Partial pyruvate kinase deficiency aggravates the phenotypic expression of band 3 deficiency in a family with hereditary spherocytosis

Zwieten, Rob van; Oirschot, Brigitte A. van; Veldthuis, Martijn; Dobbe, Johannes G. G.; Streekstra, Geert J.; Solinge, Wouter W. van; Schutgens, Roger E. G.; Wijk, Richard van

doi:10.1002/ajh.23899

Cited by 29 publications

(34 citation statements)

References 18 publications

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“…Modifier alleles have also been observed in other erythroid disorders, like HS, which exhibits substantial clinical heterogeneity, even within an individual pedigree (Iolascon and Avvisati, 2008). For example, partial pyruvate kinase deficiency due to a PKLR mutation has been observed to aggravate HS disease severity by additively affecting RBC fragility (van Zwieten et al, 2015). However, most modifiers remain to be identified and larger studies are needed to define the extent to which these disorders are simply monogenic, as opposed to being on the spectrum of more complex disorders.…”

Section: An Overview Of Disorders Affecting Erythropoiesismentioning

confidence: 99%

Advances in understanding erythropoiesis: evolving perspectives

2016

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Red blood cells (RBCs) are generated from haematopoietic stem and progenitor cells (HSPCs) through the step-wise process of differentiation known as erythropoiesis. In this review, we discuss our current understanding of erythropoiesis and highlight recent advances in this field. During embryonic development, erythropoiesis occurs in three distinct waves comprising first, the yolk sac-derived primitive RBCs, followed sequentially by the erythro-myeloid progenitor (EMP) and HSPC-derived definitive RBCs. Recent work has highlighted the complexity and variability that may exist in the hierarchical arrangement of progenitors responsible for erythropoiesis. Using recently defined cell surface markers, it is now possible to enrich the erythroid progenitors and precursors to a much greater extent than has been possible before. While a great deal of knowledge has been gained on erythropoiesis from model organisms, our knowledge of this process is being refined through human genetic studies. Genes mutated in erythroid disorders can now be identified more rapidly by the use of next-generation sequencing techniques. Genome-wide association studies on erythroid traits in healthy populations have also revealed new modulators of erythropoiesis. All of these recent developments have significant promise not only for increasing our understanding of erythropoiesis, but also for improving our ability to intervene when RBC production is perturbed in disease.

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Section: An Overview Of Disorders Affecting Erythropoiesismentioning

confidence: 99%

Advances in understanding erythropoiesis: evolving perspectives

2016

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“…PKD has the potential to cause severe symptoms and is often overlooked. Thus, a delay in diagnosis is common . In our study, the patient required transfusion every 3 weeks, which was the major cause of falsely normal PK levels and positive direct Coombs tests.…”

Section: Discussionmentioning

confidence: 74%

A novel PKLR gene mutation identified using advanced molecular techniques

Luo

Yonghong

Jia

et al. 2018

Pediatric Transplantation

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This study's purposes were to diagnose intractable hemolytic anemia and to provide guiding treatment for the affected family members. We performed NGS in a panel of 600 genes for blood diseases on a patient with obscure hemolytic anemia and her parents. We confirmed the diagnosis of pyruvate kinase deficiency, identified a novel homozygous mutation of the PKLR gene (NM_000298: exon 6: c.T941C: p.I314T), and ruled out other blood diseases in the Chinese family. Furthermore, amniotic fluid was taken from the mother during the second trimester, and DNA was extracted to analyze the type of PKLR gene mutation. The proband received cord blood and bone marrow from the second child of the mother for hematopoietic stem cell transplantation and achieved normal hematopoiesis. The genetic characterization analysis and genotype-phenotype correlation study of PKLR gene suggested that NGS was an effective method to confirm the molecular diagnosis of intractable hemolytic anemia. The identification of the mutation aided in prenatal diagnosis in the second pregnancy and the effective clinical management of the affected family.

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“…Combined defects of red cell membrane and/or metabolism are very rare, and the fact that carriership for a metabolic defect may be a modifier for the clinical expression of a membrane defect is still debated [32, 33]; in particular, the copresence of beta-thalassemia trait seems to reduce the degree of haemolysis in patients with hereditary spherocytosis [34–37]. In the presented cases the clinical phenotype does not differ from the HX cases reported in literature (Table 2), thus excluding a synergetic effect between HX and the concomitant disorders.…”

Section: Discussionmentioning

confidence: 99%

Hereditary Xerocytosis due to Mutations inPIEZO1Gene Associated with Heterozygous Pyruvate Kinase Deficiency and Beta-Thalassemia Trait in Two Unrelated Families

Fermo

Vercellati

Marcello

et al. 2017

Case Reports in Hematology

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Hereditary xerocytosis (HX) is a rare disorder caused by defects of RBC permeability, associated with haemolytic anaemia of variable degree and iron overload. It is sometimes misdiagnosed as hereditary spherocytosis or other congenital haemolytic anaemia. Splenectomy is contraindicated due to increased risk of thromboembolic complications. We report the clinical, haematological, and molecular characteristics of four patients from two unrelated Italian families affected by HX, associated with beta-thalassemia trait and heterozygous pyruvate kinase deficiency, respectively. Two patients had been splenectomised and displayed thrombotic episodes. All patients had iron overload in the absence of transfusion, two of them requiring iron chelation. The diagnosis of HX was confirmed by LoRRca Osmoscan analysis showing a left-shifted curve. PIEZO1 gene sequencing revealed the presence of mutation p.E2496ELE, showing that this is one of the most frequent mutations in this disease. The concomitant defects did not aggravate the clinical phenotype; however, in one patient, the initial diagnosis of pyruvate kinase deficiency delayed the correct diagnosis of HX for many years and resulted in splenectomy followed by thrombotic complications. The study underlines the importance of a precise diagnosis in HX, particularly in view of splenectomy, and the need of a molecular confirmation of suspected RBC enzymopathy.

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Partial pyruvate kinase deficiency aggravates the phenotypic expression of band 3 deficiency in a family with hereditary spherocytosis

Cited by 29 publications

References 18 publications

Advances in understanding erythropoiesis: evolving perspectives

Advances in understanding erythropoiesis: evolving perspectives

A novel PKLR gene mutation identified using advanced molecular techniques

Hereditary Xerocytosis due to Mutations inPIEZO1Gene Associated with Heterozygous Pyruvate Kinase Deficiency and Beta-Thalassemia Trait in Two Unrelated Families

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