Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The PK-LR gene was studied in 23 patients with congenital haemolytic anaemia associated with erythrocyte pyruvate kinase (PK) deficiency. Twenty-seven different mutations were detected among the 42 mutated alleles identified: 19 missense mutations, four splice site mutations and one nonsense, one single base deletion and two large deletions. Seventeen of them (107G, 278T, 403T, 409A, 661A, 859C, 958A, 1094T, 1190T, 1209A, 1232C, 1369G, 507A, IVS9 -1c, IVS9 +43c [corrected] del C224, del 5006bp IVS3--> nt 1431) were new. Although all the exons, the flanking regions and the promoter were sequenced in all cases, we failed to detect the second expected mutation in four subjects. To correlate genotype to phenotype, the molecular results were related to the biochemical properties of the mutant enzymes by an analysis of the three-dimensional structure of erythrocyte PK. The new mutant 409A, found in association with the large deletion of 5006 bp in a newborn baby who died soon after birth, was functionally characterized by mutagenesis and in vitro expression of the protein to investigate its contribution in the severity of the clinical pattern. However, the biochemical data obtained for the mutant enzyme cannot explain the severe anaemia found in the PK-deficient patient hemizygous for this mutation.
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PMID:Red cell pyruvate kinase deficiency: 17 new mutations of the PK-LR gene. 1595 13

Red cell pyruvate kinase (PK) deficiency is the most frequent enzyme abnormality of the glycolytic pathway causing hereditary non-spherocytic haemolytic anaemia. The degree of haemolysis varies widely, ranging from very mild or fully compensated forms, to life-threatening neonatal anaemia and jaundice necessitating exchange transfusions. Erythrocyte PK is synthesized under the control of the PK-LR gene located on chromosome 1. To date, more than 150 different mutations in the PK-LR gene have been associated with PK deficiency. First attempts to delineate the biochemical and clinical consequences of the molecular defect were mainly based on the observation of the few homozygous patients and on the analysis of the three-dimensional structure of the enzyme. More recently, the comparison of the recombinant mutants of human red cell PK with the wild-type enzyme has enabled the effects of amino acid replacements on the enzyme molecular properties to be determined and help to correlate genotype to clinical phenotype.
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PMID:Red cell pyruvate kinase deficiency: molecular and clinical aspects. 1598 40

We report the case of a man with severe X-linked sideroblastic anemia, severe iron overload, and hepatic cirrhosis who died of hepatocellular carcinoma. Evaluation of family members using DNA sequencing revealed that he was hemizygous for the novel ALAS2 mutation R452H (exon 9; nt 1407 G --> A). The proband's brother, an ALAS2 R452H hemizygote, had mild anemia and mild iron overload. Four female relatives were ALAS2 R452H heterozygotes, but they had mild or no anemia and no iron overload. Sequencing of TFR2, HFE, FPN1 (SLC40A1), HAMP, HJV, and the erythrocyte pyruvate kinase genes of family members was also performed. We thus detected the novel TFR2 missense mutation I449V (exon 10; nt 1345 A --> G) in the proband's wife and daughter, neither of whom had anemia or iron overload. Possible explanations for the disparate red blood cell and iron phenotypes of the proband and his family members are discussed.
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PMID:Disparate phenotypic expression of ALAS2 R452H (nt 1407 G --> A) in two brothers, one with severe sideroblastic anemia and iron overload, hepatic cirrhosis, and hepatocellular carcinoma. 1654 Mar 54

Deficiencies of enzymes involved in erythrocyte metabolism can have significant effects on erythrocyte function and survival. Animals with pyruvate kinase (PK) or phosphofructokinase (PFK) deficiencies have shortened erythrocyte life spans and regenerative anemia. PK-deficient dogs (but not PK-deficient cats) develop progressive myelofibrosis and osteosclerosis of bone marrow and hemochromatosis and cirrhosis of the liver. PFK-deficient dogs have sporadic episodes of hyperventilation-induced intravascular hemolysis and hemoglobinuria. Cytochrome b5 reductase (Cb5R) deficiency in dogs and cats results in persistent methemoglobinemia and cyanotic mucous membranes. Severe deficiency of glucose-6-phosphate dehydrogenase, the rate-controlling enzyme in the pentose phosphate pathway, resulted in anemia with eccentrocytosis in an American saddlebred colt. Horses with erythrocyte flavin adenine dinucleotide (FAD) deficiency have both eccentrocytosis (attributable to severe deficiency in glutathione reductase activity) and methemoglobinemia (attributable to Cb5R deficiency); the dual enzyme deficiency occurs because FAD is a required cofactor for both enzymes. Erythrocyte enzyme deficiencies do not usually shorten life expectancy, except for PK-deficient dogs and potentially PFK-deficient dogs during a hemolytic crisis. Although enzyme deficiencies are rare causes of anemia and methemoglobinemia, the ability to diagnose deficient animals allows for the possibility of eliminating these undesirable traits in future breeding. DNA-based assays are available for PK and PFK deficiencies; whereas, biochemical tests of enzyme activity are required for other deficiencies. Continued research is needed to document additional enzyme deficiencies that likely occur and to develop additional DNA-based assays to detect heterozygous animals.
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PMID:Pathogenesis, laboratory diagnosis, and clinical implications of erythrocyte enzyme deficiencies in dogs, cats, and horses. 1678 7

Red cell pyruvate kinase (PK) deficiency is the most frequent enzyme abnormality of glycolysis causing chronic non-spherocytic haemolytic anaemia. The disease is transmitted as an autosomal recessive trait, clinical symptoms usually occurring in compound heterozygotes for two mutant alleles and in homozygotes. The severity of haemolysis is highly variable, ranging from very mild or fully compensated forms to life-threatening neonatal anaemia necessitating exchange transfusions. Erythrocyte PK is synthesised under the control of the PK-LR gene located on chromosome 1. One hundred eighty different mutations in PK-LR gene, mostly missense, have been so far reported associated to PK deficiency. First attempts to delineate the genotype-phenotype association were mainly based on the analysis of the enzyme's three-dimensional structure and the observation of the few homozygous patients. More recently, the comparison of the recombinant mutants of human red cell PK with the wild-type enzyme has enabled the effects of amino acid replacements on the enzyme molecular properties to be determined. However, the clinical manifestations of red cell enzyme defects are not merely dependent on the molecular properties of the mutant protein but rather reflect the complex interactions of additional factors, including genetic background, concomitant functional polymorphisms of other enzymes, posttranslational or epigenetic modifications, ineffective erythropoiesis and differences in splenic function.
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PMID:Pyruvate kinase deficiency: the genotype-phenotype association. 1736 88

A common cause of hereditary nonspherocytic hemolytic anemia is pyruvate kinase deficiency, which is associated with lifelong chronic hemolysis. Pyruvate kinase deficiency has a worldwide distribution with a higher prevalence in the Caucasian population, and especially in Europe and North America. It is inherited in an autosomal fashion and over 180 different mutations have been described. Investigation of hemolytic anemia in Northern Ireland has uncovered 4 new cases of pyruvate kinase deficiency. Molecular investigation revealed a total of six different mutations. One mutation (p.Arg495Val) is reported here for the first time in a homozygous patient. Another mutant PKLR allele harbored a nonsense and frameshift mutation in cis: c.[721G>T; 826delG]. Considering the three previously described Irish cases of pyruvate kinase deficiency, this study raises the total number of pyruvate kinase-deficient Irish patients to seven in which a total of nine mutant PKLR alleles were identified. This indicates the absence of a founder pyruvate kinase mutation in the Northern Ireland population. Although pyruvate kinase deficiency is prevalent in the Caucasian population it is not reflected in the number of individuals diagnosed in Northern Ireland. Hence, many cases of pyruvate kinase deficiency may remain undetected possibly due to the resultant anemia being mild.
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PMID:Pyruvate kinase deficient hemolytic anemia in the Northern Irish population. 1757 81

Significant hyperbilirubinaemia, anemia, and splenomegaly are common features in patients with severe haemolysis due to pyruvate kinase (PK) deficiency. Until now, severe neonatal PK deficiency has not been associated with fatal liver disease at this age. We present two neonatal cases of severe PK deficiency complicated with progressive fatal liver disease. The patients presented with severe haemolysis, progressive cholestasis, and hepatosplenomegaly, and both patients ultimately developed liver failure at a very young age. Despite extensive investigations, no specific explanation for liver disease and failure was found. We suggest that the PK deficiency itself directly led to liver dysfunction.
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PMID:Pyruvate kinase deficiency associated with severe liver dysfunction in the newborn. 1765 6

Erythrocyte pyruvate kinase (PK) is an important glycolytic enzyme, and manipulation of its regulatory behavior by allosteric modifiers is of interest for medicinal purposes. Human-erythrocyte PK was expressed in Rosetta cells and purified on an Ni-NTA column. A search of the small-molecules database of the National Cancer Institute (NCI), using the UNITY software, led to the identification of several compounds with similar pharmacophores as fructose-1,6-bisphosphate (FBP), the natural allosteric activator of the human kinases. The compounds were subsequently docked into the FBP binding site using the programs FlexX and GOLD, and their interactions with the protein were analyzed with the energy-scoring function of HINT. Seven promising candidates, compounds 1-7, were obtained from the NCI, and subjected to kinetics analysis, which revealed both activators and inhibitors of the R-isozyme of PK (R-PK). The allosteric effectors discovered in this study could prove to be lead compounds for developing medications for the treatment of hemolytic anemia, sickle-cell anemia, hypoxia-related diseases, and other disorders arising from erythrocyte PK malfunction.
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PMID:Identification of novel allosteric regulators of human-erythrocyte pyruvate kinase. 1802 74

The objective of this study was to examine clinical signs, laboratory parameters, and course of disease in Abyssinian and Somali cats with pyruvate kinase (PK) deficiency. The clinical course of 25 PK-deficient cats was followed over a time period of 0.8-11.3 years (median 4.3). Eleven cats (age 0.8-7.8 years, median 4.4) did not show signs according to the owners. In 14 cats (age 0.1-5 years, median 1.7) the owners noted lethargy (10), diarrhoea (seven), pale mucous membranes (six), inappetence (six), poor coat quality (six), weight loss (four), icterus (four), and pica (two). Sixteen cats had been used for breeding at least once before diagnosis. Laboratory abnormalities included anaemia (70%), increased aggregated reticulocyte counts (94%), hyperglobulinaemia (80%), hyperbilirubinaemia (53%), and increased liver enzymes (47%). Six of 25 affected cats died (four) or were euthanased (two) at ages ranging from 1.3 to 11.3 years (median 4.1) presumably because of PK-deficiency. These findings emphasise that PK deficiency shows variation in age of onset and severity of signs. As PK-deficient cats can be asymptomatic testing for PK deficiency before breeding is strongly recommended.
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PMID:Clinical course of pyruvate kinase deficiency in Abyssinian and Somali cats. 1807 99

Evaluation of two patients with transfusion dependent anemia revealed RBC pyruvate kinase to be 33% and 41% of the mean normal value, with normal or high values of other RBC enzymes. Parental PK activities were just below normal in three of four of the parents. Subsequent DNA analysis revealed both patients to be compound heterozygotes for PKLR gene mutations, two of which are previously undescribed. Borderline low pyruvate kinase activities with increased in other RBC enzyme activities should prompt consideration of measurement of parental enzyme activities, and confirmation by DNA analysis if available.
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PMID:Relative red blood cell enzyme levels as a clue to the diagnosis of pyruvate kinase deficiency. 1872 18


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