Butyrylcholinesterase Deficiency via the BCHE Gene
- Summary and Pricing
- Clinical Features and Genetics
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The great majority of tests are completed within 18 days.
Although several acquired conditions may affect BChE activity (liver or renal diseases, malnutrition, pregnancy, malignancy), >80% of patients with BChE deficiency have pathogenic sequence variants in the BCHE gene. For example, all 17 patients presenting increased sensitivity to the muscle relaxant succinylcholine and lower BChE activity harbored causative sequence variants in the BCHE gene (Primo-Parmo et al. 1996). In another study, 52 out of 65 patients with post-succinylcholine apnea carried causative sequence variants in the BCHE gene (Yen et al. 2003).
Butyrylcholinesterase deficiency is an enzyme disorder characterized by prolonged apnea after the application of muscle relaxants (suxamethonium or mivacurium) to patients in connection with surgical anesthesia (Garcia et al. 2011). Butyrylcholinesterase (EC 188.8.131.52; BChE), also referred to as pseudocholinesterase, is closely related to the enzyme acetylcholinesterase (EC 184.108.40.206; AChE) and is secreted in most tissues as well as in plasma (Strelitz et al. 2014). Although the physiological function of BChE has not been fully established, this enzyme is considered to play a toxicological and pharmacological role in detoxifying or catabolizing ester-containing medications (Nogueira et al. 1990). In addition, individuals diagnosed with BChE deficiency are generally asymptomatic, except for an increased sensitivity to the muscle relaxants suxamethonium and mivacurium, which are two BChE substrates used as myorelaxants, particularly for procedures requiring for tracheal intubation (Gätke et al. 2007; Delacour et al. 2014). In patients with normal BChE levels, these muscle relaxants are rapidly hydrolyzed in plasma, often within 10 min of administration (Dimov et al. 2012). On the other hand, individuals with BChE deficiency hydrolyze these drugs at a significantly slower rate, which consequently results in a prolonged neuromuscular block that ultimately leads to apnea (Primo-Parmo et al. 1996; Yen et al. 2003). Prolonged neuromuscular block often occurs in patients with >70% BChE deficiency (Garcia et a. 2011).
BChE deficiency is an autosomal recessive enzyme disorder that is mainly caused by pathogenic sequence variants in the BCHE gene. The BCHE gene is located on chromosome 3q26.1, consists of 3 coding exons, and spans approximately 64 kb (Allderdice et al. 1991; Gnatt et al 1990). It has been estimated that 10%-20% of the human population carries at least one variant BCHE allele (Soliday et al. 2010). The mutational spectrum of the BCHE gene includes 72 causative sequence variants, which include 61 missense/nonsense substitutions, 3 small deletions, 4 small insertions, 1 small insertion/deletion, and 1 gross insertion (Stenson et al. 2003). Most of these reported pathogenic sequence variants impart adverse effects on BChE activity by altering its catalytic function or protein expression, thus resulting in a significant decrease or absence of BChE (Maekawa et al. 1997; Delacour et al. 2014).
Full Sanger gene sequencing of all 3 coding exons of the BCHE gene is performed. The full coding region of each exon plus ~10 bp of flanking non-coding DNA on either side are sequenced. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.
Indications for Test
The ideal BChE test candidates have a family history of BChE deficiency as indicated by low plasma levels and/or enzyme activity.
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- Genetic Counselor Team - email@example.com
- Kym Bliven, PhD - firstname.lastname@example.org
- Allderdice PW, Gardner HA, Galutira D, Lockridge O, LaDu BN, McAlpine PJ. 1991. The cloned butyrylcholinesterase (BCHE) gene maps to a single chromosome site, 3q26. Genomics 11(2): 452-454. PubMed ID: 1769657
- Delacour H, Lushchekina S, Mabboux I, Bousquet A, Ceppa F, Schopfer LM, Lockridge O, Masson P. 2014. Characterization of a novel BCHE "silent" allele: point mutation (p.Val204Asp) causes loss of activity and prolonged apnea with suxamethonium. PLoS One 9(7): e101552. PubMed ID: 25054547
- Dimov D, Kanev K, Dimova I. 2012. Correlation between butyrylcholinesterase variants and sensitivity to soman toxicity. Acta Biochimica Polonica 59(2): 313-316. PubMed ID: 22696303
- Garcia DF, Oliveira TG, Molfetta GA, Garcia LV, Ferreira CA, Marques AA, Silva WA Jr. 2011. Biochemical and genetic analysis of butyrylcholinesterase (BChE) in a family, due to prolonged neuromuscular blockade after the use of succinylcholine. Genetics and Molecular Biology 34(1): 40-44. PubMed ID: 21637541
- Gätke MR, Bundgaard JR, Viby-Mogensen J. 2007. Two novel mutations in the BCHE gene in patients with prolonged duration of action of mivacurium or succinylcholine during anaesthesia. Pharmacogenetics and Genomics 17(11): 995-999. PubMed ID: 18075469
- Gnatt A, Prody CA, Zamir R, Lieman-Hurwitz J, Zakut H, Soreq H. 1990. Expression of alternatively terminated unusual human butyrylcholinesterase messenger RNA transcripts, mapping to chromosome 3q26-ter, in nervous system tumors. Cancer Research 50(7): 1983-1987. PubMed ID: 2317787
- Maekawa M, Sudo K, Dey DC, Ishikawa J, Izumi M, Kotani K, Kanno T. 1997. Genetic mutations of butyrylcholine esterase identified from phenotypic abnormalities in Japan. Clinical Chemistry 43(6 Pt 1): 924-929. PubMed ID: 9191541
- Nogueira CP, McGuire MC, Graeser C, Bartels CF, Arpagaus M, Van der Spek AF, Lightstone H, Lockridge O, La Du BN. 1990. Identification of a frameshift mutation responsible for the silent phenotype of human serum cholinesterase, Gly 117 (GGT----GGAG). American Journal of Human Genetics 46(5): 934-942. PubMed ID: 2339692
- Primo-Parmo SL, Bartels CF, Wiersema B, van der Spek AF, Innis JW, La Du BN. 1996. Characterization of 12 silent alleles of the human butyrylcholinesterase (BCHE) gene. American Journal of Human Genetics 58(1): 52-64.
PubMed ID: 8554068
- Primo-Parmo SL, Bartels CF, Wiersema B, van der Spek AF, Innis JW, La Du BN.1996. Characterization of 12 silent alleles of the human butyrylcholinesterase (BCHE) gene. American Journal of Human Genetics 58(1): 52-64.
- Soliday FK, Conley YP, Henker R. 2000. Pseudocholinesterase deficiency: a comprehensive review of genetic, acquired, and drug influences. American Association of Nurse Anesthesists Journal 78(4): 313-320. PubMed ID: 20879632
- Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, Abeysinghe S, Krawczak M, Cooper DN. 2003. Human Gene Mutation Database (HGMD): 2003 update. Human Mutation 21(6): 577-581. PubMed ID: 12754702
- Strelitz J, Engel LS, Keifer MC2. 2014. Blood acetylcholinesterase and butyrylcholinesterase as biomarkers of cholinesterase depression among pesticide handlers. Occupational and Environmental Medicine 71(12): 842-847. PubMed ID: 25189163
- Yen T, Nightingale BN, Burns JC, Sullivan DR, Stewart PM. 2003. Butyrylcholinesterase (BCHE) genotyping for post-succinylcholine apnea in an Australian population. Clinical Chemistry 49(8): 1297-1308. PubMed ID: 12881446
Bi-Directional Sanger Sequencing
Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org). As required, DNA is extracted from the patient specimen. PCR is used to amplify the indicated exons plus additional flanking non-coding sequence. After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions. In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.
As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.
Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).
In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.
Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.
In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.
In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.
Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.
Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.
Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.
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- A completed requisition form must accompany all specimens.
- Billing information along with specimen and shipping instructions are within the requisition form.
- All testing must be ordered by a qualified healthcare provider.
(Delivery accepted Monday - Saturday)
- Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
- For small babies, we require a minimum of 1 ml of blood.
- Only one blood tube is required for multiple tests.
- Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
- During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
- In cold weather, include an unfrozen ice pack in the shipping container as insulation.
- At room temperature, blood specimen is stable for up to 48 hours.
- If refrigerated, blood specimen is stable for up to one week.
- Label the tube with the patient name, date of birth and/or ID number.
(Delivery accepted Monday - Saturday)
- Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
- For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
- DNA may be shipped at room temperature.
- Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
- We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.
(Delivery preferred Monday - Thursday)
- PreventionGenetics should be notified in advance of arrival of a cell culture.
- Culture and send at least two T25 flasks of confluent cells.
- Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
- Send specimens in insulated, shatterproof container overnight.
- Cell cultures may be shipped at room temperature or refrigerated.
- Label the flasks with the patient name, date of birth, and/or ID number.
- We strongly recommend maintaining a local back-up culture. We do not culture cells.