Anesthesiology 2001; 95:600 – 6 © 2001 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Response to Mivacurium in a Patient Compound Heterozygous for a Novel and a Known Silent Mutation in the Butyrylcholinesterase Gene Genotyping by Sequencing Mona R. Gätke, M.D.,* Doris Østergaard, M.D.,† Jens R. Bundgaard, Ph.D.,‡ France Varin, B.Pharm., Ph.D.,§ Jørgen Viby-Mogensen, M.D., D.M.Sc., F.R.C.A. Background: Patients who are homozygous for the atypical mutation, compound heterozygous for atypical and silent mu- tations, or homozygous for silent mutations (SS) respond to mivacurium with extensively prolonged neuromuscular block. Although important, exact phenotyping of these patients is difficult. This article presents the pharmacodynamics and phar- macokinetics of a normal dose of mivacurium in a patient with phenotype SS, including a pedigree analysis and delineation of the molecular genetic method used to identify the genotype. Methods: The neuromuscular block following administration of mivacurium, at a dose of 0.14 mg/kg, was monitored in a 30-yr-old healthy man with use of a mechanosensor and mecha- nomyography, and times to different levels of recovery were measured. Venous samples for determination of the mivacu- rium isomers were collected during the interval 134 – 494 min after administration of mivacurium, and the terminal half-lives were calculated. Butyrylcholinesterase activity, phenotype, and genotype were determined for both the patient and the family. Complete nucleotide sequencing was used to identify the genotype. Results: A train-of-four ratio of 0.75 was reached 469 min after the injection of mivacurium. The terminal elimination half-lives of the mivacurium isomers, cis-trans and trans-trans, were 90 min. Complete nucleotide sequencing revealed two point mutations, the known silent variant S7 and a previously undescribed mutation of amino acid residue 170 introducing a stop codon. Conclusions: The patient was compound heterozygous for silent mutations in the butyrylcholinesterase gene. The re- sponse to mivacurium was an extensively prolonged duration of action. Identification of the rare silent mutations presup- poses access to modern molecular genetic methods such as complete nucleotide sequencing. IN patients with the usual butyrylcholinesterase gene (BCHE, plasma cholinesterase gene), mivacurium is rap- idly hydrolyzed in plasma and the duration of action is short. However, about 24.0% of the white population carries at least one genetic variant allele of the butyryl- cholinesterase enzyme (BChE; E.C. 3.1.1.8), 1 which may result in slow hydrolysis of mivacurium and, conse- quently, a prolonged neuromuscular block. 2 Patients who are homozygous for the atypical mutation (AA), compound heterozygous for the atypical and a silent mutation (AS), or homozygous for silent mutations (SS) respond to mivacurium with extensively prolonged du- rations of action. 3–11 Thus, after administration of miva- curium at a dose of 0.12– 0.2 mg/kg, the time to full spontaneous recovery is 6 – 8 h for these patients, 5–10 as opposed to 30 min for patients with normal BChE. 12 Before the implementation of molecular genetic meth- ods, blood samples from patients with suspected abnor- mal phenotypes were analyzed by means of a combina- tion of conventional laboratory methods, such as measurement of BChE activity and biochemical inhibitor reactions, and analyses of pedigrees. 13 Unfortunately, the results of these investigations do not always allow correct phenotyping or correct prediction of the re- sponse to muscle relaxants, 8,13 and as many as 25% of patients referred to the Danish Cholinesterase Research Unit cannot be classified by means of traditional bio- chemical methods. 13 With techniques of DNA analysis it is possible to establish the genotype of a patient, and at least four articles have been published on clinical re- sponse in patients with genotypes AA and AS. 7–10 How- ever, none have documented the genotype of a patient with SS phenotype to whom mivacurium has been administered. This article presents the pharmacodynamics and phar- macokinetics of a normal dose of mivacurium in a pa- tient with phenotype SS, along with a pedigree analysis and description of the molecular genetic method (com- plete nucleotide sequencing of BCHE) used to identify the genotype, i.e., compound heterozygous occurrence for two silent mutations. This article is featured in “This Month in Anesthesiology.” Please see this issue of ANESTHESIOLOGY, page 5A.  * Research Fellow,  Professor, Danish Cholinesterase Research Unit, Depart- ment of Anaesthesia and Intensive Care, ‡ Senior Biochemist, Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital. † Associate Professor of Anaesthesia, Department of Anaesthesiology, Herlev University Hospital, Herlev, Denmark. § Professor, Faculty of Pharmacy, Uni- versity of Montreal, Montreal, Canada. Received from the Danish Cholinesterase Research Unit, Department of An- aesthesia and Intensive Care, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Submitted for publication October 26, 2000. Accepted for publication March 9, 2001. Supported by grants from Rigshospitalet, Copen- hagen University Hospital, Copenhagen, Denmark (to Dr. Gätke); H:S Research Foundation, Copenhagen, Denmark; and Novo Nordisk Foundation, Copenha- gen, Denmark (Dr. Viby-Mogensen). S & W Foundation, Copenhagen, Denmark, donated the Eppendorf Master Cycler thermocycler. Presented in part at the 25th Congress of The Scandinavian Society of Anaesthesiologists, Aarhus, Denmark, June 11, 1999. Address reprint requests to Dr. Gätke: Department of Anaesthesia and Inten- sive Care, 4132 Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Address electronic mail to: mgatke@rh.dk. Individual article reprints may be purchased through the Journal Web site, www.anesthesiology.org. Anesthesiology, V 95, No 3, Sep 2001 600