Rhabdomyolysis following Severe Physical Exercise in a Patient with Predisposition to Malignant Hyperthermia

A 21-year-old man suffered from exertional heat stroke with impaired consciousness and rhabdomyolysis after strenuous physical exercise. Within two weeks the patient recovered completely without any specific therapy. Based on the symptoms and laboratory investigations, this episode suggested a moderate form of malignant hyperthermia. An in vitro contracture test was performed and a predisposition to malignant hyperthermia was diagnosed; other muscular diseases were excluded by histological examination. At present, the in vitro contracture test is the only method used to determine susceptibility to malignant hyperthermia and should be performed when the diagnosis is suggested on clinical grounds.

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Identification of variants of the ryanodine receptor type 1 in patients with exertional heat stroke and positive response to the malignant hyperthermia in vitro contracture test

British Journal of Anaesthesia ◽

10.1093/bja/aew047 ◽

2016 ◽

Vol 116 (4) ◽

pp. 566-568 ◽

Cited By ~ 18

Author(s):

N Roux-Buisson ◽

N Monnier ◽

E Sagui ◽

A Abriat ◽

C Brosset ◽

...

Keyword(s):

Malignant Hyperthermia ◽

Ryanodine Receptor ◽

Positive Response ◽

Heat Stroke ◽

Receptor Type ◽

Exertional Heat Stroke ◽

In Vitro Contracture Test

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Evidence for Susceptibility to Malignant Hyperthermia in Patients with Exercise-induced Rhabdomyolysis

Anesthesiology ◽

10.1097/00000542-200101000-00019 ◽

2001 ◽

Vol 94 (1) ◽

pp. 95-100 ◽

Cited By ~ 146

Author(s):

Frank Wappler ◽

Marko Fiege ◽

Markus Steinfath ◽

Kamayni Agarwal ◽

Jens Scholz ◽

...

Keyword(s):

Malignant Hyperthermia ◽

Receptor Gene ◽

Heat Stroke ◽

Histologic Examination ◽

In Vitro Contracture Test ◽

Genetic Abnormalities ◽

History Of ◽

Exercise Induced ◽

Muscle Biopsies

Background Malignant hyperthermia (MH), heat stroke, and exercise-induced rhabdomyolysis (ER) were suspected to be related syndromes. However, it is not known whether individuals with history of ER have an increased incidence of susceptibility to MH. To establish an association between ER and susceptibility to MH, the authors determined the MH status in patients with a history of MH-like episodes induced by physical stress. Methods Twelve unrelated patients with ER, 18 patients with anesthesia-induced MH, and 28 controls were investigated with the in vitro contracture test (IVCT) according to the European MH Group protocol and the ryanodine contracture test. In addition, all patients were screened for genetic mutations, and histology was performed on muscle specimens. Results Ten ER patients had positive IVCT results, one patient had a negative test result, and one patient showed equivocal responses. Samples from patients with positive IVCT results showed pronounced contractures after exposition to ryanodine, as opposed to specimens from patients with negative IVCT results, which developed contractures slowly. Three ER patients had mutations at the ryanodine receptor gene. All anesthesia-induced MH patients had positive IVCT results, two of them presented the C1840T mutation. The control patients had normal contracture test results and no typical MH mutations. Histologic examination determined no specific myopathies in any patient. Conclusions Regarding these results, the authors recommend performing muscle biopsies for histologic examination and IVCT in patients with ER. In addition, the patient should be seen by a neurologist and screened for genetic abnormalities to shed light on the genetics of MH.

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Suspected Malignant Hyperthermia Reactions in New Zealand

Anaesthesia and Intensive Care ◽

10.1177/0310057x0203000410 ◽

2002 ◽

Vol 30 (4) ◽

pp. 453-461 ◽

Cited By ~ 17

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.

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In-vitro Contracture Test with Theophylline - An Alternative in Diagnosis of Malignant Hyperthermia?

Anesthesiology ◽

10.1097/00000542-200209002-01201 ◽

2002 ◽

Vol 96 (Sup 2) ◽

pp. A1201

Author(s):

Marko Fiege ◽

Frank Wappler ◽

Ralf Weisshorn ◽

Kerstin Kolodzie ◽

Jochen Schulte am Esch

Keyword(s):

Malignant Hyperthermia ◽

In Vitro Contracture Test

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Determination of a positive malignant hyperthermia (MH) disposition without the in vitro contracture test in families carrying the RYR1 Arg614Cys mutation

Clinical Genetics ◽

10.1034/j.1399-0004.2001.600205.x ◽

2001 ◽

Vol 60 (2) ◽

pp. 117-124 ◽

Cited By ~ 2

Author(s):

H Rueffert ◽

D Olthoff ◽

C Deutrich ◽

UG Froster

Keyword(s):

Malignant Hyperthermia ◽

In Vitro Contracture Test

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

Anesthesiology ◽

10.1097/aln.0b013e3181862a0d ◽

2008 ◽

Vol 109 (4) ◽

pp. 625-628 ◽

Cited By ~ 25

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.

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Scanning for Mutations of the Ryanodine Receptor (RYR1) Gene by Denaturing HPLC: Detection of Three Novel Malignant Hyperthermia Alleles

Clinical Chemistry ◽

10.1373/49.5.761 ◽

2003 ◽

Vol 49 (5) ◽

pp. 761-768 ◽

Cited By ~ 31

Author(s):

Angela Tammaro ◽

Adele Bracco ◽

Santolo Cozzolino ◽

Maria Esposito ◽

Antonietta Di Martino ◽

...

Keyword(s):

Skeletal Muscle ◽

Malignant Hyperthermia ◽

Ryanodine Receptor ◽

Sudden Increase ◽

Gene Encoding ◽

In Vitro Contracture Test ◽

Ryr1 Gene ◽

Molecular Tests ◽

Anesthetic Agents

Abstract Background: Malignant hyperthermia (MH) is a fatal autosomal dominant pharmacogenetic disorder characterized by skeletal muscle hypertonicity that causes a sudden increase in body temperature after exposure to common anesthetic agents. The disease is genetically heterogeneous, with mutations in the gene encoding the skeletal muscle ryanodine receptor (RYR1) at 19q13.1 accounting for up to 80% of the cases. To date, at least 42 RYR1 mutations have been described that cause MH and/or central core disease. Because the RYR1 gene is huge, containing 106 exons, molecular tests have focused on the regions that are more frequently mutated. Thus the causative defect has been identified in only a fraction of families as linked to chromosome 19q, whereas in others it remains undetected. Methods: We used denaturing HPLC (DHPLC) to analyze the RYR1 gene. We set up conditions to scan the 27 exons to identify both known and unknown mutations in critical regions of the protein. For each exon, we analyzed members from 52 families with positive in vitro contracture test results, but without preliminary selection by linkage analysis. Results: We identified seven different mutations in 11 MH families. Among them, three were novel MH alleles: Arg44Cys, Arg533Cys, and Val2117Leu. Conclusion: Because of its sensitivity and speed, DHPLC could be the method of choice for the detection of unknown mutations in the RYR1 gene.

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