Blood Journal
Leading the way in experimental and clinical research in hematology

Erythrocyte Pyruvate Kinase Deficiency in Non-spherocytic Hemolytic Anemia: A System of Multiple Genetic Markers?

  1. WOLF W. ZUELZER, M.D., Director of Laboratories,
  2. ABNER R. ROBINSON, M.S., Senior Research Associate, and
  3. THERESA H. J. HSU, M.D., Senior Research Associate
  1. Child Research Center of Michigan and the Departments of Pediatrics of Children’s Hospital of Michigan, and of Wayne State University School of Medicine, Detroit, Michigan.
  2. Children's Hospital of Michigan; Director, Child Research Center of Michigan; Professor of Pediatric Research, Wayne State University School of Medicine.
  3. Child Research Center of Michigan.

Abstract

Extreme intrafamilial differences between PK-deficient phenotypes regarding hemolysis, ATP stability, and glucose consumption were observed in two pedigrees in which the index cases had severe nonspherocytic hemolytic anemia. Genetic analysis was consistent with heterozygosity for two distinct interacting mutants in minimally affected relatives of severely anemic homozygotes. Neither the mature erythrocytes of the former nor the reticulocyte-rich cell populations of the latter showed accumulation of glycolytic intermediates, but 2,3-DPG was elevated in both. Despite severe PK deficiency, red cell survival in the minimal type was near normal, glucose consumption was unaffected in three of four subjects tested, and ATP maintenance in vitro was adequate, in contrast to the severe type in which these parameters were grossly depressed.

The genetic and pathophysiologic implications of these findings are discussed. The possibility is considered that defective glycolysis may play a subordinate role in the hemolytic process associated with PK deficiency and that the enzyme defect may be a genetic marker for as yet unknown erythrocytic abnormalities involving an increase of 2,3-DPG and possibly primary membrane lesions creating excessive demands on the energy metabolism of the erythrocytes. Regardless of the mode of gene action, it is concluded that the nonspherocytic hemolytic anemias associated with PK deficiency are genetically and phenotypically heterogeneous, and that the genetic diagnosis cannot rest on PK assay alone.

  • Submitted September 18, 1967.
  • Accepted December 9, 1967.