Molecular Genetic Testing for Malignant Hyperthermia Susceptibility

2004 ◽  
Vol 100 (5) ◽  
pp. 1076-1080 ◽  
Author(s):  
Thierry Girard ◽  
Susan Treves ◽  
Evgueni Voronkov ◽  
Martin Siegemund ◽  
Albert Urwyler
Keyword(s):  
Genetic Testing ◽  
Malignant Hyperthermia ◽  
Elective Surgery ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Malignant Hyperthermia Susceptibility ◽  
Restriction Enzyme Digestion ◽  
In Vitro Contracture Test ◽  
Genetic Test Results

Background For more than 30 yr, the in vitro contracture test (IVCT) was the only appropriate diagnostic tool for malignant hyperthermia (MH). After the introduction of molecular genetics into MH research, guidelines for molecular genetic diagnosis of MH susceptibility were published. The aim of this study was to establish applicability of the guidelines, sensitivity, and specificity of genetic testing in MH and advantages for studied patients. Methods The IVCT was performed following the guidelines of the European MH Group. Mutation analyses were performed by amplification of genomic DNA by polymerase chain reaction and restriction enzyme digestion. Results Two hundred eight individuals underwent MH testing between January 2001 and April 2003. In 32 of 67 initially genetic-tested patients, the familial mutation was identified, and they were diagnosed as MH susceptible. The IVCT followed negative genetic test results in 20 patients, and all but one had negative IVCT results. Three patients were scheduled to undergo elective surgery, and IVCT and genetic testing were performed simultaneously. All three had positive IVCT results and were carriers of their familial mutation. Conclusions In families with known MH mutations, there is a 50% chance of reliably confirming MH susceptibility by noninvasive testing. The authors found the negative predictive value of genetic testing to be 0.95 (95% confidence interval, 0.75-0.99), but for patient safety, they still recommend following the guidelines for genetic testing in MH and therefore performing an IVCT in case of negative genetic results.

Suspected Malignant Hyperthermia Reactions in New Zealand

2002 ◽  
Vol 30 (4) ◽  
pp. 453-461 ◽  
Author(s):  
A. N. Pollock ◽  
E. E. Langton ◽  
K. Couchman ◽  
K. M. Stowell ◽  
M. Waddington
Keyword(s):  
New Zealand ◽  
Malignant Hyperthermia ◽  
Dna Analysis ◽  
Anaesthetic Agent ◽  
Clinical Signs ◽  
Malignant Hyperthermia Susceptibility ◽  
In Vitro Contracture Test ◽  
Grading Scale ◽  
Clinical Grading

Early clinical signs, triggering agents, time to onset of reaction, mortality and methods of treatment were identified in 123 suspected malignant hyperthermia reactions. In vitro contracture test results were compared with clinical signs and the Malignant Hyperthermia Clinical Grading Scale. Increased end-tidal carbon dioxide is the earliest sign when not preceded by masseter spasm. Earlier diagnosis reduces the incidence of rigidity and severe metabolic acidosis. The combination of suxamethonium and a potent volatile anaesthetic agent triggers an earlier reaction compared with a volatile agent alone. There has been zero mortality since 1981, essentially due to a combination of advanced monitoring capability, increased anaesthetist awareness of malignant hyperthermia, and dantrolene availability. DNA analysis has identified nine New Zealand families with ryanodine receptor gene mutations. A positive DNA test indicates malignant hyperthermia susceptibility with “causative” mutations but discordance requires that negative DNA tests are confirmed with in vitro contracture test. This test also demonstrated the shortcomings of the Malignant Hyperthermia Clinical Grading Scale.

scholarly journals Muscle Biopsy and In Vitro  Contracture Test in Subjects with Idiopathic HyperCKemia

2008 ◽  
Vol 109 (4) ◽  
pp. 625-628 ◽  
Author(s):  
Alessandro Malandrini ◽  
Alfredo Orrico ◽  
Carmen Gaudiano ◽  
Simona Gambelli ◽  
Lucia Galli ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Muscle Biopsy ◽  
Malignant Hyperthermia Susceptibility ◽  
Manual Muscle Testing ◽  
In Vitro Contracture Test ◽  
Muscle Testing ◽  
Malignant Hyperthermia Susceptible ◽  
Fiber Size ◽  
Precise Diagnosis

Background Persistent high creatine kinase (CK) levels may reflect underlying subclinical myopathies. In most cases, pathogenesis is unknown and clinical management is unclear. Though clinically asymptomatic, these subjects are potentially susceptible to malignant hyperthermia. Methods The authors analyzed 37 subjects with persistent elevation of CK without significant weakness or other neurologic symptoms. Neurologic examination was performed according to manual muscle testing. Muscle biopsy and the in vitro contracture test were performed in all subjects. Results Twenty-three subjects (51.1%) were completely asymptomatic. The others had minor symptoms such as occasional cramps (11 subjects, 24.4%), fatigue (5 subjects, 11.1%), a combination of cramps and fatigue (5 subjects, 11.1%), and muscle pain (1 case, 2.2%). Muscle biopsy enabled precise diagnosis in 3 cases and was normal in 3 cases. The more frequent changes were variation in fiber size (31.1%), a combination of nuclear internalization and variation in fiber size (26.6%), nuclear internalization (6.6%), minor mitochondrial changes (4.4%), and neurogenic atrophy (4.4%). Immunocytochemical analysis was normal in all patients. In vitro contracture testing detected one malignant hyperthermia-susceptible and one malignant hyperthermia-equivocal subject. Conclusions The evidence of malignant hyperthermia susceptibility by in vitro contracture test seems to be relatively infrequent among subjects with idiopathic hyperCKemia, but the incidence of true malignant hyperthermia in idiopathic hyperCKemia is unknown. Muscle biopsy should be considered a useful, though not very sensitive, diagnostic tool in idiopathic hyperCKemia, because it enables potentially treatable disorders, such as inflammatory myopathies, to be discovered. No uniform morphologic finding typical of idiopathic hyperCKemia or malignant hyperthermia susceptibility was identified by muscle biopsy.

Detection of Proton Release from Cultured Human Myotubes to Identify Malignant Hyperthermia Susceptibility

2002 ◽  
Vol 97 (5) ◽  
pp. 1059-1066 ◽  
Author(s):  
Werner Klingler ◽  
Christoph Baur ◽  
Michael Georgieff ◽  
Frank Lehmann-Horn ◽  
Werner Melzer
Keyword(s):  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Metabolic Activation ◽  
Malignant Hyperthermia Susceptibility ◽  
Proton Release ◽  
Release Channel ◽  
Proton Secretion ◽  
In Vitro Contracture Test ◽  
Human Myotubes

Background Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle. During general anesthesia, a life-threatening hypermetabolic state may occur resulting from increased release of Ca2+ from the sarcoplasmic reticulum in skeletal muscle. Diagnosis of MH susceptibility requires surgical muscle biopsies to measure force in response to chemical stimulation (in vitro contracture test, IVCT). Here, the authors investigated an alternative way of discriminating MH-susceptible (MHS) from normal (MHN) subjects by using cultured human myotubes and measuring proton release as an indicator of cellular metabolism. Methods Myotubes were stimulated with the Ca2+ release channel agonist 4-chloro-m-cresol (4-CmC), leading to metabolic activation and proton secretion. The rate of extracellular acidification was recorded with a silicon sensor chip. Results A stepwise increase in 4-CmC concentration led to a phasic-tonic increase in the acidification rate. The response, measured at different concentrations of 4-CmC, was considerably larger in cultures from MHS compared with MHN subjects and correlated well with the force response in the IVCT. Conclusions The enhanced metabolism of cultured skeletal myotubes, likely originating from an increased myoplasmic Ca2+ concentration, can be monitored by studying the proton secretion rate. Because the method seems to be able to distinguish normal from pathologic phenotypes, it is a promising technique for possible future use in less invasive MH testing.

scholarly journals Masseter muscle rigidity and the role of DNA analysis to confirm malignant hyperthermia susceptibility

2019 ◽  
Vol 47 (1) ◽  
pp. 60-68 ◽  
Author(s):  
Kate Hudig ◽  
Neil Pollock ◽  
Terasa Bulger ◽  
Roslyn G Machon ◽  
Andrew Woodhead ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Malignant Hyperthermia ◽  
Masseter Muscle ◽  
Dna Analysis ◽  
Malignant Hyperthermia Susceptibility ◽  
Muscle Rigidity ◽  
Autosomal Dominant Disorder ◽  
In Vitro Contracture Test ◽  
Normal Individuals

Malignant hyperthermia (MH) is an uncommon, autosomal dominant disorder of skeletal muscle, triggered by inhalational anaesthetics or depolarizing muscle relaxants. Masseter muscle rigidity (MMR) can be regarded as potentially a preceding sign for an MH reaction. Susceptibility to MH can be determined by the in vitro contracture test (IVCT) or DNA analysis where a familial variant is known. Our aims were to review patients with MMR, where IVCT and DNA analysis had been undertaken, to determine if DNA analysis could be used as an initial screening tool for MH susceptibility, and, by reviewing standard monitored variables (SMVs), to determine if any clinical characteristics could be used to differentiate between MMR patients who are MH susceptible (MHS) and those who are not. Patients with MMR were identified from the Palmerston North Hospital MH Reactions Database. IVCT and DNA analysis results were documented. DNA testing was performed retrospectively in the majority of patients as many patients had presented before DNA analysis was available. Forty-one patients were analysed. Fourteen were DNA positive/IVCT positive and six DNA positive only (48% in total), seven were IVCT positive/DNA negative and 14 were IVCT normal. Increased creatine kinase (>18,000 units/L) was consistent with MH susceptibility. Severity of MMR was not linked to MH susceptibility. This study confirmed that DNA analysis can be used as a first-line test for MH susceptibility in patients presenting with MMR (consistent with European MH Group recommendations). Creatine kinase was the only SMV that was significantly different between MHS and MH normal individuals.

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