Deficiency erythrocytes

Hokin-Neaverson M, Jefferson JW Deficient erythrocyte Na,K-ATPase activity in different affective states in bipolar affective states in bipolar affective disorder and normalization by lithium therapy. Neuropsychobiology 22 18-25, 1989a Hokin-Neaverson M, Jefferson JW Erythrocyte sodium pump activity in bipolar affective disorder and other psychiatric disorders. Neuropsychobiology 22 1-7, 1989b... 

The classic function of TPI is to adjust the rapid equilibrium between the two triosephosphates, glycerinealdehyde-3-phosphate and DH AP. Patients with TPI deficiency have unimpressive alterations in glucose utilization, ATP and lactate production. Modeling studies and experimental data suggested that the physiological ATP level was maintained due to the activation of enzymes involved in the pen-tosephosphate and glycolytic pathways (Fig. 8.2) [80, 81]. The interconnection of the two pathways with increased activities can compensate for the reduced TPI activity of deficient cells in TPI-deficient erythrocytes [80, 81]. 

An appropriate stimulation of erythropoiesis is induced by the anemia. A reticulocytosis is apparent within 5 days and is maximal at 7 to 10 days after the onset of hemolysis. Even if there is continued drug exposure, the acute hemolysis usually resolves after 1 week. This spontaneous recovery reflects replacement of the older, enzyme-deficient erythrocytes by younger red cells with sufficient G6PD activity to withstand oxidative injury. Provided there is normally functioning bone marrow, the continued loss of aging red cells is compensated by the erythropoietic marrow response. 

Pyruvate Idnase deficiency (OMIM 266200) is the most common cause of nonspherocytic hemolytic anemia due to defective glycolysis. The allelic frequency is estimated to be around 2%. The consequent lack of sufficient energy, which is required for normal functioning and cellular survival, shortens the life span of the mature PK-deficient erythrocyte. Consequently, PK-deficient patients display a phenotype of nonspherocytic hemolytic anemia albeit with variable clinical severity. The clinical symptoms vary from neonatal death to a well-compensated hemolytic anemia. Patients benefit in general from a splenectomy. Pyruvate kinase deficiency is transmitted as an autosomal recessive disease. To date, more than 130 mutations in PKLR have been reported to be associated with pyruvate kinase deficiency (see Figure 21-10 for overview see reference 221). Most (70%) of these mutations are missense mutations affecting conserved residues in structurally and functionally important domains of PK. Splice site mutations, a deletion. 

Cappadoro, M., Giribaldi, G., O Brien, E., Turrini, F., Mannu, F., Ulliers, D., Simula, G., Luzzatto, L., and Arese, P. (1998). Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum may explain malaria protection in G6PD deficiency. Blood 92, 2527-2534. 

Daddona, P. E., Wiesmann, W. P., Lambros, C., Kelley, W. N., and Webster, H. K. (1984). Fluman malaria parasite adenosine deaminase. Characterization in host enzyme-deficient erythrocyte culture. ]. Biol. Chem. 259,1472-1475. 

Effects of ascorbic acid on glucose-6-phosphate dehydrogenase-deficient erythrocytes studies in an aninial model. 

Favism Hemolytic anemia due to the ingestion of fava beans or after inhalation of poUen from the Vicia fava plant hy persons with glucose-6-phosphate dehydrogenase deficient erythrocytes. [NiH]... 

In summary, it is proposed that the most hopeful prospect for therapy of this condition would be to search for a specific inhibitor of orotate transport across cell membranes. This is likely to affect the metabolism of pyrimidines in only two tissues, liver and erythrocytes, and, unless it gives rise to toxic accumulations of orotate in the liver, could help to reduce pyrimidine nucleotide levels in pyrimidine 5 nucleotidase deficient erythrocytes. A trial of a specific inhibitor of uridine kinase might also be appropriate, and the final choice of a therapeutic approach will depend on the demonstration of which of these two alternative pathways amenable to therapeutic intervention contributes most to erythrocyte pyrimidine nucleotide accumulation. 

This paper reports in vitro studies to investigate mechanisms for the formation and degradation of dATP in ADA deficient erythrocytes from these two children. 

Table 1. Metabolism of adenosine and deoxyadenosine in ADA deficient erythrocytes.

The studies with AR and dAR in these ADA deficient red cells have given results identical with previous studies in normal erythrocytes where ADA deficiency was simulated using the inhibitor erythro-9 (2 hydroxy-3-nonyl) adenine EHNA. They confirm that AR and, to a lesser extent, dAR, can be converted by the ADA deficient erythrocyte to the three corresponding nucleotides in roughly the same proportion (10 1.0 0.1) presumably by the same nucleotide kinases. 

Erythrocytes from a child with purine nucleoside phosphorylase (PNP) deficiency (Watson et al - this symposium) and high levels of inosine and guanosine, deoxyinosine and deoxyguanosine in plasma and urine do not show intracellular accumulation of any of these nucleosides. The finding of high intracellular levels of dAR in the ADA deficient erythrocyte is thus in accord with a unique transport system for adenosine-type compounds associated with both adenosine kinase (AK) and ADA in the human red cell. 

Prolidase deficiency Erythrocytes, leukocytes, 19pl3.2 fibroblasts 170100... 

Oxoprolinase deficiency has been identified in eight patients, who lack a consistent clinical syndrome. Urinary excretion of 5-oxoproline is elevated but less than in glutathione synthetase deficiency. Erythrocytes contain an incomplete y-glutamyl cycle they lack both y-glutamyl transpeptidase and 5-oxoprolinase. 

ADA is involved in an important step in purine salvage by converting adenosine to inosine. ADA deficient erythrocytes accumulate adenosine triphosphate and convert inosine monophosphate to inosine triphosphate at an increased rate. The accumulation of adenosine or another product in these infants may be lymphocytotoxic or interfere with pyrimidine biosynthesis by... 

Iron-deficient bird erythrocytes synthesize i-AL at a diminished rate (43, 53). When intact iron-deficient erythrocytes (not hemolyzed ones) are preincubated for 30 min with Fe++ the rate of 5-AL synthesis increases two to three times. 

The mechanism by which PRPP stabilizes APRT against heat inactivation is not yet clarified, but it would be reasonable to assume that PRPP is inducing a conformational change in the APRT molecule resulting in thermal stability, and that the increased heat stability of the enzyme in the UlS hemolysate is due to the increased level of PRPP in such cells. Indeed, both increased specific activity and thermal stability of the APRT in LNS hemolysates have been attributed to stabilization of the enzyme by the elevated concentration of PRPP accumulation in the HGPRT deficient erythrocytes (ll,12). In view of the fact however, that the increased stability of APRT is observed in dialyzed hemolysates, the postulated conformational change would have to be irreversible, unless the stabilizing PRPP is bound to the enzyme. 

Fig.2 Recovery of the label administered as C-adenine from incubations with intact normal and HG-PRT deficient erythrocytes.

This model is also supported by the results shown in slide 4 (Fig.2). Normal and HG-PRT deficient erythrocytes were washed and incubated with C-adenine in autologous serum. In normal cells, along with IMP and AMP, the major endproduct was hypoxanthine. In normal cells IMP and AMP were formed in considerable amounts, but in mutant cells only traces of IMP and AMP were recovered. This illustrates the importance of the salvage pathway involving HG-PRT. 

Glader, B. E. (1976) Salicylate-induced injury of pyruvate-kinase-deficient erythrocytes. New Engl. J. Med., 294, 916. 

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