Butyrylcholinesterase Deficiency

A number sign (#) is used with this entry because butyrylcholinesterase deficiency (BCHED) can be caused by homozygous or compound heterozygous mutation in the BCHE gene (177400) on chromosome 3q26. Severe cholinesterase deficiency results in postanesthetic apnea.

Description

Individuals deficient in butyrylcholinesterase (BCHE) appear asymptomatic, apart from a heightened sensitivity to muscle relaxants such as suxamethonium (succinylcholine) and mivacurium, 2 BCHE carboxylester substrates. In individuals with usual BCHE levels, these drugs are rapidly hydrolyzed in plasma and their duration of action is short (less than 10 minutes). BCHE deficiency results in slower hydrolysis of these drugs and, consequently, a prolonged neuromuscular block, leading to apnea. Prolonged neuromuscular block occurs with BCHE deficiencies of marked severity (impairment over 70%). Although many acquired conditions may affect BCHE activity (e.g., liver or renal diseases, malnutrition, pregnancy, malignancy), BCHE deficiency is mainly due to mutations in the BCHE gene (summary by Delacour et al., 2014).

Clinical Features

Mutant alleles at the BCHE (CHE1) locus are responsible for suxamethonium sensitivity. Homozygous persons sustain prolonged apnea after administration of the muscle relaxant suxamethonium in connection with surgical anesthesia. The activity of pseudocholinesterase in the serum is low and its substrate behavior is atypical. In the absence of the relaxant, the homozygote is at no known disadvantage. The dibucaine number (percentage inhibition by dibucaine) identifies 3 genotypes--usual, intermediate, and atypical (Kalow and Genest, 1957). Two further alleles are a silent allele and an allele identified by fluoride inhibition. Heterogeneity of the 'silent' cholinesterase genes was indicated by the studies of Rubinstein et al. (1970). There is phenotypic diversity in suxamethonium sensitivity resulting from an allelic series. Some of the subjects with sensitive genotypes have apnea lasting 2 or 3 hours, whereas the apnea in other sensitive genotypes is considerably shorter (Lehmann and Liddell, 1972).

Inheritance

BCHE deficiency shows autosomal recessive inheritance (Delacour et al., 2014).

Diagnosis

Garcia et al. (2011) noted that a mutation detection approach has been used for the investigation and characterization of the BCHE variants in individuals who present reduced plasmatic enzyme activity and need to undergo anesthetic procedures.

Population Genetics

Using a rapid screening test, Motulsky and Morrow (1968) demonstrated a low frequency of BCHE heterozygotes among Congolese Africans, Japanese, Taiwanese, Filipinos and Eskimos. U.S. Caucasians, Greeks, Yugoslavs and East Indians had a relatively high frequency (2.8 to 3.3%). They predicted a low frequency of suxamethonium apnea in the low frequency groups.

Lubin et al. (1971) used an automated screening method to study heterozygote frequency of BCHE in a group of 2,317 persons. Among Caucasians, the ratio of male to female heterozygotes was 1.85 to 1.

Deficiency of pseudocholinesterase is unusually frequent among Alaskan Eskimos (Gutsche et al., 1967). In an Eskimo population with a gene frequency for serum cholinesterase deficiency exceeding 10%, Scott et al. (1970) determined normal enzyme levels at various ages and the degree of overlap of heterozygous and homozygous classes. Curiously, 3 presumably allelic forms of serum cholinesterase deficiency were found in 1 small Eskimo population (Scott and Wright, 1976).

Manoharan et al. (2006) tested 226 plasma samples from a Vysya community in India and found that 9 unrelated individuals had no detectable BCHE activity. DNA sequencing revealed that all silent BCHE samples were homozygous for a missense mutation in the BCHE gene (L335P; 177400.0014). The authors calculated that the frequency of homozygous silent BCHE in the Vysya community was 1 in 24 (4%), a value 4,000-fold higher than that observed in European and American populations, and noted that the Vysyas constitute about 16% of the population of India.

Molecular Genetics

McGuire et al. (1989) found that the 'atypical' (A) dibucaine-resistant BCHE phenotype described by Kalow and Staron (1957) was caused by an asp70-to-gly (D70G; 177400.0001) mutation in the BCHE gene. Individuals who are homozygous for the A variant fail to hydrolyze succinylcholine and mivacurium in the circulation, thus allowing a huge overdose to paralyze the breathing muscles. The genetic variant most frequently found in cases of prolonged apnea is the A variant, which reduces the binding affinity for succinylcholine 100-fold (Lockridge, 2015).

In 7 persons with a 'silent' BCHE phenotype from 2 unrelated families, Nogueira et al. (1989, 1990) identified a homozygous frameshift mutation mutation (177400.0002) in the BCHE gene as the cause of an exaggerated response to succinylcholine. Individuals homozygous for specific silent variants or compound heterozygous for the atypical allele and a fluoride (e.g., 177400.0003) or a silent allele have prolonged apnea (Lockridge, 2015).

Bartels et al. (1992) found that the basis of the K variant phenotype described by Rubinstein et al. (1978) was an ala539-to-thr (A539T; 177400.0005) substitution in the BCHE gene. The allele produced a 30% reduction of serum butyrylcholinesterase activity. The most common BCHE variant is the K variant. Individuals homozygous for the K variant have a normal response to succinylcholine and mivacurium (Lockridge, 2015).

Primo-Parmo et al. (1996) identified 12 silent alleles of the BCHE gene in 17 apparently unrelated patients who were selected by their increased sensitivity to succinylcholine. All of these alleles were characterized by single-nucleotide substitutions or deletions leading to distinct changes in the structure of the enzyme molecule. Replacement of single amino acid residues resulted from 9 of the nucleotide substitutions.

Yen et al. (2003) genotyped 65 Australian patients referred after prolonged post-succinylcholine apnea and identified 52 patients with primary hypocholinesterasemia attributable to BCHE mutations. The most common genotype abnormality was compound homozygous dibucaine (177400.0001)/homozygous K variant (177400.0005), accounting for 44% of inherited BCHE deficiency. Compound heterozygosity for dibucaine and K variant was the second most frequent genotype identified; there were no cases of simple homozygosity.

History

The finding in the late 1950s that an impairment of a phase I reaction, hydrolysis of the muscle relaxant succinylcholine by butyrylcholinesterase, was inherited served as an early stimulus for the development of pharmacogenetics (Kalow, 1962). At almost the same time, Evans et al. (1960) observed that a common genetic variation in a phase II pathway of drug metabolism, N-acetylation (243400), could result in striking differences in the half-life and plasma concentrations of drugs metabolized by N-acetyltransferase. Weinshilboum (2003) reviewed the subject of inheritance and drug response beginning from these 2 historic examples. Evans and McLeod (2003) discussed pharmacogenomics more broadly, from the standpoints of drug disposition, drug targets, and side effects.