Response to mivacurium in a patient compound heterozygous for a novel and a known silent mutation in the butyrylcholinesterase gene - Genotyping by sequencing
Mr. Gatke et al., Response to mivacurium in a patient compound heterozygous for a novel and a known silent mutation in the butyrylcholinesterase gene - Genotyping by sequencing, ANESTHESIOL, 95(3), 2001, pp. 600-606
Citations number
33
Categorie Soggetti
Aneshtesia & Intensive Care","Medical Research Diagnosis & Treatment
Background: Patients who are homozygous for the atypical mutation, compound
heterozygous for atypical and silent mutations, or homozygous for silent m
utations (SS) respond to mivacurium with extensively prolonged neuromuscula
r block. Although important, exact phenotyping of these patients is difficu
lt. This article presents the pharmacodynamics and pharmacokinetics of a no
rmal dose of mivacurium in a patient with phenotype SS, including a pedigre
e 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 mechanomyography, and times to different levels of rec
overy were measured. Venous samples for determination of the mivacurium iso
mers were collected during the interval 134-494 min after administration of
mivacurium, and the terminal half-lives were calculated. Butyrylcholineste
rase activity, phenotype, and genotype were determined for both the patient
and the family. Complete nucleotide sequencing was used to identify the ge
notype.
Results: A train-of-four ratio of 0.75 was reached 469 min after the inject
ion of mivacurium. The terminal elimination half-lives of the mivacurium is
omers, cis-trans and trans-trans, were 90 min. Complete nucleotide sequenci
ng revealed two point mutations, the known silent variant S7 and a previous
ly 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 response to mivacurium was an extensive
ly prolonged duration of action. Identification of the rare silent mutation
s presupposes access to modern molecular genetic methods such as complete n
ucleotide sequencing.