ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Gene test interpretation: Malignant hyperthermia susceptibility genes (RYR1, CACNA1S, and STAC3)

Gene test interpretation: Malignant hyperthermia susceptibility genes (RYR1, CACNA1S, and STAC3)
Literature review current through: Jan 2024.
This topic last updated: Oct 25, 2022.

INTRODUCTION — This monograph discusses interpretation and possible interventions following genetic testing for three genes (RYR1, CACNA1S, and STAC3) that can cause susceptibility to malignant hyperthermia (MHS).

It is not intended to replace clinical judgment in the decision to test or in the care of the individual who was tested. These details are discussed separately in UpToDate [1]. (See 'Resources' below.)

HOW TO READ THE REPORT

Genotype – Determine which genes were tested and whether testing involved gene sequencing or evaluating a panel of variants. Gene sequencing should include all coding exons of these three genes. Interrogating only specific variants or subsets of coding exons is considered suboptimal.

Clinical correlation – Determine whether testing was performed to evaluate a positive personal or family history of malignant hyperthermia (MH)/MHS or for healthy screening, or if the variant was identified as a secondary or incidental finding. Ascertain whether the individual and/or any close relative has had symptoms that could be attributed to MHS and whether they have received a halogenated inhalational anesthetic agent or succinylcholine.

Personal or family history of MH/MHS and pathogenic or likely pathogenic variant — For an individual with a personal or family history of MH/MHS who has a pathogenic or likely pathogenic variant in the RYR1 or CACNA1S gene, the diagnosis of MHS is confirmed.

STAC3-related MHS is inherited in an autosomal recessive pattern, and interpretation of this result requires further testing (such as testing parents). An MHS or genetics expert should be consulted.

If testing is performed for a family history of MHS, it is prudent to confirm that the variant identified in the tested individual is the same variant present in the relative with MHS, whenever possible. If such an individual was only tested for variants in one of the three MHS genes or only underwent partial testing of RYR1 (so-called "hot-spot" sequencing) and testing was negative, further testing is needed. Consultation with an MHS or genetics expert is likely to be helpful. (See 'Resources' below.)

Secondary (incidental) finding — If testing was done for healthy screening or evaluation of another condition and the individual is found to have a pathogenic or likely pathogenic variant in RYR1 or CACNA1S, they should be considered to have MHS until proven otherwise.

STAC3-related MHS is inherited in an autosomal recessive pattern; interpretation of a pathogenic or likely pathogenic variant in STAC3 requires further testing.

Variant of uncertain significance (VUS) — Pathogenicity of many variants in MHS genes remains uncertain. Typically, this is because there is insufficient information to determine whether the variant is associated with MHS or is merely a benign change from the reference sequence. When such a variant is encountered in clinical testing, it is most often classified as a VUS.

It can be challenging to make a proper clinical-molecular diagnosis in such individuals; their likelihood of having MHS depends on their pretest probability of disease. They can be treated "as if" they have MHS and can continue to check periodically for information on the variant using a database (such as EMHG or ClinVar) or consulting with a genetics or MHS specialist, or they can undergo contracture testing. (See 'Resources' below and 'Contracture testing' below.)

MHS GENETICS AND PATHOPHYSIOLOGY

Inheritance — Most MHS is inherited in an autosomal dominant pattern; inheritance of a pathogenic variant in an MHS gene from one parent is sufficient to cause MHS. The family history may fail to show classic autosomal dominant pattern (figure 1), since some relatives may not have been exposed to a halogenated inhalation anesthetic, and not all exposures cause a malignant hyperthermia (MH) event.

Specific genes

RYR1 — Ryanodine receptors (RyRs) are large homotetrameric ion channels that release calcium from intracellular stores during excitation-contraction coupling [2]. There are three tissue-specific genes. The skeletal muscle gene is RYR1 [3].

Pathogenic variants in RYR1 are the most common cause of MHS [3]. Hundreds of variants in RYR1 have been classified, although only a minority are pathogenic or likely pathogenic. From a comprehensive report of 335 variants in RYR1, 86 were classified as pathogenic or likely pathogenic, 30 were benign or likely benign, and 219 were variants of uncertain significance (VUS) [4].

In addition to MHS, some pathogenic variants in RYR1 can cause exertional rhabdomyolysis, atypical periodic paralyses, and central core disease (CCD), a congenital myopathy associated with hypotonia and weakness [2]. An association with statin myopathy is unclear. Other pathogenic variants in RYR1 are associated with myopathy inherited in an autosomal recessive pattern. (See 'Myopathy' below and "Muscle enzymes in the evaluation of neuromuscular diseases", section on 'Periodic paralyses' and "Congenital myopathies", section on 'Central core disease'.)

CACNA1S — CACNA1S encodes the alpha-1 subunit of the dihydropyridine (DHP) receptor, a skeletal muscle voltage-activated calcium channel upstream of the RyR [5].

Pathogenic variants in CACNA1S can cause MHS, susceptibility to hypokalemic periodic paralysis (hypoKPP), or thyrotoxic periodic paralysis [6].

STAC3 — STAC3 encodes a protein that interacts with the alpha-1 subunit of the DHP receptor.

Pathogenic variants in STAC3 can cause MHS as well as STAC3-related congenital myopathy (also called Bailey-Bloch congenital myopathy or Native American myopathy [NAM]).

Mechanism of hypermetabolic reaction — MH is a hypermetabolic reaction with skeletal muscle rigidity and elevated body temperature due to sustained muscle contraction [3]. It generally requires a triggering exposure (halogenated inhalational anesthetic agent or succinylcholine).

Often the first sign of MH in an anesthetized patient is hypercapnia (increase in end-tidal carbon dioxide [CO2]). This is thought to occur due to excessive muscle contraction leading to acidosis. The rapid increase in body temperature and rhabdomyolysis can be fatal if not treated urgently. The exact mechanism(s) by which implicated anesthetics interact with the variant receptors is not well understood.

In some individuals, a hypermetabolic state may be induced by increased body temperature or intensive exercise. (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Non-anesthesia-related MH-like episodes'.)

Importantly, not all exposures to a triggering agent in an individual with MHS will necessarily cause MH, and prior reactions or lack of reactions do not predict future reactions.

CLINICAL IMPLICATIONS

Counseling — Malignant hyperthermia (MH) is a life-threatening condition that can occur when an individual with MHS is exposed to certain volatile anesthetics and succinylcholine (also called suxamethonium). (See "Susceptibility to malignant hyperthermia: Evaluation and management".)

Individuals with MHS should receive education and counseling of the following (algorithm 1):

Inform all clinicians providing surgical or anesthesia care about the diagnosis of MHS and that they must avoid halogenated anesthetic gasses and succinylcholine. (See 'Anesthesia' below.)

Wear a medic-alert bracelet to make their MHS status visible to any clinicians caring for them. Information is available from MHS organizations. (See 'MHS organizations' below.)

Share the diagnosis with all first-degree relatives so they can have the option for testing if desired. (See 'Implications for relatives' below.)

Maintain hydration, especially with exercise; avoid hyperthermia; and be especially careful in hot humid weather. (See 'Myopathy' below.)

Individuals with a VUS in an MHS gene should inform all clinicians about their VUS and the possibility that they may have MHS. Other implications depend on the perceived likelihood of MHS.

Contracture testing — The in vitro contracture test (IVCT) is performed on a muscle biopsy (typical size, 1.5 to 2 inches) [7]. Testing is definitive if positive, but sensitivity is estimated at only approximately 85 percent. (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Contracture test'.)

This test is only available in a few specialized centers. Because it involves an invasive procedure, it is generally reserved for individuals for whom there is a strong suspicion of MHS (clinical event or strongly positive family history) and for whom a causative genetic variant cannot be identified. It may be performed more commonly in European countries than in the United States.

IVCT is rarely performed in individuals with a pathogenic or likely pathogenic variant in an MHS gene on genetic testing or in those who test negative for a known familial pathogenic variant.

Anesthesia — MHS has incomplete penetrance; not all exposures will cause an MH event. Thus, the presence of an MH-like reaction is highly suggestive of MHS, but the absence of a clinical event cannot be used to exclude the possibility of MHS. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Variable expressivity'.)

Prevention of MH – Individuals with a pathogenic variant in an MHS gene and/or a positive contracture test should not be exposed to halogenated inhalational anesthetic agents or succinylcholine (suxamethonium). (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Management of anesthesia in malignant hyperthermia-susceptible patients'.)

Individuals with possible MHS (based on a history suggestive of MH or diagnosis of MHS in a relative) should follow the same principles until tested.

When receiving any anesthetic, these individuals should have close monitoring of core body temperature, minute ventilation, other vital signs, and end-tidal carbon dioxide (CO2), in addition to standard American Society of Anesthesiologists (ASA)-recommended monitoring [8].

Treatment of MH – Principle treatments for MH include (see "Malignant hyperthermia: Diagnosis and management of acute crisis"):

Dantrolene

Supportive care

-Discontinuation of implicated drug(s)

-Hyperventilation to correct acidosis

-Cooling to reduce body temperature

-Treatment of metabolic abnormalities, rhabdomyolysis, and/or arrhythmias as needed

Myopathy — Some individuals with pathogenic variants in MHS genes may have an exertional myopathy or exertional rhabdomyolysis in addition to MHS. Syndromes are summarized in the table (table 1). Myopathies may be apparent early in life (eg, severe scoliosis due to muscle weakness), or may be mild and unappreciated until adulthood. An association with statin-induced myopathy is unclear. (See "Rhabdomyolysis: Epidemiology and etiology" and "Rhabdomyolysis: Clinical manifestations and diagnosis".)

These individuals should avoid dehydration, especially during exercise, and should be careful in hot, humid weather due to the risk of nonexertional heat illness (heat stroke). (See "Exertional heat illness in adolescents and adults: Management and prevention".)

Early use of an antipyretic for fever is prudent. (See "Pathophysiology and treatment of fever in adults", section on 'Treatment of fever and hyperpyrexia'.)

IMPLICATIONS FOR RELATIVES — All first-degree relatives of an individual with MHS should be offered testing (termed "cascade testing"). Other relatives may also be candidates for cascade testing (eg, grandchildren, if children are not available). Ideally, the pathogenic variant is first identified in an affected individual, and relatives can be tested for that variant.

Genetic testing is generally preferred because it is noninvasive. Results are sufficient for diagnosis if positive or if negative for a known familial variant, with caveats mentioned above. (See 'How to read the report' above.)

Genetic testing can be performed at any age. Unlike hereditary cancer syndromes, where genetic testing carries major implications for prevention and surveillance, MHS is a risk factor for a complication that can occur at any age and is easy to avoid once the diagnosis is established. Some data suggest that the penetrance of MHS (likelihood of a reaction if exposed to a triggering agent) is higher in childhood than in adulthood. Thus, there is not a strong rationale to delay testing until adulthood.

RESOURCES

Guidelines and UpToDate topics

Guidelines – (See "Society guideline links: Malignant hyperthermia".)

Anesthesia – (See "Anesthesia for children with myopathy and for children who undergo muscle biopsy".)

MH susceptibility – (See "Susceptibility to malignant hyperthermia: Evaluation and management".)

MH acute management (See "Malignant hyperthermia: Diagnosis and management of acute crisis".)

Genetics experts

Genetic counselors – National Society of Genetic Counselors (NSGC)

Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)

MHS organizations

Malignant hyperthermia association of the United States (MHAUS) – https://www.mhaus.org/healthcare-professionals/

24-hour emergency support from MHAUS – 1-800-MH-HYPER (1-800-644-9737)

European Malignant Hyperthermia Group – emhg.org/

Malignant Hyperthermia Group of Australia and New Zealand (MHANZ) – https://malignanthyperthermia.org.au/malignant-hyperthermia-group-of-australia-and-new-zealand/

RYR1 Foundation – ryr1.org/

ACKNOWLEDGMENT — Dr. Biesecker contributed to this article in his personal capacity. The views expressed are his own and do not necessarily represent the views of the National Institutes of Health or the United States Government.

Topic 139246 Version 2.0

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟