ExtractA new variant of glucose phosphate isomerase (GPI) deficiency (type Nordhorn) associated with congenital nonspherocytic hemolytic anemia is described. The propositus, an 18-month-old boy of German origin, has suffered since birth from a severe to moderate macrocytic anemia, which is characterized by low mean corpuscular hemoglobin concentration (28%), high reticulocytosis (45—60%), normal osmotic fragility,type Iautohemolysis, and short erythrocyte life-span (51Cr t = 2 days). With the exception of GPI, the activities of most erythrocyte enzymes are increased. GPI activity is decreased to 22% of the normal. The father and mother exhibit GPI activities between 36% and 47% of normal. No difference is demonstrable between the enzyme of the propositus and normal subjects concerning Michaelis-Menten constant for fructose 6-phosphate, pH optimum, and thermal optimum. The stability of the enzyme is decreased in the propositus and in all affected maternal relatives. The enzyme of the paternal relatives is stable. On starch-gel electrophoresis the enzyme of the father is normal (three bands). In the hemolysate of the mother a fourth cathodally migrating band is demonstrable in addition to the three normal bands. The propositus exhibits only one band with a cathodal mobility of 132% of the main band of normal subjects. It is suggested that the propositus is double heterozygous for two abnormal alleles. The heterozygote mother contributes an allele which produces a thermolabile enzyme of decreased activity and abnormal electrophoretic mobility, whereas the father contributes an allele without enzymatic activity.The enzyme defect is also manifest in the leukocytes of the propositus (39% of normal activity). The thermolability is evident in the leukolysates of the propositus and in those of his mother.When erythrocyte glucose consumption and lactate formation are compared with nonenzymopenic, reticulocyte-rich blood, which has no metabolic defect, the rate of glycolysis is markedly impaired in the propositus. Glucose 6-phosphate, the substrate