Glucose Phosphate Isomerase Deficiency with Congenital Nonspherocytic Hemolytic Anemia: A New Variant (Type Nordhorn) I. Clinical and Genetic Studies

Abstract

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, h,as suffered since birth from a severe to moderate macrocytic anemia, which is characterized by low mean corpuscular hemoglobin concentration (28y0), high reticulocytosis (45-60yo), normal osmotic fragility, type I autohemolysis, 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 22y0 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, p H 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. O n 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 132y0 of the main band of normal subjects. I t 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 (%yo 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

The characterization of gene mutations for human glucose phosphate isomerase deficiency associated with chronic hemolytic anemia.

“…The substrates of this enzyme, fructose-6-phosphate and G6P, are intermediates in glycolysis and gluconeogenesis, as well as intermediates in the pentose phosphate cycle. In humans, GPI deficiency comprises the third most common hereditary enzyme defect of red cells after G6P dehydrogenase deficiency and pyruvate kinase deficiency and has the typical manifestation of nonspherocytic hemolytic anemia (1)(2)(3)(4)(5)(6)(7)(8)(9). It has been reported that severe GPI deficiency can be a cause of hydrops fetalis in humans (10).…”

Glucose Phosphate Isomerase Deficiency with Congenital Nonspherocytic Hemolytie Anemia: A New Variant (Type Nordhorn). II. Purification and Biochemical Properties of the Defective Enzyme

“…T h e results obtained with hemolysates of GPI-Nordliorn [8] are different from those of the wild type enLyme: abnormal electroplloretic migration and increased t h e~m a l lability. T h e elevated isoelectric point of 9.80 is in accordance to the electrophoretic study wllicll sllows a migration of 132%.…”

Glucose phosphate isomerase deficiency: biochemical and molecular genetic studies on the enzyme variants of two patients with severe haemolytic anaemia

“…GPI of case 2 and his parents had already been studied earlier in our laboratory (GPI Nordhorn, SchroÈ ter et al 1974 [25]) but for better comparison some of the data relevant for this study are included in Table 1. Unfortunately the parents of case 2 were not available for the present investigation.…”

“…On clinical presentation at the date of gene analysis the patient suered from jaundice with a serum bilirubin level of 7 mg/dl, but no other symptoms. The enzyme variant of case 2 had already been named in a previous publication GPI`Nordhorn' [25].…”

“…The GPI electrophoresis was performed as described earlier [25] using TRIS-Citric acid buer. In contrast to family 2, case 1 and her parents' enzymes showed no deviation from the normal electrophoretic mobility.…”