SCIENTIFIC BACKGROUND

CACNA1S, RYR1

Scientific Background

Malignant hyperthermia (MH) is a genetically caused Ca2+ regulatory disorder of the skeletal muscles. In genetically predisposed individuals, the administration of volatile anaesthetics (fluranes) and depolarising muscle relaxants (e.g., suxamethasone) can lead to a potentially life-threatening hypermetabolism. The symptoms are very variable and range from moderate forms with low severity to a fulminant MH crisis. In the early phase, classic signs of a fulminant MH crisis are tachycardia, hypercapnia, hypoxemia and masseter spasms; in the late phase, acidosis, hyperkalemia, rhabdomyolysis and hyperthermia are added. The antidote dantrolene has reduced the mortality rate in MH crises to <5%. The prevalence of MH in the German population is estimated at 1:10,000. The incidence of a fulminant MH crisis is about 1:60.000. In predisposed patients the administration of trigger substances must be avoided. Without trigger substances there is usually an unapparent myopathy.

 

Pathogenic variants in the ryanodine receptor 1 (RYR1) and the dihydropyridine receptor (voltage-dependent L-type calcium channel, CACNA1S) are associated with a predisposition for MH. Heredity is autosomal dominant with incomplete penetrance. Variants in one of these genes could be identified in about 75% of MH families. The detection of a causative variant enables the identification of other relatives at risk by means of target diagnostics. However, so far only about 50 variants have been categorized as causative by the European Malignant Hyperthermia Group (EMHG). In addition, the studies did not identify variants in the RYR1 or CACNA1S gene in all affected patients, so that a negative molecular genetic finding does not rule out the presence of MH. Therefore, where suspicion exists and there are negative genetic findings or if variants of unclear significance are detected, an in vitro muscle contraction test (IVCT) should be performed to confirm the diagnosis.

 

References

Gonsalves et al. 2019, Clin Pharmacol Ther 105:1338

GENES

CACNA1S, RYR1

ASSOCIATED TESTS

How to order

LATEST ARTICLES

Duchenne muscular dystrophy, a rare inherited muscle disorder characterized by progressive muscle weakness and degeneration that leads to difficultie...

Read more

May 12 is International Nurses Day. It is celebrated on Florence Nightingale’s birthday. She pioneered the field of modern nursing through her dedi...

Read more

Hair loss is a common problem that affects millions of men and women around the world. While genetics is believed to be the most significant factor c...

Read more

Depression is a serious mental health issue affecting over 280 million people worldwide. Recent research has revealed a potential link between gut he...

Read more

If you are unlucky enough to suffer from migraines, you will know that a migraine is not just a bad headache. The headache and accompanying symptoms ...

Read more

Autism spectrum disorder (ASD) is a neurological developmental disorder that affects brain development and function. This affects how people learn, b...

Read more

Researchers have developed a method called "Mendelian Phenotype Search Engine" (MPSE) to identify which sick infants in the neonatal intensive care u...

Read more

Did you know that wisdom teeth are actually an evolutionary leftover from our ancient ancestors that no longer serve their original purpose? These mo...

Read more

Azoospermia is a medical condition characterized by the absence of sperm in the ejaculate and is a major cause of male infertility. It affects 1 in 1...

Read more

Science has traditionally been a male dominated subject; however, women have also been hard at work in this field for decades. We put together this i...

Read more