Ceppa F

References (9)

Title : Characterization of four BCHE mutations associated with prolonged effect of suxamethonium - Brazzolotto_2021_Pharmacogenomics.J_21_165
Author(s) : Brazzolotto X , Courcelle S , Sauvanet C , Guillon V , Igert A , Kononchik J , Nachon F , Ceppa F , Delacour H
Ref : Pharmacogenomics J , 21(2):165-173 : , 2021
Abstract : Butyrylcholinesterase (BChE) deficiency is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or mivacurium) in patients who have mutations in the BCHE gene. Here, we report the characterization of four BCHE mutations associated with prolonged effect of suxamethonium (amino acid numbering based on the matured enzyme): p.20delValPheGlyGlyThrValThr, p.Leu88His, p.Ile140del and p.Arg386Cys. Expression of recombinant BCHE mutants, kinetic analysis and molecular dynamics were undertaken to understand how these mutations induce BChE deficiency. Three of the mutations studied (p.20delValPheGlyGlyThrValThr, p.Ile140del and p.Arg386Cys) lead to a "silent" BChE phenotype. Recombinant BCHE expression studies for these mutants revealed BChE activity levels comparable to untransfected cells. Only the last one (hBChE-L88H) presented BChE activity in the transfected cell culture medium. This BChE mutant (p.Leu88His) is associated with a lower k(cat) value compare to the wild-type enzyme. Molecular dynamics simulations analyses suggest that a destabilization of a structure implicated in enzyme activity (-loop) can explain the modification of the kinetic parameter of the mutated protein.
ESTHER : Brazzolotto_2021_Pharmacogenomics.J_21_165
PubMedSearch : Brazzolotto_2021_Pharmacogenomics.J_21_165
PubMedID: 33024248

Title : Use of IFCC guidelines to verify acetylcholinesterase reference interval in adults determined with ChE check mobile testing system -
Author(s) : Lefrere B , Servonnet A , Ceppa F , Dorandeu F , Delacour H
Ref : Clinical Chemistry & Laboratory Medicine , 55 :e268 , 2017
PubMedID: 28467310

Title : Butyrylcholinesterase deficiency - Delacour_2016_Ann.Biol.Clin.(Paris)_74_279
Author(s) : Delacour H , Dedome E , Courcelle S , Hary B , Ceppa F
Ref : Ann Biol Clin (Paris) , 74 :279 , 2016
Abstract : Butyrylcholinesterase (EC 3.1.1.8; BChE) is a sister enzyme of acetylcholinesterase. Though BChE lacks obvious physiological functions, it is of toxicological and pharmacological importance in detoxifying or catabolising ester-containing drugs. Furthermore, individuals deficient in BChE appear asymptomatic, apart from a heightened sensitivity to the muscle relaxants suxamethonium and mivacurium, two BChE substrates used as myorelaxant. Although many acquired conditions may affect BChE activity, BChE deficiency is mainly due to mutations in the BCHE gene (OMIM 177400). Currently, more than 70 natural mutations have been documented in human BCHE. They have an adverse effect on BChE activity by affecting the catalytic functioning or the protein expression. However, the atypical variant (rs1799807) is the most frequently involved in prolonged apnea.
ESTHER : Delacour_2016_Ann.Biol.Clin.(Paris)_74_279
PubMedSearch : Delacour_2016_Ann.Biol.Clin.(Paris)_74_279
PubMedID: 27237801

Title : [Prolonged neuromuscular block in a patient with butyrylcholinesterase deficiency] - Mabboux_2016_Arch.Pediatr_23_497
Author(s) : Mabboux I , Hary B , Courcelle S , Ceppa F , Delacour H
Ref : Arch Pediatr , 23 :497 , 2016
Abstract : Succinylcholine is a neuromuscular block whose duration of action depends on rapid hydrolysis by butyrylcholinesterase (BChE). In patients with common BChE activities, succinylcholine duration of action is short (10min). BChE deficiency induces a slower hydrolysis of the drug and consequently prolonged neuromuscular block, leading to apnea. We report a case of prolonged neuromuscular block after administration of succinylcholine in a 14-year-old boy. Biological investigations revealed a marked BChE deficiency (1099U/L) related to the presence of three point mutations in the BCHE gene in a compound heterozygous state: p.Asp70Gly (rs1799807), p.Ala539Tyr (rs1803274), and p.Phe118Valfs*12 (rs398124632). The diagnosis of genetic BChE deficiency (OMIM 177400) was retained. This case is intended to present the pathophysiology of genetic BChE deficiency, its management, and the diagnostic strategy to be implemented.
ESTHER : Mabboux_2016_Arch.Pediatr_23_497
PubMedSearch : Mabboux_2016_Arch.Pediatr_23_497
PubMedID: 27017361

Title : Characterization of a Novel BCHE Silent Allele: Point Mutation (p.Val204Asp) Causes Loss of Activity and Prolonged Apnea with Suxamethonium - Delacour_2014_PLoS.One_9_e101552
Author(s) : Delacour H , Lushchekina SV , Mabboux I , Bousquet A , Ceppa F , Schopfer LM , Lockridge O , Masson P
Ref : PLoS ONE , 9 :e101552 , 2014
Abstract : Butyrylcholinesterase deficiency is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or mivacurium) in patients who have mutations in the BCHE gene. Here, we report a case of prolonged neuromuscular block after administration of suxamethonium leading to the discovery of a novel BCHE variant (c.695T>A, p.Val204Asp). Inhibition studies, kinetic analysis and molecular dynamics were undertaken to understand how this mutation disrupts the catalytic triad and determines a "silent" phenotype. Low activity of patient plasma butyrylcholinesterase with butyrylthiocholine (BTC) and benzoylcholine, and values of dibucaine and fluoride numbers fit with heterozygous atypical silent genotype. Electrophoretic analysis of plasma BChE of the proband and his mother showed that patient has a reduced amount of tetrameric enzyme in plasma and that minor fast-moving BChE components: monomer, dimer, and monomer-albumin conjugate are missing. Kinetic analysis showed that the p.Val204Asp/p.Asp70Gly-p.Ala539Thr BChE displays a pure Michaelian behavior with BTC as the substrate. Both catalytic parameters Km = 265 microM for BTC, two times higher than that of the atypical enzyme, and a low Vmax are consistent with the absence of activity against suxamethonium. Molecular dynamic (MD) simulations showed that the overall effect of the mutation p.Val204Asp is disruption of hydrogen bonding between Gln223 and Glu441, leading Ser198 and His438 to move away from each other with subsequent disruption of the catalytic triad functionality regardless of the type of substrate. MD also showed that the enzyme volume is increased, suggesting a pre-denaturation state. This fits with the reduced concentration of p.Ala204Asp/p.Asp70Gly-p.Ala539Thr tetrameric enzyme in the plasma and non-detectable fast moving-bands on electrophoresis gels.
ESTHER : Delacour_2014_PLoS.One_9_e101552
PubMedSearch : Delacour_2014_PLoS.One_9_e101552
PubMedID: 25054547

Title : Characterization of a novel butyrylcholinesterase point mutation (p.Ala34Val), silent with mivacurium - Delacour_2014_Biochem.Pharmacol_92_476
Author(s) : Delacour H , Lushchekina SV , Mabboux I , Ceppa F , Masson P , Schopfer LM , Lockridge O
Ref : Biochemical Pharmacology , 92 :476 , 2014
Abstract : Butyrylcholinesterase deficiency is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or mivarcurium) in patients who have mutations in the BCHE gene. Here, we report a case of prolonged neuromuscular block after administration of mivacurium leading to the discovery of a novel BCHE variant (c.185C>T, p.Ala34Val). Inhibition studies, kinetic analysis and molecular dynamics were undertaken to understand how this mutation remote from the active center determines the "silent" phenotype. Low activity of patient plasma butyrylcholinesterase with butyrylthiocholine (BTC) and benzoylcholine, and values of dibucaine and fluoride numbers fit with a heterozygous enzyme of type atypical/silent. Kinetic analysis with succinyldithiocholine (SCdTC) as the substrate showed that Ala34Val BChE was inactive against this substrate. However, with BTC, the mutant enzyme was active, displaying an unexpected activation by excess substrate. Competitive inhibition of BTC by mivacurium gave a Ki=1.35mM consistent with the lack of activity with the related substrate SCdTC, and with the clinical data. Molecular dynamic simulations revealed the mechanism by which mutation Ala34Val determines the silent phenotype: a chain of intramolecular events leads to disruption of the catalytic triad, so that His438 no longer interacts with Ser198, but instead forms hydrogen bonds either with residues Glu197 and Trp82, or peripheral site residue Tyr332. However, at high BTC concentration, initial binding of substrate to the peripheral site triggers restoration of a functional catalytic triad, and activity with BTC.
ESTHER : Delacour_2014_Biochem.Pharmacol_92_476
PubMedSearch : Delacour_2014_Biochem.Pharmacol_92_476
PubMedID: 25264279

Title : Rapid detection of BCHE atypical variant (p.Asp70Gly) by high resolution melting curve analysis - Mabboux_2014_Ann.Biol.Clin.(Paris)_72_543
Author(s) : Mabboux I , Dos Santos M , Courcelle S , Hary B , Ceppa F , Delacour H
Ref : Ann Biol Clin (Paris) , 72 :543 , 2014
Abstract : Butyrylcholinesterase (BChE) deficiency is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or mivacurium). Although many acquired conditions may affect BChE activity, BChE deficiency is mainly due to mutations in the BCHE gene (MIM 177400). Though close to 70 natural mutations have been documented in human BCHE, the atypical variant (rs1799807) is the most frequently involved in prolonged apnea. We describe an HRM method for the detection of this variant. Thirty-four patients with known genotype [5 wild-type (U/U), 12 heterozygous (U/A), 17 homozygous (A/A) - A: atypical allele of BCHE, U: usual allele of BCHE -] were screened with the HRM analysis. Within and between-run precision were also evaluated. In silico prediction of HRM curves was performed in order to evaluate the potential impact of the other SNPs described within the PCR product on the HRM diagnostic accuracy. HRM analysis for the BCHE atypical variant genotyping is a simple, rapid, sensitive and low cost method.
ESTHER : Mabboux_2014_Ann.Biol.Clin.(Paris)_72_543
PubMedSearch : Mabboux_2014_Ann.Biol.Clin.(Paris)_72_543
PubMedID: 25336127

Title : [Prolonged succinylcholine-induced apnoea associated with cholinesterase silent plasma variant] - Ceppa_2005_Ann.Fr.Anesth.Reanim_24_425
Author(s) : Ceppa F , Kenane N , Chellak S , Bigaillon C , Burnat P
Ref : Annales Francaises d Anesthesie et de Reanimation , 24 :425 , 2005
Abstract : Mivacurium and succinylcholine are short-acting neuromuscular blocking drugs. The duration of their action depends on their rapid hydrolysis by plasma cholinesterase or butyrylcholinesterase. More than thirty genetic variants of this enzyme have been described but the atypical variant is the most frequently involved in prolonged apnoea following the administration of these two myorelaxants. We present one case of patient who presented a five hours long apnoea associated with null cholinesterase activity and detection of a butyrylcholinesterase silent variant (Sil-1, 1 for 100,000 persons in population) after sequencing.
ESTHER : Ceppa_2005_Ann.Fr.Anesth.Reanim_24_425
PubMedSearch : Ceppa_2005_Ann.Fr.Anesth.Reanim_24_425
PubMedID: 15826794

Title : Rapid identification of atypical variant of plasma butyrylcholinesterase by PCR - Ceppa_2002_Clin.Chem.Lab.Med_40_799
Author(s) : Ceppa F , Gidenne S , Benois A , Fontan E , Burnat P
Ref : Clinical Chemistry & Laboratory Medicine , 40 :799 , 2002
Abstract : Human butyrylcholinesterase is the enzyme responsible of mivacurium and succinylcholine metabolism, which may be significantly impaired when mutation Asp70Gly is found in patients. We describe a simple PCR method for the detection of this variant. Thirteen out of sixteen patients tested after prolonged apnea were positive for the presence of this mutation (50.0% homozygotes and 31.3% heterozygotes), suggesting that this test contributes to the explanation of some clinical events and to their prevention in relatives of these patients.
ESTHER : Ceppa_2002_Clin.Chem.Lab.Med_40_799
PubMedSearch : Ceppa_2002_Clin.Chem.Lab.Med_40_799
PubMedID: 12392308