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Genes Aug 2022The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by anemia and the presence of ring sideroblasts in the bone marrow.... (Review)
Review
The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by anemia and the presence of ring sideroblasts in the bone marrow. Ring sideroblasts are abnormal erythroblasts with iron-loaded mitochondria that are visualized by Prussian blue staining as a perinuclear ring of green-blue granules. The mechanisms that lead to the ring sideroblast formation are heterogeneous, but in all of them, there is an abnormal deposition of iron in the mitochondria of erythroblasts. Congenital sideroblastic anemias include nonsyndromic and syndromic disorders. Acquired sideroblastic anemias include conditions that range from clonal disorders (myeloid neoplasms as myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms with ring sideroblasts) to toxic or metabolic reversible sideroblastic anemia. In the last 30 years, due to the advances in genomic techniques, a deep knowledge of the pathophysiological mechanisms has been accomplished and the bases for possible targeted treatments have been established. The distinction between the different forms of sideroblastic anemia is based on the study of the characteristics of the anemia, age of diagnosis, clinical manifestations, and the performance of laboratory analysis involving genetic testing in many cases. This review focuses on the differential diagnosis of acquired disorders associated with ring sideroblasts.
Topics: Anemia, Sideroblastic; Humans; Iron; Mutation; Myelodysplastic Syndromes; Neoplasms
PubMed: 36140729
DOI: 10.3390/genes13091562 -
Mediterranean Journal of Hematology and... 2022
PubMed: 36119458
DOI: 10.4084/MJHID.2022.067 -
Scientific Reports Aug 2022Acquired sideroblastic anemia, characterized by bone marrow ring sideroblasts (RS), is predominantly associated with myelodysplastic syndrome (MDS). Although somatic...
Acquired sideroblastic anemia, characterized by bone marrow ring sideroblasts (RS), is predominantly associated with myelodysplastic syndrome (MDS). Although somatic mutations in splicing factor 3b subunit 1 (SF3B1), which is involved in the RNA splicing machinery, are frequently found in MDS-RS, the detailed mechanism contributing to RS formation is unknown. To explore the mechanism, we established human umbilical cord blood-derived erythroid progenitor-2 (HUDEP-2) cells stably expressing SF3B1. SF3B1 expressing cells showed higher proportion of RS than the control cells along with erythroid differentiation, indicating the direct contribution of mutant SF3B1 expression in erythroblasts to RS formation. In SF3B1 expressing cells, ABCB7 and ALAS2, known causative genes for congenital sideroblastic anemia, were downregulated. Additionally, mis-splicing of ABCB7 was observed in SF3B1 expressing cells. ABCB7-knockdown HUDEP-2 cells revealed an increased frequency of RS formation along with erythroid differentiation, demonstrating the direct molecular link between ABCB7 defects and RS formation. ALAS2 protein levels were obviously decreased in ABCB7-knockdown cells, indicating decreased ALAS2 translation owing to impaired Fe-S cluster export by ABCB7 defects. Finally, RNA-seq analysis of MDS clinical samples demonstrated decreased expression of ABCB7 by the SF3B1 mutation. Our findings contribute to the elucidation of the complex mechanisms of RS formation in MDS-RS.
Topics: 5-Aminolevulinate Synthetase; Anemia, Sideroblastic; Humans; Mutation; Myelodysplastic Syndromes; Phosphoproteins; RNA Splicing Factors
PubMed: 36028755
DOI: 10.1038/s41598-022-18921-2 -
Journal of Clinical Immunology Jan 2023Sideroblastic anaemia with B-cell immunodeficiency, periodic fever and developmental delay (SIFD) syndrome is a novel rare autoinflammatory multisystem disorder. We... (Review)
Review
BACKGROUND AND PURPOSE
Sideroblastic anaemia with B-cell immunodeficiency, periodic fever and developmental delay (SIFD) syndrome is a novel rare autoinflammatory multisystem disorder. We performed a systematic review of the available clinical and therapeutics aspects of the SIFD syndrome.
METHODS
A systematic review according to PRISMA approach, including all articles published before the 30 of July 2021 in Pubmed and EMBASE database, was performed.
RESULTS
The search identified 29 publications describing 58 unique patients. To date, 41 unique mutations have been reported. Onset of disease is very early with a median age of 4 months (range 0-252 months). The most frequent manifestations are haematologic such as microcytic anaemia or sideroblastic anaemia (55/58), recurrent fever (52/58), neurologic abnormalities (48/58), immunologic abnormalities in particular a humoral immunodeficiency (48/58), gastrointestinal signs and symptoms (38/58), eye diseases as cataract and retinitis pigmentosa (27/58), failure to thrive (26/58), mucocutaneous involvement (29/58), sensorineural deafness (19/58) and others. To date, 19 patients (35.85%) died because of disease course (16) and complications of hematopoietic cell stems transplantation (3). The use of anti-TNFα and hematopoietic cell stems transplantation (HCST) is dramatically changing the natural history of this disease.
CONCLUSIONS
SIFD syndrome is a novel entity to consider in a child presenting with recurrent fever, anaemia, B-cell immunodeficiency and neurodevelopmental delay. To date, therapeutic guidelines are lacking but anti-TNFα treatment and/or HCST are attractive and might modify the clinical course of this syndrome.
Topics: Child; Humans; Anemia, Sideroblastic; Immunologic Deficiency Syndromes; Fever; Mutation; Developmental Disabilities
PubMed: 35984545
DOI: 10.1007/s10875-022-01343-0 -
Cureus Jul 2022We report a case of a 59-year-old male who developed pancytopenia and multiorgan failure attributed to copper deficiency from exogenous consumption of zinc tablets....
We report a case of a 59-year-old male who developed pancytopenia and multiorgan failure attributed to copper deficiency from exogenous consumption of zinc tablets. During the six months preceding his presentation, he had experienced increasing shortness of breath, lightheadedness, and fatigue. Laboratory studies revealed pancytopenia with profound anemia (hemoglobin level 2.8 g/dL) along with evidence of acute kidney injury and acute heart failure; the patient was presumed to have multiorgan failure due to profound anemia. Bone marrow biopsy revealed dyspoiesis suggestive of myelodysplastic syndrome (MDS). There were no cytogenetic abnormalities observed. However, the blood workup analysis found low copper and ceruloplasmin levels, whereas zinc levels were excessively elevated (257 mg/dL). Upon inquiry, the patient reported taking an over-the-counter zinc supplement of an unknown quantity for over a year. After two months of copper treatment, his blood count returned to normal. This case highlights a rare presentation of zinc-induced copper deficiency resulting in pancytopenia and severe anemia-related multiorgan failure. A growing number of hematological disorders are being linked to copper deficiency. Copper deficiency pancytopenia is a reversible condition that often goes unnoticed and can be misdiagnosed as MDS because it has similar hematological characteristics.
PubMed: 35971347
DOI: 10.7759/cureus.26789 -
Cureus Jul 2022Pyridoxine deficiency is a rare but identifiable cause of sideroblastic anemia, depression, and peripheral neuropathy. Platinum-based chemotherapeutic drugs display...
Pyridoxine deficiency is a rare but identifiable cause of sideroblastic anemia, depression, and peripheral neuropathy. Platinum-based chemotherapeutic drugs display structural similarity to pyridoxine, which interferes with the absorption and hence the efficacy of the drug. If left untreated, it can lead to irreversible axonal loss and permanent deficits, leading to falls. Our case is a highly unusual scenario of isolated pyridoxine deficiency presenting as peripheral neuropathy and depression as a delayed side effect of chemotherapeutic drugs.
PubMed: 35967133
DOI: 10.7759/cureus.26725 -
Diagnostics (Basel, Switzerland) Jul 2022Ring sideroblasts are commonly seen in myelodysplastic neoplasms and are a key condition for identifying distinct entities of myelodysplastic neoplasms according to the... (Review)
Review
Ring sideroblasts are commonly seen in myelodysplastic neoplasms and are a key condition for identifying distinct entities of myelodysplastic neoplasms according to the WHO classification. However, the presence of ring sideroblasts is not exclusive to myelodysplastic neoplasms. Ring sideroblasts are as well either encountered in non-clonal secondary acquired disorders, such as exposure to toxic substances, drug/medicine, copper deficiency, zinc overload, lead poison, or hereditary sideroblastic anemias related to X-linked, autosomal, or mitochondrial mutations. This review article will discuss diseases associated with ring sideroblasts outside the context of myelodysplastic neoplasms. Knowledge of the differential diagnoses characterized by the presence of ring sideroblasts in bone marrow is essential to prevent any misdiagnosis, which leads to delayed diagnosis and subsequent management of patients that differ in the different forms of sideroblastic anemia.
PubMed: 35885655
DOI: 10.3390/diagnostics12071752 -
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 -
Internal Medicine (Tokyo, Japan) Dec 2022Vitamin B6 (VB6) is essential to heme synthesis, and its deficiency can lead to anemia. VB6 deficiency anemia is typically microcytic, hypochromic, and sideroblastic....
Vitamin B6 Deficiency Anemia Attributed to Levodopa/Carbidopa Intestinal Gel Therapy for Parkinson's Disease: A Diagnostic Pitfall for Myelodysplastic Syndrome with Ring Sideroblasts.
Vitamin B6 (VB6) is essential to heme synthesis, and its deficiency can lead to anemia. VB6 deficiency anemia is typically microcytic, hypochromic, and sideroblastic. VB6 deficiency is a well-recognized complication of levodopa/carbidopa therapy, as metabolism of levodopa to dopamine is VB6-dependent, and carbidopa irreversibly forms bonds and deactivates VB6. We herein report a 75-year-old man with advanced Parkinson's disease who developed severe VB6 deficiency anemia due to levodopa/carbidopa intestinal gel therapy. His anemia was promptly resolved with simple oral supplementation of pyridoxal phosphate hydrate. VB6 deficiency anemia can mimic myelodysplastic syndrome and thus is an important differential diagnosis for patients administered levodopa/carbidopa.
Topics: Male; Humans; Aged; Carbidopa; Levodopa; Parkinson Disease; Vitamin B 6 Deficiency; Anemia; Vitamin B 6; Pyridoxine; Drug Combinations; Myelodysplastic Syndromes; Antiparkinson Agents; Gels
PubMed: 35569990
DOI: 10.2169/internalmedicine.9577-22 -
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