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Haematologica Dec 2018variants have previously been described in patients with myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2). encodes the mitochondrial tyrosyl-tRNA...
variants have previously been described in patients with myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2). encodes the mitochondrial tyrosyl-tRNA synthetase, which is responsible for conjugating tyrosine to its cognate mt-tRNA for mitochondrial protein synthesis. Here we describe 14 individuals from 11 families presenting with sideroblastic anemia and variants that we identified using a sideroblastic anemia gene panel or exome sequencing. The phenotype of these patients ranged from MLASA to isolated congenital sideroblastic anemia. As in previous cases, inter- and intra-familial phenotypic variability was observed, however, this report includes the first cases with isolated sideroblastic anemia and patients with biallelic variants that have no clinically ascertainable phenotype. We identified ten novel variants and three previously reported variants. amino-acylation assays of five novel missense variants showed that three had less effect on the catalytic activity of YARS2 than the most commonly reported variant, p.(Phe52Leu), associated with MLASA2, which may explain the milder phenotypes in patients with these variants. However, the other two missense variants had a more severe effect on YARS2 catalytic efficiency. Several patients carried the common c.572 G>T, p.(Gly191Val) variant (minor allele frequency =0.1259) in with a rare deleterious variant. We have previously shown that the p.(Gly191Val) variant reduces YARS2 catalytic activity. Consequently, we suggest that biallelic variants, including severe loss-of-function alleles in of the common p.(Gly191Val) variant, should be considered as a cause of isolated congenital sideroblastic anemia, as well as the MLASA syndromic phenotype.
Topics: Acidosis, Lactic; Adolescent; Anemia, Sideroblastic; Female; Genetic Association Studies; Genetic Diseases, X-Linked; Germ-Line Mutation; Humans; Infant; MELAS Syndrome; Male; Middle Aged; Mitochondrial Proteins; Mutation, Missense; Tyrosine-tRNA Ligase; Young Adult
PubMed: 30026338
DOI: 10.3324/haematol.2017.182659 -
Biochimica Et Biophysica Acta.... May 2021Previous reports revealed that mutation of mitochondrial inner-membrane located protein SFXN1 led to pleiotropic hematological and skeletal defects in mice, associated...
Previous reports revealed that mutation of mitochondrial inner-membrane located protein SFXN1 led to pleiotropic hematological and skeletal defects in mice, associated with the presence of hypochromic erythroid cell, iron overload in mitochondrion of erythroblast and the development of sideroblastic anemia (SA). However, the potential role of sfxn1 during erythrocyte differentiation and the development of anemia, especially the pathological molecular mechanism still remains elusive. In this study, the correlation between sfxn1 and erythroid cell development is explored through zebrafish in vivo coupled with human hematopoietic cells assay ex vivo. Both knockdown and knockout of sfxn1 result in hypochromic anemia phenotype in zebrafish. Further analyses demonstrate that the development of anemia attributes to the biosynthetic deficiency of hemoglobin, which is caused by the biosynthetic disorder of heme that associates with one‑carbon (1C) metabolism process of mitochondrial branch in erythrocyte. Sfxn1 is also involved in the differentiation and maturation of erythrocyte in inducible human umbilical cord blood stem cells. In addition, we found that functional disruption of sfxn1 causes hypochromic anemia that is distinct from SA. These findings reveal that sfxn1 is genetically conserved and essential for the maturation of erythrocyte via facilitating the production of hemoglobin, which may provide a possible guidance for the future clinical treatment of sfxn1 mutation associated hematological disorders.
Topics: Anemia; Animals; Cell Differentiation; Embryo, Nonmammalian; Erythrocytes; Erythropoiesis; Hemoglobins; Mutation; Phenotype; Sodium-Glucose Transporter 1; Zebrafish; Zebrafish Proteins
PubMed: 33524530
DOI: 10.1016/j.bbadis.2021.166096 -
Biomedical Reports May 2017The aim of the present review was to summarize and discuss previous findings concerning renal manifestations of primary mitochondrial disorders (MIDs). A literature...
The aim of the present review was to summarize and discuss previous findings concerning renal manifestations of primary mitochondrial disorders (MIDs). A literature review was performed using frequently used databases. The study identified that primary MIDs frequently present as mitochondrial multiorgan disorder syndrome (MIMODS) at onset or in the later course of the MID. Occasionally, the kidneys are affected in MIDs. Renal manifestations of MIDs include renal insufficiency, nephrolithiasis, nephrotic syndrome, renal cysts, renal tubular acidosis, Bartter-like syndrome, Fanconi syndrome, focal segmental glomerulosclerosis, tubulointerstitial nephritis, nephrocalcinosis, and benign or malign neoplasms. Among the syndromic MIDs, renal involvement has been most frequently reported in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome, Kearns-Sayre syndrome, Leigh syndrome and mitochondrial depletion syndromes. Only in single cases was renal involvement also reported in chronic progressive external ophthalmoplegia, Pearson syndrome, Leber's hereditary optic neuropathy, coenzyme-Q deficiency, X-linked sideroblastic anemia and ataxia, myopathy, lactic acidosis, and sideroblastic anemia, pyruvate dehydrogenase deficiency, growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death, and hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis syndrome. The present study proposes that the frequency of renal involvement in MIDs is probably underestimated. Diagnosis of renal involvement follows general guidelines and treatment is symptomatic. Thus, renal manifestations of primary MIDs require recognition and appropriate management, as they determine the outcome of MID patients.
PubMed: 28515908
DOI: 10.3892/br.2017.892 -
Stem Cell Research & Therapy Dec 2012Erythrocytes contain oxygen-carrying hemoglobin to all body cells. Impairments in the generation of erythrocytes, a process known as erythropoiesis, or in hemoglobin... (Review)
Review
Erythrocytes contain oxygen-carrying hemoglobin to all body cells. Impairments in the generation of erythrocytes, a process known as erythropoiesis, or in hemoglobin synthesis alter cell function because of decreased oxygen supply and lead to anemic diseases. Thus, understanding how erythropoiesis is regulated during embryogenesis and adulthood is important to develop novel therapies for anemia. The zebrafish, Danio rerio, provides a powerful model for such study. Their small size and the ability to generate a large number of embryos enable large-scale analysis, and their transparency facilitates the visualization of erythroid cell migration. Importantly, the high conservation of hematopoietic genes among vertebrates and the ability to successfully transplant hematopoietic cells into fish have enabled the establishment of models of human anemic diseases in fish. In this review, we summarize the current progress in our understanding of erythropoiesis on the basis of zebrafish studies and highlight fish models of human anemias. These analyses could enable the discovery of novel drugs as future therapies.
Topics: Anemia; Anemia, Dyserythropoietic, Congenital; Anemia, Hypochromic; Anemia, Sideroblastic; Animals; Ankyrins; Cation Transport Proteins; Disease Models, Animal; Erythrocytes; Erythropoiesis; Genetic Diseases, X-Linked; Hemochromatosis; Spherocytosis, Hereditary; Zebrafish
PubMed: 23257067
DOI: 10.1186/scrt146 -
American Journal of Medical Genetics.... Jul 2022Myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2) is an autosomal recessive mitochondrial disorder caused by pathogenic variants in YARS2. YARS2 variants...
Decompensation of cardiorespiratory function and emergence of anemia during pregnancy in a case of mitochondrial myopathy, lactic acidosis, and sideroblastic anemia 2 with compound heterozygous YARS2 pathogenic variants.
Myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2) is an autosomal recessive mitochondrial disorder caused by pathogenic variants in YARS2. YARS2 variants confer heterogeneous phenotypes ranging from the full MLASA syndrome to a clinically unaffected state. Symptom onset is most common in the first decade of life but can occur in adulthood and has been reported following intercurrent illness. Early death can result from respiratory muscle weakness and cardiomyopathy. We report a case of MLASA2 with compound heterozygous YARS2 pathogenic variants; a known pathogenic nonsense variant [NM_001040436.3:c.98C>A (p.Ser33Ter)] and a likely pathogenic missense variant not previously associated with disease [NM_001040436.3:c.948G>T (p.Arg316Ser)]. The proband initially presented with a relatively mild phenotype of myopathy and lactic acidosis. During pregnancy, anemia emerged as an additional feature and in the postpartum period she experienced severe decompensation of cardiorespiratory function. This is the first reported case of pregnancy-related complications in a patient with YARS2-related mitochondrial disease. This case highlights the need for caution and careful counseling when considering pregnancy in mitochondrial disease, due to the risk of disease exacerbation and pregnancy complications.
Topics: Acidosis, Lactic; Adult; Anemia, Sideroblastic; Female; Humans; Mitochondrial Myopathies; Muscular Diseases; Pregnancy; Tyrosine-tRNA Ligase
PubMed: 35393742
DOI: 10.1002/ajmg.a.62755 -
Indian Journal of Hematology & Blood... Jul 2020Anemia associated with alcoholism has numerous causes, most common being megaloblastic anemia and acquired sideroblastic anemia (SA). The bone marrow aspirate (BMA) and...
Anemia associated with alcoholism has numerous causes, most common being megaloblastic anemia and acquired sideroblastic anemia (SA). The bone marrow aspirate (BMA) and bone marrow iron (BMIr) findings and their correlation with peripheral blood smear (PBS) have not been extensively described in literature. We aim to study the spectrum of hematological abnormalities in chronic alcoholics. Complete blood count (CBC), PBS, BMA and BMIr of 71 chronic alcoholics were studied retrospectively over a period of 3 years. The slides were reviewed by 2 pathologists. The clinical history, CBC, PBS, BMA and BMIr findings were recorded. Out of 71 patients, 68 (95.77%) had anaemia. Red cell morphology varied from normocytic-normochromic, microcytic-hypochromic, macrocytic, to dimorphic anaemia. Principal findings seen on BMA were erythroid hyperplasia and megaloblastic maturation. BMIr was available in 41 patients; iron stores were decreased in 2 (4.88%), normal in 14 (34.15%), increased in 25 (60.97%). Seven (17.07%) cases showed presence of ring sideroblasts. Chronic alcoholics show a variety of abnormalities in BMA, which closely mimic many haematological disorders. A history of alcoholism should always be taken in these circumstances. SA should be ruled out in all chronic alcoholics with anaemia not responding to vitamin B/folic acid, even with macrocytic picture on PBS.
PubMed: 32647433
DOI: 10.1007/s12288-019-01188-5 -
Scientific Reports May 2022X-linked sideroblastic anemia (XLSA), the most common form of congenital sideroblastic anemia, is caused by a germline mutation in the erythroid-specific...
X-linked sideroblastic anemia (XLSA), the most common form of congenital sideroblastic anemia, is caused by a germline mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene. In XLSA, defective heme biosynthesis leads to ring sideroblast formation because of excess mitochondrial iron accumulation. In this study, we introduced ALAS2 missense mutations on human umbilical cord blood-derived erythroblasts; hereafter, we refer to them as XLSA clones. XLSA clones that differentiated into mature erythroblasts showed an increased frequency of ring sideroblast formation with impaired hemoglobin biosynthesis. The expression profiling revealed significant enrichment of genes involved in ferroptosis, which is a form of regulated cell death induced by iron accumulation and lipid peroxidation. Notably, treatment with erastin, a ferroptosis inducer, caused a higher proportion of cell death in XLSA clones. XLSA clones exhibited significantly higher levels of intracellular lipid peroxides and enhanced expression of BACH1, a regulator of iron metabolism and potential accelerator of ferroptosis. In XLSA clones, BACH1 repressed genes involved in iron metabolism and glutathione synthesis. Collectively, defective heme biosynthesis in XLSA clones could confer enhanced BACH1 expression, leading to increased susceptibility to ferroptosis. The results of our study provide important information for the development of novel therapeutic targets for XLSA.
Topics: 5-Aminolevulinate Synthetase; Anemia, Sideroblastic; Erythroblasts; Ferroptosis; Genetic Diseases, X-Linked; Heme; Humans; Iron; Mutation
PubMed: 35637209
DOI: 10.1038/s41598-022-12940-9 -
American Journal of Hematology Aug 2023
Topics: Humans; Myelodysplastic Syndromes; Anemia, Sideroblastic; Activin Receptors, Type II; Immunoglobulin Fc Fragments
PubMed: 37222267
DOI: 10.1002/ajh.26960 -
American Journal of Hematology Apr 2019Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include... (Review)
Review
DISEASE OVERVIEW
Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T).
DIAGNOSIS
MDS-RS is a lower-risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥ 15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥450 × 10(9)/L and large atypical megakaryocytes.
MUTATIONS AND KARYOTYPE
Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations. Cytogenetic abnormalities are uncommon in both.
RISK STRATIFICATION
Most patients with MDS-RS-SLD are stratified into lower-risk groups by the revised-IPSS. Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic transformation.
TREATMENT
Anemia and iron overload are complications seen in both and are managed similar to lower-risk MDS and MPN. The advent of luspatercept, a first-in-class erythroid maturation agent will tremendously boost the ability to manage anemia. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs remains uncertain.
Topics: Anemia, Refractory; Anemia, Sideroblastic; Erythroblasts; Female; Humans; Iron Overload; Male; Mutation; Myelodysplastic-Myeloproliferative Diseases; Thrombocytosis
PubMed: 30618061
DOI: 10.1002/ajh.25397 -
Frontiers in Pediatrics 2021X-linked sideroblastic anemia with ataxia (XLSA/A) is a rare X-liked inherited disease, which was linked to the ABCB7 gene mutations. So far, five families have been...
X-linked sideroblastic anemia with ataxia (XLSA/A) is a rare X-liked inherited disease, which was linked to the ABCB7 gene mutations. So far, five families have been reported worldwide. We present the first Chinese family of XLSA/A with novel ABCB7 gene mutation (c.2024A > G) and make a retrospective literature review. All affected patients were male. Age of symptom onset was <2 years old. The main symptoms included ataxia, delay in motor development, and mild sideroblastic anemia with obviously increased erythrocyte protoporphyrin. In this case, he had new symptoms that had not been reported in other cases such as epilepsy and cryptorchidism. We also discuss the possible molecular mechanism linking ABCB7 gene mutations to sideroblastic anemia and ataxia.
PubMed: 34354969
DOI: 10.3389/fped.2021.692459