Erythrocyte enzymopathies

Numerous enzymes, including those of the hexose monophosphate and glycolytic pathways, are active in the red cell. They are required for the generation of ATP and the reductants NADH and NADPH. 2,3-Diphosphoglycerate, an intermediate of glucose metabolism, is a key regulator of the affinity of haemoglobin for oxygen, and accessory enzymes are also active for the synthesis of glutathione, disposal of oxygen free radicals, and for nucleotide metabolism. With the exception of heavy metal poisoning and rare cases of myelodysplasia, most red cell enzyme deficiency disorders are inherited. They may cause haematological abnormalities, (most commonly nonspherocytic haemolytic anaemias, but also rarely polycythaemia or methaemoglobinaemia, manifest with autosomal recessive or sex-linked inheritance), and may also be associated with nonhaematological disease when the defective enzyme is expressed throughout the body. Some may mirror important metabolic disorders, without producing haematological problems, making them of diagnostic value. Others are of no known clinical consequence. With rare exceptions, it is impossible to differentiate the enzymatic defects from one another by clinical or routine laboratory methods. Diagnosis depends on the combination of (1) accurate ascertainment of the family history; (2) morphological observations—these can determine whether haemolysis is present, rule out some causes of haemolysis (e.g. hereditary spherocytosis and other red blood cell membrane disorders), and diagnose pyrimidine 5′-nucleotidase deficiency (prominent red cell stippling); (3) estimation of red cell enzyme activity; and (4) molecular analysis. The most common red cell enzyme defects are glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, glucose-6-phosphate isomerase deficiency, pyrimidine 5′-nucleotidase deficiency—which may also induced by exposure to environmental lead—and triosephosphate isomerase deficiency.