title: Two novel mutations in the BCHE gene in patients with prolonged duration of action of mivacurium or succinylcholine during anaesthesia.
abstract: BACKGROUND
  Butyrylcholinesterase (BChE) hydrolyses the neuromuscular blocking agents, succinylcholine and mivacurium used during general anaesthesia. Hereditary low BChE activity may result in an extensively prolonged duration of action of these drugs, especially in patients who are homozygous for the atypical or silent variants. We present three novel mutations in the butyrylcholinesterase gene (BCHE) identified in three families in which a member had experienced severely prolonged duration of action of succinylcholine.
  
  
  METHODS
  As the phenotypes of the three probands could not be established with certainty using conventional biochemical tests, DNA samples were collected from two of the probands and four relatives. Genotypes were determined using complete nucleotide sequencing.
  
  
  RESULTS
  Three novel mutations were identified: BCHE*FS126, BCHE*I3E4-14C and BCHE*328D. The proband in family 1 was genotyped as BCHE*115D*I3E4-14C/BCHE*FS126, whereas the proband in family 3 was compound heterozygous for BCHE*328D and BCHE*142M. In both patients, BChE activity was below detection limit, and they experienced an extensively prolonged duration of action of succinylcholine. The proband in family 2 was not sequenced, but a relative was heterozygous for BCHE*FS126. BCHE*I3E4-14C was in linkage with a known silent variant.
  
  
  CONCLUSIONS
  Two novel variants of BCHE are silencing the enzyme function. BCHE*FS126 results in a truncated protein lacking the active site and is therefore inactive. The second variant is BCHE*328D, also resulting in an inactive protein, as this change in amino acid is radical and furthermore situated in the gorge harbouring the active site. These variants result in extensively prolonged duration of action of succinylcholine.
authors: Danish Cholinesterase Research Unit, Department of Anaesthesia, Centre of Head and Orthopaedics, Copenhagen University Hospital, Rigshospitalet, Denmark. mongat01@heh.regionh.dk
authors: Mona R
authors: MR
authors: Gätke
authors: Jens R
authors: JR
authors: Bundgaard
authors: Jørgen
authors: J
authors: Viby-Mogensen
mesh_terms: D000758:Anesthesia; D002091:Butyrylcholinesterase / Q000172:deficiency / Q000235:genetics*; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D000077590:Mivacurium; D009154:Mutation / Q000235:genetics*; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology*; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D013390:Succinylcholine / Q000494:pharmacology*
chemical_list: D007546:Isoquinolines; D009467:Neuromuscular Depolarizing Agents; D003473:Neuromuscular Nondepolarizing Agents; D000077590:Mivacurium; D002091:Butyrylcholinesterase; D013390:Succinylcholine