Pyruvate
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64 stran : ilustrace, tabulky
- MeSH
- hematologie MeSH
- hemolytické anemie MeSH
- krevní nemoci MeSH
- pyruvátkinasa nedostatek MeSH
- Publikační typ
- příručky MeSH
- NLK Obory
- hematologie a transfuzní lékařství
... Foreword -- Chapter 1 | Introduction to this book -- References -- 11 -- Chapter 2 | Thalassaemias and pyruvate ... ... overview of the conditions -- Overview of the thalassaemias -- P thalassaemias a thalassaemias -- Pyruvate ... ... expenditure -- Dietary intake -- Protein, fluids and fibre -- Dietary intake and energy expenditure in pyruvate ... ... formation during adolescence -- Special considerations and limitations -- Physical activity and pyruvate ...
178 stran : ilustrace ; 24 cm
64 stran : ilustrace, tabulky
Vous ne connaissez peut-être pas le déficit en pyruvate kinase (PK). C'est une maladie enzymatique héréditaire rare qui affecte la glycolyse utilisée par les globules rouges pour fabriquer de l'énergie. Elle se manifeste par une anémie hémolytique. Les symptômes varient énormément d'un individu à l'autre, ce qui rend le diagnostic difficile. Et la gestion de cette maladie consiste essentiellement en des traitements de soutien.Rédigé par des experts dans le domaine, 'Fast Facts : Déficit en pyruvate kinase' fournit une introduction complète de la maladie et donne des détails sur : • l'anomalie sous-jacente • son mode de transmission et la relation entre le génotype et le phénotype • la manière dont la maladie se manifeste • les fondamentaux du diagnostic et la manière de différencier la maladie d'un groupe hétérogène d'anomalies hémolytiques • la surveillance et la gestion des complications qui peuvent se produire.'Fast Facts : Déficit en pyruvate kinase' sera d'un intérêt essentiel pour les professionnels de santé, les hématologues, les oncologues, les pédiatres, les spécialistes en médecine interne, les infirmiers en hématologie et les étudiants en médecine... en fait à tous ceux qui souhaitent en savoir plus sur cette anomalie génétique rare.
- MeSH
- hematologie MeSH
- hemolytické anemie MeSH
- krevní nemoci MeSH
- pyruvátkinasa nedostatek MeSH
- Publikační typ
- příručky MeSH
- NLK Obory
- hematologie a transfuzní lékařství
Účel studie: Deficit pyruvátkinázy (PK) je druhý nejčastější enzymatický defekt vedoucí k hemolytické anemii. Cílem práce je demonstrovat klinické a laboratorní nálezy u deficitu PK u prvních dětských pacientů v České republice definovaných na molekulární úrovni. Pacienti a metody: Čtyři děti (10 měsíců – 7 let) byly vyšetřeny pro závažnou nesférocytární hemolytickou anemii s hladinou hemoglobinu 64–97 g/l. Všechny děti vyžadovaly po porodu fototerapii a transfuzi, dvě dokonce výměnnou transfuzi. V klinickém nálezu dominovala bledost, subikterus sklér a kůže. Standardními metodami byla vyloučena porucha membrány erytrocytu, hemoglobinopatie a kongenitální dyserytropoetická anemie. Byla stanovena aktivita PK a provedena sekvenace genu kódujícího PK. Pro zvýšení hladin feritinu byla vyšetřena hladina hepcidinu. Výsledky: Všechny děti mají makrocytární anemii. Hodnoty bilirubinu se pohybují v rozmezí 38–89 μmol/l. Aktivita PK je u všech dětí snížená (23–32 %). Dva pacienti jsou smíšení heterozygoti pro mutace c.1529C>A (p.Arg510Gln) a c.1594C>T (p.Arg532Trp) a jeden pro mutace c.1493G>A (p.Arg498His) a c.1529C>A (p.Arg510Gln). V jednom případě se jedná o homozygotní deleci v exonu 11, která nebyla dosud popsána. Tento pacient s nejtěžším průběhem nemoci má vysokou hladinu feritinu, avšak sníženou hladinu hepcidinu, což se může podílet na přetížení železem. Byla vyloučena koincidence s hemochromatózou typu I. Závěr: Deficit PK může být u novorozence příčinou závažné anemie a hyperbilirubinemie vyžadující někdy výměnnou transfuzi a opakované podání transfuzí v kojeneckém věku, jejichž frekvence se většinou postupně snižuje. Deficit PK může být provázen i přetížením železem s nutností chelatační léčby. V české populaci je onemocnění zatím poddiagnostikováno.
Purpose of the study: Pyruvate kinase deficiency (PK) is the second most common enzymatic defect leading to hemolytic anemia. The aim is to demonstrate the clinical and laboratory findings in PK defi - ciency in the first pediatric patients in the Czech Republic who were defined at the molecular level. Patients and methods: Four children (10 months – 7 years) were examined for severe nonspherocytic hemolytic anemia with hemoglobin levels 64–97 g/l. All the children required transfusions and phototherapy after delivery, two of them even an exchange transfusion. The clinical finding was dominantly characterized by pallor, subicterus of sclerae and skin. Erythrocyte membrane disorder, hemoglobinopathies and congenital dyserythropoietic anemia were excluded using standard methods. PK activity was determined and sequencing of the gene encoding PK was done. Because of increased ferritin levels, hepcidin level was measured. Results: All children have macrocytic anemia with bilirubin values from 38 to 89 micromol/l. PK activity is decreased in all children (23–32%). Two patients are mixed heterozygotes for mutations c.1529C>A (p.Arg510Gln) and c.1594C>T (p.Arg532Trp) and one for the c.1493G>A (p.Arg498His) and c.1529C>A (p.Arg510Gln) mutations. In one case, a homozygous deletion in exon 11, which has not yet been described, was found. This patient with the most severe course of the disease has a high ferritin level, but a reduced level of hepcidin, which may contribute to iron overload. Coincidence with type I hemochromatosis was excluded. Conclusion: PK deficiency in the newborn may cause severe anemia and hyperbilirubinemia sometimes requiring an exchange transfusion and repeated administration of transfusions in infancy; their frequency is usually gradually reduced. PK deficiency may also be associated with iron overload and the need for chelation therapy. In the Czech population this disease is still underdiagnosed.
- Klíčová slova
- nesférocytární hemolytická anemie, hepcidin,
- MeSH
- biologické markery analýza krev MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- ferritiny diagnostické užití krev MeSH
- financování organizované MeSH
- glykolýza MeSH
- hemolytická nesférocytická kongenitální anemie diagnóza enzymologie genetika MeSH
- lidé MeSH
- nedostatek glukóza-6-fosfátdehydrogenázy diagnóza MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- přetížení železem MeSH
- pyruvátkinasa genetika metabolismus nedostatek MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
INTRODUCTION: Pyruvate kinase (PK) deficiency is a rare, under-recognised, hereditary condition that leads to chronic haemolytic anaemia and potentially serious secondary complications, such as iron overload, cholecystitis, pulmonary hypertension and extramedullary haematopoiesis. It is an autosomal recessive disease caused by homozygous or compound heterozygous mutations in the PKLR gene. Due to its rarity and clinical heterogeneity, information on the natural history and long-term clinical course of PK deficiency is limited, presenting major challenges to patient management, the development of new therapies and establishing disease-specific treatment recommendations. The Pyruvate Kinase Deficiency Global Longitudinal (Peak) Registry is an initiative to address the gaps in the knowledge of PK deficiency. This manuscript describes the objectives, study design and methodology for the Peak Registry. METHODS AND ANALYSIS: The Peak Registry is an observational, longitudinal, global registry of adult and paediatric patients with a genetically confirmed diagnosis of PK deficiency. The Peak Steering Committee is composed of 11 clinicians and researchers with experience in the diagnosis and management of PK deficiency from 10 countries, a patient representative and representatives from the sponsor (Agios Pharmaceuticals). The registry objective is to foster an understanding of the longitudinal clinical implications of PK deficiency, including its natural history, treatments and outcomes, and variability in clinical care. The aim is to enrol up to 500 participants from approximately 60 study centres across 20 countries over 7 years, with between 2 and 9 years of follow-up. Data will include demographics, diagnosis history, genotyping, transfusion history, relevant clinical events, medications, emergency room visits and hospitalisations. ETHICS AND DISSEMINATION: Registry protocol and informed consent forms are approved by institutional review boards/independent ethics committees at each study site. The study is being conducted in accordance with the Declaration of Helsinki. Registry data will be published in peer-reviewed journal articles and conference publications. TRIAL REGISTRATION NUMBER: NCT03481738.
- MeSH
- dítě MeSH
- dospělí MeSH
- hemolytická nesférocytická kongenitální anemie * diagnóza genetika MeSH
- homozygot MeSH
- lidé MeSH
- pyruvátkinasa genetika MeSH
- vrozené poruchy metabolismu pyruvátu * genetika MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 [59%] of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin (P = .007), lower indirect bilirubin (P = .005), and missense PKLR mutations (P = .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at www.clinicaltrials.gov as #NCT02053480.
- MeSH
- aktivace enzymů MeSH
- cholecystektomie škodlivé účinky metody MeSH
- dítě MeSH
- dospělí MeSH
- fenotyp MeSH
- genetické asociační studie * MeSH
- genotyp MeSH
- hemolytická nesférocytická kongenitální anemie diagnóza etiologie metabolismus terapie MeSH
- kojenec MeSH
- kombinovaná terapie MeSH
- krevní transfuze MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- pyruvátkinasa nedostatek metabolismus MeSH
- splenektomie škodlivé účinky metody MeSH
- určení symptomu MeSH
- vrozené poruchy metabolismu pyruvátu diagnóza etiologie metabolismus terapie MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- MeSH
- biologické markery MeSH
- krevní transfuze MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- management nemoci MeSH
- mutace MeSH
- mutační analýza DNA MeSH
- přetížení železem diagnóza epidemiologie etiologie metabolismus MeSH
- prevalence MeSH
- pyruvátkinasa nedostatek MeSH
- železo metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
Mycobacterium tuberculosis (Mtb) causes both acute tuberculosis and latent, symptom-free infection that affects roughly one-third of the world's population. It is a globally important pathogen that poses multiple dangers. Mtb reprograms its metabolism in response to the host niche, and this adaptation contributes to its pathogenicity. Knowledge of the metabolic regulation mechanisms in Mtb is still limited. Pyruvate kinase, involved in the late stage of glycolysis, helps link various metabolic routes together. Here, we demonstrate that Mtb pyruvate kinase (Mtb PYK) predominantly catalyzes the reaction leading to the production of pyruvate, but its activity is influenced by multiple metabolites from closely interlinked pathways that act as allosteric regulators (activators and inhibitors). We identified allosteric activators and inhibitors of Mtb PYK originating from glycolysis, citrate cycle, nucleotide/nucleoside inter-conversion related pathways that had not been described so far. Enzyme was found to be activated by fructose-1,6-bisphosphate, ribose-5-phosphate, adenine, adenosine, hypoxanthine, inosine, L-2-phosphoglycerate, l-aspartate, glycerol-2-phosphate, glycerol-3-phosphate. On the other hand thiamine pyrophosphate, glyceraldehyde-3-phosphate and L-malate were identified as inhibitors of Mtb PYK. The detailed kinetic analysis indicated a morpheein model of Mtb PYK allosteric control which is strictly dependent on Mg2+ and substantially increased by the co-presence of Mg2+ and K+.
