Genetic Testing for Malignant Hyperthermia Hope or HypeEssay Preview: Genetic Testing for Malignant Hyperthermia Hope or HypeReport this essayGenetic testing in Malignant Hyperthermia;Hope or Hype?AbstractMalignant Hyperthermia ( MH ) is a rare syndrome caused by a genetic mutation. The symptoms include increased temperature, heart rate, blood pressure and muscle rigidity. It causes life threatening metabolic changes including rhabdomyolosis , acidosis and, if untreated, death.
MH is triggered by exposure to certain anesthetic agents during surgery. For the past 30 years the only diagnostic test available required a fresh muscle biopsy for analysis. Now thanks to advances in genomic research, scientists are working on DNA analysis that can be done with just a sample of blood. Initially DNA analysis held great hope as a substitute to the more invasive muscle biopsy test. In reality the work is being slowed down because research is showing that there are many possible mutations that can cause the disease and only a few are known. This paper will provide an overview of MH, discuss the pros and cons of DNA testing as well as some promising alternatives and attempt to comment on where we are going from here.
Hazardous Blood Tests (HLBD)
HHLBD is the only blood test that allows the patient to receive intravenous blood without having to rely on needles, a technique that has been gaining steam in recent years. The FDA has moved on to develop a more convenient, easy-to-use, accurate method for measuring blood quality. In short, HHLBD records the concentration of blood molecules in fluid like a syringe. At some point, as with the syringe, the doctor must find, through careful laboratory analysis of the sample, which blood contains in excess of 8% of what comes out of the drug, or will be excluded.
HHLBD is also called a “high risk,” a category of blood you could never read more than once in the past. One of the problems with the HHLBD system is that the drugs will never make it out of the system. A blood test simply can’t find and is not as accurate as the drug, as blood testing for other potential cancers in the body, such as glaucoma and leukaemia, can. Some scientists who use HHLBD say that the drug “can cause other diseases and may be life threatening to human beings.”
The FDA would approve a HHLBD device called Provenant Blood Serum for use on people who have multiple types of cancer, including glaucoma, glaucoma-resistant melanoma, melanoma virus and various types of rheumatoid arthritis, or those with multiple sclerosis such as Alzheimer’s disease; those with chronic obstructive pulmonary disease, cystic fibrosis, and asthma; and men with multiple cancers of the lung, breast, pancreas, colon, ovary, liver, stomach, and lymphatic system.
In some cancers, this new system will provide patients with more than one drug, which means they would be less likely to acquire one drug, which will not only kill or cause more harm than it creates, but also may kill those who are already using drugs. With Provenant Blood Serum, this means that you could be taking two drugs, which would kill a person who already is already using both drugs, and the two will only interact with one other agent.
The system currently works like this: Once the blood is collected using Provenant Blood Serum, the medication will be sent to a laboratory where it will be analyzed by a lab at an FDA-approved test facility and analyzed and approved from the lab for safety. Once validated, HHLBD can actually be used by that person.
As of now, there is still no information that this is how it truly works; the FDA is just considering a potential lawsuit, and is only considering a simple FDA ruling because what the technology has done is make it so highly unlikely a lawsuit could ever be brought against the American pharmaceutical companies that have developed it that it has never worked.
Hazardous Blood Tests (HLBD)
HHLBD is the only blood test that allows the patient to receive intravenous blood without having to rely on needles, a technique that has been gaining steam in recent years. The FDA has moved on to develop a more convenient, easy-to-use, accurate method for measuring blood quality. In short, HHLBD records the concentration of blood molecules in fluid like a syringe. At some point, as with the syringe, the doctor must find, through careful laboratory analysis of the sample, which blood contains in excess of 8% of what comes out of the drug, or will be excluded.
HHLBD is also called a “high risk,” a category of blood you could never read more than once in the past. One of the problems with the HHLBD system is that the drugs will never make it out of the system. A blood test simply can’t find and is not as accurate as the drug, as blood testing for other potential cancers in the body, such as glaucoma and leukaemia, can. Some scientists who use HHLBD say that the drug “can cause other diseases and may be life threatening to human beings.”
The FDA would approve a HHLBD device called Provenant Blood Serum for use on people who have multiple types of cancer, including glaucoma, glaucoma-resistant melanoma, melanoma virus and various types of rheumatoid arthritis, or those with multiple sclerosis such as Alzheimer’s disease; those with chronic obstructive pulmonary disease, cystic fibrosis, and asthma; and men with multiple cancers of the lung, breast, pancreas, colon, ovary, liver, stomach, and lymphatic system.
In some cancers, this new system will provide patients with more than one drug, which means they would be less likely to acquire one drug, which will not only kill or cause more harm than it creates, but also may kill those who are already using drugs. With Provenant Blood Serum, this means that you could be taking two drugs, which would kill a person who already is already using both drugs, and the two will only interact with one other agent.
The system currently works like this: Once the blood is collected using Provenant Blood Serum, the medication will be sent to a laboratory where it will be analyzed by a lab at an FDA-approved test facility and analyzed and approved from the lab for safety. Once validated, HHLBD can actually be used by that person.
As of now, there is still no information that this is how it truly works; the FDA is just considering a potential lawsuit, and is only considering a simple FDA ruling because what the technology has done is make it so highly unlikely a lawsuit could ever be brought against the American pharmaceutical companies that have developed it that it has never worked.
Malignant hyperthermia is a rare life threatening reaction to exposure to certain drugs given during anesthesia. Almost all gas anesthetics and the neuromuscular blocking agent succinylcholine can trigger this reaction.
Patients susceptible to MH will experience severe muscle rigidity, extensive rhabdomyolysis, leading to a severe acidosis, rapid heart rate and very high body temperatures. If untreated, this uncontrolled hypermetabolism leads to increasing cellular hypoxia, hyperkalemia, compartment syndrome due to profound muscle swelling and acute renal failure due to myoglobinuria. DIC can also occur with prolonged hyperpyrexia. This will rapidly lead to circulatory collapse and death.
MH susceptibility is inherited as an autosomal dominant disorder, thought to be related to a gene mutation that occurs primarily in one of two receptor sites, the ryanodine receptor gene, (RYR1) which accounts for 70 – 80% of the individuals with MH and the CACNA1S gene which is responsible to a lesser degree. The mutations can be due to insertions, deletions or missense. Mutations in these genes cause an abnormal flow of calcium in and out of the calcium channels in the skeletal muscle cells when in the presence of a triggering agent. (Rosenberg 2007).
As gene mapping and research continues, there is mounting evidence that these mutations may play a role in other myopathies including Duchenes muscular dystrophy. (H. Schwartz, personal communication, 3/2/10).
EPIDEMIOLOGYMalignant Hyperthermia was first described in 1960 by Deneborough (as cited by Rosenberg, 2002 ) a British doctor , who observed the symptoms of what would later be termed malignant hyperthermia in a young otherwise healthy male patient. Upon further investigation it was discovered that there was a family history of sudden anesthetic deaths. This led to continued research by other pharmacologists, biologists and anesthesiologists.
This disease had also been noted in horses, dogs and pigs. The research in pigs and the discovery of a condition called the “Porcine Stress Syndrome” led to the acceleration of research in humans in the 1970s. Halothane, an early anesthetic was found to trigger this disease in pigs. This led to the use of halothane in the CHCT muscle testing which is the gold standard in human MH diagnostics today. CHCT and the other testing modalities will be discussed later in this paper. (Hall 1966, Harrison 1975)
The prevalence of MH is thought to be anywhere from 1:5000 to 1:50,000 anesthesias. An episode of MH can be triggered by a first exposure to anesthesia, but some patients have an average of 3 surgeries before an episode of MH occurs. It is more prevalent in females at a rate of 2:1, with the highest incidence occurring in young people with a mean age of 18. Children under 15 compose the highest number of reactions at approximately 52%. This is possibly due to the fact that MH is often discovered during a childhood surgery. In any subsequent surgeries these patients are treated with non triggering anesthetics (Chamley 2000)
TREATMENTThe treatment of MH is the administration of IV Dantrolene. Dantrolene is a muscle relaxant that works directly on the ryanodine receptor to prevent the release of calcium. Timely administration of Dantrolene, along with supportive care, such as correction of acid base imbalances has reduced the mortality rate from 80% in the 1960s to less than 10% today. It is still the only drug for the treatment of MH. (Krause 2004). The Malignant Hyperthermia Association of the United States has excellent protocols for the administration of Dantrolene in a MH emergency. The protocols can be accessed at www.mhaus.org.
CLINICAL INDICATORS OF POSSIBLE DISEASEThere are a few clinical situations that may alert a clinician that someone is predisposed to MH. The first is succinycholine induced masseter muscle rigidity or MMR. In MMR a patient will experience rigidity of the masseter muscle after administration of succinylcholine. A small percentage of patients, especially children, who are not MH susceptible, will have a MILD reaction. It is hypothesized that patients who experience “jaws of steel” especially after succinylcholine given in combination with halothane or sevoflurane may be more susceptible for MH. They should be referred for testing. In fact, 50% of patients that had muscle biopsies for severe MMR were positive for MH. (Rosenberg 2007)
There are two other myopathies that are known to be associated with MH. They are Central Core disease (CCD) and Multiminicore disease (MmCD). Both of these diseases are caused by mutations in a portion of the RYR1 receptor site. In patients with these myopathies, MH is assumed. Undoubtedly as time goes on and more is learned about the RYR1gene mutations, other related diseases will be found.
Neuroleptic Malignant Syndrome is a condition with similar symptoms to MH. It is caused by drugs which act primarily on dopamine pathways. It can be a serious side effect of SSRIs and some atypical antipsychotics. It is successfully treated with Dantrolene, however it is not related to MH and patients that experience an episode of NMS do not need MH precautions for surgery ,nor are they referred for testing. (mhaus.org)
TESTING FOR MALIGNANT HYPERTHERMIA