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Blood Jan 2019The sideroblastic anemias (SAs) are a group of inherited and acquired bone marrow disorders defined by pathological iron accumulation in the mitochondria of erythroid... (Review)
Review
The sideroblastic anemias (SAs) are a group of inherited and acquired bone marrow disorders defined by pathological iron accumulation in the mitochondria of erythroid precursors. Like most hematological diseases, the molecular genetic basis of the SAs has ridden the wave of technology advancement. Within the last 30 years, with the advent of positional cloning, the human genome project, solid-state genotyping technologies, and next-generation sequencing have evolved to the point where more than two-thirds of congenital SA cases, and an even greater proportion of cases of acquired clonal disease, can be attributed to mutations in a specific gene or genes. This review focuses on an analysis of the genetics of these diseases and how understanding these defects may contribute to the design and implementation of rational therapies.
Topics: Anemia, Sideroblastic; Erythroid Precursor Cells; Genetic Diseases, X-Linked; Humans; Iron
PubMed: 30401706
DOI: 10.1182/blood-2018-08-815951 -
Journal of Blood Medicine 2020Sideroblastic anemia (SA) consists of a group of inherited and acquired anemias of ineffective erythropoiesis characterized by the accumulation of ring sideroblasts in... (Review)
Review
Sideroblastic anemia (SA) consists of a group of inherited and acquired anemias of ineffective erythropoiesis characterized by the accumulation of ring sideroblasts in the bone marrow due to disrupted heme biosynthesis. Congenital sideroblastic anemia (CSA) is rare and has three modes of inheritance: X-linked (XLSA), autosomal recessive (ARCSA), and maternal. Acquired SA is more common and can be a result of myelodysplastic syndromes (MDS) or other, generally reversible causes. The diagnostic approach to SA includes a work-up for reversible causes and genetic testing for CSA based on clinical suspicion, family history and genetic pedigree. The treatment of SA depends on the underlying etiology but remains primarily supportive with vitamin B6 supplementation for select cases of XLSA, thiamine for thiamine-responsive megaloblastic anemia subtype, red blood cell transfusions for symptomatic patients and iron chelation therapy for iron overload. The management of anemia in MDS subtypes with ring sideroblasts remains unique and includes the recently approved erythroid maturation agent, Luspatercept. Although there is currently no curative therapy for CSA, anecdotal reports of hematopoietic stem cell transplant demonstrate remissions in selective, non-syndromic cases. This review summarizes the genetics, pathophysiology, diagnosis and treatment of SA for general practitioners and clinical hematologists.
PubMed: 33061728
DOI: 10.2147/JBM.S232644 -
Metabolites Aug 2022Given its remarkable property to easily switch between different oxidative states, iron is essential in countless cellular functions which involve redox reactions. At... (Review)
Review
Given its remarkable property to easily switch between different oxidative states, iron is essential in countless cellular functions which involve redox reactions. At the same time, uncontrolled interactions between iron and its surrounding milieu may be damaging to cells and tissues. Heme-the iron-chelated form of protoporphyrin IX-is a macrocyclic tetrapyrrole and a coordination complex for diatomic gases, accurately engineered by evolution to exploit the catalytic, oxygen-binding, and oxidoreductive properties of iron while minimizing its damaging effects on tissues. The majority of the body production of heme is ultimately incorporated into hemoglobin within mature erythrocytes; thus, regulation of heme biosynthesis by iron is central in erythropoiesis. Additionally, heme is a cofactor in several metabolic pathways, which can be modulated by iron-dependent signals as well. Impairment in some steps of the pathway of heme biosynthesis is the main pathogenetic mechanism of two groups of diseases collectively known as porphyrias and congenital sideroblastic anemias. In porphyrias, according to the specific enzyme involved, heme precursors accumulate up to the enzyme stop in disease-specific patterns and organs. Therefore, different porphyrias manifest themselves under strikingly different clinical pictures. In congenital sideroblastic anemias, instead, an altered utilization of mitochondrial iron by erythroid precursors leads to mitochondrial iron overload and an accumulation of ring sideroblasts in the bone marrow. In line with the complexity of the processes involved, the role of iron in these conditions is then multifarious. This review aims to summarise the most important lines of evidence concerning the interplay between iron and heme metabolism, as well as the clinical and experimental aspects of the role of iron in inherited conditions of altered heme biosynthesis.
PubMed: 36144223
DOI: 10.3390/metabo12090819 -
Research in Microbiology 2001In contrast to bacteria, mitochondria contain only a few ATP binding cassette (ABC) transporters in their inner membrane. The known mitochondrial ABC proteins fall into... (Review)
Review
In contrast to bacteria, mitochondria contain only a few ATP binding cassette (ABC) transporters in their inner membrane. The known mitochondrial ABC proteins fall into two major classes that, in the yeast Saccharomyces cerevisiae, are represented by the half-transporter Atm1p and the two closely homologous proteins Mdl1p and Mdl2p. In humans two Atm1p orthologues (ABC7 and MTABC3) and two proteins homologous to Mdll/2p have been localized to mitochondria. The Atm1p-like proteins perform an important function in mitochondrial iron homeostasis and in the maturation of Fe/S proteins in the cytosol. Mutations in ABC7 are causative of hereditary X-linked sideroblastic anemia and cerebellar ataxia (XLSA/A). MTABC3 may be a candidate gene for the lethal neonatal syndrome. The function of the mitochondrial Mdl1/2p-like proteins is not clear at present with the notable exception of murine ABC-me that may transport intermediates of heme biosynthesis from the matrix to the cytosol in erythroid tissues.
Topics: ATP-Binding Cassette Transporters; Animals; DEAD-box RNA Helicases; Eukaryotic Cells; Fungal Proteins; Humans; Iron; Mammals; Mitochondria; RNA Helicases; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Sequence Deletion
PubMed: 11421280
DOI: 10.1016/s0923-2508(01)01204-9 -
Cureus Oct 2022A 57-year-old gentleman presented to the hospital with progressive fatigue and dyspnea on exertion three months after recovering from COVID-19. He was noted to have...
A 57-year-old gentleman presented to the hospital with progressive fatigue and dyspnea on exertion three months after recovering from COVID-19. He was noted to have severe anemia with reticulocytopenia. After excluding vitamin deficiencies and heavy metal toxicities, a bone marrow aspirate and biopsy were performed, which showed erythroid predominant trilineage maturing hematopoiesis with 79% ring sideroblasts and no dysplasia. SF3B1 mutation was negative. He was diagnosed with sideroblastic anemia and became transfusion-dependent. He was treated with an erythropoiesis-stimulating agent and luspatercept with transient improvement in anemia. After 12 months of treatment, anemia spontaneously improved. Repeat bone marrow biopsy showed hypercellular marrow with 39% ringed sideroblasts. We suspect that this possibly was a delayed manifestation of COVID-19 infection.
PubMed: 36258806
DOI: 10.7759/cureus.30275 -
Molecular Genetics and Metabolism... Dec 2019Mitochondrial myopathy, lactic acidosis and sideroblastic anemia 1 (MLASA1) is a rare disease caused by biallelic pathogenic variants in the gene. There are eleven... (Review)
Review
Mitochondrial myopathy, lactic acidosis and sideroblastic anemia 1 (MLASA1) is a rare disease caused by biallelic pathogenic variants in the gene. There are eleven MLASA1 patients reported worldwide with the majority of the patients originating from the Shiraz region of Iran. The rarity of this disease poses challenges to counseling patients due to a lack of natural history data. This report reviews what is known regarding MLASA1 and describes two brothers with MLASA1 who were cared for over the course of 10 years at the University of California Los Angeles. The brothers suffered from chronic anemia, transfusion dependency and muscle wasting that lead to respiratory insufficiency and death in one of the brothers.
PubMed: 31641589
DOI: 10.1016/j.ymgmr.2019.100517 -
Haematologica Jun 2011
Topics: Anemia, Sideroblastic; Erythroblasts; Humans
PubMed: 21632840
DOI: 10.3324/haematol.2011.044628 -
Clinical Case Reports Jan 2023Sideroblastic anemia is a heterogeneous group of disorders typified by the presence of ring sideroblasts in the bone marrow and has congenital and acquired types....
Sideroblastic anemia is a heterogeneous group of disorders typified by the presence of ring sideroblasts in the bone marrow and has congenital and acquired types. Sideroblastic anemia is a rare event in pregnancy. We report a case of a 32-year-old female patient, gravida 4 para 3, 27th weeks pregnant, who presented to the emergency department complaining of palpitation and generalized weakness for 2 weeks. She was found to have severe normochromic normocytic anemia, with hemoglobin of 4.2 g/dl, and low reticulocytes count of 13 × 10/μl. She gave a history of recurrent anemia, which had only occurred during pregnancy. Her bone marrow aspirate showed many ring sideroblasts concluding the diagnosis of sideroblastic anemia (SA). Further investigation revealed a significantly low pyridoxine level (vitamin B6) of (8 nmol/L). The Hb level improved with vitamin B6 replacement, without any transfusion support.
PubMed: 36644616
DOI: 10.1002/ccr3.6814 -
Blood Oct 2020
Topics: Aged, 80 and over; Anemia, Sideroblastic; Arteriosclerosis; Biopsy; Blood Transfusion; Blood Vessels; Bone Marrow; Deferasirox; Female; Humans; Iron; Iron Overload; Metals, Heavy; Myelodysplastic-Myeloproliferative Diseases; Thrombocytosis; Transfusion Reaction; Treatment Failure
PubMed: 33091139
DOI: 10.1182/blood.2020007779