causal for MH, although causality has been proven for only about 30 DNA changes. In order to prove that a DNA is causal, either families must be identified where DNA change pattern is consistent with biopsy proven susceptibility or, in the laboratory, the DNA change must be incorporated in cultured muscle cells, and the calcium release in the cell under the influence of caffeine or halothane must show changes found in MH.

(20)
Why is testing for MH expensive and not incorporated into routine screening prior to surgery?

The technology for detecting DNA changes requires specialized equipment and expertise. Searching for so many DNA changes increases the cost. A special problem is that in MH, there is no single mutation responsible found in most patients who are MH susceptible. For example, in certain geographic vicinities, a single mutation may be found in up to 20% of families, but that same mutation might not be found in more than a small percent of susceptibles of a different ethnic group or located in a different geographic vicinity. By contrast, in a disorder such as Cystic Fibrosis, a single mutation is found in more than 80% of those afflicted.

Because of the expense of genetic testing and the low likelihood of a patient experiencing an MH episode, it is not economically feasible to screen all patients having surgery for MH.

(21)
Should patients who experience heatstroke or rhabdomyolysis (muscle breakdown) with exercise be tested for MH?

Again, a very controversial question. A physician and/or neurologist should first evaluate these patients by routine measures for evidence of other disorders. At present, we advise that patients with these signs should undergo genetic testing following contracture testing, except if there is a family history of MH.

(22)
Should patients who develop muscle breakdown as a result of taking lipid-lowering drugs (i.e., statins) be tested for MH?

There is not enough evidence to link MH to the predisposition of muscle breakdown from such drugs and therefore genetic testing, as a clinical test, is not recommended. More research is needed.

(23)
Should patients who experienced Neuroleptic Malignant Syndrome (NMS) or Serotonin Syndrome be tested for MH?

For an explanation of these syndromes, go to the NMSIS Website. There does not appear to be a relation at the genetic level between MH and these syndromes. Different drugs than anesthetics cause these conditions through a different mechanism than for MH, although dantrolene may be effective in the treatment of NMS.

(24)
How can I contribute to further research and study of the genetics of MH?

The best way is to make a contribution to MHAUS earmarked for the “molecular diagnostic fund.”  Becoming a member of MHAUS also assists in this effort.

(25)
Has MHAUS assisted in the development of the test for laboratories to offer the clinical test?

Yes. MHAUS has supported the testing centers with small grants.

(26)
Is genetic testing available in other countries?

Yes. There are several genetic testing centers in Europe (please see the European Malignant Hyperthermia Group website for further information on European genetic testing centers), and one in Canada, Brazil, New Zealand and Australia that we are aware of.


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