On the diagnosis of erythrocyte enzyme defects in the presence of high reticulocyte counts

Lakomek, M.; Schröter, W.; Maeyer, G De; Winkler, H.

doi:10.1111/j.1365-2141.1989.tb07730.x

Cited by 36 publications

(27 citation statements)

References 23 publications

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“…Thus, the physiopathologic adaptation of this patient with null PKLR seems to be attributable to circulating immature erythroid cells. 50 This immaturity of the circulating cells could reflect the observed residual PK activity attributable to M2PK protein left after the PK isoenzyme gene switch, covering the patient's minimal metabolic demands. Contrary to the expected reduced erythrocyte glycolytic rate in our RPK-deficient patient, we detected increased concentrations of the glycolytic pathway intermediates ATP, adenosine diphosphate (ADP), adenosine monophosphate (AMP), and 2,3-diphosphoglycerate (2,3-DPG).…”

Section: Discussionmentioning

confidence: 99%

Life-threatening nonspherocytic hemolytic anemia in a patient with a null mutation in the PKLR gene and no compensatory PKM gene expression

Díez

Gilsanz

Martínez

et al. 2005

Blood

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IntroductionPyruvate kinase (PK; EC 2.7.1.40) is a key enzyme of the glycolytic pathway responsible for irreversibly catalyzing the conversion of phosphoenolpyruvate to pyruvate. In humans, pyruvate kinase activity is provided by 4 isoenzymes encoded by 2 structural genes. 1 The PKLR gene on chromosome 1 codes for the R-type PK (RPK) (exclusively in mature red blood cells [RBCs]) and the L-type PK (in liver) isoforms under the control of tissue-specific promoters. RPK is a 200-kDa tetramer with 4 identical subunits, each consisting of 4 domains. 1 The active site of RPK occurs at a domain interface, and the allosteric site is found in domain C. 2 The PKM gene on chromosome 15 codes for 2 different M-type PK (MPK) forms, M1 (brain and skeletal muscle) and M2 (fetal and most adult tissues), produced by alternative splicing. 3,4 Undifferentiated erythroid precursor cells express the M2PK isoenzyme earlier than mature RBCs express the RPK isoenzyme. [5][6][7] Because of the tissue-specific expression patterns of the genes, only mutations in the PKLR gene lead to erythrocyte PK deficiency. 8 PK deficiency severely affects RBC metabolism, causing adenosine triphosphate (ATP) depletion, which ultimately leads to hemolysis. Clinical symptoms vary considerably from mild to severe anemia. For the patient, anemia may mean transfusion dependence and may even be life threatening. Pathologic signs of PK deficiency are usually observed when enzyme activity is less than 25% normal activity and patients are generally homozygotes or compound heterozygotes with 2 different mutant alleles. 9 Most cases of PK deficiency are caused by the production of mutant enzymes with abnormal biochemical properties. Thus far, molecular analyses have identified at least 133 different mutations in the PKLR structural gene. 10 Most are missense mutations, but there are also reports of point mutations, deletions, or insertions that led to more drastic changes, such as alterations of the splicing site, frameshift, early termination mutations, and disruption of erythroid-specific promoters. [10][11][12][13][14] Most mutations constitute single-base substitutions, predicting amino acid changes of conserved residues in structurally and functionally important domains of the RPK tetramer. 15 Mutations that affect PKLR transcription, 14,16 or processing of its premRNA, 13,[17][18][19][20][21][22] are less common. To date, only a few homozygous PK null mutations have been identified. The first reported was the relatively common "PK gypsy," consisting of a large deletion at exon 11 23 with premature termination of its translation losing 10% of the original sequence at the C-terminus (exon 11 is deleted, and 35 aberrant residues are added); afterward, 2 one-base deletions and one transition at a split site 11 were reported. More recently, the first homozygous nonsense mutation was reported, 24 which causes premature termination of translation resulting in a truncated protein lacking a 33-residue C-terminal fragment.Here, we report a novel homozygous PKLR gene...

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Section: Discussionmentioning

confidence: 99%

Life-threatening nonspherocytic hemolytic anemia in a patient with a null mutation in the PKLR gene and no compensatory PKM gene expression

Díez

Gilsanz

Martínez

et al. 2005

Blood

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“…Diagnosis of PKD is based on the demonstration of reduced activity or qualitative anomalies of the speci®c erythrocyte enzyme, since most patients have less than 25% of normal activity [6]. Detection is particularly dicult in newborn babies with severe haemolytic anaemia and high reticulocytosis, as reticulocytes have high enzyme activity.…”

Section: Discussionmentioning

confidence: 99%

Hydrops fetalis associated with erythrocyte pyruvate kinase deficiency

Ferreira

Morais

Costa

et al. 2000

European Journal of Pediatrics

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The authors report a case of hydrops fetalis due to severe pyruvate kinase de®ciency, the most unusual clinical manifestation of this disease. Conclusion Pyruvate kinase de®ciency, as other erythrocyte enzymopathies, must be considered in the dierential diagnosis of non-immune hydrops fetalis. This has important implications for clinical investigations, therapy and genetic counselling. Key words Pyruvate kinase á Haemolytic anaemia á Hydrops fetalis á MutationsAbbreviations G6PD glucose-6-phosphate dehydrogenase á GPI glucose phosphate isomerase á PK pyruvate kinase á PKD pyruvate kinase de®ciency

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“…The data about G-6-PD deficiency in sub jects with severe hemolytic disorders such as sickle cell diseases are affected by a high retic ulocyte number, and the G-6-PD activity may fall within the normal range despite the pres ence of the G-6-PD A -gene [1,22]. Our re sults show that the procedure described by Herz et al [16] for reducing the reticulocyte number before the assessment of G-6-PD sta tus allow a reliable discrimination between G-6-PD+ and G-6-PD-patients with sickle cell disease.…”

Section: Discussionmentioning

confidence: 99%

Glucose-6-Phosphate Dehydrogenase Deficiency and Sickle Cell Disease in Brazil

Saad¹,

Costa²

1992

Hum Hered

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The frequency of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency was determined in 54 male patients with sickle cell diseases: 31 sickle cell anemia (SS), 14 sickle cell hemoglobinopathyc (SC) and 9 HbS/β-thalassemia (S/B-thal) by a combination of quantitative assay, fluorescent spot test and electrophoresis. Of the 54 patients tested, 7 were found to be G-6-PD deficient (G-6-PD-) (3 SS, 3 SC and 1 S/B-thal) and 47 G-6-PD normal (G-6-PD+) (6 G-6-PD A and 41 G-6-PD B). All the deficient patients were G-6-PD A-. The frequency of G-6-PD deficiency did not differ significantly from that observed in the general population. Compared to patients who were not G-6-PD-, there were no significant differences in the hemoglobin concentration and reticulocyte count in patients with sickle cell diseases who were G-6-PD-.

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On the diagnosis of erythrocyte enzyme defects in the presence of high reticulocyte counts

Cited by 36 publications

References 23 publications

Life-threatening nonspherocytic hemolytic anemia in a patient with a null mutation in the PKLR gene and no compensatory PKM gene expression

Life-threatening nonspherocytic hemolytic anemia in a patient with a null mutation in the PKLR gene and no compensatory PKM gene expression

Hydrops fetalis associated with erythrocyte pyruvate kinase deficiency

Glucose-6-Phosphate Dehydrogenase Deficiency and Sickle Cell Disease in Brazil

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