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Pseudocholinesterase deficiency is an
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
inherited
blood plasma Blood plasma is a light Amber (color), amber-colored liquid component of blood in which blood cells are absent, but which contains Blood protein, proteins and other constituents of whole blood in Suspension (chemistry), suspension. It makes up ...
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
abnormality in which the body's production of butyrylcholinesterase (BCHE; pseudocholinesterase aka PCE) is impaired. People who have this abnormality may be sensitive to certain anesthetic drugs, including the muscle relaxants succinylcholine and mivacurium as well as other
ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
local anesthetics.


Signs and symptoms

The effects are varied depending on the particular drug given. When anesthetists administer standard doses of these anesthetic drugs to a person with pseudocholinesterase deficiency, the patient experiences prolonged paralysis of the respiratory muscles, requiring an extended period of time during which the patient must be mechanically ventilated. Eventually the muscle-paralyzing effects of these drugs will wear off despite the deficiency of the pseudocholinesterase enzyme. If the patient is maintained on a mechanical respirator until normal breathing function returns, there is little risk of harm to the patient. Because it is rare in the general population, pseudocholinesterase deficiency is sometimes overlooked when a patient does not wake up after surgery. If this happens, there are two major complications that can arise. First, the patient may lie awake and paralyzed while medical providers try to determine the cause of the patient's unresponsiveness. Second, the breathing tube may be removed before the patient is strong enough to breathe properly, potentially causing respiratory arrest. This enzyme abnormality is a
benign Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
condition unless a person with pseudocholinesterase deficiency is exposed to the offending
pharmacological Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between ...
agents.


Complications

The main complication resulting from pseudocholinesterase deficiency is the possibility of respiratory failure secondary to succinylcholine or mivacurium-induced neuromuscular paralysis. Individuals with pseudocholinesterase deficiency also may be at increased risk of toxic reactions, including sudden cardiac death, associated with recreational use of the aromatic ester
cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...
.


Genetics

The body has two primary ways of metabolizing choline esters. This is via the common, neuronal "
acetylcholinesterase Acetylcholinesterase (HUGO Gene Nomenclature Committee, HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme th ...
" (ACHE) and the blood plasma carried "butyrylcholinesterase" (BCHE), described here. Several
single-nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a ...
s in the BCHE gene have been identified, such as the D98G missense SNP chr3:165830741 A->G (Asp to Gly at 98) rs1799807 present in 1% of the populace (e.g. dibucaine-resistant "atypical" enzyme at 41% of normal activity), and the A567T missense SNP chr3:165773492 G->A (Ala to Thr at 567) rs1803274 (common K-variant "Kalow" at -7% of normal activity). Many uncommon variants, with greater effects on enzyme activity, are known, such as S1, F1, and F2. Genes encoding cholinesterase 1 (CHE1) and CHE2 have been mapped to 3q26.1-q26.2. One gene is silent. Specifically there are sixteen possible genotypes, expressed as ten phenotypes; six of these phenotypes are associated with a marked reduction in the hydrolysis of succinylcholine. The plasma cholinesterase activity level is genetically determined by four alleles identified as silent (s), usual
allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...
(u), dibucaine (d), or fluoride (f); also, this allele can be absent (a). The inherited defect is caused by either the presence of an atypical PCE or complete absence of the enzyme. Cholinesterases are enzymes that facilitate
hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
of the esters of choline. Acetylcholine, the most commonly encountered of these esters, is the mediator of the whole cholinergic system. Acetylcholine is immediately inactivated “in situ” by a specific acetylcholinesterase in the ganglia of the autonomic nervous system (preganglionic and postganglionic in the
parasympathetic nervous system The parasympathetic nervous system (PSNS) is one of the three divisions of the autonomic nervous system, the others being the sympathetic nervous system and the enteric nervous system. The autonomic nervous system is responsible for regulat ...
and almost exclusively preganglionic in the sympathetic nervous system), in the synapses of the central nervous system, and in the neuromuscular junctions. The affinity of PCE is lower for acetylcholine, but higher for other esters of choline, such as butyrylcholine, benzoylcholine, and succinylcholine, and for aromatic esters (e.g., procaine, chloroprocaine, tetracaine). Normal PCE is produced in the liver, has a plasma half-life of 8 to 12 days, and can be found in plasma, erythrocytes, glial tissue, liver, pancreas, and bowel. When succinylcholine is used for anesthesia, its high plasma concentration immediately after intravenous injection decreases rapidly in normal individuals because of the rapid action of plasma PCE. In case of an atypical PCE or complete absence of PCE, the effect of the injected succinylcholine can last for up to 10 hours.title=Syndromes: Rapid Recognition and Perioperative Implications , Cholineseterase deficiency


Drug reactions

These patients should notify others in their family who may be at risk for carrying one or more abnormal butyrylcholinesterase gene alleles. Drugs to avoid: * Succinylcholine, also known as suxamethonium, which is commonly given to paralyse skeletal muscles as part of a general anaesthetic for surgery. A dose that would paralyze the average individual for 5-10 minutes can paralyze the enzyme-deficient individual for up to 8 hours. If this condition is recognized by the anesthesiologist early, then there is rarely a problem, as the patient can be kept intubated and sedated until the muscle relaxation resolves. If not identified, residual paralysis can cause serious complications due to weakness of the muscles of respiration after the patient's breathing support has been ceased. * Mivacurium, like succinylcholine, is a
muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeu ...
and will have prolonged action in those with butyrylcholinesterase deficiency. * Pilocarpine (trade name Salagen) is used to treat dry mouth. As the name suggests, dry mouth is a medical condition that occurs when saliva production goes down. There are a variety of causes of dry mouth including side effect of various drugs. * Butyrylcholine - this is rarely used to treat exposure to nerve agents, pesticides, toxins, etc. * Drugs containing
Huperzine A Huperzine A, a Lycopodium alkaloid, was first isolated in 1983 from ''Huperzia serrata'', a plant used in Chinese folk medicine. Huperzine A also exists in other Huperzia species, including ''H. elmeri'', ''H. carinat'', and ''H. aqualupian'' ...
and Donepezil, which are used to slow the progression of
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
. * Drugs containing propionylcholine and
acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
* Parathion, an agricultural pesticide * Procaine, a local anaesthetic agent used before and during various surgical or dental procedures. Procaine causes loss of feeling in the skin and surrounding tissues.Daniel R Alexander. (2006). "Pseudocholinesterase Deficiency"
eMedicine
Retrieved June 16, 2008


Diagnosis

This inherited condition can be diagnosed with a blood test. If the total cholinesterase activity in the patient's blood is low, this may suggest an atypical form of the enzyme is present, putting the patient at risk of sensitivity to suxamethonium and related drugs. Inhibition studies may also be performed to give more information about potential risk. In some cases, genetic studies may be carried out to help identify the form of the enzyme that is present.


Prevention

Patients with known pseudocholinesterase deficiency may wear a medic-alert bracelet that will notify healthcare workers of increased risk from administration of succinylcholine, and use a non-depolarising neuromuscular-blocking drug for general anesthesia, such as rocuronium.


Prognosis

Prognosis for recovery following administration of succinylcholine is excellent when medical support includes close monitoring and respiratory support measures. In nonmedical settings in which subjects with pseudocholinesterase deficiency are exposed to cocaine, sudden cardiac death can occur.


Frequency

For homozygosity, the incidence is approximately 1:2,000-4,000, whereas the incidence for
heterozygosity Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...
increases to up to 1:500. The variant EaEa genotype, homozygous absent, is approximately 1:3200. The gene for the dibucaine-resistant atypical cholinesterase appears to be widely distributed. Among Caucasians, males are affected almost twice as often as females. The frequency for heterozygosity is low among black people, Japanese and non-Japanese Asians, South Americans, Australian Aboriginal peoples, and Arctic
Inuit Inuit (singular: Inuk) are a group of culturally and historically similar Indigenous peoples traditionally inhabiting the Arctic and Subarctic regions of North America and Russia, including Greenland, Labrador, Quebec, Nunavut, the Northwe ...
(in general). However, there are a few Inuit populations (e.g., Alaskan Inuit) with an unusually high gene frequency for PCE deficiency. A relatively high frequency also was reported among Jews from Iran and Iraq, Caucasians from North America, Great Britain, Portugal, Yugoslavia, and Greece.


Arya Vysyas

Multiple studies done both in and outside India have shown an increased prevalence of pseudocholinesterase deficiency amongst the Arya Vysya community. A study performed in the
India India, officially the Republic of India, is a country in South Asia. It is the List of countries and dependencies by area, seventh-largest country by area; the List of countries by population (United Nations), most populous country since ...
n state of
Tamil Nadu Tamil Nadu (; , TN) is the southernmost States and union territories of India, state of India. The List of states and union territories of India by area, tenth largest Indian state by area and the List of states and union territories of Indi ...
in
Coimbatore Coimbatore (Tamil: kōyamputtūr, ), also known as Kovai (), is one of the major Metropolitan cities of India, metropolitan cities in the States and union territories of India, Indian state of Tamil Nadu. It is located on the banks of the Noyy ...
on 22 men and women from this community showed that 9 of them had pseudocholinesterase deficiency, which translates to a prevalence that is 4000-fold higher than that in European and American populations.


Persian Jews

Pseudocholinesterase deficiency is common within the Persian and Iraqi Jewish populations. Approximately one in 10 Persian Jews are known to have a mutation in the gene causing this disorder and thus one in 100 couples will both carry the mutant gene and each of their children will have a 25% chance of having two mutant genes, and thus be affected with this disorder. This means that one out of 400 Persian Jews is affected with this condition.Cedars-Sinai Medical Genetics Institute. (2009). "Genetic Screening in the Persian Jewish Community"

Retrieved July 20, 2011.


References


External links


Cholinesterase Test
- Lab Tests Online {{DEFAULTSORT:Pseudocholinesterase Deficiency Anesthesia Complications of surgical and medical care Enzymes