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Butyrylcholinesterase deficiency is an autosomal recessive pharmacogenetic disorder characterized by prolonged neuromuscular blockade and apnea following administration of ester‐type muscle relaxants. The BCHE gene (HGNC:983) encodes plasma butyrylcholinesterase, which hydrolyzes succinylcholine and mivacurium. Loss‐of‐function variants in BCHE reduce enzyme activity, leading to extended drug half‐life and delayed recovery after anesthesia (HP:0002101).
A Definitive gene–disease association is supported by over 100 unrelated probands across multiple ethnicities, segregation in affected families, and concordant functional studies demonstrating loss of catalytic activity. Key variants include c.185C>T (p.Ala62Val) in a heterozygous silent allele presenting with prolonged mivacurium block (PMID:25264279) and c.695T>A (p.Val232Asp) in a patient with extended suxamethonium apnea (PMID:25054547).
Inheritance is autosomal recessive. Case reports describe at least 1 family with two affected siblings and parental heterozygosity for atypical alleles. Two unrelated Chinese patients with absent serum activity carried novel variants p.Phe474Leu and p.Phe502Leu among others, confirmed by family screening for carrier status (PMID:15563885). In aggregate, >30 pathogenic alleles have been identified in ≥100 probands with enzyme activity ≤5% of wild‐type.
In vitro kinetic assays and molecular dynamics simulations demonstrate that p.Ala62Val disrupts the catalytic triad, abolishing activity against succinyldithiocholine while preserving residual butyrylthiocholine hydrolysis at high substrate, with restoration of His438–Ser198 interaction under saturating conditions (PMID:25264279). The BCHE knockout mouse recapitulates human silent phenotypes, confirming haploinsufficiency and supporting a detoxification role for BChE in vivo (PMID:17192674).
BCHE deficiency is reliably diagnosed by combined enzymatic phenotyping and targeted genetic testing for known pathogenic alleles. Genetic confirmation informs anesthetic management, guiding avoidance or dose adjustment of succinylcholine and mivacurium to prevent prolonged apnea. Routine screening of BCHE in high‐risk populations or prior to procedures requiring neuromuscular blockers can prevent life‐threatening complications.
Key Take‐home: Definitive evidence supports autosomal recessive BCHE deficiency as a clinically actionable pharmacogenetic disorder where genetic testing guides anesthetic choices to avert prolonged apnea.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrong≥30 pathogenic alleles in ≥100 probands; segregation observed in families Functional EvidenceStrongEnzyme kinetics, molecular dynamics, and knockout mouse model replicate human phenotype |