BCHE mutation screening   Butyrylcholinesterase deficiency  OMIM 177400
 Pseudocholinesterase deficiency,  Postanesthetic Apnea, Suxamethonium sensitivity 

Mutations in the BCHE1 gene lead to variant enzyme forms with changed substrate behavior, reduced activity, or the absence of the enzyme butyrylcholinesterase. This plasma enzyme hydrolyses acetylcholine, propionylcholin, butyrylcholin and exogenous cholin ester-containing drugs such as the muscle relaxants suxamethonium (succinylcholin) and mivacurium, and ester-type local anesthetics like procain. It also acts as a scavenger against organophosphorus and carbamate compounds of pesticides like parathion13), chemical warfare agents like Sarin and narcotics like cocain and heroin.

Butyrylcholinesterase is attributed a function in the neural system, its precise role however is still subject of research. The homozygous BCHE K-variant has been associated with early onset Alzheimer disease 6). The association of BCHE genotypes with Alzheimer disease susceptibility or development as well as cognitive functions in general is discussed 14, 15).

BCHE1 on chromosome 3q26.1-q26.2 encodes a 602 amino acid protein including a 28 amino acid leader peptide. The enzyme is composed of 4 identical subunits of 574 amino acids, each containing an active catalytic site. The gene is located on 4 exons of which one is non-coding.

The autosomal recessive condition called suxamethonium sensitivity or peudocholinesterase deficiency is asymptomatic in the absence of exogenous cholin ester-containing drugs and chemical compounds. Homozygous or compound heterozygous carriers of BCHE mutations can remain unrecognized until an adverse response to cholin ester-compounds occurs as in postanesthetic apnea or pesticide and cocain poisoning.

In persons carrying BCHE mutations and undergoing surgical anesthesia, the combination with cholin ester-containing muscle relaxants can lead to prolonged post-anesthetic apnea requiring respiratory support due to a slower or absent enzymatic degradation of the muscle relaxant and continued neuromuscular blockade.

Apnea after suxamethonium injection normally lasts approximately 5 min. In BCHE mutation carriers, apnea can last from 10 min to 2 or 3 hours depending on the patient’s genotype.

By measuring the inhibition of the enzymatic activity in the presence or absence of the specific inhibitors dibucain and sodium fluoride, three main BCHE genotypes have been recognized:

  • Qualitative variants like the atypical 1) and fluoride-resistant 2) that show less inhibition with dibucain or fluoride than the normal genotype.

  • Quantitative variants like the K 3), J 4) and H-variant 5) showing reduced enzymatic activity.

  • “silent” genotypes, like silent 1, showing absent or extremely reduced (<10%) enzymatic activity.

Following the cloning and sequencing of the BCHE gene 7, 8), the molecular basis, particularly of the heterogeneous atypical and silent BCHE phenotypes, could be unraveled. This enables DNA-based genotyping of individual patients and populations 9-12).

The most common BCHE-mutations are the K-variant Ala539Thr in exon 4 with an estimate homozygote frequency of 1:100 and the dibucain-resitant 1 variant Asp70Gly in exon 2 with a homozygote frequency of 1:3000 in the Caucasian population. A still growing number of more than 45 missence, nonsence, insertion, deletion and splice site mutations in all 3 coding exons of the gene have been reported 5).

The screening of the BCHE gene for mutations supports the clinical diagnosis of peudocholinesterase deficiency and enables detection of asymptomatic carriers of mutant alleles.

When suspecting peudocholinesterase deficiency, we offer a tiered analysis of the BCHE gene: Partial sequence analysis of exon 2 (e.g. Asp70Gly ) and exon 4 (e.g. Ala539Thr), followed by the complete mutation screening of exon 2 and exon 3.

When mutations are found, we recommend analyzing the corresponding BCHE-alleles of the patient's relatives to detect asymptomatic carrier of the gene defect.

1)  Kalow and Genest (1957) Can. J. Biochem. Physiol. 35:339-346
2)   Harris and Whittaker (1961) Nature 191:496-498
3)   Rubinstein et al. (1978) J. Med. Genet. 15:27-29
  Garry et al. (1976) J. Med. Genet. 13:38-42
5)   Whittaker and Britten (1987) Hum.
Hered. 40:54-58
  Ghebremedhin et al. (2007) Acta Neuropathol. 114: 359-363

McTiernan et al. (1987) Proc. Natl. Acad. Sc. USA 84:6682-6686
  Arpagaus et al. (1990) Biochem. 29:124-131
  Primo-Parmo et al. (1996) Am. J. Hum. Genet. 58:52-64

 Cerf et al. (2002) Anesth. Analg. 94:461-466
 Yen et al. (2003) Clin. Chem. 49:1297-1308

 Fantozzi Garcia et al. (2011) Genet. Mol. Biol. 34:40-44
 Lockridge and Masson (2000) Neurotoxicology 21:113-126

 Lehmann et al. (1997) Hum. Mol.
Genet. 6:1933-1936
15)  Manoharan et al. (2007) J. Neural Transm. 114:939-945

Please contact us for an estimate for this analysis.
We usually provide results of the initial screening for mutations in exon 2 and 4 within 3 days after receipt of the sample.
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