Genotype-phenotype relationships in butyrylcholinesterase deficiency: a systematic review

Butyrylcholinesterase (BChE) deficiency is a recessive condition that can cause prolonged paralysis after suxamethonium or mivacurium. Conventional phenotyping using dibucaine and fluoride inhibition can overlook heterozygous carriers. The aim of this systematic review was to identify studies reporting paired BCHE genotype and biochemical phenotype data to propose a risk-assessment protocol.

We searched PubMed, EMBASE, and the Cochrane Library (1946-2024; PROSPERO CRD420250627891) for human studies reporting both BCHE genotype and biochemical phenotype. Extracted data included enzyme activity, dibucaine and fluoride numbers, and the genotyping method used. Study quality was assessed using the JBI Critical Appraisal Tools.

A total of 30 studies met the inclusion criteria. Among 290 patients included, 92 (32%) had a normal, 110 (38%) an atypical, 66 (23%) an intermediate phenotype, and 22 (7%) had no measurable enzyme activity. Of those with a normal phenotype, 66 (72%) carried at least one BCHE variant. Atypical phenotypes were associated with reduced enzyme activity and with carriage of multiple variants. Patients with absent activity harboured frameshift or nonsense variants. The A-variant (p.Asp98Gly) and K-variant (p.Ala567Thr) were the most frequent.

Genetic testing in suspected BChE deficiency provides valuable information beyond biochemical phenotyping, particularly in multi-allelic cases. Inhibition studies are insensitive to detecting variants with null or modest biological effects. Heterogeneity across studies precludes delivering a standardised diagnostic algorithm. An assessment framework integrating genotyping and phenotyping may facilitate variant annotation and improve diagnostic accuracy, risk stratification, and genetic counselling.

PROSPERO (CRD420250627891).