Etiology

There are 2 mammalian PK genes, but only the PKLR gene is expressed in red cells. The human PKLR gene is located on chromosome 1q21. More than 180 mutations are reported in this structural gene, which codes for a 574–amino acid protein that forms a functional tetramer. These mutations include missense, splice site, and insertion-deletion alterations. Most affected patients are compound heterozygotes for 2 different PK gene defects. The many possible combinations likely account for the variability in clinical severity. The mutations 1456 C to T and 1529 G to A are the most common mutations in the white population.

Clinical Manifestations and Laboratory Findings

The clinical manifestations of PK deficiency vary from severe neonatal hemolytic anemia to mild, well-compensated hemolysis first noted in adulthood. Severe jaundice and anemia may occur in the neonatal period, and kernicterus has been reported. The hemolysis in older children and adults varies in severity, with hemoglobin values ranging from 8 to 12 g/dL associated with some pallor, jaundice, and splenomegaly. Patients with these findings usually do not require transfusion. A severe form of the disease has a relatively high incidence among the Amish of the Midwestern United States. PK deficiency may provide protection against falciparum malaria; there is no demographic support for this observation, however.

Polychromatophilia and mild macrocytosis reflect the elevated reticulocyte count. Spherocytes are uncommon, but a few spiculated pyknocytes may be found. The non-incubated osmotic fragility is normal. Diagnosis relies on demonstration of a marked reduction of RBC PK activity or an increase in the Michaelis-Menten dissociation constant (K_m) for its substrate, phosphoenolpyruvate (high K_m variant). Other RBC enzyme activity is normal or elevated, reflecting the reticulocytosis. No abnormalities of hemoglobin are noted. The white cells have normal PK activity and must be rigorously excluded from the red cell hemolysates used to measure PK activity. Heterozygous carriers usually have moderately reduced levels of PK activity.

Treatment

Phototherapy and exchange transfusions may be indicated for hyperbilirubinemia in newborns. Transfusions of packed RBCs are necessary for severe anemia or for aplastic crises. If the anemia is consistently severe or if frequent transfusions are required, splenectomy should be performed after the child is 5-6 yr of age. Although it is not curative, splenectomy may be followed by higher hemoglobin levels and by strikingly high (30-60%) reticulocyte counts. Death resulting from overwhelming pneumococcal sepsis has followed splenectomy; thus, immunization with vaccines for encapsulated organisms should be given before splenectomy, and prophylactic penicillin should be administered after the procedure.

Deficiencies of Enzymes of the Hexose Monophosphate Pathway

The most important function of the hexose monophosphate pathway is to maintain glutathione in its reduced state (GSH) as protection against the oxidation of RBCs (see Fig. 457-1). Approximately 10% of the glucose taken up by RBCs passes through this pathway to provide the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) necessary for the conversion of oxidized glutathione to GSH. Maintenance of GSH is essential for the physiologic inactivation of oxidant compounds, such as hydrogen peroxide, that are generated within RBCs. If glutathione, or any compound or enzyme necessary for maintaining it in the reduced state, is decreased, the SH groups of the RBC membrane are oxidized and the hemoglobin becomes denatured and may precipitate into RBC inclusions called Heinz bodies. Once Heinz bodies have formed, an acute hemolytic process results from damage to the RBC membrane by the precipitated hemoglobin, the oxidant agent, and the action of the spleen. The damaged RBCs then are rapidly removed from the circulation.