A Case Report of Primary Neonatal Hypocholinesterase Caused by Homozygous Frameshift Mutation of the utyrylcholinesterase (BCHE) Gene and Review of Literature.

BACKGROUND: Primary neonatal hypocholinesterase is rare; its genetic pattern and mutation still need to be further studied. METHODS: The patient and his parents are studied using next-generation sequencing technology. RESULTS: A boy one day after birth is admitted to the Neonatal Intensive Care Unit at our hospital after experiencing intermittent vomiting for 12 hours. The patient's serum cholinesterase level (113 - 283 U/L) is lower than normal value (4,000 - 12,600 U/L). Many factors of low serum cholinesterase are excluded. We highly suspect that it may be related to congenital factors. Molecular genetic test results show that the patient carried the BCHE gene (NM_000055.2) and has homozygous frameshift mutations at exon 2 c.401dupA (p.Asn134fs) of chromosome 3q26. It is a pathogenicity mutation. This locus mutation belongs to a novel pathogenic mutation. As a result of this mutation, the 134th amino acid Asn began to frameshift and the translation is terminated early. It can cause the Encoding of protein to truncate and lose its normal function. His parents' serum cholinesterase levels (father: 5,135 U/L; mother: 4,367 U/L) are in the normal value range, but his parents carried a heterozygous BCHE gene. CONCLUSIONS: This study suggests that gene sequence detection should be carried out early in hypocholinesterase of nknown cause in neonates. This study can not only improve understanding of the etiology and pathological mechanism of hypocholinesterase, but also it can enlarge the hypocholinesterase gene mutation spectrum.

Butyrylcholinesterase deficiency and its clinical importance in anaesthesia: a systematic review.

Butyrylcholinesterase deficiency prolongs the effects of the drugs it degrades; succinylcholine and mivacurium. Existing literature on butyrylcholinesterase deficiency is dominated by genetic and biochemical studies. We searched MEDLINE, Embase, Web of Science and Biosis to systematically review the causes and clinical consequences of butyrylcholinesterase deficiency. We considered outcomes clinically relevant if neuromuscular blockade, induced by succinylcholine or mivacurium, was assessed using clinical criteria or neuromuscular monitoring. We included 66 studies: 25 randomised controlled trials; 13 clinically controlled trials; 26 prospective observational studies; 1 retrospective study; and 1 qualitative study. Data heterogeneity precluded quantitative synthesis. Studies described genetic, physiological, acquired or pharmacologically induced causes of butyrylcholinesterase deficiency. The prolongation of neuromuscular blockade by butyrylcholinesterase deficiency was most pronounced with homozygosity of a genetic variant, but other more common factors included increasing age, pregnancy, severe liver disease, burn injuries and drug interactions.

A novel mutation in the BCHE gene and phenotype identified in a child with low butyrylcholinesterase activity: a case report.

BACKGROUND: Butyrylcholinesterase (BChE), an ester hydrolase produced mainly by the liver, hydrolyzes certain short-acting neuromuscular blocking agents, like succinylcholine and mivacurium that are widely used during anesthesia. Patients with BChE deficiency are possibly in danger of postanesthetic apnea. Hereditary BChE deficiency results from the mutations of BCHE gene located on chromosome 3, 3q26.1-q26.2, between nucleotides 165,490,692-165,555,260. CASE PRESENTATION: This study describes a novel mutation in a child with BChE deficiency. In general, this child appeared healthy and well-developed with a normal appearance. However, the results of Wechsler Intelligence Scale showed that the full-scale intelligence quotient (FIQ) was 53, classified into the group with the minor defect. The BChE activity was 32.0 U/L, considerably lower than the normal lower limit (reference range: 5000-12,000 U/L). Sanger sequencing showed that there were 2 mutations in the exon 2 of BCHE gene of this child. One is a heterozygous mutation rs764588882 (NM_000055.3: c.401_402insA, p.Asn134Lysfs*23). The other one is a heterozygous mutation (NM_000055.3: c.73A > T, p.Lys25Ter) that has never been reported before. The two mutations lead to a premature stop of transcription. CONCLUSIONS: Double heterozygous recessive mutations are the cause of BChE deficiency of this boy in this study, including a novel mutation c.73A > T. Intellectual disability is a new phenotype that is probably associated with this mutation.

Butyrylcholinesterase regulates central ghrelin signaling and has an impact on food intake and glucose homeostasis.

BACKGROUND: Ghrelin is the only orexigenic hormone known to stimulate food intake and promote obesity and insulin resistance. We recently showed that plasma ghrelin is controlled by butyrylcholinesterase (BChE), which has a strong impact on feeding and weight gain. BChE knockout (KO) mice are prone to obesity on high-fat diet, but hepatic BChE gene transfer rescues normal food intake and obesity resistance. However, these mice lack brain BChE and still develop hyperinsulinemia and insulin resistance, suggesting essential interactions between BChE and ghrelin within the brain. METHODS: To test the hypothesis we used four experimental groups: (1) untreated wild-type mice, (2) BChE KO mice with LUC delivered by adeno-associated virus (AAV) in combined intravenous (i.v.) and intracerebral (i.c.) injections, (3) KO mice given AAV for mouse BChE (i.v. only) and (4) KO mice given the same vector both i.v. and i.c. All mice ate a 45% calorie high-fat diet from the age of 1 month. Body weight, body composition, daily caloric intake and serum parameters were monitored throughout, and glucose tolerance and insulin tolerance tests were performed at intervals. RESULTS: Circulating ghrelin levels dropped substantially in the KO mice after i.v. AAV-BChE delivery, which led to normal food intake and healthy body weight. BChE KO mice that received AAV-BChE through i.v. and i.c. combined treatments not only resisted weight gain on high-fat diet but also retained normal glucose and insulin tolerance. CONCLUSIONS: These data indicate a central role for BChE in regulating both insulin and glucose homeostasis. BChE gene transfer could be a useful therapy for complications linked to diet-induced obesity and insulin resistance.

Unknown Pseudocholinesterase Deficiency in a Patient Undergoing TIVA with Planned Motor Evoked Potential Monitoring: A Case Report.

Pseudocholinesterase abnormalities are a genetic cause of aberrant metabolism of the depolarizing muscle relaxant succinylcholine. This article examines a case where succinylcholine was chosen to facilitate intubation due to its ultra short duration and the request of the surgeon to monitor motor evoked potentials. Following succinylcholine administration the neurophysiologist was unable to obtain motor evoked potentials. This case study highlights the intraoperative and postoperative management of an elderly patient with an unknown pseudocholinesterase deficiency.

Prolonged Paralysis Following Emergent Cesarean Section with Succinylcholine Despite Normal Dibucaine Number.

Prolonged paralysis due to a quantitative or qualitative deficiency of pseudocholinesterase activity is an uncommon but known side effect of succinylcholine. We describe a patient who experienced prolonged paralysis following administration of succinylcholine for general anesthesia and endotracheal intubation for an emergent cesarean section despite laboratory evidence of normal enzyme function. The patient required mechanical ventilation in the intensive care unit for several hours following surgery. The patient was extubated following return of full muscle strength and had a good outcome. The enzyme responsible for the metabolism of succinylcholine, pseudocholinesterase, was determined to be low in quantity in this patient but was functionally normal. This low level, by itself, was unlikely to be solely responsible for the prolonged paralysis. The patient likely had an abnormal pseudocholinesterase enzyme variant that is undetectable by standard laboratory tests.

Awareness during emergence from anaesthesia: significance of neuromuscular monitoring in patients with butyrylcholinesterase deficiency.

BACKGROUND: Butyrylcholinesterase deficiency can result in prolonged paralysis after administration of succinylcholine or mivacurium. We conducted an interview study to assess whether patients with butyrylcholinesterase deficiency were more likely to have experienced awareness during emergence from anaesthesia if neuromuscular monitoring had not been applied. METHODS: Patients referred during 2004-2012 were included. Data on the use of neuromuscular monitoring were available from a previous study. Interviews, conducted by telephone, included questions about awareness and screening for post-traumatic stress disorder. Reports of panic, hopelessness, suffocation, or a feeling of being dead or dying resulted in the experience being classified further as distressful. Patients were categorized as aware or unaware by investigators blinded to use of neuromuscular monitoring. RESULTS: Ninety-five patients were eligible to be interviewed. Of the 70 patients interviewed, 35 (50%) were aware while paralysed during emergence. Of these, 28 (80%) were not monitored with a nerve stimulator when awakened, compared with 17 (49%) of the 35 unaware patients (P=0.012, Fisher's exact test). Thirty (86%) aware patients reported distress compared with seven (20%) unaware patients (P<0.001). The aware patients scored higher in screening for post-traumatic stress disorder (P=0.006, Mann-Whitney U-test). CONCLUSIONS: Butyrylcholinesterase deficiency is a major risk factor for distressing awareness during emergence. Lack of neuromuscular monitoring increases the risk significantly. Neuromuscular monitoring should be applied even when using short-acting neuromuscular blocking agents.

Premature awakening and underuse of neuromuscular monitoring in a registry of patients with butyrylcholinesterase deficiency.

BACKGROUND: Patients with butyrylcholinesterase (BChE) deficiency can experience prolonged paralysis after receiving suxamethonium or mivacurium. We hypothesized that patients suspected of BChE deficiency had a higher risk of being awakened while paralysed and having respiratory complications if neuromuscular monitoring was not applied before awakening. METHODS: We retrospectively included patients referred to the Danish Cholinesterase Research Unit between 2004 and 2012 on suspicion of BChE deficiency. We collected data on genotype, BChE activity, neuromuscular blocking agents administered, neuromuscular monitoring, and postoperative respiratory complications, defined as arterial oxygen desaturation <90%, assisted ventilation, reintubation of the trachea, and pulmonary aspiration. Patients were classified as prematurely awakened if anaesthesia had been terminated while the patient was still paralysed. RESULTS: We included 123 patients. Neuromuscular monitoring was applied before awakening in 48 (39%) patients. A nerve stimulator was never used or only after attempted awakening in the remaining 75 (61%) patients. Premature awakening occurred in 75 (100%) and 14 (29%) of the unmonitored and monitored patients, respectively (P<0.001, Fisher's exact test). In 11 of the monitored patients, the results of neuromuscular monitoring were interpreted as equipment failure or were disregarded. Respiratory complications occurred in 19 (25%) and five (10%) of the unmonitored and monitored patients, respectively (P=0.06). CONCLUSIONS: Patients with BChE deficiency are at higher risk of being awakened while paralysed if neuromuscular monitoring is not applied or used; neuromuscular monitoring is recommended whenever a neuromuscular blocking agent is administered.

PSEUDOCHOLINESTERASE DEFICIENCY IN A OCTOGENARIAN UNDERGOING TOTAL INTRAVENOUS ANESTHESIA; IMPLICATIONS FOR NEUROMONITORING.

Pseudocholinesterase deficiency manifests as prolonged motor blockade after the administration of succinylcholine. A previously unknown homozygous form of the disease, became apparent during a lumbar laminectomy seriously limiting the ability to monitor motor evoked potentials and perform electromyelography (EMG). Moreover, concerns were raised as to how the enzyme deficiency would affect the metabolism of remifentanil and other esters during a total intravenous anesthetic. We present the perioperative management of the patient and a literature review of the syndrome. The patient provided written permission for the authors to publish this report. At our institution, IRB review and approval is not required for a single case report.

Use of neuromuscular monitoring to detect prolonged effect of succinylcholine or mivacurium: three case reports.

Mutations in the butyrylcholinesterase gene can lead to a prolonged effect of the neuromuscular blocking agents, succinylcholine and mivacurium. If the anaesthesiologist is not aware of this condition, it may result in insufficient respiration after tracheal extubation. However, this can be avoided with the use of objective neuromuscular monitoring if used adequately. Three case reports of prolonged effect of succinylcholine or mivacurium were presented to illustrate the importance of neuromuscular monitoring during anaesthesia. In the first case, continuous intraoperative neuromuscular monitoring allowed a prolonged neuromuscular blockade to be discovered prior to tracheal extubation of the patient. The patient was extubated after successful reversal of the neuromuscular blockade. On the contrary, neuromuscular monitoring was not used during anaesthesia in the second patient; hence, the prolonged effect of the neuromuscular blocking agent was not discovered until after extubation. In the third patient, the lack of response to nerve stimulation was interpreted as a technical failure and the prolonged effect of succinylcholine was discovered when general anaesthesia was terminated. Both patients had insufficient respiration. They were therefore re-sedated, transferred to the intensive care unit and the tracheas were extubated after full recovery from neuromuscular blockade. We recommend the use of monitoring every time these agents are used, even with short-acting drugs like succinylcholine and mivacurium.

[Residual relaxant block due to pseudocholinesterase deficiency - First manifestation in an elderly patient]. / Kasuistik: Relaxansüberhang durch Pseudocholinesterasemangel - Erstmanifestation in höherem Alter.

Pseudocholinesterase or butyrylcholinesterase (BChE) inactivates the relaxant drugs mivacurium and suxamethonium. A deficiency in plasma activity of this enzyme may result in prolonged muscular paralysis and subsequently the need for an extended duration of mechanical ventilation. We report the case of a 65-year-old patient who was diagnosed with butyrylcholinesterase deficiency for the first time during elective surgery. Neuromuscular monitoring constitutes a central diagnostic asset in ensuring patient safety.

Laser captured hepatocytes show association of butyrylcholinesterase gene loss and fibrosis progression in hepatitis C-infected drug users.

UNLABELLED: Chronic hepatitis C virus (HCV) infection is complicated by hepatic fibrosis. Hypothesizing that early fibrogenic signals may originate in cells susceptible to HCV infection, hepatocyte gene expression was analyzed from persons with chronic HCV at different stages of liver fibrosis. Four HCV-infected subjects with precirrhosis liver fibrosis (Ishak fibrosis 3-5) were matched for age, race, and gender to five HCV-infected subjects with no evidence of fibrosis (Ishak fibrosis 0). Hepatocytes from each subject were isolated from liver biopsies using laser capture microdissection. Transcriptome profiling was performed on hepatocyte RNA using hybridization arrays. We found that hepatocytes in precirrhosis fibrosis were depleted for genes involved in small molecule and drug metabolism, especially butyrylcholinesterase (BCHE), a gene involved in the metabolism of drugs of abuse. Differential expression of BCHE was validated in the same tissues and cross-sectionally in an expanded cohort of 143 HCV-infected individuals. In a longitudinal study, serum BCHE activity was already decreased at study inception in 19 fibrosis progressors compared with 20 fibrosis nonprogressors (P < 0.05). Nonprogressors also had decreased BCHE activity over time compared with initial values, but these evolved a median (range) 8.6 (7.8-11.4) years after the study period inception (P < 0.05). Laser captured portal tracts were enriched for immune related genes when compared with hepatocytes but precirrhosis livers lost this enrichment. CONCLUSION: Chronic HCV is associated with hepatocyte BCHE loss years before hepatic synthetic function is impaired. These results indicate that BCHE may be involved in the pathogenesis of HCV-related fibrosis among injection drug users.

Hepatocellular BChE as a therapeutic target to ameliorate hypercholesterolemia through PRMT5 selective degradation to restore LDL receptor transcription.

AIMS: Individuals with nonalcoholic hepatosteatosis (NAFLD) have a worse atherogenic lipoprotein profile and are susceptible to cardiovascular diseases. The MEK-ERK signaling cascades are central regulators of the levels of LDL receptor (LDLR), a major determinant of circulating cholesterol. It is elusive how hepatic steatosis contributes to dyslipidemia, especially hypercholesterolemia. MAIN METHODS: The effects of BChE on signaling pathways were determined by immunoblotting in a BChE knockout hepatocyte cell line. DiI-LDL probe was used to explore the effect of BChE expression on LDL internalization. Co-immunoprecipitation and LC-MS were used to explore the interacting proteins with BChE. Finally, a hepatocyte-restricted BChE silencing mouse model was established by AAV8-Tbg-shRNA, and the hypercholesterolemia was induced by 65% kcal% high-fat, high-sucrose diet feeding. MAIN FINDINGS: Here we demonstrate that butyrylcholinesterase (BChE) governs the LDL receptor levels and LDL uptake capacity through the MEK-ERK signaling cascades to promote Ldlr transcription. BChE interacts and co-localizes with PRMT5, a protein methylation modifier controlling the ERK signaling. PRMT5 regulates LDLR-dependent LDL uptake and is a substrate of chaperone-mediated autophagy (CMA). BChE deficiency induces the PRTM5 degradation dependent on CMA activity, possibly through facilitating the HSC70 (Heat shock cognate 71 kDa) recognition of PRMT5. Remarkably, in vivo hepatocyte-restricted BChE silencing reduces plasma cholesterol levels substantially. In contrast, the BChE knockout mice are predisposed to hypercholesterolemia. SIGNIFICANCE: Taken together, these findings outline a regulatory role for the BChE-PRMT5-ERK-LDLR axis in hepatocyte cholesterol metabolism, and suggest that targeting liver BChE is an effective therapeutic strategy to treat hypercholesterolemia.

Prolonged toxic effects after cocaine challenge in butyrylcholinesterase/plasma carboxylesterase double knockout mice: a model for butyrylcholinesterase-deficient humans.

Death and toxicity after cocaine use do not correlate with cocaine blood levels. One explanation for this observation is that cocaine abusers may posses one or more of the 58 possible known mutations in the butyrylcholinesterase gene (BCHE). Butyrylcholinesterase (BChE) serves as the primary cocaine hydrolase producing a nontoxic product ecgonine methyl ester. A reduction in endogenous levels of BChE may result in increased metabolism by hepatic carboxylesterase to produce norcocaine, a toxic product. Humans have carboxylesterase in tissues but not in plasma, whereas wild-type mice have significant amounts of carboxylesterase in tissues and plasma. Knockout mice with no plasma carboxylesterase were created to eliminate the contribution of plasma carboxylesterase in cocaine hydrolysis, thereby simulating human enzyme levels. This study tested the hypothesis that reductions in BChE such as those in humans with BChE mutations contribute to increased toxicity after cocaine use. Carboxylesterase and BChE double knockout mice, models for humans with BChE deficiency, were challenged with a nonlethal dose of 100 mg/kg (-)-cocaine. Carboxylesterase/BChE double knockout mice demonstrated toxic signs significantly longer than did wild-type and carboxylesterase knockout mice. The carboxylesterase/BChE-deficient mice took approximately 2.5 times as long to recover from cocaine toxicities, including the following: hypothermia, hyperactivity, stereotypical behavior, ocular effects, and dorsiflexion of the tail. The carboxylesterase/BChE double knockout mouse model demonstrates the importance of endogenous BChE for protection against cocaine toxicity and provides an in vivo system for studying drug sensitivity of humans who carry a BChE mutation.

Prolonged neuromuscular paralysis following rapid-sequence intubation with succinylcholine.

OBJECTIVE: To report a case of severely prolonged succinylcholine-induced neuromuscular paralysis in a patient with previously undiagnosed butyrylcholinesterase deficiency. CASE SUMMARY: A 54-year-old female was admitted for surgical drainage of a groin abscess. She was given propofol 200 mg and succinylcholine 160 mg (1 mg/kg) intravenously to induce sedation and paralysis for endotracheal intubation. Thirty minutes after the 19-minute procedure, the patient showed no evidence of spontaneous recovery of respiration. She was transferred to the intensive care unit and 11 hours later was successfully weaned from the ventilator and extubated. A butyrylcholinesterase level of 552 IU/L (reference range 2673-6592) confirmed butyrylcholinesterase deficiency. Six months later, in compliance with institutional review board/human subjects research requirements, the patient returned for a dibucaine inhibition test and second butyrylcholinesterase assay; the butyrylcholinesterase level in the second assay was 789 IU/L. The dibucaine inhibition test result was 61.1% (reference range 81.6-88.3), suggesting that the adverse drug effect had a pharmacogenetic basis. Use of the Naranjo probability scale indicated a probable relationship between the prolonged neuromuscular paralysis and succinylcholine therapy in this patient. DISCUSSION: Succinylcholine remains the drug of choice to facilitate rapid-sequence endotracheal intubation during induction of anesthesia and in patients undergoing emergency procedures who are at risk for gastroesophageal regurgitation. Its short duration of action is due to rapid hydrolysis by the endogenous enzyme butyrylcholinesterase. Rarely, patients with butyrylcholinesterase deficiency may show marked sensitivity to succinylcholine, manifested clinically by severely prolonged neuromuscular paralysis and apnea. CONCLUSIONS: Butyrylcholinesterase deficiency may go undiagnosed for decades until succinylcholine is used in a surgical procedure. When it does occur, a butyrylcholinesterase level should be obtained and a dibucaine inhibition test should be conducted to test for unrecognized hereditary butyrylcholinesterase deficiency. If a pharmacogenetic basis is confirmed, the patient should receive information about the condition, implications, inheritance, and need for family testing.

Rocuronium antagonized by sugammadex for series of electroconvulsive therapy (ECT) in a patient with pseudocholinesterase deficiency.

We report the anesthetic management of a patient with catatonic schizophrenia and pseudocholinesterase deficiency, using the nondepolarizing neuromuscular blocking drug, rocuronium, reversed by its specific reversal agent, sugammadex, for a series of electroconvulsive therapy sessions. Rocuronium and sugammadex were used every 48 hours for 8 consecutive times and proved to be an effective and safe combination in a situation where succinylcholine was contraindicated.

[Congenital pseudocholinesterase deficiency]. / Wrodzony niedobór cholinesterazy osoczowej.

BACKGROUND: Congenital pseudocholinesterase (pChe) deficiency is a rare genetic abnormality which may lead to prolonged duration of action of muscle relaxants that are hydrolysed by pChe. We describe two cases in which mivacurium resulted in neuromuscular block lasting several hours. CASE REPORTS: Two non-related male patients, aged 26 and 7 years, scheduled for elective ENT surgery, received propofol, desflurane, remifentanil and mivacurium. At the end of the surgery it was not possible to reverse the neuromuscular blockade, and there were no responses to TOF or post-tetanic stimulation. Neuromuscular transmission returned spontaneously after 7, and 4 h, respectively. Postoperative assay revealed severe pChe deficiency in both patients, with values of 3393 UL(-1)and 2558 UL(-1), respectively (normal range 5100-11700 UL(-1). Family screening confirmed the presence of pChe deficiency in both cases. CONCLUSION: In any case of unexpected prolonged muscle relaxation after mivacurium, pChe deficiency should be considered and its activity measured.When confirmed, careful family screening is mandatory.

Hereditary pseudocholinesterase deficiency discovery after electroconvulsive therapy.

Inherited pseudocholinesterase deficiency refers to an uncommon defect in the butyrylcholinesterase enzyme which can result in prolonged muscle paralysis due to delayed breakdown of choline ester paralytic anaesthetic agents. We describe a 25-year-old woman receiving electroconvulsive therapy (ECT) for treatment of depression in whom motor function did not recover adequately after administration of succinylcholine. Investigated post-ECT, she was found to have severe pseudocholinesterase deficiency. Implications of pseudocholinesterase deficiency for ECT treatment and anaesthetic strategies are discussed.

Selective Pseudo-irreversible Butyrylcholinesterase Inhibitors Transferring Antioxidant Moieties to the Enzyme Show Pronounced Neuroprotective Efficacy In Vitro and In Vivo in an Alzheimer's Disease Mouse Model.

A series of multitarget-directed ligands (MTDLs) was designed by functionalizing a pseudo-irreversible butyrylcholinesterase (BChE) inhibitor. The obtained hybrids were investigated in vitro regarding their hBChE and hAChE inhibition, their enzyme kinetics, and their antioxidant physicochemical properties (DPPH, ORAC, metal chelating). In addition, in vitro assays were applied to investigate antioxidant effects using murine hippocampal HT22 cells and immunomodulatory effects on the murine microglial N9 cell line. The MTDLs retained their antioxidative properties compared to the parent antioxidant-moieties in vitro and the inhibition of hBChE was maintained in the submicromolar range. Representative compounds were tested in a pharmacological Alzheimer's disease (AD) mouse model and demonstrated very high efficacy at doses as low as 0.1 mg/kg. The most promising compound was also tested in BChE-/- mice and showed reduced efficacy. In vivo neuroprotection by BChE inhibition can be effectively enhanced by incorporation of structurally diverse antioxidant moieties.