Pyruvate kinase (PK) deficiency (MIM 266200) is the most common enzyme deficiency resulting in hereditary hemolytic anemia. The disorder has a worldwide distribution and is characterized clinically by lifelong chronic hemolysis of variable severity. Splenectomy often results in amelioration of the hemolytic process in more severely affected patients, but is less effective in milder cases. Defective PK catalysis in affected erythrocytes generally results in elevated concentrations of 2,3-diphosphoglycerate (2,3-DPG) and decreased ATP levels relative to cells of comparable age.
PK is encoded by two genes, gene symbol for PK locus encoding L and R isozymes (PKLR) and gene symbol for PK locus encoding M isozymes (PKM). PKLR is expressed in the liver and in red cells; different splice forms are found in liver and in erythrocytes. PKM is expressed in muscle, leukocytes, and many other tissues. Allosteric (M2) and nonallosteric (M1) splice forms of PKM exist. The erythrocyte enzyme deficiency is due to mutations of the PKLR gene. Many different mutations have been identified, but more than one-half of the PK deficiency mutations among Europeans are 1529G→A (Arg510Gln). PK deficiency is inherited as an autosomal recessive disorder. The red cells of heterozygotes usually have 40 to 60 percent of the PK activity of normal red cells, and heterozygotes are almost always clinically normal.
Deficiencies of other red cell glycolytic enzymes are less common than is PK deficiency. Severe deficiencies of hexokinase (MIM 235700), glucosephosphate isomerase (GPI) (MIM 172400), phosphofructokinase (PFK) (MIM 171850), aldolase (MIM 103850), triosephosphate isomerase (TPI) (MIM 190450), phosphoglycerate kinase (PGK) (MIM 311800), bisphosphoglycerate mutase/phosphatase (BPGM/BPGP) (MIM 222800), and lactate dehydrogenase (LDH) (MIM 150100) have been documented, and in most cases, mutations have been identified at the DNA level. All of these enzyme deficiencies are autosomal except for PGK, which is X-linked. Deficiencies of BPGM and bisphosphoglycerate phosphatase are associated with mild erythrocytosis secondary to virtual absence of 2,3-DPG. LDH deficiency is also not associated with hemolysis, but in one form there is myopathy. All others are associated with hemolytic anemia of variable severity with partial response to splenectomy, except for PFK deficiency, which usually has a compensated hemolytic process.
GPI deficiency is second to PK deficiency in frequency; all tissues have decreased GPI activity, but clinical manifestations are usually limited to a chronic hemolytic process, although in some instances, mental retardation and myopathy may occur. In PFK deficiency (glycogen storage disease type VII), clinical hallmarks are male predominance with early onset gout, compensated hemolytic process, and prominent myopathy. Severe deficiency of aldolase activity has been documented in only four patients. TPI deficiency is clinically usually the most severe of the enzymatic defects of the glycolytic pathway; it is characterized by multisystem disease, including progressive neurologic dysfunction, increased susceptibility to infections, cardiomyopathy, and death usually during early childhood. All body tissues investigated are deficient in TPI. Hemolytic anemia and a variety of neurologic abnormalities most frequently accompany PGK deficiency in hemizygous males; the phenotypic picture is ...