1Departments of Anaesthesia and Research, Kantonsspital, University of Basel, CH-4031 Basel, Switzerland. 2Institute for Clinical Chemistry and Laboratory Diagnosis, University of Jena, D-07743 Jena, Germany. 3Department of Biochemistry, University College Cork, Cork, Republic of Ireland. 4Northern Genetics Service, Molecular Genetics Unit, Newcastle upon Tyne NE2 4AA, UK*Corresponding author
This article is accompanied by Editorial III.
Accepted for publication: September 12, 2000
Abstract
Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic disease triggered by several anaesthetic agents. The in vitro muscle contracture test (IVCT) is the standard test to establish an individuals risk of susceptibility to MH. Clinical practitioners and geneticists of the European MH Group have agreed on the present guidelines for the detection of MH susceptibility using molecular genetic techniques and/or IVCT to predict the risk of MH.
Br J Anaesth 2001; 86: 2837
Keywords: complications, malignant hyperthermia; genetic factors, molecular genetics
Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic disease triggered by commonly used potent inhalation anaesthetics and/or succinylcholine. The in vitro muscle contracture test (IVCT) is the standard test to establish an individuals risk of susceptibility to MH.1 The European MH Group has developed a standardized protocol for the IVCT and has initiated and fostered international collaborative molecular genetic studies to investigate the molecular basis of MH. Data from these studies demonstrate that MH displays a high level of locus heterogeneity. Thus, it is not feasible to diagnose MH susceptibility, and, more specifically, to exclude MH risk, on the basis of a simple genetic test alone. However, it is of utmost importance to avoid false MH-negative (MHN) diagnoses because of the potential risk of MH during general anaesthesia for these patients and their offspring. These general obstacles notwithstanding, there may be specific situations where genetic data provide additional diagnostic information or contribute information independent of IVCT. It is the purpose of this document to outline recommended procedures for the potential diagnostic use of such genetic findings depending on the different clinical situations that may arise.
Referrals
The usual route of entry for individuals into MH investigations follows a suspected MH crisis and referral of the patient to an MH Investigation Unit, where diagnostic procedures and genetic counselling should be performed according to Figure 1.
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An IVCT is performed on the patient or, if the patient is too young or has not survived the anaesthetic event, his or her parents. If MH susceptibility status is confirmed by IVCT, then there is a clinical responsibility to offer the IVCT to the relatives of the index case, assuming autosomal dominant inheritance and starting with first-degree relatives.
Genetic investigations
Mutation analysis
At this stage, molecular genetic testing for causative mutations in the ryanodine receptor gene (RYR1) of the index case could lead to quicker results for the rest of the kinship. An up-to-date list of mutations that have been shown to directly alter RYRI caffeine or halothane sensitivity is shown in Table 1.
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Segregation analysis
Once the MH status of the extended pedigree (e.g. 10 informative meioses) has been determined by the IVCT, it may be possible to undertake genetic segregation analysis with markers close to known MH susceptibility loci. An up-to-date list of recommended markers and details of genetic modelling compiled by the European Malignant Hyperthermia Group, Genetics Section, is available on the internet (http://www.emhg.org).
Rarely, a single pedigree may be sufficiently large to establish linkage to a candidate locus with a high probability (lod score >3.0). In such a situation the question arises as to whether or not haplotype analysis can be used to assign MH status. Under these circumstances, individuals carrying the high-risk haplotype should be regarded as susceptible to MH even without confirmation by a positive IVCT. The converse is not true, that is, identification of the low-risk haplotype does not equate with MHN status and such individuals should have IVCT determination of their MH status.
In families where linkage to a candidate gene, RYR1 or another locus, is suggested but not firmly established (i.e. lod score <3.0) haplotype analysis for predictive testing is not appropriate due to the high level of locus heterogeneity in MH. In such families, however, it is desirable to search for unknown mutations in the suggested candidate gene for research purposes.
Failure to reach a lod score of +3.0 in a single family due to the occurrence of a single individual in whom there is recombination between the haplotype and IVCT-determined MH status will require closer scrutiny and possible reassessment of the genetic and bioassay results to attempt to resolve the basis of the discordance. For predictive diagnosis in such families, the more conservative estimation, i.e. the higher risk outcome (either the MH susceptibility test result from the IVCT or the high-risk haplotype) should be the basis for the clinical decision.
Appendix
MH Investigation Units in Europe
Austria
Prof. H. Gilly
Klinik für Anästhesie und allgemeine Intensivmedizin der Universität Wien
Spitalgasse 23
A-1090 Wien
Prof. W.W. Lingnau
Univ. Klinik für Anaesthesie und Allgemeine Intensivmedizin
Anichstrasse 35
A-6020 Innsbruck
Belgium
Prof. L. Heytens
Department of Intensive Care
Universitair Ziekenhuis Antwerpen
Wilrijkstraat 10
B-2650 Edegem
Denmark
Dr K. Glahn
The Danish Malignant Hyperthermia Register
Department of Anaesthesia
Herlev University Hospital
DK-2730 Herlev
France
Prof. R. Krivosic-Horber
Département dAnesthésie Réanimation
Hôpital B
Centre Hospitalier Régional Universitaire
Bd. du Proffesseur J. Leclercq
F-59037 Lille
Prof. Y. Nivoche
Département d'Anesthésie
Hôpital Robert Debré
48 Bd. Serurier
F-75935 Paris Cedex 19
Germany
Prof. W. Mortier
Klinik für Kinder- und Jugendmedizin der Universität Bochum
St Josefs-Hospital
Alexandrinenstrasse 5
D-44791 Bochum
Priv.-Doz. Dr F. Wappler
University Hospital Eppendorf
Department of Anaesthesiology
Martinistrasse 52
D-20246 Hamburg
Prof. D. Olthoff
Klinik und Poliklinik für Anästhesiologie und Intensivtherapie der Universität Leipzig
Liebigstrasse 20a
D-04103 Leipzig
Dr I. Tzanova
Klinik für Anästhesie
Uniklinik Mainz
Langenbeckstrasse 1
D-55131 Mainz
Prof. F. Lehmann-Horn
Institut für angewandte Physiologie der Universität Ulm
Albert-Einstein-Allee 11
D-89081 Ulm
Dr M. Anetseder
Institut für Anästhesiologie der Universität Würzburg
Josef Schneider Strasse 2
D-97080 Würzburg
Iceland
Prof. S. Sigurdsson
Department of Physiology
University of Iceland
IS-101 Reykjavik
Ireland
Prof. J.J.A. Heffron
Department of Biochemistry
University College
Cork
Italy
Dr V. Tegazzin
Department of Anaesthesiology
Traumatic-Orthopaedic Hospital
Via Facciolati 71
I-35127 Padova
Prof. V. Brancadoro
Institute of Anaesthesiology
Università degli Studi di Napoli Frederico II
Via S. Pansini 5
I-80131 Napoli
Dr S. Cozzolino
Settore Biofarmacologico A.O. Cardarelli
Via S. Giacomo dei Capri 66
I-80131 Napoli
The Netherlands
Dr M. Snoek
Department of Anaesthesiology
CWZ, C40-01
PO Box 9015
N-6500 Nijmegen
Norway
Dr T. Fagerlund
Institute of Medical Genetics
Ullevål Sykehus
N-0407 Oslo
Sweden
Dr G. Islander
Department of Anaesthesia
University Hospital
S-221 85 Lund
Switzerland
Prof. A. Urwyler
Departement Anästhesie
Universitätskliniken
Kantonsspital
CH-4031 Basel
UK
Prof. F.R. Ellis
MH Investigation Unit
Clinical Sciences Building
St Jamess University Hospital
Leeds LS9 7TF
Footnotes
* for the European Malignant Hyperthermia Group
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