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Science Translational Medicine May 2016Diamond Blackfan anemia (DBA) and myelodysplastic syndrome (MDS) with isolated del(5q) are severe macrocytic anemias; although both are associated with impaired ribosome...
Diamond Blackfan anemia (DBA) and myelodysplastic syndrome (MDS) with isolated del(5q) are severe macrocytic anemias; although both are associated with impaired ribosome assembly, why the anemia occurs is not known. We cultured marrow cells from DBA (n = 3) and del(5q) MDS (n = 6) patients and determined how heme (a toxic chemical) and globin (a protein) are coordinated. We show that globin translation initiates slowly, whereas heme synthesis proceeds normally. This results in insufficient globin protein, excess heme and excess reactive oxygen species in early erythroid precursors, and CFU-E (colony-forming unit-erythroid)/proerythroblast cell death. The cells that can more rapidly and effectively export heme or can slow heme synthesis preferentially survive and appropriately mature. Consistent with these observations, treatment with 10 μM succinylacetone, a specific inhibitor of heme synthesis, improved the erythroid cell output of DBA and del(5q) MDS marrow cultures by 68 to 95% (P = 0.03 to 0.05), whereas the erythroid cell output of concurrent control marrow cultures decreased by 4 to 13%. Our studies demonstrate that erythropoiesis fails when heme exceeds globin. Our data further suggest that therapies that decrease heme synthesis (or facilitate heme export) could improve the red blood cell production of persons with DBA, del(5q) MDS, and perhaps other macrocytic anemias.
Topics: Adult; Anemia; Anemia, Diamond-Blackfan; Anemia, Macrocytic; Erythroid Cells; Erythropoiesis; Female; Flow Cytometry; Globins; Heme; Humans; Myelodysplastic Syndromes; Reactive Oxygen Species
PubMed: 27169803
DOI: 10.1126/scitranslmed.aaf3006 -
Journal of General Internal Medicine Oct 2022
Topics: Anemia, Macrocytic; Folic Acid; Humans; Vitamin B 12 Deficiency
PubMed: 35194742
DOI: 10.1007/s11606-022-07451-2 -
Clinical Medicine & Research Sep 2006
Review
Topics: Anemia, Macrocytic; Anemia, Megaloblastic; Folic Acid Deficiency; Humans; Megaloblasts; Vitamin B 12 Deficiency
PubMed: 16988104
DOI: 10.3121/cmr.4.3.236 -
BMJ Case Reports Dec 2019Hypocupremia is a rare and under-recognised cause of bone marrow dysplasia and myeloneuropathy. A 47-year-old Caucasian woman had progressive ascending peripheral...
Hypocupremia is a rare and under-recognised cause of bone marrow dysplasia and myeloneuropathy. A 47-year-old Caucasian woman had progressive ascending peripheral neuropathy and gait ataxia over 3 months and fatigue, dyspnoea and unintentional weight loss over 8 months. She had profound macrocytic anaemia and neutropenia. Initial workup included normal serum vitamin B Bone marrow biopsy was suggestive of copper deficiency. Serum copper levels were later confirmed to be undetectable. The patient received oral copper repletion which resulted in complete normalisation of haematological abnormalities 16 weeks later. However, neurological deficits persisted. This case describes a delayed diagnosis of hypocupremia as initially suggested through invasive testing. Associating myeloneuropathy with cytopenia is imperative for accurate and prompt diagnosis of hypocupremia, which can be confirmed by serum analysis alone. Developing an accurate differential diagnosis can help prevent unnecessary procedures. Furthermore, initiating prompt copper repletion prevents further neurological impairment. Neurological deficits are often irreversible.
Topics: Anemia, Macrocytic; Bone Marrow; Copper; Dental Cements; Female; Gait Ataxia; Humans; Middle Aged; Neutropenia; Zinc
PubMed: 31796451
DOI: 10.1136/bcr-2019-230025 -
American Journal of Hematology Jan 2000Thymomas are often associated with autoimmune disorders. We report on a 45-year-old female patient with thymoma and hypogammaglobulinemia (Good's syndrome) who developed...
Thymomas are often associated with autoimmune disorders. We report on a 45-year-old female patient with thymoma and hypogammaglobulinemia (Good's syndrome) who developed symptomatic macrocytic anemia (Hb 4.4 g/dl, MCV 112 fl) and thrombocytosis (Plt 442 G/l). Besides hypogammaglobulinemia (IgG 589 mg/dl), an inverted ratio of CD4(+)/CD8(+) cells was seen. The bone marrow biopsy showed a slightly hypercellular bone marrow with normal granulopoiesis, normal megakaryopoiesis and a mild dyserythropoiesis without any ring-sideroblasts. The in-vitro stem cell culture from the bone marrow revealed an atypical growth of macroclusters, reduced BFU-E and CFU-GEMM colony growth, whereas the CFU-GM colony growth was within the normal range. The chromosomal analysis showed a normal karyotype. The plasma vitamin B(12) and folate levels were within normal ranges, and we could not detect any autoantibodies. These findings excluded the differential diagnoses pure red cell aplasia (PRCA) and pernicious anemia. After resection of the thymoma of mixed cell type, the macrocytic anemia and thrombocytosis disappeared. The clinical course was complicated by a cerebral palsy and a life-threatening fungal septicemia after surgery. In the third year after thymectomy, hyporegenerative macrocytic anemia and thrombocytosis reappeared and an immunosuppressive treatment with prednisolone (1 mg/kg BW) was started. After initiation of the prednisolone therapy, reticulocyte counts increased and macrocytic anemia as well as thrombocytosis disappeared. The normalization of these laboratory parameters during glucocorticoid therapy suggests that in rare cases the constellation of macrocytic anemia, thrombocytosis and hypogammaglobulinemia may be due to an underlying immunologic mechanism.
Topics: Agammaglobulinemia; Anemia, Macrocytic; Bone Marrow Cells; Cells, Cultured; Erythrocyte Indices; Female; Hematopoietic Stem Cells; Hemoglobins; Humans; Immunosuppressive Agents; Karyotyping; Middle Aged; Platelet Count; Prednisolone; Reticulocyte Count; Thrombocytosis; Thymoma; Thymus Neoplasms
PubMed: 10602167
DOI: 10.1002/(sici)1096-8652(200001)63:1<38::aid-ajh9>3.0.co;2-9 -
British Journal of Haematology Sep 1999
Topics: Aged; Anemia, Macrocytic; Chromosome Deletion; Chromosomes, Human, Pair 5; Female; Humans; Karyotyping; Syndrome
PubMed: 10519982
DOI: 10.1046/j.1365-2141.1999.106004841.x -
The Journal of Physiology Sep 2018Folate (folic acid) deficiency and mutations in folate-related genes in humans result in megaloblastic anaemia. Folate metabolism, which requires the enzyme methionine...
KEY POINTS
Folate (folic acid) deficiency and mutations in folate-related genes in humans result in megaloblastic anaemia. Folate metabolism, which requires the enzyme methionine synthase reductase (MTRR), is necessary for DNA synthesis and the transmission of one-carbon methyl groups for cellular methylation. In this study, we show that the hypomorphic Mtrr mutation in mice results in late-onset and sex-specific blood defects, including macrocytic anaemia, extramedullary haematopoiesis and lymphopenia. Notably, when either parent carries an Mtrr allele, blood phenotypes result in their genetically wildtype adult daughters, the effects of which are parent specific. Our data establish a new model for studying the mechanism of folate metabolism in macrocytic anaemia aetiology and suggest that assessing parental folate status might be important when diagnosing adult patients with unexplained anaemia.
ABSTRACT
The importance of the vitamin folate (also known as folic acid) in erythrocyte formation, maturation and/or longevity is apparent since folate deficiency in humans causes megaloblastic anaemia. Megaloblastic anaemia is a type of macrocytic anaemia whereby erythrocytes are enlarged and fewer in number. Folate metabolism is required for thymidine synthesis and one-carbon metabolism, though its specific role in erythropoiesis is not well understood. Methionine synthase reductase (MTRR) is a key enzyme necessary for the progression of folate metabolism since knocking down the Mtrr gene in mice results in hyperhomocysteinaemia and global DNA hypomethylation. We demonstrate here that abnormal folate metabolism in mice caused by Mtrr homozygosity leads to haematopoietic phenotypes that are sex and age dependent. Specifically, Mtrr female mice displayed macrocytic anaemia, which might be due to defective erythroid differentiation at the exclusion of haemolysis. This was associated with increased renal Epo mRNA expression, hypercellular bone marrow, and splenic extramedullary haematopoiesis. In contrast, the male response differed since Mtrr male mice were not anaemic but did display erythrocytic macrocytosis and lymphopenia. Regardless of sex, these phenotypes were late onset. Remarkably, we also show that when either parent carries an Mtrr allele, a haematological defect results in their adult wildtype daughters. However, the specific phenotype was dependent upon the sex of the parent. For instance, wildtype daughters of Mtrr females displayed normocytic anaemia. In contrast, wildtype daughters of Mtrr males exhibited erythrocytic microcytosis not associated with anaemia. Therefore, abnormal folate metabolism affects adult haematopoiesis in an age-, sex- and parent-specific manner.
Topics: Age Factors; Anemia, Megaloblastic; Animals; Cells, Cultured; Female; Ferredoxin-NADP Reductase; Folic Acid; Folic Acid Deficiency; Hematopoiesis; Homozygote; Male; Mice; Mice, Inbred C57BL; Sex Factors
PubMed: 30024025
DOI: 10.1113/JP276419 -
Scientific Reports Aug 2016Tribbles homolog 2 (Trib2) is a member of Tribbles protein pseudokinases and involves in apoptosis, autoimmunity, cancer, leukemia and erythropoiesis, however, the...
Tribbles homolog 2 (Trib2) is a member of Tribbles protein pseudokinases and involves in apoptosis, autoimmunity, cancer, leukemia and erythropoiesis, however, the physiological function of Trib2 in hematopoietic system remains to be elucidated. Here, we report that Trib2 knockout (KO) mice manifest macrocytic anemia and increase of T lymphocytes. Although Trib2 deficient RBCs have similar half-life as the control RBCs, Trib2 KO mice are highly vulnerable to oxidant-induced hemolysis. Endogenous Trib2 mRNA is expressed in early hematopoietic progenitors, erythroid precursors, and lymphoid lineages, but not in mature RBCs, myeloid progenitors and granulocytes. Consistently, flow cytometric analysis and in vitro colony forming assay revealed that deletion of Trib2 mainly affected erythroid lineage development, and had no effect on either granulocyte or megakaryocyte lineages in bone marrow. Furthermore, a genetic approach using double knockout of Trib2 and C/ebpα genes in mice suggested that Trib2 promotes erythropoiesis independent of C/ebpα proteins in vivo. Finally, ectopic expression of human Trib2 in zebrafish embryos resulted in increased expression of erythropoiesis-related genes and of hemoglobin. Taking all data together, our results suggest that Trib2 positively promotes early erythrocyte differentiation and is essential for tolerance to hemolysis.
Topics: Anemia, Macrocytic; Animals; Calcium-Calmodulin-Dependent Protein Kinases; Erythroid Precursor Cells; Erythropoiesis; Gene Expression Regulation; Hemolysis; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Protein Serine-Threonine Kinases; Zebrafish
PubMed: 27550848
DOI: 10.1038/srep31444 -
The American Journal of Clinical... Jan 2009It is not known whether the improved folate status from mandatory folic acid fortification had any impact on indexes and prevalence of anemias in the United States.
Hemoglobin and hematocrit values are higher and prevalence of anemia is lower in the post-folic acid fortification period than in the pre-folic acid fortification period in US adults.
BACKGROUND
It is not known whether the improved folate status from mandatory folic acid fortification had any impact on indexes and prevalence of anemias in the United States.
OBJECTIVE
We investigated trends in indexes and prevalence of anemia and macrocytosis with a focus on comparison of prefortification data with postfortification data.
DESIGN
Hemoglobin, hematocrit, mean corpuscular volume (MCV) and prevalences and likelihood of anemia and macrocytosis were determined for 26,596 adults examined in the National Health and Nutrition Examination Surveys, 1988-2004.
RESULTS
From 1988-1994 to 1999-2004, hemoglobin modestly but significantly improved from 15.1 to 15.4 g/dL (approximately 2.0%; P < 0.0001) and from 13.3 to 13.6 g/dL (approximately 2.3%; P < 0.0001) in men and women, respectively. There was a significant increase in MCV from 1988-1994 to 1999-2004 in men (from 90.2 to 90.7; P = 0.0123) and older (>60 y) men (from 91.6 to 92.4; P = 0.0105) and in women (from 90.7 to 91.4; P = 0.0141). Only in women was the prevalence of anemia significantly lower in 1999-2004 than in 1988-1994 (27.9% reduction; P = 0.0005). The odds of having anemia in the postfortification period relative to the prefortification period was 0.64 (95% CI: 0.54, 0.75; P < 0.0001) in women and 0.79 (95% CI: 0.62, 0.99; P < 0.0433) in men. In general, the prevalence of macrocytosis and the odds of having macrocytosis did not change significantly from 1988-1994 to 1999-2004.
CONCLUSION
The improvement in hemoglobin and the decreased prevalence of anemia from 1988-1994 to 1999-2004, especially in women, may be attributable to improved folate status, increased vitamin/mineral supplements use, and other unknown causes after the initiation of folic acid fortification. The cause of increased MCV in men, and in older persons of both sexes, warrants further investigation.
Topics: Adult; Anemia, Iron-Deficiency; Anemia, Macrocytic; Confidence Intervals; Erythrocyte Indices; Female; Folic Acid; Food, Fortified; Hematinics; Hematocrit; Hemoglobins; Humans; Likelihood Functions; Male; Middle Aged; Nutrition Surveys; Nutritional Status; Odds Ratio; Prevalence; Sex Factors; United States; Young Adult
PubMed: 19056553
DOI: 10.3945/ajcn.2008.26287 -
Seminars in Hematology Apr 2011A number of human disorders, dubbed ribosomopathies, are linked to impaired ribosome biogenesis or function. These include but are not limited to Diamond Blackfan anemia... (Review)
Review
A number of human disorders, dubbed ribosomopathies, are linked to impaired ribosome biogenesis or function. These include but are not limited to Diamond Blackfan anemia (DBA), Shwachman Diamond syndrome (SDS), and the 5q- myelodysplastic syndrome (MDS). This review focuses on the latter two non-DBA disorders of ribosome function. Both SDS and 5q- syndrome lead to impaired hematopoiesis and a predisposition to leukemia. SDS, due to bi-allelic mutations of the SBDS gene, is a multi-system disorder that also includes bony abnormalities, and pancreatic and neurocognitive dysfunction. SBDS associates with the 60S subunit in human cells and has a role in subunit joining and translational activation in yeast models. In contrast, 5q- syndrome is associated with acquired haplo-insufficiency of RPS14, a component of the small 40S subunit. RPS14 is critical for 40S assembly in yeast models, and depletion of RPS14 in human CD34(+) cells is sufficient to recapitulate the 5q- erythroid defect. Both SDS and the 5q- syndrome represent important models of ribosome function and may inform future treatment strategies for the ribosomopathies.
Topics: Anemia, Diamond-Blackfan; Anemia, Macrocytic; Bone Marrow Diseases; Chromosome Deletion; Chromosomes, Human, Pair 5; Exocrine Pancreatic Insufficiency; Humans; Lipomatosis; Ribosomes; Shwachman-Diamond Syndrome
PubMed: 21435510
DOI: 10.1053/j.seminhematol.2011.01.002