Congenital cholinesterase deficiency (succinylcholine apnea). Cholinesterase is an enzyme best known for its role in regulation of nerve impulse transmission via breakdown of acetylcholine at the nerve synapse and neuromuscular junction. There are two categories of cholinesterase: acetylcholinesterase (“true cholinesterase”), found in RBCs and nerve tissue; and serum cholinesterase (“pseudocholinesterase”). Cholinesterase deficiency became important when it was noted that such patients were predisposed to prolonged periods of apnea after administration of succinylcholine, a competitor to acetylcholine. Serum cholinesterase inactivates succinylcholine, but acetylcholinesterase does not. Serum cholinesterase deficiency may be congenital or acquired; the congenital type is uncommon but is responsible for most of the cases of prolonged apnea. The patient with congenital deficiency seems to have an abnormal (“atypical”) cholinesterase, of which several genetic variants have been reported.

Laboratory diagnosis. Serum cholinesterase assay is currently the best screening test for cholinesterase deficiency. If abnormally low values are found, it is necessary to perform inhibition procedures with dibucaine and fluoride to distinguish congenital deficiency (atypical cholinesterase) from acquired deficiency of the normal enzyme. Deficiency of normal enzyme may cause prolonged succinylcholine apnea but not predictably and usually only in very severe deficiency. Acute or chronic liver disease is the most frequent etiology for acquired deficiency. Hypoalbuminemia is frequently associated in hepatic or nonhepatic etiologies. A considerable number of drugs lower serum cholinesterase levels and thus might potentiate the action of succinylcholine.

Cholinesterase levels are also decreased in organic phosphate poisoning; this affects both RBC and plasma enzyme levels. Screening tests have been devised using “dip-and-read” paper strips. These are probably satisfactory for ruling out phosphate insecticide poisoning but are not accurate in diagnosis of potential for succinylcholine apnea.

Alpha-1 antitrypsin deficiency. Alpha-1 antitrypsin (AAT) is a serine protease inhibitor that inactivates trypsin but whose primary importance is inactivation of neutrophil elastase that breaks down elastic fibers and collagen. AAT is produced by the liver and comprises about 90% of the globulins that migrate on electrophoresis in the alpha-1 region. AAT deficiency has been associated with two different diseases: pulmonary emphysema in adults (relatively common) and cirrhosis in children (rare). This type of emphysema is characteristically, although not invariably, more severe in the lower lobes. A substantial number of those with homozygous antitrypsin deficiency are affected; reports differ on whether heterozygotes have an increased predisposition to emphysema or to pulmonary disease.

Laboratory diagnosis. The most useful screening test at present is serum protein electrophoresis; the alpha-1 globulin peak is absent or nearly absent in homozygotes. More definitive diagnosis, as well as separation of severe from intermediate degrees of deficiency, may be accomplished by quantitation of AAT using immunoassay methods such as immunonephelometry or immunodiffusion. Estrogen therapy (birth control pills) may elevate AAT levels. Since this protein is one of the acute-phase reactants involving the alpha-1 and alpha-2 globulin group on electrophoresis, values are frequently elevated in acute or severe chronic infections, sarcoidosis, inflammation, active rheumatoid-collagen disease, steroid therapy, tissue destruction, and some cases of malignancy. In some cases, measurement of other acute-phase reactants, such as C-reactive protein or serum haptoglobin, might help decide whether AAT might be elevated for this reason. Conditions besides congenital deficiency that reduce AAT activity include severe protein loss, severe renal disease, malabsorption, and thyroiditis.

The gene for AAT is located on the long arm of chromosome 14 (14q). There are a considerable number of allelic variants of the AAT gene (often called protease inhibitor gene or Pi). Most normal persons have an MM phenotype; most carriers are MZ; and most symptomatic deficiency patients are ZZ. Definitive diagnosis can be made in most cases by DNA probe, either direct analysis with M and Z probes, or by restriction fragment linkage polymorphism (RFLP) methods.

Biotinidase deficiency. Biotin is a water-soluble vitamin that is present in most common foods and, in addition, can be synthesized by GI tract bacteria. Biotin is a cofactor for activity of several carboxylase enzymes that are found in the carboxylic acid cycle, leucine metabolism, and proprionic acid metabolism. Biotinidase converts the precursor substance biocytin to biotin. Biotinidase deficiency prevents conversion of biocytin from dietary sources and forces dependence on biotin produced by GI tract bacteria. Suppression of these bacteria or inactivation of biotin by certain substances such as the glycoprotein avidin in egg white (most commonly caused by eating large quantities of raw eggs) can precipitate biotin deficiency. Other possible causes of biotin deficiency include chronic hemodialysis, long-term total parenteral nutrition without biotin supplement, and occasionally long-term anticonvulsant therapy. Symptoms include retarded growth, weakness, ataxia, hair loss, skin rash, metabolic acidosis, and sometimes convulsions.

Laboratory diagnosis. Neonatal screening for biotinidase deficiency can be done on heelstick blood spotted on filter paper using a variety of assay methods. The same methods can be used on venous blood.