Congenital Nonspherocytic Hemolytic Anemia Research Articles

Congenital nonspherocytic hemolytic anemias. Enzymatic deficiencies.

A specific diagnosis must be established in congenital nonspherocytic hemolytic anemia, for guidance in therapy and family counseling. Diagnostic methods have recently progressed rapidly and include determination of deficiencies in the activity of certain enzymes. Further definitions of enzymatic deficiencies are anticipated.

Characterization of Glucose-6-Phosphate Dehydrogenase in Sardinian Children with Congenital Nonspherocytic Haemolytic Anaemia

Characterization of Glucose-6-Phosphate Dehydrogenase in Sardinian Children with Congenital Nonspherocytic Haemolytic Anaemia

Anemia, cataracts, and seizures in patient with glucose-6-phosphate dehydrogenase deficiency

CONGENITAL CONGENITAL nonspherocytic hemolytic anemia is a heterogenous group of hemolytic disorders characterized by disturbances of glycolytic metabolism in the erythrocyte. One category has been associated with defects in the Embden-Meyerhof pathway of glucose metabolism; patients with erythrocytes defective in pyruvate kinase1and triose phosphate isomerase2activity have been described. Another group has been associated with diminished glucose-6-phosphate dehydrogenase (G-6-PD) activity. This abnormality results in an inability to generate reduced triphosphopyridine nucleotide (TPNH) in the hexose monophosphate shunt. Deficient erythrocyte G-6-PD activity is associated with a number of hemolytic diseases of variable severity. In some cases, red cells deficient in this enzyme activity do not ordinarily hemolyze unless the patient is exposed to certain oxidizing drugs, such as primaquine.3This manifestation occurs in 10% to 15% of American Negro men as a sex-linked recessive trait. On the other hand, most affected Caucasians show almost constant hemolysis. Because

Anemia, Cataracts, and Seizures in Patient With Glucose-6-Phosphate Dehydrogenase Deficiency

CONGENITAL CONGENITAL nonspherocytic hemolytic anemia is a heterogenous group of hemolytic disorders characterized by disturbances of glycolytic metabolism in the erythrocyte. One category has been associated with defects in the Embden-Meyerhof pathway of glucose metabolism; patients with erythrocytes defective in pyruvate kinase1and triose phosphate isomerase2activity have been described. Another group has been associated with diminished glucose-6-phosphate dehydrogenase (G-6-PD) activity. This abnormality results in an inability to generate reduced triphosphopyridine nucleotide (TPNH) in the hexose monophosphate shunt. Deficient erythrocyte G-6-PD activity is associated with a number of hemolytic diseases of variable severity. In some cases, red cells deficient in this enzyme activity do not ordinarily hemolyze unless the patient is exposed to certain oxidizing drugs, such as primaquine.3This manifestation occurs in 10% to 15% of American Negro men as a sex-linked recessive trait. On the other hand, most affected Caucasians show almost constant hemolysis. Because

CONGENITAL NONSPHEROCYTIC HEMOLYTIC ANEMIA ASSOCIATED WITH ERYTHROCYTE GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY IN A NEGRO FAMILY

This paper describes a Negro family with congenital nonspherocytic hemolytic anemia associated with glucose-6-phosphate dehydrogenase deficiency. All four affected males in this family showed a hemolytic anemia characterized by low hemoglobin, reticulocytosis, and jaundice. There was no detectable G-6-P D in the red cells and about a tenth of normal enzyme activity in the white cells. By starch gel electrophoresis, the G-6-P D was present as a single band which migrated at the rate of 104% of normal. Physico-chemical studies revealed a marked increase of the Michaelis constant for both G-6-P and TPN, a marked lability of the enzyme upon heating at 40°C and 48°C, and a single narrow peak at pH 9.0. Most of these features were similar to those seen in the Oklahoma I variant. Four of the females in the family were studied (two sisters, the mother, and a maternal aunt of the propositus); all showed a lesser degree of anemia and reticulocytosis but no jaundice, except in the mother. There was a decrease of haptoglobins and both the mother and one sister showed a decrease of erythrocyte survival time as measured by chromium-51. The female members had between 11 and 26% of normal G-6-P D activity in the red cells and between 35 and 63% of normal enzyme activity in the white cells. Starch gel electrophoresis in the mother and aunt showed a single band which migrated at 110% of normal with a trail at the position of the affected males. The presence of a milder degree of hemolysis in the heterozygous carriers of the gene for G-6-P D deficiency associated with congenital nonspherocytic hemolytic anemia provides further support for the Lyon hypothesis in man.

Congenital Nonspherocytic Hemolytic Anemia, Associated with Glutathione Deficiency of the Erythrocytes Hematologic, Biochemical and Genetic Studies

Abstract1. A new biochemical defect of erythrocytes is described: glutathione deficiency (reduced glutathione less than 10 per cent of the amount of reduced glutathione in normal erythrocytes).2. The defect is associated with a clinical picture of congenital nonspherocytic hemolytic anemia which is fairly well compensated.3. The results of a family study are consistent with an autosomal recessive pattern of inheritance.4. Labeling with Na2Cr51O4 has a damaging effect on glutathione-deficient erythrocytes. The erythrocyte life span, as estimated by a serological method (Ashby), was markedly shortened (30 days instead of 100-120 days).5. Red cell destruction could be increased by the administration of primaquine.6. Secondary to the glutathione deficiency, low glyoxalase activity was observed. The glutathione-reducing capacity, glycolytic activity, and the ATP level of the abnormal red cells were found to be within the normal range.7. On incubation of the glutathione-deficient erythrocytes in vitro with glycine-C14 and glutamine-C14, no formation of labeled glutathione could be demonstrated.

Metabolic aspects of erythrocytes and leukocytes in a case of congenital non-spherocytic haemolytic anaemia.

Metabolic aspects of erythrocytes and leukocytes in a case of congenital non-spherocytic haemolytic anaemia.

EXTREME HEMOLYSIS AND RED-CELL DISTORTION IN ERYTHROCYTE PYRUVATE KINASE DEFICIENCY. I. MORPHOLOGY, ERYTHROKINETICS AND FAMILY ENZYME STUDIES.

BIZARRE morphologic abnormalities of the erythrocytes are generally not considered a prominent feature of congenital nonspherocytic hemolytic anemias.1 , 2 We have observed a child with a severe congenital nonspherocytic hemolytic anemia associated with a deficiency of erythrocyte pyruvate kinase in whom morphologic abnormalities of the red cells were profound. The bizarre red-cell abnormality was in some respects similar to that observed in the syndrome of acanthocytosis associated with absence of serum beta-lipoprotein.3 Of additional interest was the finding that the mother of the patient was not only a heterozygote for the pyruvate kinase (PK) deficiency but was also a carrier of . . .

METABOLIC ASPECTS OF RED CELLS IN CONGENITAL NON-SPHEROCYTIC HAEMOLYTIC ANAEMIA.

METABOLIC ASPECTS OF RED CELLS IN CONGENITAL NON-SPHEROCYTIC HAEMOLYTIC ANAEMIA.

Erythrocyte Pyruvate Kinase Deficiency Resulting in Congenital Nonspherocytic Hemolytic Anemia

Erythrocyte Pyruvate Kinase Deficiency Resulting in Congenital Nonspherocytic Hemolytic Anemia

HEMOCHROMATOSIS AND CONGENITAL NONSPHEROCYTIC HEMOLYTIC ANEMIA IN SIBLINGS.

The unusual occurrence of both congenital nonspherocytic hemolytic anemia and hemochromatosis in a brother and sister is reported. The strikingly similar clinicopathologic abnormalities, including extraordinarily severe cardiac lesions in these relatively young siblings, is discussed.

ERYTHROCYTE PYRUVATE KINASE DEFICIENCY RESULTING IN CONGENITAL NONSPHEROCYTIC HEMOLYTIC ANEMIA.

HEREDITARY spherocytosis with its associated hemolytic anemia is generally easily recognized and satisfactorily treated with splenectomy. A rarer group of hemolytic anemias, however, is sometimes confused with hereditary spherocytosis because of the occasional presence of small numbers of spherocytes in association with varying degrees of abnormality in the incubated osmotic fragility test. In this later group of congenital nonspherocytic hemolytic anemias splenectomy has often been performed but usually does not produce a clinical cure. Because splenectomy is generally of inconsistent value, this type of anemia must be accurately differentiated for the sake of proper treatment and accurate prognosis. . . .

Heterogeneity of thalassemia major.

Previous communications1,2concerning A2hemoglobin in parents of subjects with thalassemia major reported normal levels in a small minority. Fetal hemoglobin percentage was determined in some of these individuals and was noted to be unexpectedly high in all but one. The single exception was the mother of 2 children originally diagnosed as having thalassemia major. Later investigation of this family resulted in reclassification of diagnosis to congenital nonspherocytic hemolytic anemia. It was suggested2that patients diagnosed as having Mediterranean anemia do not represent a homogeneous group as regards pathogenesis and heredity. The present report details further observations concerning these families and presents evidence for heterogeneity of thalassemia major. Material and Methods The pedigrees of 3 subjects with thalassemia major who have been followed in the Pediatric Hematology Clinic of the Babies Hospital have been investigated for evidence of heredity transmission of the gene for thalassemia minor.

Congenital nonspherocytic hemolytic anemia. Report of two cases.

Congenital nonspherocytic hemolytic anemia. Report of two cases.

Pyruvate Kinase (PK) Deficiency Hereditary Nonspherocytic Hemolytic Anemia

Abstract 1. The erythrocytes of seven patients conforming to the criteria of Type II congenital nonspherocytic hemolytic anemia have been demonstrated to have a specific deficiency in the glycolytic enzyme pyruvate kinase. Other glycolytic enzymes, glucose-6-phosphate and 6-phosphogluconic dehydrogenases, and certain non-glycolytic erythrocyte enzymes are normally active. The leukocytes of these patients possess normal pyruvate kinase activity. 2. Although no inhibitors were detected, the exact nature of the enzymatic defect remains to be elucidated. 3. Family studies provide strong evidence for a genetically determined disorder and are consistent with an autosomal recessive transmission of the defect. A partial enzyme deficiency, not reflected in clinical disease, is present in heterozygotes. The symptomatic disease, though variable in severity, appears to be due to homozygosity for the defect. 4. It is suggested that the enzyme deficiency is pathogenetically related to the premature demise of the red cells in vivo. 5. The name "pyruvate kinase (PK) deficiency hereditary nonspherocytic hemolytic anemia" is proposed for these patients.

Congenital nonspherocytic hemolytic anemia.

It has been well demonstrated in man and in other species that the fundamental expression of a hereditary chemical disorder may be the deletion of a single metabolic or enzymic step. The extent to which such loss in enzymic activity is due to dimimished amounts or to a qualitative inefficiency of the enzyme has been a matter of considable interest. The latter possibility has appeared particularly tenable since the outstanding demonstrations by Pauling, Itano, et al1and by Ingram and Hunt2,3of the qualitative changes in sickle hemoglobin. Erythrocytic glucose-6-phosphate dehydrogenase (G-6-PD) has been studied in 2 varieties4,5of a hereditary defect of this enzyme, primaquine-sensitive hemolytic anemia,6-9and recently10a certain type of congenital nonspherocytic hemolytic anemia. Although the active G-6-PD in primaquinesensitive erythrocytes from Negro males is qualitatively similar, if not identical, to that from normal persons, the G-6-PD of a Caucasian male

Enzymatic anomaly of erythrocytes in congenital nonspherocytic hemolytic anemia. 2.

Two families of congenital nonspherocytic hemolytic anemia were reported. A metabolic abnormality in the erythrocytes from the patients was demonstrated, consisting of a low content of GSH, an abnormality in the GSH stability test and a low activity of G6PD. These abnormalities were also found in the erythrocytes from the mothers in a milder degree, while there was no abnormalities in the erythrocytes from the fathers. An aggravation of hemolysis and metabolic disturbances mentioned above was observed following administration of Domian (6-sulfanilamido-2, 4-dimethylpyrimidine) to the patient. It was also argued by way of experiment that the difference between the so-called congenital nonspherocytic hemolytic anemia and drug-induced hemolytic anemia is not essential, but only quantitative, so that both disorders belong highly probably to the same entity of enzymopathy fromm the viewpoint of pathogenesis of hemolysis.

Demonstration of metabolic anomaly of congenital nonspherocytic hemolytic anemia and beneficial effect of vitamin B12 upon it.

1) A case of congenital nonspherocytic hemolytic anemia was reported. A metabolic abnormality in the erythrocytes from the patient was demonstrated, consisting of a low content of reduced glutathione, an abnormality in the reduced glutathione stability test, and a low activity of glucose-6-phosphate dehydrogenase. These abnormalities were also found in the erythrocytes from the mother to a milder degree, while there was no abnormalities in the erythrocytes from the father. This is the first case in Japan, of this type of hemolytic anemia in which an enzymatic anomaly of the erythrocytes was demonstrated. 2) The treatment with large dose of vitamin B12 brought about a relief from jaundice, when an increase of reduced glutathione content in the erythrocytes and an improvement of reduced glutathione instability were observed, although the activity of glucose-6-phosphate dehydrogenase in the erythrocytes remained in a constantly low level. 3) The in-vitro effect of vitamin B12 on gulcose-6-phosphate dehydrogenase was investigated. The relationship between vitamin B12 and glutathione metabolism was discussed. 4) Genetic mode of the disease was discussed.

Metabolic abnormalities of erythrocytes from patients with congenital nonspherocytic hemolytic anemia

Summary The clinical course, hematologic data, and red cell glutathione and glucose-6-phosphate dehydrogenase studies are reported for 6 patients who had a congenital nonspherocytic hemolytic anemia. On the basis of these findings the patients could be divided into three groups. Group 1 consists of three Caucasian boys belonging to two families. The anemia and reticulocytosis were mild, red cell morphology was normal, red cell glutathione was unstable in the presence of acetylphenylhydrazine, and glucose-6-phosphate dehydrogenase activity was absent. Glutathione and enzyme studies on the family members indicated that these abnormalities were genetically determined and that their transmission was sex-linked. A Caucasian boy and a Negro girl comprise Group 2. The anemia and reticulocytosis were quite marked, and the erythrocytes were macrocytic, slightly hypochromic, and occasionally target shaped and finely stippled. Nucleated red cells were usually present in the peripheral blood. Glutathione and enzyme studies were normal. Group 3 consists of a 15-year-old Caucasian girl who was first described by Lange and Akeroyd. 11 She had a severe hemolytic anemia between 21/2 and 10 years of age, and inclusion bodies were observed in the red cells. Frequent epileptic seizures and blackcolored urine were also noted. Whole blood glutathione values and the glutathione stability test were abnormal. Erythrocyte glucose-6-phosphate dehydrogenase activity was increased. The father's peripheral blood count was normal, but his glutathione and enzyme values were similar to those observed in the patient. These studies emphasize the importance of biochemical techniques in shedding light on the mechanism of hemolysis and the pattern of inheritance of congenital hemolytic disorders. Even though our knowledge of the etiologic role of many of these metabolic aberrations is incomplete, newer paths for exploration are becoming apparent. When these pathways are finally mapped, therapeutic application of this knowledge may become possible.

ENZYME DEFICIENCY IN ERYTHROCYTES IN CONGENITAL NONSPHEROCYTIC HEMOLYTIC ANEMIA

Two cases of congenital nonspherocytic hemolytic anemia are reported. The patients were brothers and both showed severe metabolic defects in the erythrocytes, consisting of a low content of reduced glutathione, markedly abnormal reduced glutathione stability test, and a very low activity of glucose-6-phosphate dehydrogenase. These metabolic defects were also found in the erythrocytes from the mother but to a milder degree. While both children showed evidences of chronic hemolytic anemia, the mother was found to be healthy. This clinical discrepancy between mother and children is thought to be the result of the degree of the severity of the metabolic defects. The occurrence of the chronic hemolytic process in these patients in the absence of exposure to drugs indicates that the erythrocyte deficient in glucose-6-phosphate dehydrogenase does not necessarily require the injurious effect of a drug to undergo hemolysis. In view of the above findings, it is suggested that reduced glutathione stability test and an assay of glucose-6-phosphate dehydrogenase be performed in all instances where the diagnosis of congenital nonsphenocytic hemolytic anemia is made.