Butyrylcholinesterase deficiency

Did You Know?

• The condition can be diagnosed with a blood test measuring total cholinesterase activity; inhibition studies or genetic studies may provide further information.
• Patients with known deficiency may wear a medic-alert bracelet to notify healthcare workers of increased risk from succinylcholine.
• For general anesthesia, a non-depolarising neuromuscular-blocking drug such as rocuronium may be used instead.

Signs and symptoms

The effects depend on the specific drug given. Standard doses of succinylcholine or mivacurium in a person with this deficiency cause prolonged paralysis of the respiratory muscles, requiring extended mechanical ventilation. Eventually the muscle-paralyzing effects wear off despite the enzyme deficiency; if the patient is maintained on a respirator until normal breathing returns, there is little risk of harm. Because the condition is rare, it may be overlooked when a patient does not wake after surgery. Two major complications can then arise: the patient may lie awake and paralyzed while providers investigate, or the breathing tube may be removed before the patient can breathe properly, potentially causing respiratory arrest. The abnormality is benign unless the person is exposed to offending agents. The main complication is respiratory failure secondary to neuromuscular paralysis from succinylcholine or mivacurium. Individuals may also be at increased risk of toxic reactions, including sudden cardiac death, from recreational use of cocaine.

Genetics

The body metabolizes choline esters primarily through neuronal acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE). Several single-nucleotide polymorphisms in the BCHE gene have been identified, including the D98G missense SNP (rs1799807) present in 1% of the populace, which produces a dibucaine-resistant atypical enzyme with about 41% of normal activity, and the A567T missense SNP (rs1803274), the common K-variant (Kalow) with about 7% of normal activity. Many uncommon variants with greater effects on enzyme activity exist, 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. There are sixteen possible genotypes expressed as ten phenotypes, six of which are associated with marked reduction in hydrolysis of succinylcholine. Plasma cholinesterase activity is genetically determined by four alleles: silent (s), usual (u), dibucaine (d), or fluoride (f); the allele can also be absent (a). The inherited defect results from either an atypical enzyme or complete absence of the enzyme. BChE is produced in the liver, has a plasma half-life of 8 to 12 days, and is found in plasma, erythrocytes, glial tissue, liver, pancreas, and bowel. When succinylcholine is used, its high plasma concentration decreases rapidly in normal individuals due to plasma BChE; in atypical or absent BChE, the effect can last up to 10 hours.

Drug reactions

Patients should notify family members who may be at risk for carrying abnormal butyrylcholinesterase gene alleles. Drugs to avoid include succinylcholine (suxamethonium), which can paralyze an enzyme-deficient individual for up to 8 hours instead of the usual 5–10 minutes; if recognized early, the patient can be kept intubated and sedated until the muscle relaxation resolves. Mivacurium also has prolonged action in those with this deficiency. Other drugs to avoid are pilocarpine (Salagen), butyrylcholine, drugs containing Huperzine A and donepezil, drugs containing propionylcholine and acetylcholine, parathion, and procaine.

Frequency

Butyrylcholinesterase deficiency occurs in about 1 in 2,000 to 4,000 people who inherit two copies of the variant gene, while about 1 in 500 people carry one copy. Among Caucasians, the condition affects males nearly twice as often as females. The carrier rate is low in Black, Japanese, other Asian, South American, Australian Aboriginal, and most Inuit populations, though Alaskan Inuit show an unusually high frequency. Higher rates also appear among Jews from Iran and Iraq, and Caucasians from North America, Britain, Portugal, Yugoslavia, and Greece. In India, the Arya Vysya community has a markedly elevated prevalence; a study in Coimbatore found that 9 out of 22 community members had the deficiency, a rate 4,000 times higher than in European and American populations.