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Duchenne muscular dystrophy and malignant hyperthermia: A genetic study of the ryanodine receptor in 47 patients

Rohde, Doris; Schmitt, Hubert J.; Winterpacht, Andreas; Münster, Tino

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European Journal of Anaesthesiology: June 2014 - Volume 31 - Issue 6 - p 341-342
doi: 10.1097/EJA.0000000000000053

Editor,

Duchenne muscular dystrophy (DMD) belongs to the heterogeneous group of progressive muscular diseases that vary in clinical manifestation and inheritance. DMD is characterised by early onset in childhood with rapid progression of muscular weakness leading to loss of walking ability in adolescence. Progressive respiratory failure and cardiac muscle involvement finally lead to death by the third decade of life. DMD is caused by a recessive mutation in the DMD gene located on locus Xp21 leading to complete loss of the muscle protein dystrophin.1 Due to X-chromosomal recessive inheritance, male patients are predominately affected by DMD with an incidence of approximately one in 3500 male births.

Patients affected by DMD are susceptible to perioperative complications when undergoing general anaesthesia. A variety of critical events such as hyperkalaemia, hyperthermia, tachycardia, rhabdomyolysis and cardiac arrest have been reported previously in patients exposed to inhalational anaesthetic agents or depolarising muscle relaxants.2 In the past, these complications have been interpreted by some as indicators of malignant hyperthermia.3

In this study, we sequenced the ryanodine receptor 1 (RYR1) gene in 47 patients with DMD searching for malignant hyperthermia causative mutations in the skeletal muscle RYR1 gene.

After approval of the local ethics committee (Ethical Committee No. 3636, Ethical Committee of Erlangen University Hospital, Erlangen, Germany, Chairperson Prof. Dr Peter Betz), and obtaining the patients’ informed consent, a sample of whole blood was taken. DNA was extracted from peripheral blood lymphocytes, amplified via PCR assay and sequenced in search of the most common malignant hyperthermia causative mutations in the RYR1 gene. In total, 28 of the most common causative mutations for malignant hyperthermia, as published by the European Malignant Hyperthermia Group,4 were analysed in 16 different exons of the RYR1 gene. We analysed all published mutations except the mutations located on exon 44, wherein we experienced technical difficulties and were not able to amplify the DNA to a level matching our quality standards.

We did not find any tested malignant hyperthermia causative mutation in the RYR1 gene. Although the sample is small and a risk of malignant hyperthermia cannot be completely excluded by genetic testing,5 this finding supports the hypothesis that the perioperative metabolic complications in patients with DMD are probably not linked to the genetic disease malignant hyperthermia. From the genetic point of view, a link between the autosomal dominant inherited disease malignant hyperthermia and the recessive X-linked DMD is statistically quite unlikely. Despite the absence of changes in the RYR1 gene, studies in the mdx mouse (which carries a null mutation of the dystrophin gene and is used as a model of muscular dystrophy) indicate that the function of the ryanodine receptor may be altered indirectly as a result of abnormal calcium homeostasis caused by defective or absent dystrophin.6 Metabolic reactions could also be attributed to an abnormal fragility of the cell membrane, which is caused by the complete loss of the cytoskeletal protein dystrophin in skeletal muscle. Although clinical reports state that malignant hyperthermia like phenomena such as rhabdomyolysis, hyperkalaemia and hyperthermia in patients with DMD occur in association with malignant hyperthermia triggering agents, the exact mechanism explaining the pathophysiology is still not clear. Most reports present cases during childhood at ages between 2 and 10 years. This may reflect the fact that with ongoing disease, muscle is replaced by fat and fibrosis.1 Another explanation may be that in older patients, the diagnosis of DMD is mostly known (the median age of diagnosis is 5 years)7 and inhalational anaesthetic agents or depolarising muscle relaxants have, therefore, not been used.

Inhalational anaesthetics and depolarising muscle relaxants however, may trigger a variety of metabolic reactions through an interaction with, and disruption of, the defective cell membrane in dystrophin-deficient muscle cells. These metabolic reactions are triggered by the same agents triggering malignant hyperthermia, but via a different pathophysiology. Therefore, patients with DMD should be monitored carefully when undergoing general anaesthesia and the well known triggering substances should not be administered.

Acknowledgements relating to this article

Assistance with the study: we are grateful to Dr Stephanie Meißner who worked on this project until she died in November 2010.

Financial support and sponsorship: this work was supported by a research grant from the ‘Deutsche Gesellschaft für Muskelkranke, e.V’.

Conflicts of interest: none.

References

1. Blake DJ, Weir A, Newey SE, Davies KE. Function and genetics of dystrophin and dystrophin-related proteins in muscle. Physiol Rev 2002; 82:291–329.
2. Hayes J, Veyckemans F, Bissonnette B. Duchenne muscular dystrophy: an old anesthesia problem revisited. Paediatr Anaesth 2008; 18:100–106.
3. Brownell AK. Malignant hyperthermia: relationship to other diseases. Br J Anaesth 1988; 60:303–308.
4. European Malignant Hyperthermia Group. Causative mutations for malignant hyperthermia in ryanodine receptor RYR1. http://www.emhg.org/genetics/mutations-in-ryr1 [Accessed 10 January 2014].
5. Urwyler A, Deufel T, McCarthy T, West S. Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia. Br J Anaesth 2001; 86:283–287.
6. Bellinger AM, Reiken S, Carlson C, et al. Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Nat Med 2009; 15:325–330.
7. Muenster T, Mueller C, Forst J, et al. Anaesthetic management in patients with Duchenne muscular dystrophy undergoing orthopaedic surgery: a review of 232 cases. Eur J Anaesthesiol 2012; 29:489–494.
© 2014 European Society of Anaesthesiology