Non‐spherocytic Haemolytic Anaemia in Mother and Son Associated with Hexokinase Deficiency

Newman, Peter F. J.; Muir, Alison; Parker, A. C.

doi:10.1111/j.1365-2141.1980.tb06010.x

Cited by 13 publications

(4 citation statements)

References 13 publications

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“…This fact seems to indi cate that the main mechanism of anemia in hexoki nase deficiency is probably mediated by an increased phagocytosis of enzyme-deficient cells rather than hemolysis itself. Pieces of evidence that favor this conclusion are, certainly, the increased number of au tologous IgG that are bound to antihexokinase-IgGloaded erythrocytes (table 5), the observation by Newman et al [26] that in vitro a marked phagocyto sis of hexokinase-deficient cells was observed, and the observation that splenectomy usually stabilizes blood hemoglobin concentration and makes blood transfu sions unnecessary [21,22,[25][26][27][28]. Thus, hexokinase deficiency causes a cellular ATP depletion and favors autologous IgG binding and phagocytosis.…”

Section: Discussionmentioning

confidence: 87%

Human Red Blood Cell Loading with Hexokinase-Inactivating Antibodies

Magnani

Rossi²,

Bianchi³

et al. 1989

Acta Haematol

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The primary cause of red cell destruction in enzymopathies of anaerobic glycolysis remains controversial and difficult to investigate especially because the erythrocyte population in enzymopenic patients is largely heterogeneous. We have shown that loading human erythrocytes with monospecific enzyme-inactivating antibodies could be useful in understanding the biochemical modifications occurring in enzymopenic erythrocytes and the mechanisms leading to red cell destruction. Hexokinase-inactivating antibodies were prepared and loaded in human erythrocytes using a procedure of encapsulation based on hypotonic hemolysis, isotonic resealing and reannealing. Red blood cells loaded with anti-hexokinase IgG showed 20 ± 3% residual hexokinase activity while all other enzymes were normal. Lactate production by these cells was 30% of controls while the amount of glucose metabolized in the hexose monophosphate pathway (HMP) was unchanged under resting conditions. However, in the presence of methylene blue HMP rates were only 12% of controls. Determination of adenine nucleotide levels suggests that the antihexokinase-loaded red blood cells are not able to maintain, in vitro, their ATP level as well as their 2,3-diphosphoglycerate. Osmotic fragility, methemoglobin, and reduced glutathione content were near normal. These and other properties of the antihexokinase-loaded erythrocytes were similar to those found in cases of hexokinase deficiency. When the antibody-loaded erythrocytes were chromatographed on immobilized Protein A columns 66-70% of cells were retained by the column against 0-10% of controls suggesting that hexokinase inactivation promotes autologous IgG binding. Since the phenomenon is known to be associated with red cell phagocytosis, it could be concluded that in hexokinase deficiency red cells are mainly removed by phagocytosis, and that hemolysis probably occurs in cases of oxidative stress when the production of a large amount of reducing equivalents (NADPH) is needed but not provided by the hexokinase-deficient erythrocytes.

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Section: Discussionmentioning

confidence: 87%

Human Red Blood Cell Loading with Hexokinase-Inactivating Antibodies

Magnani

Rossi²,

Bianchi³

et al. 1989

Acta Haematol

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“…The patient's cells appear to concentrate in the 2-3 lightest cell fractions, as is evident from the extreme pyruvate kinase deficiency measured in these cells. Compared to the activity of the enzyme hexokinase, which is noted for its high activity in premature red cells [11, 16,17] and compared to the activity in the corresponding fractions of patients with hemolytic anemia of nonmetabolic etiology and reticulocytosis, it was estimated that the residual pyruvate kinase activity in these cells is less than 2% of normal.…”

Section: Discussionmentioning

confidence: 99%

Diagnosis of pyruvate kinase deficiency in a transfusion‐dependent patient with severe hemolytic anemia

Rijksen¹,

Schipper-Kester

Staal

1990

American J Hematol

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In a 2-yr old girl a hemolytic anemia was present since birth requiring multiple blood transfusions. Pyruvate kinase deficiency was suspected on the basis of a marginal enzyme activity, but could not be established due to the presence of massive numbers of donor cells in her peripheral blood. However, by density fractionation we succeeded in the isolation of a small fraction of the patient's own cells, in which a severe pyruvate kinase deficiency could be detected. In contrast hexokinase and glucose-6-phosphate dehydrogenase activities were extremely high, which is indicative that a very immature cell population is present in this fraction. In immunofluorescence studies a clear crossreaction was apparent with anti M2-type pyruvate kinase antibodies, whereas only a faint reaction with anti L-type could be detected. Despite the presence of a slight amount of L-type immunoreactive material, the residual activity in the patient's cell fraction could only be attributed to M2-type pyruvate kinase as was shown by cellulose acetate electrophoresis.

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“…Fractions from 1 to h represent red cells of increasing density (age). produce phenotypic heterogeneity (Paglia et ul, 1981;Newman et al, 1980;Rijksen & Staal, 1978). However, recent results from this laboratory have proved that all multiple forms of human erythrocyte hexokinase possess similar kinetic and regulatory properties (Stocchi et al, 1982) and that all HK isozymic forms increase in trisomy of HK gene (Magnani et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

“…In some cases the mutant enzyme was found to show modified substrate affinities (Keitt, 1969;Moseretal. 1970:Nechelesetal, 1970:Goebeletal, 1972:Siimesetul, 1979Newman et ul, 1980), in others reduced heat stability (Keitt, 1969;Board et al, 1978: Newman et al, 1980, or modified regulatory properties (Rijksen & Staal, 1978: Rijksen et al, 1983. Few papers report only a reduced enzyme activity with no additional enzyme abnormalities (Beutler et al, 1978;Paglia et ul, 1981).…”

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confidence: 99%

Human erythrocyte hexokinase deficiency: a new variant with abnormal kinetic properties

Magnani¹,

Stocchi²,

Canestrari³

et al. 1985

Br J Haematol

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A 14-month-old child who had a haemolytic episode when he was 5 years old, and with psychomotor retardation, was found to have decreased red cell hexokinase activity. The mutant enzyme was characterized by an increased affinity for glucose associated with an increased inhibition constant for glucose-1,6-diphosphate. Affinity for Mg ATP2-, heat stability and pH-optimum were normal. The isozymic pattern of the red cell enzyme was normal but all the molecular forms were present in reduced amounts. The kinetics of decay of hexokinase during cell ageing was also normal. Glucose consumption of the hexokinase deficient cells was 60-65% of the controls while the amount metabolized through the hexose monophosphate shunt was unchanged. Red cell 2,3-diphosphoglycerate and glucose-6-phosphate levels were normal in the proband but reduced in the erythrocytes of his parents, who were heterozygous for the defect but had normal haematological data. Comparison with the 13 previously reported cases of hexokinase deficiency confirms the broad phenotypic variability that characterizes this disorder.

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Non‐spherocytic Haemolytic Anaemia in Mother and Son Associated with Hexokinase Deficiency

Cited by 13 publications

References 13 publications

Human Red Blood Cell Loading with Hexokinase-Inactivating Antibodies

Human Red Blood Cell Loading with Hexokinase-Inactivating Antibodies

Diagnosis of pyruvate kinase deficiency in a transfusion‐dependent patient with severe hemolytic anemia

Human erythrocyte hexokinase deficiency: a new variant with abnormal kinetic properties

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