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1
Rodriguez-Sevilla, Juan Jose, Xavier Calvo, and Leonor Arenillas. "Causes and Pathophysiology of Acquired Sideroblastic Anemia." Genes 13, no. 9 (August 30, 2022): 1562. http://dx.doi.org/10.3390/genes13091562.
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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.
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Bakshi, NasirA, and Yasmeen Abulkhair. "Transfusion dependent congenital sideroblastic anemia." Journal of Applied Hematology 4, no. 4 (2013): 160. http://dx.doi.org/10.4103/1658-5127.127906.
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Caliskan, Umran, Huseyin Tokgoz, and Hasan Yuksekkaya. "A NOVEL Mutation of the Erythroid-Specific Aminolevulinate Synthase 2 Gene IN A Patient with Pyridoxine Responsive Sideroblastic Anemia and Deferasirox Responsive Hemochromatosis." Blood 114, no. 22 (November 20, 2009): 5105. http://dx.doi.org/10.1182/blood.v114.22.5105.5105.
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Abstract Abstract 5105 A-14 years-old man, admitted to our clinic with weakness and paleness since one month. He has hepatosplenomegaly. Blood tests and peripheral blood smear showed anemia that severe hypochromic, microcytic anemia. There is ringed sideroblasts without dysplastic hematopoiesis in bone marrow cytology. Liver tests were normal. A liver biopsy showed heavy parenchymal iron deposition and grade-III fibrosis. Screening for HFE gene mutations was negative. MR imaging demonstrated that severe iron accumulation in liver and heart. ALAS2 gene screening showed that novel mutation in exon 7 (Gly390Gly, c.1170, C□T). Eventually, was diagnosed as sideroblastic anemia and hemochromatosis. He was treated successfully with pyridoxine and chelating agent (deferasirox, IGL-670). The findings suggest that the Gly390Gly in ALAS2 mutation causes sideroblastic anemia and hemochromatosis, without hereditary hemochromatosis gene mutations. This mutation cause sideroblastic anemia is clinically pyridoxine-responsive. Deferasirox is effective agent for reduce hepatic iron loading in this condition. Disclosures Off Label Use: deferasiroks was used for hemochromatosis secondary to congenital syderoblastic anemia.
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Abu-Zeinah, Ghaith, Maria T. DeSancho, Mustafa Al-Kawaaz, and Julia Geyer. "Delayed diagnosis of congenital sideroblastic anemia." Seminars in Hematology 55, no. 4 (October 2018): 177–78. http://dx.doi.org/10.1053/j.seminhematol.2017.09.001.
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Hanina, Sophie, Barbara J. Bain, Barnaby Clark, and D. Mark Layton. "Congenital sideroblastic anemia in a female." American Journal of Hematology 93, no. 9 (August 7, 2018): 1181–82. http://dx.doi.org/10.1002/ajh.25196.
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Gupta, SanjeevKumar, Seema Rao, Rakhee Kar, Seema Tyagi, and HaraPrasad Pati. "Congenital sideroblastic anemia: A report of two cases." Indian Journal of Pathology and Microbiology 52, no. 3 (2009): 424. http://dx.doi.org/10.4103/0377-4929.55015.
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Fujiwara, Tohru, and Hideo Harigae. "Pathophysiology and genetic mutations in congenital sideroblastic anemia." Pediatrics International 55, no. 6 (December 2013): 675–79. http://dx.doi.org/10.1111/ped.12217.
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Kim, Min Hee, Sanjay Shah, Roberta H. Adams, Sylvia Bottomley, and Niketa C. Shah. "Reduced Toxicity Allogeneic Transplant for Congenital Sideroblastic Anemia." Biology of Blood and Marrow Transplantation 22, no. 3 (March 2016): S252. http://dx.doi.org/10.1016/j.bbmt.2015.11.677.
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Van Dijck, Ruben, Alice M. Goncalves Silva, and Anita W. Rijneveld. "Luspatercept as Potential Treatment for Congenital Sideroblastic Anemia." New England Journal of Medicine 388, no. 15 (April 13, 2023): 1435–36. http://dx.doi.org/10.1056/nejmc2216213.
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Kreuziger, Lisa M. Baumann, Alexandra Wolanskyj, and David P. Steensma. "Lack of Efficacy of Pyridoxine (Vitamin B6) Treatment In Acquired Idiopathic Sideroblastic Anemia, Including Refractory Anemia with Ring Sideroblasts." Blood 116, no. 21 (November 19, 2010): 2919. http://dx.doi.org/10.1182/blood.v116.21.2919.2919.
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Abstract Abstract 2919 Background: Sideroblastic anemias can be either hereditary due to congenital mutations in factors critical for iron processing or heme biosynthesis, or acquired; acquired sideroblastic anemias may be induced by alcohol or medications, but are usually idiopathic. Pyridoxine, a form of vitamin B6, plays a critical role in heme synthesis as a cofactor for δ-aminolevulinic acid synthetase (ALAS). Some subtypes of congenital sideroblastic anemia, such as those associated with mutations in the ALAS2 gene encoding the erythrocyte-expressed isoform of ALAS, may respond to pyridoxine therapy at doses ranging from 5–500 mg/day. Anecdotal reports of improvement with pyridoxine therapy in cases of acquired idiopathic sideroblastic anemia (AISA) have led to widespread clinical use of this agent in patients with refractory anemia with ring(ed) sideroblasts (RARS) and refractory cytopenia with multilineage dysplasia associated with ring sideroblasts (RCMD-RS). However, there are no systematic studies of the effectiveness of pyridoxine in AISA. Methods: We reviewed clinical and laboratory data from 231 adult patients with marrow aspirate-proven AISA (i.e., RARS or RCMD-RS, based on 2001 WHO criteria) evaluated at our institution between 1994 and 2007. Responses to pyridoxine were assessed using 2006 International Working Group (IWG) standardized criteria for MDS (erythroid response with hemoglobin increase by '1.5 mg/dl). The relationship between response to pyridoxine and disease subtype or International Prognostic Scoring System (IPSS) stratification was assessed using χ2 test, using a p-value limit of <0.05 for statistical significance. Results: 86 of the 231 patients (42%) were treated with pyridoxine for an average of 19 months (range 1–114 months) at a mean dose of 167 mg/day (range 50–600 mg/day). Sufficient follow-up data to allow response evaluation were available from 74 (86%) of the 86 patients who received pyridoxine. Only 5/86 patients (6.8%) receiving pyridoxine met IWG response criteria for hematological improvement, but 3 of these 5 patients also received erythropoetin and 1 also received prednisone concomitantly with pyridoxine therapy. Therefore, only 1/86 (1.4%) patient's improvement in hemoglobin could be attributed to pyridoxine monotherapy. ALAS2 genotype data were not available from these 5 patients. The dose of pyridoxine was not associated with response to therapy (187.5 mg daily in responders vs. 157 mg daily in non-responders (p=0.60). Patients with RCMD-RS were more likely to be treated with vitamin B6 compared to patients with RARS (p=<0.001), possibly because of more severe anemia, but response to pyridoxine did not differ significantly between subtypes (3/49 vs. 2/25, response in RARS vs. RCMD-RS; p=0.76). Among the 74 evaluable patients, 3/46 patients in the low IPSS risk group responded to pyridoxine, compared to 2/24 of patients in the Intermediate-1 risk group and 0/4 in the Intermediate-2 risk group (p=0.82). Adverse effects associated with pyridoxine included new onset of irreversible symptomatic peripheral neuropathy in 2/86 patients (2.3%). Conclusions: Pyridoxine is commonly prescribed to patients with AISA in clinical practice, and this agent is often continued for a long period of time despite lack of evidence of objective response. Pyridoxine is an ineffective therapy in AISA that induces symptomatic peripheral neuropathy in some patients. Therefore, pyridoxine therapy should be limited to patients with known or suspected congenital mutations that confer pyridoxine responsiveness, and therapeutic trials should be brief to avoid adverse effects. Disclosures: No relevant conflicts of interest to declare.
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Ducamp, Sarah, and Mark D. Fleming. "The molecular genetics of sideroblastic anemia." Blood 133, no. 1 (January 3, 2019): 59–69. http://dx.doi.org/10.1182/blood-2018-08-815951.
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Abstract 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.
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Lichtenstein, Daniel A., Andrew W. Crispin, Anoop K. Sendamarai, Dean R. Campagna, Klaus Schmitz-Abe, Cristovao M. Sousa, Martin D. Kafina, et al. "A recurring mutation in the respiratory complex 1 protein NDUFB11 is responsible for a novel form of X-linked sideroblastic anemia." Blood 128, no. 15 (October 13, 2016): 1913–17. http://dx.doi.org/10.1182/blood-2016-05-719062.
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Jfri, Abdulhadi, Therese El-Helou, Kevin A. Watters, Annie Bélisle, Ivan V. Litvinov, and Elena Netchiporouk. "Congenital sideroblastic anemia associated with B cell immunodeficiency, periodic fevers, and developmental delay: A case report and review of mucocutaneous features." SAGE Open Medical Case Reports 7 (January 2019): 2050313X1987671. http://dx.doi.org/10.1177/2050313x19876710.
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This is a 40-year-old woman with sideroblastic anemia with B cell immunodeficiency, periodic fevers, and developmental delay syndrome, who has genital and extragenital lichen sclerosus on the abdomen and the upper back that have become erythematous and painful during febrile episodes. This report summarizes the published cases of sideroblastic anemia with B cell immunodeficiency, periodic fevers, and developmental delay and highlights associated mucocutaneous features.
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Fernández-Murray, J. Pedro, Sergey V. Prykhozhij, J. Noelia Dufay, Shelby L. Steele, Daniel Gaston, Gheyath K. Nasrallah, Andrew J. Coombs, et al. "Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia." PLOS Genetics 12, no. 1 (January 28, 2016): e1005783. http://dx.doi.org/10.1371/journal.pgen.1005783.
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Ishida, Hiroyuki, Toshihiko Imamura, Akira Morimoto, Tohru Fujiwara, and Hideo Harigae. "Five-aminolevulinic acid: New approach for congenital sideroblastic anemia." Pediatrics International 60, no. 5 (May 2018): 496–97. http://dx.doi.org/10.1111/ped.13558.
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Long, Zhangbiao, Hongmin Li, Yali Du, and Bing Han. "Congenital sideroblastic anemia: Advances in gene mutations and pathophysiology." Gene 668 (August 2018): 182–89. http://dx.doi.org/10.1016/j.gene.2018.05.074.
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Fujiwara, Tohru, and Hideo Harigae. "Molecular pathophysiology and genetic mutations in congenital sideroblastic anemia." Free Radical Biology and Medicine 133 (March 2019): 179–85. http://dx.doi.org/10.1016/j.freeradbiomed.2018.08.008.
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Chakraborty, Pranesh K., Klaus Schmitz-Abe, Erin K. Kennedy, Hapsatou Mamady, Turaya Naas, Danielle Durie, Dean R. Campagna, et al. "Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD)." Blood 124, no. 18 (October 30, 2014): 2867–71. http://dx.doi.org/10.1182/blood-2014-08-591370.
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Key PointsSIFD is a syndromic form of congenital sideroblastic anemia associated with immunodeficiency, periodic fevers, and developmental delay. SIFD is due to partial loss-of-function mutations in the CCA-adding enzyme TRNT1.
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Krasolnikova, M. V. "Chelation therapy in children." Medical Council 1, no. 1 (December 30, 2016): 123–27. http://dx.doi.org/10.21518/2079-701x-2016-1-123-127.
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Iron overload (RV) is a condition caused by excessive intake of iron, and in the absence of the specific mechanisms for its excretion - excessive accumulation in tissues and their subsequent lesion leading to functional organ failure [1]. This condition most commonly occurs as a result of regular replacement therapy with erythrocyte mass in the treatment of various anemias. According to statistics, about 500 sick children and 2 000 adults develops post-transfusion RV in Russia in every year [2]. It develops in the context of hereditary anemia (major and intermediate forms of beta-thalassemia, other hemoglobinopathies, severe membrane and enzyme defects, congenital sideroblastic and dyserythropoetic anemia, constitutional hypo- and aplastic anemia) or acquired diseases (acquired aplastic anemia, myelodysplastic syndrome (MDS), myelofibrosis, etc.). [3--5].
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Berman, Jason N., Pedro Fernandez-Murray, Gheyath Nasrallah, Noelia Dufay, Conrad V. Fernandez, Ameer Jarrar, Andrew J. Coombs, and Christopher McMaster. "Glycine Supplementation – A Novel Therapeutic Strategy for Congenital Sideroblastic Anemia." Blood 120, no. 21 (November 16, 2012): 2087. http://dx.doi.org/10.1182/blood.v120.21.2087.2087.
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Abstract Abstract 2087 Congenital sideroblastic anemias (CSA) are inherited diseases, characterized by ineffective haematopoiesis, typically severe microcytic anemia and bone marrow sideroblasts representing excess iron deposition in the mitochondria of the erythroid precursors. More than 40% of CSA cases are attributed to mutations in the X-linked gene ALAS2. ALAS2 encodes the mitochondrial enzyme aminolevulinic acid synthase-2, which utilizes glycine to form 5-aminolevulinic acid (5-ALA), a crucial precursor in heme synthesis. Another gene, SLC25A38, has recently been implicated in the abnormal heme development noted in CSA. The function of the SLC25A38 protein product is uncertain, although it is thought to be an erythroid specific mitochondrial carrier family protein, transporting glycine across mitochondrial membranes. We employed yeast and zebrafish model systems in parallel to evaluate the absence of SLC25A38 or ALAS2 on heme synthesis in vivo and identify potential therapeutic strategies. HEM1 (ALAS2 homologue) mutant yeast were completely unable to make heme, whereas heme synthesis was significantly reduced in YDL119c (SLC25A38 homologue) mutant yeast. To monitor heme synthesis, we utilized a beta-galactosidase reporter linked to Pcyc1, which is only active following binding of the yeast Hap1 transcription activator in the presence of heme. Both HEM1 and YDL119c mutant yeast showed no beta-galactosidase activity, however activity in the YDL119c mutant was returned to 30% with the addition of 5-ALA and to 40% following treatment with glycine. Microarray studies of untreated and glycine treated YDL119c mutant yeast revealed increased expression of genes required to synthesize vitamin B6, a cofactor for the Hem1 enzyme in yeast and humans. Morpholino (MO)-mediated knockdown of the zebrafish homologues of SLC25A38 (slc25a38a and slc25a38b) or alas2 correlated with decreased hemoglobin levels by o-dianisidine staining and increased embryonic malformation and mortality. 5-ALA treatment either by addition to the egg water or by injection into the yolk failed to restore hemoglobinization in alas2 morphant embryos. By contrast, the addition of glycine to the egg water resulted in upregulation of hemoglobin to near normal levels in the majority of slc25a38a/b double morphant embryos. Our study demonstrates conserved heme synthesis pathways through evolution across species and further supports the contention that SLC25A38 functions as a glycine transporter. Most significantly, glycine supplementation emerged as an effective therapeutic strategy to restore heme synthesis in CSA caused by SLC25A38 deficiency, providing the rationale to support use of glycine in a clinical trial that is under development for these patients. Disclosures: McMaster: DeNovaMed: Equity Ownership.
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Medeiros, B. C., J. F. Kolhouse, P. J. Cagnoni, J. Ryder, Y. Nieto, R. Rabinovitch, E. J. Shpall, S. I. Bearman, R. B. Jones, and P. A. McSweeney. "Nonmyeloablative allogeneic hematopoietic stem cell transplantation for congenital sideroblastic anemia." Bone Marrow Transplantation 31, no. 11 (May 28, 2003): 1053–55. http://dx.doi.org/10.1038/sj.bmt.1704038.
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Kucerova, Jana, Monika Horvathova, Petra Belohlavkova, Jaroslav Cermak, and Vladimir Divoky. "New Mutation in ALAS2 as the Cause of X-Linked Sideroblastic Anemia Responsive to Pyridoxine: Comparison of ALAS2-Defective and DMT1-Defective BFU-E Growth." Blood 114, no. 22 (November 20, 2009): 4051. http://dx.doi.org/10.1182/blood.v114.22.4051.4051.
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Abstract Abstract 4051 Poster Board III-986 Congenital sideroblastic anemias (SA) are hypochromic microcytic anemias with secondary iron overload. Local iron accumulation in mitochondria results in the formation of ringed sideroblasts in the bone marrow. Defects in heme synthesis, Fe-S cluster biogenesis and export have been reported in SA patients. X-linked sideroblastic anemia is a rare gonosomal recessive disorder, resulting from mutations in erythroid-specific delta-aminolevulinate synthase (ALAS2), the first enzyme of heme biosynthesis. It affects mostly males. Few cases of affected females, due to skewed X-inactivation pattern favoring the mutant allele have been reported. Inefficiency of ALAS2 leads to decreased heme production and ineffective erythropoiesis. We investigated a group of 4 young males (average age 28) with congenital SA. Two of the patients had family history of SA and iron overload in males corresponding with the X-linked inheritance. All the patients had hemoglobin level lower than 119 g/L, mean corpuscular volume under 71 fL, increased serum ferritin and numerous sideroblasts in their bone marrow. We performed screening of all exons and promoter region of ALAS2. One patient was negative for ALAS2 mutation, and is a candidate for SLC25A38 mutation screening which only recently has been published as the second most frequent lesion in congenital SA. In two patients we found previously published R452H and R452C mutations; a novel K156E substitution was discovered in one patient. All these three patients responded partially to high dose of pyridoxine. K156 is a conserved amino acid residue and K156E substitution is SIFT predicted as affecting the protein function (the functional study is ongoing). This mutation was not found in 40 healthy controls or 10 patients with myelodysplastic syndrome with SA (RARS, RCMD-RS). Based on our previous study with DMT-1-deficient erythroid progenitors (Priwitzerova et al. Blood 2004;103:3991-2), we also evaluated a possible erythropoietic defect of ALAS2-mutant erythroid progenitors using methylcellulose-based colony assays. We observed that the in vitro growth of all aforementioned ALAS2-mutant patient's erythroid progenitors (BFU-Es) is not affected, which is in contrast to the defective growth of DMT1-mutant erythroid progenitors. These results suggest that impaired heme synthesis is better tolerated by erythroid progenitors than general iron deficiency due to the block in erythroid iron uptake by DMT1 and that the defect in heme synthesis does not fully account for the impaired hemoglobinization and poor growth of DMT1-defective BFU-Es. These data support the role of iron in other processes involved in erythroid-colony development apart from heme synthesis. In conclusion, we present a novel K156E ALAS2 mutation leading to pyridoxine-responsive X-linked sideroblastic anemia. Using BFU-E assays we also submit that lesions in iron-dependent proteins apart from defective heme synthesis contribute to impaired erythroid colony formation in previously described DMT1-mutant erythroid progenitors. Grant support: Ministry of Health Czech Republic grants NS9935-3 and NS10281-3 and Ministry of Education, Youth and Sports program MSM 6198959205. Disclosures: No relevant conflicts of interest to declare.
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Rose, Christian, Claire Oudin, Martine Fournier, Alexandre Bouquet, Luca Inchiappa, Bernard Grandchamp, Laurent Gouya, and Caroline Kannengiesser. "A New ALAS2 Mutation Inducing a Male Lethal X-Linked Sideroblastic Anemia." Blood 122, no. 21 (November 15, 2013): 2199. http://dx.doi.org/10.1182/blood.v122.21.2199.2199.
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Abstract X-linked Sideroblastic Anemia (XLSA, MIM# 300751) is due to mutations in the erythroid-specific form of 5-aminolevulinate synthase (ALAS2) gene. Main features of this condition are microcytic anemia, iron deposits in the mitochondria of erythroid precursors (ring sideroblasts) and an X linked pattern of inheritance. However, up to one third of described cases have been reported in females mainly due to a highly skewed X-chromosome inactivation (Ducamp, Kannengiesser et al. 2011). We report for the first time in a large four generations pedigree a new mutation in ALAS2 gene inducing a Male Lethal X-linked Syndrome ascertained through an adult heterozygous female with a mild form of congenital sideroblastic anemia (CSA). The propositus of this non consanguineous family (Fig 1; individual III;9) was a female from European ancestry. She exhibited a unexplained congenital, non regenerative, macrocytic (MCV 107fL, moderate anemia (Hb 10.4 g/dL), (first assessment at 6 years old). RBC transfusions were required only twice during pregnancy. The diagnosis of CSA was made at 23 years old when the bone marrow aspiration performed, showed 38% of ring sideroblasts. Erythrocyte protoporphyrin concentration was measured in the female proband carrying an ALAS2 mutation. The protoporphyrin concentration was within the normal range of values: 1.6 µmoles/L of red blood cells (less than 1.9 µmoles/L of red blood cells), as previously observed in XLSA cases. The level of serum ferritin was 224ng/ml (N:11-306) and transferrin saturation was 90%. A heterozygote ALAS2 deleterious missense mutation c.622G>T,p.Val208Phe affecting a conserved amino acid was found. A constitutive skewed X-chromosome inactivation was demonstrated as previously reported in affected females with XLSA. However erythroid bone marrow precursor did not exhibited different pattern repartition in term of apoptosis or dyserythropoisesis. Her daughter and her mother exhibited the same mutation but did not have skewed X-chromosome inactivation and were unaffected with a normal blood count. A close inspection of the pedigree confirms a large female predominance (22 females/ 7 males) over four generations (/F/M ratio 3.1). No affected male were identified in the pedigree. Moreover a high level of miscarriage was found only in female carrying the ALAS2 mutation, as shown in the pedigree (Fig. 1). Adding the number of miscarriage (18 over the four generations) to the number of males alive the ratio of M/F over 4 generation is close of 1: 1.04 (24/23). These data highly suggest an X-linked dominant disorder with pre natal male lethality. Our pedigree confirms the non redundant role of the erythroid-specific form of delta-aminolevulinate synthase in foetal hematopoïesis; Moreover our propositus case showed that in case of X-linked Sideroblastic Anemia (XLSA) affected female, a research of excess of miscarriage in the pedigree should be considered and should evocate a male lethal XLSA. This should have an impact in term of genetic counselling. Disclosures: No relevant conflicts of interest to declare.
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Caudill, J. S., H. Imran, J. C. Porcher, and D. P. Steensma. "Congenital sideroblastic anemia associated with germline polymorphisms reducing expression of FECH." Haematologica 93, no. 10 (October 1, 2008): 1582–84. http://dx.doi.org/10.3324/haematol.12597.
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Ayas, M., A. Al-Jefri, M. M. Mustafa, M. Al-Mahr, L. Shalaby, and H. Solh. "Bone marrow transplantation (BMT) in patients with congenital sideroblastic anemia (CSA)." Journal of Pediatric Hematology/Oncology 22, no. 4 (July 2000): 385. http://dx.doi.org/10.1097/00043426-200007000-00087.
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Kim, Min Hee, Sanjay Shah, Sylvia S. Bottomley, and Niketa C. Shah. "Reduced-toxicity allogeneic hematopoietic stem cell transplantation in congenital sideroblastic anemia." Clinical Case Reports 6, no. 9 (August 1, 2018): 1841–44. http://dx.doi.org/10.1002/ccr3.1667.
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Furuyama, Kazumichi, and Kiriko Kaneko. "Iron metabolism in erythroid cells and patients with congenital sideroblastic anemia." International Journal of Hematology 107, no. 1 (November 14, 2017): 44–54. http://dx.doi.org/10.1007/s12185-017-2368-0.
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Patil, Ashish S., Nalla Anuraag Reddy, and Harsha Prasada Lashkari. "Congenital sideroblastic anemia in a child with biliary atresia: An association?" Pediatric Hematology Oncology Journal 8, no. 3 (September 2023): 179–81. http://dx.doi.org/10.1016/j.phoj.2023.07.005.
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Ohba, Rie, Kazumichi Furuyama, Kenichi Yoshida, Tohru Fujiwara, Noriko Fukuhara, Yasushi Onishi, Atsushi Manabe, et al. "Clinical and genetic characteristics of congenital sideroblastic anemia: comparison with myelodysplastic syndrome with ring sideroblast (MDS-RS)." Annals of Hematology 92, no. 1 (September 16, 2012): 1–9. http://dx.doi.org/10.1007/s00277-012-1564-5.
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Imataki, Osamu, Shumpei Uchida, Makiko Uemura, and Norimitsu Kadowaki. "Graft failure after reduced-intensity stem cell transplantation for congenital sideroblastic anemia." Pediatric Hematology and Oncology 36, no. 1 (January 2, 2019): 46–51. http://dx.doi.org/10.1080/08880018.2019.1578844.
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Schmitz-Abe, Klaus, Szymon J. Ciesielski, Paul J. Schmidt, Dean R. Campagna, Fedik Rahimov, Brenda A. Schilke, Marloes Cuijpers, et al. "Congenital sideroblastic anemia due to mutations in the mitochondrial HSP70 homologue HSPA9." Blood 126, no. 25 (December 17, 2015): 2734–38. http://dx.doi.org/10.1182/blood-2015-09-659854.
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Key Points Mutations in HSPA9 cause CSAs that may be inherited in a recessive or pseudodominant manner. HSPA9 loss-of-function alleles are often inherited in trans with a common coding single nucleotide polymorphism associated with altered gene expression.
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Zhang, Yingchi, Jingliao Zhang, Wenbin An, Yang Wan, Jie Gao, Lihong Shi, Tao Cheng, and Xiaofan Zhu. "Mutation of a GATA1 Binding Site in ALAS2 Intron 1 Arrests Murine Erythroid Development In Vivo." Blood 128, no. 22 (December 2, 2016): 2425. http://dx.doi.org/10.1182/blood.v128.22.2425.2425.
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Abstract Congenital sideroblastic anemia (CSA) comprises a heterogeneous group of genetic disorders characterized by decreased heme synthesis and the presence of bone marrow (BM) ring sideroblasts. The most common form of CSA is X-linked sideroblastic anemia (XLSA, OMIM#300751), which is caused by mutations in the gene encoding 5-aminolevulinic acid synthase 2 (ALAS2). However, to date the experimentally confirmed ALAS2 mutations mostly occurred at the exons of ALAS2 and are missense mutations. In our study, we identified a non-coding GATA1 binding site mutation in ALAS2 intron 1 in a large XLSA pedigree. We addressed the functions of the GATA1 binding site in ALAS2 intron 1 in vivoby generating mice lacking this GATA site and its flanking sequence (13bp) and found that this deletion led to an embryonic lethal phenotype due to severe anemia, indicating that this fragment is indispensable during erythroid development. Next we demonstrated that GATA1 activated ALAS2 transcription by forming an enhancer loop with TAL1, LDB1 and Pol II through GATA binding sites in the promoter and in introns 1 and 8. Finally, we discovered that int-1-GATA site deletion completely abolished ALAS2 transcription due to disruption of the enhancer loop and a simultaneous lack of Pol II enrichment at the intron 1 enhancer region and promoter. Our findings first revealed the essential roles of GATA1 binding site in ALAS2 intron 1 in erythroid development in vivo and uncovered the mechanisms how GATA1 regulated the expression of ALAS2. We believe that these findings will be of wide general interest and will provide valuable information for the clinical diagnosis of XLSA patients with unknown mutations. Disclosures No relevant conflicts of interest to declare.
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Saito, Kei, Tohru Fujiwara, Shunsuke Hatta, Chie Suzuki, Noriko Fukuhara, Yasushi Onishi, Yukio Nakamura, and Hideo Harigae. "Generation and Molecular Characterization of Human Ring Sideroblasts." Blood 132, Supplement 1 (November 29, 2018): 3613. http://dx.doi.org/10.1182/blood-2018-99-111066.
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Abstract (Background) Sideroblastic anemias are heterogeneous congenital and acquired refractory anemias characterized by bone marrow ring sideroblasts, reflecting excess mitochondrial iron deposition. While the disease is commonly associated with myelodysplastic syndrome, the congenital forms of sideroblastic anemias comprise a diverse class of syndromic and non-syndromic disorders, which are caused by the germline mutation of genes involved in iron-heme metabolism in erythroid cells. Although the only consistent feature of sideroblastic anemia is the bone marrow ring sideroblasts, evidence on the detailed molecular characteristics of ring sideroblasts is scarce owing to a lack of the biological models. We have recently established ring sideroblasts by inducing ALAS2 gene mutation based on human-induced pluripotent stem cell-derived erythroid progenitor (HiDEP) cells (ASH 2017) and have further extended the molecular characterization of human ring sideroblasts to gain new biological insights. (Method) We targeted the GATA-1-binding region of intron 1 of the human ALAS2 gene in HiDEP cells and established two independent clones [X-linked sideroblastic anemia (XLSA) clones]. A co-culture with OP9 stromal cells (ATCC) was conducted with IMDM medium supplemented with FBS, erythropoietin, dexamethasone, MTG, insulin-transferrin-selenium, and ascorbic acid. To obtain human primary erythroblasts, CD34-positive cells isolated from cord blood were induced in a liquid suspension culture (Fujiwara et al. JBC 2014). Bone marrow glycophorin A (GPA)-positive erythroblasts of patients with XLSA and normal individuals were separated using the MACS system (Miltenyi Biotec GmbH, Bergisch Gladbach, Germany) after obtaining written informed consent. For transcription profiling, Human Oligo chip 25K (Toray) was used. (Results) We previously demonstrated that co-culture with OP9 cells in the medium supplemented with 100 uM sodium ferrous citrate (SFC) promoted erythroid differentiation of XLSA clones, which enabled the establishment of ring sideroblasts (ASH 2017). To confirm the importance of SFC in terminal erythroid differentiation, we further demonstrated that the addition of SFC, and not transferrin-loaded iron, induced the frequency of GPA+ cells and TfR1-GPA+ mature erythroid population, based on primary erythroblasts derived from human CD34-positive cells. Subsequently, to reveal the molecular mechanism by which abnormal iron mitochondrial iron accumulation occurs by co-culture with SFC, we evaluated the expressions of various metal transporters, demonstrating that the addition of SFC significantly increased the expressions of mitoferrin 1 (MFRN1; a ferrous iron transporter in mitochondria), divalent metal transporter 1 (DMT1), and Zrt- and Irt-like protein 8 (ZIP8; a transmembrane zinc transporter, recently known as a ferrous iron transporter) in the XLSA clone than the wild-type cells, which would have contributed to the formation of ring sideroblasts. Moreover, we performed expression analyses to elucidate the biochemical characteristics of ring sideroblasts. After co-culture with OP9 in the presence of SFC, ring sideroblasts exhibited more than two-fold upregulation and downregulation of 287 and 143 genes, respectively, than the wild-type cells. Interestingly, when compared with the expression profiling results before co-culture (ASH 2017), we noticed prominent upregulation of gene involved in anti-apoptotic process (p = 0.000772), including HSPA1A, superoxide dismutase (SOD) 1, and SOD2. In addition, we conducted a microarray analysis based on GPA-positive erythroblasts from an XLSA patient and a normal individual. The analysis revealed significant upregulation of genes involved in the apoptosis process, as represented by apoptosis enhancing nuclease, DEAD-box helicase 47, and growth arrest and DNA-damage-inducible 45 alpha, and anti-apoptotic genes, such as HSPA1A and SOD2. Concomitantly, when the XLSA clone was co-cultured with OP9 in the presence of SFC, the apoptotic cell frequency as well as DNA fragmentation were significantly reduced compared with the XLSA clone co-cultured without SFC, indicating that ring sideroblasts avoid cell death by inducing anti-apoptotic properties. (Conclusion) Further characterization of the XLSA model would help clarify its molecular etiology as well as establish novel therapeutic strategies. Disclosures Fukuhara: Celgene: Research Funding; Chugai: Research Funding; Daiichi-Sankyo: Research Funding; Boehringer Ingelheim: Research Funding; Eisai: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Janssen: Honoraria, Research Funding; Japan Blood Products Organization: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Mitsubishi Tanabe: Research Funding; Mundipharma: Honoraria, Research Funding; MSD: Research Funding; Nippon-shinyaku: Research Funding; Novartis pharma: Research Funding; Ono: Honoraria, Research Funding; Otsuka Pharmaceutical: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Symbio: Research Funding; Solasia: Research Funding; Sumitomo Dainippon: Research Funding; Taiho: Research Funding; Teijin Pharma: Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; Takeda: Honoraria; Baxalta: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Bayer Yakuhin: Research Funding; Alexionpharma: Research Funding; AbbVie: Research Funding; Astellas: Research Funding; Nihon Ultmarc: Research Funding.
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Crispin, Andrew, Chaoshe Guo, Caiyong Chen, Dean R. Campagna, Paul J. Schmidt, Daniel Lichtenstein, Chang Cao, et al. "Mutations in the iron-sulfur cluster biogenesis protein HSCB cause congenital sideroblastic anemia." Journal of Clinical Investigation 130, no. 10 (August 31, 2020): 5245–56. http://dx.doi.org/10.1172/jci135479.
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Puy, Hervé, Karim Zoubida, Lyoumi Said, Lydie M. Da Costa, and Gouya Laurent. "Heme-Related Blood Disorders." Blood 122, no. 21 (November 15, 2013): SCI—18—SCI—18. http://dx.doi.org/10.1182/blood.v122.21.sci-18.sci-18.
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Abstract Heme biosynthesis in erythroid cells is intended primarily for the formation of hemoglobin. As in every cell, this synthesis requires a multi-step pathway that involves eight enzymes including the erythroid-specific δ-aminolevulinate synthase (ALAS2, the first regulated enzyme that converts glycine and succinyl CoA into ALA) and the ubiquitous ferrochelatase (FECH, the final enzyme). Heme biosynthesis also requires membrane transporters that are necessary to translocate glycine, precursors of heme, and heme itself between the mitochondria and the cytosol. Defects in normal porphyrin and/or heme synthesis and transport cause four major erythroid inherited disorders, which may or may not be associated with dyserythropoiesis (e.g., sideroblastic, microcytic anemia and/or hemolytic anemia): "X-linked" sideroblastic anemia (XLSA) and X-linked dominant protoporphyria (XLDPP) are two different and opposing disorders but related to altered gene encoding ALAS2 only. Defective activity of this enzyme due to mutations in the ALAS2 gene causes the XLSA phenotype, including microcytic, hypochromic anemia with abundant ringed sideroblasts in the bone marrow. Vice versa, gain-of-function mutations of ALAS2 are responsible of the XLDPP characterized by predominant accumulation of the hydrophobic protoporphyrin (PPIX, the last heme precursor) in the erythrocytes without anemia or sideroblasts. Furthermore, the glycine transporter (SLC25A38) and Glutaredoxin 5 genes are reported to be involved in human non-syndromic sideroblastic anemia. Congenital erythropoietic porphyria (CEP) is the rarest autosomal recessive disorder due to a deficiency in uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthetic pathway. CEP leads to excessive synthesis and accumulation of type I isomers of porphyrins in the reticulocytes, followed by intravascular hemolysis and severe anemia. The ALAS2 gene may act as a modifier gene in CEP patients (Figueras J et al, Blood. 2011;118(6):1443-51). Erythropoietic protoporphyria (EPP) results from a partial deficiency of FECH and leads similarly to XLDPP, to deleterious accumulation of PPIX in erythroid cells. Most EPP patients present intrans to a FECH gene mutation an IVS3-48C hypomorphic allele due to a splice mutation. Abnormal spliced mRNA is degraded which contributes to the lowest FECH enzyme activity and allowed EPP phenotype expression. We have identified an antisense oligonucleotide (ASO) to redirect splicing from cryptic to physiological site and showed that the ASO-based therapy mediates normal splice rescue of FECH mRNA and reduction by 60 percent of PPIX overproduction in primary cultures of EPP erythroid progenitors. Therapeutic approaches to target both ALAS2 inhibition and heme-level reduction may be useful in other erythroid disorders such as thalassemia (where reduced heme biosynthesis was shown to improve the clinical phenotype) or the Diamond-Blackfan anemia (DBA). Indeed, in some DBA patients, an unusual mRNA splicing of heme exporter FLVCR has been found, reminiscent of Flvcr1-deficient mice that develop a DBA-like phenotype with erythroid heme accumulation. Thus, FLVCR may act as a modifier gene for DBA phenotypic variability. Recent advances in understanding the pathogenesis and molecular genetic heterogeneity of heme-related disorders have led to improved diagnosis and treatment. These advances include DNA-based diagnoses for all the porphyrias and some porphyrins and heme transporters, new understanding of the pathogenesis of the erythropoietic disorders, and new and experimental treatments such as chronic erythrocyte transfusions, bone marrow or hematopoietic stem cell transplants, and experimental pharmacologic chaperone and stem cell gene therapies for erythropoietic porphyrias. Disclosures: No relevant conflicts of interest to declare.
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Uminski, Kelsey, Donald S. Houston, Jessica Hartley, Geoffrey Cuvelier, and Sara J. Israels. "Clinical Characterization of a Novel Mutation in SLC25A38 Resulting in Congenital Sideroblastic Anemia in a Canadian First Nations Population." Blood 132, Supplement 1 (November 29, 2018): 1035. http://dx.doi.org/10.1182/blood-2018-99-110343.
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Abstract Introduction: Congenital sideroblastic anemia (CSA) is an uncommon cause of inherited anemia characterized by pathologic iron accumulation. Severity of anemia and blood transfusion requirements are variable. Aberrations in iron-heme metabolism that underpin CSA result in iron overload, often preceding transfusion. The only curative therapy for CSA is hematopoietic stem cell transplantation (HSCT), offered to select patients with severe transfusion dependent anemia. Mutations in several genes have been identified to be responsible for CSA. Mutations in SLC25A38, encoding a mitochondrial glycine transporter required for heme biosynthesis, are a rare cause of CSA. Homozygosity for a novel founder missense mutation in SLC25A38 (c.560G>A) has been detected in a Canadian First Nations Northern Cree population. The associated phenotype is a severe anemia presenting in infancy and characterized by ineffective erythropoiesis and iron loading. The natural history and treatment outcomes of CSA caused by the c.560G>A mutation have not been described. Objectives: (1) To characterize the clinical features in patients homozygous for this founder mutation, including propensity to iron loading and (2) to describe the treatment course and outcomes for red cell transfusion, iron chelation, pyridoxine supplementation and HSCT. Methods: A retrospective chart review was conducted at the Winnipeg Health Sciences Centre and CancerCare Manitoba of all affected individuals homozygous for the c.560G>A mutation in SLC25A38. Results: Seven affected individuals (three females and four males) were identified. Comorbidities including dextrocardia, hypertrophic cardiomyopathy, rheumatoid arthritis and global developmental delay were noted in three members of the kindred, but there was no evidence of a syndromic form of CSA. The median age of presentation with anemia was 6 months (24 days - 4.4 years). The median age of CSA diagnosis was 1.5 years (6 months - 22 years). Alternative causes of anemia were initially suspected in five of the seven patients: iron deficiency, resulting in oral iron supplementation, and alpha thalassemia. Uniformly, individuals presented with a microcytic, hypochromic anemia, with elevated ferritin prior to first red cell transfusion. All affected individuals required red cell transfusion support, with six of seven patients requiring chronic transfusions at a median frequency of every four weeks. One individual, though chronically anemic, did not require regular transfusion support until the age of 20 years. One patient carried a successful pregnancy with transfusion support, but delivered prematurely. For all individuals, iron chelation was recommended, with six individuals starting chelation within three years of initiation of transfusions. Hepatic, cardiac, pituitary and pancreatic iron overload, and resultant organ dysfunction were noted in two subjects who did not adhere to chelation; one died of neutropenic sepsis after starting deferiprone for cardiac iron overload. Six individuals were given trials of pyridoxine supplementation, with two demonstrating a transient partial response with a rise in reticulocyte count and decrease in transfusion frequency. Three individuals underwent allogeneic HSCT (two from matched sibling donors, and one from a matched unrelated donor), at 5.5 years, 7.2 years, and 28 years. The oldest and most iron-loaded of the three died in the post-transplant period due to complications of sepsis. The other two individuals remain transfusion free, at 9 months and 15.6 years post-HSCT. Conclusions: A novel founder mutation in SLC25A38 causing CSA among individuals of Canadian First Nations Northern Cree descent results in a severe transfusion-dependent anemia. Despite a common genetic etiology, phenotypic variability was noted, with one individual having marked tolerance to anemia. A partial transient response to pyridoxine was noted in two individuals, raising the question of an alternative role for SLC25A38 in heme biosynthesis. HSCT, when performed before significant iron overloading, was beneficial. Characterization of this phenotype and evidence of successful HSCT may assist clinicians in identifying affected individuals with CSA and initiating timely and effective treatment. Disclosures No relevant conflicts of interest to declare.
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Simpson, Skyler J., Ming Y. Lim, Tracy I. George, and Anton Rets. "36‐year‐old male with X‐linked congenital sideroblastic anemia presenting as chronic microcytic anemia with iron overload." International Journal of Laboratory Hematology 44, no. 1 (November 15, 2021): 69–71. http://dx.doi.org/10.1111/ijlh.13761.
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Humbert, J., P. Wacker, F. Gumy-Pause, J. Schmid, and H. Ozsahin. "A NEW CONGENITAL SIDEROBLASTIC MICROCYTIC HYPOCHROMIC ANEMIA WITH TRANSIENT HYPOTONIA AND FACIAL DYSMORPHISM. 105." Pediatric Research 41, no. 5 (May 1997): 765. http://dx.doi.org/10.1203/00006450-199705000-00124.
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Guernsey, Duane L., Haiyan Jiang, Dean R. Campagna, Susan C. Evans, Meghan Ferguson, Mark D. Kellogg, Mathieu Lachance, et al. "Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia." Nature Genetics 41, no. 6 (May 3, 2009): 651–53. http://dx.doi.org/10.1038/ng.359.
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Gorodetsky, C., CF Morel, and I. Tein. "P.133 Expanding the phenotype of TRNT1 mutations to include Leigh syndrome." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 45, s2 (June 2018): S51. http://dx.doi.org/10.1017/cjn.2018.235.
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Background: Children with biallelic mutations in TRNT1 have multi-organ involvement with congenital sideroblastic anemia, -B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) as well as seizures, ataxia and sensorineural hearing loss. The TRNT1 gene encodes the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs accounting for phenotypic pleitropy. Neurodegenerative Leigh syndrome has not been previously reported. Methods:Case summary: A Portuguese boy presented with global developmental delay, 2 episodes of infantile Leigh encephalopathy at 8 mo and 4 yr responsive to high-dose steroids, slow neurodegeneration of cognitive, language and motor functions with optic atrophy, pigmentary retinopathy, spasticity, dystonia, and focal dyscognitive seizures, pancytopenia, transfusion dependent sideroblastic anemia, recurrent febrile infections (pulmonary, gastrointestinal), hypernatremia, with tracheostomy dependence at age 5 yr, malabsorption and TPN dependence at 9 yr, and survival to early adulthood. Neuroimaging showed symmetric hemorrhagic lesions in the thalamus, brain stem (periaqueductal grey) and cerebellum consistent with Leigh syndrome but no lactate peak on MRS. Results: Whole exome sequencing identified a homozygous missense pathogenic variant in TRNT1, c.668T>C (p.I223T) in the affected individual. Conclusions: This report expands the neurological phenotype of TRNT1 mutations and highlights the importance of considering this gene in the evaluation of Leigh syndrome.
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Inokura, Kyoko, Tohru Fujiwara, Yoko Okitsu, Noriko Fukuhara, Yasushi Onishi, Kenichi Ishizawa, Kazuya Shimoda, and Hideo Harigae. "Impact of TET2 Deficiency on Iron Metabolism in Erythroblasts: A Potential Link to Ring Sideroblast Formation." Blood 124, no. 21 (December 6, 2014): 750. http://dx.doi.org/10.1182/blood.v124.21.750.750.
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Abstract Background: Sideroblastic anemia is characterized by the presence of ring sideroblasts (RS) in the bone marrow (BM). RS are caused by iron accumulation in the mitochondria of erythroblasts and are seen in both acquired and congenital forms of sideroblastic anemia. Although dysfunction in mitochondrial metabolism has been implicated in the pathogenesis of sideroblastic anemia, the true mechanism leading to RS formation remains elusive. Clonal sideroblastic anemia is usually acquired in the context of myelodysplastic syndrome (MDS): The presence of 15% or more RS in the BM with appropriate morphologic and cytogenetic criteria for MDS is best classified as refractory anemia with ring sideroblasts (RARS), but varying quantities of RS (<15%) can also occur in refractory anemia with multilineage dysplasia (RCMD) and other myeloid malignancies as well. Intriguingly, a subset of MDS as well as myeloid malignancies has been reported to harbor a somatic mutation of the TET2gene (Delhommeau F et al., 2009; Malcovati et al., 2014), which regulates DNA demethylation by hydroxylating 5-methylcytosine to 5-hydroxymethylcytosine. Thus, because TET2 has also been shown to play an important role during erythroid differentiation (Pronier et al., 2011), TET2 may be involved in iron metabolism and/or heme biosynthesis in erythroblasts, contributing to the formation of RS. To explore this possibility, we conducted biological and molecular analyses based on TET2-knockdown mice. Methods: TET2-knockdown mice (Ayu17-449, Tet2trap) were generated by gene trap project (Shide et al., 2012). Four-month-old heterozygous Tet2trap/+ mice were used in the present study. Serum levels of iron, total iron-binding capacity, unbound-iron binding capacity and ferritin were measured by enzyme-linked immunosorbent assay. BM cells were stained for CD71 and Ter119 (BD Pharmingen, San Jose, CA, USA), and sorted into I–IV populations according to a previously reported method (Socolovsky et al., 2001). To obtain Ter119+ erythroblasts, a magnetic cell sorting system was used (Miltenyi Biotec, Auburn, CA, USA). Western blot analysis was performed with anti-mitochondrial ferritin (Santa Cruz Biotechnology, Santa Cruz, CA, USA). Prussian blue staining was used to assess iron deposition in erythroblasts. DNA methylation status was assessed with the EpiXploreTM Methylated DNA Enrichment Kit (Clontech, Mountain View, CA, USA). Statistical significance was assessed by the two-sided ttest, and p value of <0.05 were considered statistically significant. Results: Tet2trap/+ mice at 4 months exhibited mild normocytic anemia in comparison to the wild-type (WT) mice (hemoglobin; 14.5 ± 1.1 and 13.2 ± 0.6 g/dl, for WT and Tet2trap/+, respectively, p < 0.05, n = 8). Concomitantly, the number of cells in erythroid populations III–IV (polychromatic to orthochromatic erythroblasts) was decreased. Interestingly, serum iron and ferritin levels were significantly elevated in Tet2trap/+ mice (ferritin; 104.7 ± 42.4 and 171.6 ± 89.5 ng/ml, for WT and Tet2trap/+, respectively, p < 0.05, n = 8). Western blot analysis confirmed that the amount of mitochondrial ferritin was increased in Ter119+ erythroblasts from Tet2trap/+ mice compared with those from WT mice. On the other hand, BM from Tet2trap/+ mice did not show an increased number of RS. To explore the molecular mechanism by which TET2 deficiency induces iron overload, quantitative reverse transcription–polymerase chain reaction analysis was conducted with Ter119+ cells for genes involved in erythroid differentiaition, heme biosynthesis and iron metabolism. The analysis demonstrated significant downregulation of heme oxygenase 1 (Hmox1), ferrochelatase (Fech) and Tet2 in Tet2trap/+ mice, whereas the expression of erythroid-specific 5-aminolevulinate synthase (Alas2), mitoferrin (Slc25a37) and Gata1 were unchanged. Because a CpG island was idenitified in the promoter of Fech (http://genome.ucsc.edu), we evaluated its DNA methylation status and found that the CpG site of Fech shows significantly high methylation in Ter119+ cells of Tet2trap/+ mice compared with those of WT mice. As FECH catalyzes the insertion of ferrous iron into the protoporphyrin IX to produce heme, the reduced expression of Fech by TET2 deficiency may result in inhibiton of heme synthesis, leading to iron overload in mitochondria. Conclusion: TET2 is involved in iron and heme metabolism in erythroblasts. Disclosures Fujiwara: Chugai Pharmaceutical CO., LTD.: Research Funding.
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Schmelkin, Leah Ann, Matthew T. Howard, David P. Steensma, Mark D. Fleming, Vilmarie Rodriguez, Shakila Khan, Naseema Gangat, Alexandra Wolanskyj, and Mrinal M. Patnaik. "Clinico-Pathological Features and Outcomes in Patients with Congenital Sideroblastic Anemias." Blood 126, no. 23 (December 3, 2015): 3355. http://dx.doi.org/10.1182/blood.v126.23.3355.3355.
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Abstract Background: Ring sideroblasts (RS) are erythroid precursors with perinuclear mitochondrial iron accumulation seen in clonal disorders, such as myelodysplastic syndromes (MDS), and non-clonal conditions, including copper deficiency, lead poisoning, and congenital sideroblastic anemias (CSAs). CSAs involve a broad clinical and pathological spectrum related to mutations in ALAS2, ABCB7, etc. or mitochondrial aberrations (Pearson Syndrome; Myopathy, Lactic Acidosis and Sideroblastic Anemia (MLASA); etc.). MDS-RS is often associated with SF3B1 mutations, which have not been reported in other SAs. This study sought to further describe the characteristics and outcomes of patients with CSAs. Methods: After due IRB approval, we retrospectively identified all patients with a CSA diagnosis seen at our institution from 1990-2014. All bone marrow (BM) slides were re-reviewed to confirm the presence of RS. Secondary causes of SA were excluded. Genetic testing on the BM specimen was carried out when possible through research collaborations with the Boston Children's Hospital. Data was retrospectively extracted and is reported in Table 1. Data was analyzed based on the presence or absence of mitochondrial inheritance. Results: Seventeen patients with CSA were identified, 3 (17.6%) with mitochondrial inheritance. In the non-mitochondrial inheritance group, the median age at diagnosis was 29 years (range, 1-61 years). Six (42.9%) were males. At a median follow-up of 119 months (range, 1-401 months), 1 (7.1%) death was documented. The median overall survival (OS) has not been reached. Six of 14 (42.9%) underwent genetic testing, and a mutation was identified in 4 (ALAS -2, FECH -1, and a novel mutation, currently being validated). Six of 6 (100%) samples analyzed for SF3B1 mutations were negative. Median laboratory values at diagnosis included hemoglobin 9.5 g/dL, MCV 85.8, WBC 6.4, and platelets 297,000. Three (21.4%) patients had splenomegaly. Nine (64.3%) had iron overload; 3 (33%) were treated with iron chelation therapy, with only 1 documented response (≥ 500 µg/L reduction in serum ferritin). Twelve (85.7%) were treated with pyridoxine. Outcomes of pyridoxine treatment are described in Table 1. Three of 14 (21.4%) received red blood cell transfusions, and 3 (21.4%) received erythropoiesis stimulating agents (ESA). One (7.1%) patient underwent allogeneic stem cell transplant. Three patients had SAs of mitochondrial inheritance; aberrations were identified in 2 (YARS2 and a 4 kilobase mitochondrial deletion). In this group, the median age at diagnosis was 2 years (range, 1-13 years), and all were males. At a median follow-up of 173 months (range, 119-329 months), 2 (66.7%) deaths were documented. Median laboratory values at diagnosis included hemoglobin 9.0 g/dL, MCV 97.0, WBC 5.2, and platelets 175,000. Conclusions: Congenital SAs are rare, and the majority are of non-mitochondrial inheritance. The molecular basis for disease can be ascertained in less than 50% of patients. Unlike MDS with RS, CSAs are not characterized by the SF3B1 mutation, which may be used to establish clonality. With appropriate supportive care measures, survival for non-mitochondrially inherited CSA remains favorable. Table 1. Demographics and Outcomes for 17 Patients with CSA Age at Diagnosis (Years) Gender Molecular Mutation Additional Features Pyridoxine Response Iron Overload Survival (Months) Outcomes Non-Mitochondrial Inheritance 5 M R452H in ALAS2 N Y2 Y 173 Alive3 3 M Mutation being validated Splenomegaly Y2 Y 254 Alive3 6 M Unknown, PTPN11, ALAS 2, ABCB7 negative Splenomegaly N Y 137 Alive, status-post transplant 29 F Unknown1 N N/A N 131 Alive3 41 F Unknown1 N Y2 N 83 Alive4 40 M Promoter mutation in ALAS2 Splenomegaly N N 106 Alive4 31 F Unknown1 N N Y 401 Deceased 54 M Unknown1 N Lost to follow-up Y 1 Alive3 3 M FECH N N/A N 189 Alive3 1 F SCAD -VUS N Lost to follow-up Y 13 Alive3 29 F Unknown1 N N Y 205 Alive3 58 F Unknown1 N N Y 47 Alive, unknown transfusion status 61 F Unknown1 N Y2 Y 58 Alive3 23 F Unknown1 Alpha-thalassemia-2-trait Y2 N 37 Alive3 Mitochondrial Inheritance 13 M YARS2 MLASA N Y 329 Alive4 2 M Unknown, mitochondrial deletions and ABCB7 negative Myopathy, Ataxia N/A N 173 Deceased 1 M 4 kilobase mitochondrial deletion Pearson Syndrome, B cell lymphoma Y2 N 119 Deceased 1No molecular testing performed 2Sustained hemoglobin response of ≥ 1 g/dL over baseline for ≥ 12 weeks 3Transfusion-independent 4Transfusion-dependent Disclosures Steensma: Incyte: Consultancy; Onconova: Consultancy; Amgen: Consultancy; Celgene: Consultancy.
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Hatta, Shunsuke, Tohru Fujiwara, Takako Yamamoto, Mayumi Kamata, Yoshiko Tamai, Yukio Nakamura, Shin Kawamata, and Hideo Harigae. "Generation of Induced Pluripotent Stem Cell-Derived Erythroblasts from a Patient with X-Linked Sideroblastic Anemia." Blood 128, no. 22 (December 2, 2016): 76. http://dx.doi.org/10.1182/blood.v128.22.76.76.
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Abstract Congenital sideroblastic anemia (CSA) is an inherited microcytic anemia characterized by the presence of bone marrow ring sideroblasts, reflecting excess mitochondrial iron deposition. The most common form of CSA is X-linked sideroblastic anemia (XLSA), which is attributed to mutations in the X-linked gene erythroid-specific 5-aminolevulinate synthase (ALAS2). ALAS2 encodes the enzyme that catalyzes the first and rate-limiting steps in the heme biosynthesis pathway in erythroid cells. This pathway converts glycine and acetyl-coenzyme A to 5-aminolevulinic acid and also requires pyridoxal 5'-phosphate (PLP) as a cofactor. Although PLP has been used for treating XLSA, a marked proportion of patients with XLSA remain refractory to treatment (Ohba et al. Ann Hematol 2013). Therefore, to elucidate the details of the underlying molecular mechanisms that contribute to ringed sideroblast formation as well as to explore novel therapeutic strategies for XLSA, we generated induced pluripotent stem (iPS) cells from a patient with XLSA. Bone-marrow derived mesenchymal stem cells (BM-MSCs) were generated from a healthy volunteer and from the patient with XLSA, who harbored mutations in ALAS2 (c.T1737C, p.V562A). To establish iPS cells, episomal vectors encoding OCT3/4, SOX2, KLF4, L-MYC, LIN28, SHP53, and GLIS1 (gift from K. Okita, Kyoto University, Japan) were electroporated into BM-MSCs.The iPS cells were expanded in hESC medium containing DMEM/F-12 and 20% KSR (KnockoutTM Serum Replacement) (Life Technologies). We established one iPS clone from a healthy subject (NiPS) and two clones from the patient with XLSA (XiPS1 and XiPS2). G-band karyotype analysis demonstrated that all three clones had a normal karyotype. Immunocytochemical staining of the clones revealed the expression of transcription factors such as OCT3/4 and NANOG as well as surface markers such as SSEA-4 and TRA-1-60. Pluripotency of each clone was confirmed by the spontaneous differentiation of embryoid bodiesin vitro and teratoma formation in vivo. No clear characteristic differences were observed between XiPS and NiPS. Next, we evaluated the phenotype of iPS-derived erythroid precursors. The iPS cells were induced to undergo erythroid differentiation with Stemline II serum-free medium (Sigma). Both NiPS- and XiPS-derived erythroblasts were nucleated, and predominately expressed embryonic globin genes. Expression profiling of CD235a-positive erythroblasts from NiPS, XiPS1, and XiPS2, revealed 315 and 359 genes that were upregulated and downregulated (>1.5-fold), respectively, in XiPS relative to NiPS. The downregulated genes included globins (HBQ, HBG, HBE, HBD, and HBM) and genes involved in erythroid differentiation (GATA-1, ALAS2, KLF1, TAL1, and NFE2). Gene ontology analysis revealed significant (p < 0.01) enrichment of genes associated with erythroid differentiation, cellular iron homeostasis, and heme biosynthetic processes, implying that heme biosynthesis and erythroid differentiation are compromised in XiPS-derived erythroblasts. Finally, to examine whether XiPS-derived erythroblasts exhibited a phenotype reflective of defective ALAS2 enzymatic activity, we merged the microarray results with a previously reported microarray analysis in which ALAS2 was transiently knocked down using iPS-derived erythroid progenitor (HiDEP) cells (Fujiwara et al. BBRC 2014). The analysis revealed a relatively high degree of overlap regarding downregulated genes in XiPS relative to NiPS, demonstrating a >1.5-fold upregulation and downregulation of eight and 41 genes, respectively. Commonly downregulated genes included those encoding various globins (HBM, HBQ, HBE, HBG, and HBD) and ferritin (FTH1), GLRX5, ERAF, and ALAS2, which are involved in iron/heme metabolism in erythroid cells, suggesting that the phenotype of XiPS-derived erythroid cells resembles that of ALAS2-knockdown HiDEP cells. Interestingly, when the XiPS was induced to undergo erythroid differentiation by co-culture with OP9 stromal cells (ATCC), aberrant mitochondrial iron deposition was detected by prussian blue staining and electron microscope analysis. We are currently conducting biological analyses to characterize established ring sideroblasts. In summary, XiPS can be used as an important tool for clarifying the molecular etiology of XLSA and to explore novel therapeutic strategies. Disclosures Fujiwara: Chugai Pharmaceuticals. Co., Ltd.: Research Funding.
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Gagne, Katelyn E., Roxanne Ghazvinian, Daniel Yuan, Rebecca L. Zon, Kelsie Storm, Magdalena Mazur-Popinska, Laura Andolina, et al. "Pearson Marrow Pancreas Syndrome In a Cohort Of Diamond Blackfan Anemia Patients." Blood 122, no. 21 (November 15, 2013): 1226. http://dx.doi.org/10.1182/blood.v122.21.1226.1226.
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Abstract Pearson marrow pancreas syndrome (PS) is a congenital multisystem disorder characterized by sideroblastic anemia, pancreatic insufficiency, metabolic acidosis, and other defects, and is caused by mitochondrial DNA (mtDNA) deletions. Diamond Blackfan anemia (DBA) is a congenital hypoproliferative anemia with associated physical malformations, and in which mutations in ribosomal protein (RP) genes and GATA1 have been implicated. The clinical presentation of both of these bone marrow failure (BMF) syndromes shares several features including early onset of severe anemia, sporadic genetic inheritance, variable penetrance and manifestations, and episodes of spontaneous hematologic improvement. PS is less frequently occurring than DBA, with estimated incidences of < 1/1,000,000 versus 1/100,000 respectively, and therefore less often encountered by hematologists. We hypothesized that some patients in whom the leading clinical diagnosis is DBA actually have PS. To test this hypothesis, we retrospectively evaluated DNA samples from a cohort of patients that were submitted to a research study for DBA genetic testing. The study cohort consists of clinical samples and/or data from 362 patients, with a primary inclusion criterion of known or suspected congenital anemia. Prior genetic studies from this cohort have yielded the novel identification or confirmation of mutations and deletions in several genes implicated in DBA (e.g. RP genes, GATA1), which are to date identifiable in 175/362 samples (48%), a proportion consistent with that found in independent DBA registries. We screened peripheral blood DNA samples available from 173 genetically uncharacterized patients using a long PCR strategy, and found that 8 samples (4.6%) contained large mtDNA deletions. Deletion mapping and Southern blot analysis on DNA from these 8 patients confirmed the presence of a single deletion event within each patient, ranging in size from 2.3 - 7.0 kb of the 16.6 kb mitochondrial genome, existing as monomer or multimer mtDNA species, and in a proportion ranging from 55-80% of total mtDNA, all of which are consistent with the molecular diagnosis of PS. Follow-up with referring providers in the 1 month to 8 year time span since sample submission revealed that 2 of the 8 patients (25%) were subsequently diagnosed with PS. Of the remaining 6 undiagnosed patients, 2 had died from complications of bone marrow transplantation, performed for worsening cytopenias and concern for myelodysplasia; one patient died from bacterial sepsis; and 3 were alive with the provisional diagnosis of DBA. One of the 3 patients had become transfusion-independent. Review of bone marrow examinations revealed that the pathological hallmarks of ringed sideroblasts and/or vacuolization of precursors described in PS were inconsistently present or reported in the diagnostic evaluation. We conclude that PS is frequently overlooked in the diagnostic evaluation of children with congenital anemia. Establishing the diagnosis of PS, as distinct from DBA and other BMF disorders, holds important implications for patient management and family counseling. mtDNA deletion testing should be performed in the initial genetic evaluation of all patients with congenital anemia. Disclosures: Szczepanski: Octapharma AG: Investigator Other.
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Daher, Raêd, Abdellah Mansouri, Alain Martelli, Sophie Bayart, Hana Manceau, Isabelle Callebaut, Boualem Moulouel, et al. "GLRX5 mutations impair heme biosynthetic enzymes ALA synthase 2 and ferrochelatase in Human congenital sideroblastic anemia." Molecular Genetics and Metabolism 128, no. 3 (November 2019): 342–51. http://dx.doi.org/10.1016/j.ymgme.2018.12.012.
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Falcon, Corey P., and Thomas H. Howard. "An infant with Pearson syndrome: a rare cause of congenital sideroblastic anemia and bone marrow failure." Blood 129, no. 19 (May 11, 2017): 2710. http://dx.doi.org/10.1182/blood-2017-02-766881.
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Wiseman, Daniel H., Alison May, Stephen Jolles, Philip Connor, Colin Powell, Matthew M. Heeney, Patricia J. Giardina, et al. "A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD)." Blood 122, no. 1 (July 4, 2013): 112–23. http://dx.doi.org/10.1182/blood-2012-08-439083.
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Key Points A novel clinical syndrome of CSA, B-cell immunodeficiency, periodic fevers, and developmental delay is described. Bone marrow transplant resulted in complete and durable resolution of the hematologic and immunologic manifestations.
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Shamsian, Bibi Shahin, Mohammad Reza Jafari, Hassan Abolghasemi, Peyman Eshghi, Mohammad Ali Ehsani, Elham Shahgholi, Maryam Kazemi Aghdam, Atbin Latifi, and Mahnaz Jamee. "Allogenic Hematopoietic Stem Cell Transplant in Iranian Patients With Congenital Sideroblastic Anemia: A Single-Center Experience." Experimental and Clinical Transplantation 21, no. 1 (January 2023): 70–75. http://dx.doi.org/10.6002/ect.2022.0081.
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Fujiwara, Tohru, Chie Suzuki, Tetsuro Ochi, Koya Ono, Kei Saito, Noriko Fukuhara, Yasushi Onishi, et al. "Characterization of Congenital Sideroblastic Anemia Model Due to ABCB7 Defects: How Do Defects in Iron-Sulfur Cluster Metabolism Lead to Ring Sideroblast Formation?" Blood 134, Supplement_1 (November 13, 2019): 2232. http://dx.doi.org/10.1182/blood-2019-123918.
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Backgroun d: The sideroblastic anemias (SAs) are a group of congenital and acquired bone marrow disorderscharacterized by bone marrow ring sideroblasts (RSs). The disease commonly presents as myelodysplastic syndrome with RS (MDS-RS), known as an acquired clonal SA that is strongly correlated with a specific somatic mutation inSF3B1 (splicing factor 3b subunit 1), which is involved in RNA splicing machinery. Thus far, several studies have consistently revealed compromised splicing and/or expression of ABCB7 (ATP-binding cassette subfamily B member 7) in MDS-RS harboring the SF3B1 mutation. ABCB7 encodes an ATP-binding cassette family transporter localizing to the inner mitochondrial membrane, and its loss-of-function mutation causes a syndromic form of congenital SA, which is associated with cerebellar ataxia. The substrates transported by ABCB7 are predicted to be iron-sulfur clusters (ISCs), which are essential for the function of multiple mitochondrial and extramitochondrial proteins, such as ferrochelatase and aconitase (its apo-form without ISC is called IRP1; iron regulatory protein 1). However, the detailed molecular mechanisms by which defects in ISC metabolism resulting from ABCB7 defects contribute to RS formation remains to be fully elucidated. Methods: Endogenous ABCB7 was depleted based on pGIPZ lentiviral shRNAmir (Dharmacon) in human umbilical cord blood-derived erythroid progenitor (HUDEP)-2 cells (Kurita et al., PLoS ONE, 2013). Puromycin (Sigma) was used for the selection of transduced cells. To induce terminal erythroid differentiation, HUDEP-2 cells were co-cultured with OP9 stromal cells (ATCC) in Iscove's modified Dulbecco's medium supplemented with fetal bovine serum, erythropoietin, dexamethasone, monothioglycerol, insulin-transferrin-selenium, ascorbic acid, and sodium ferrous citrate (Saito and Fujiwara et al., MCB, 2019). For transcription profiling, Human Oligo Chip 25K (Toray) was used. Results: We first conducted ABCB7 knockdown in HUDEP-2 cells based on two independent shRNA plasmids. When the knockdown cells were induced to undergo erythroid differentiation,the majority of the erythroblasts exhibited aberrant mitochondrial iron deposition. Thus, we sought to clarify the potential causative link between ABCB7 defects and RS formation. Expression profiling revealed >1.5-fold up- and down-regulation of 33 and 44 genes, respectively, caused by the ABCB7 knockdown. Intriguingly, 43% of the downregulated gene ensemble (19/44 genes) included multiple ribosomal genes, such as RPS2, RPL11,and RPS12. The downregulated genes also included HMOX1 (heme oxygenase 1), implying that heme biosynthesis would be compromised by the knockdown. Gene ontology (GO) analysis revealed significant (p< 0.01) enrichment of genes associated with nuclear-transcribed mRNA catalytic process, cytoplasmic translation, and cellular iron ion homeostasis. Whereas the mRNA expression for ALAS2 (erythroid-specific 5-aminolevulinate synthase), encoding a rate-limiting enzyme of heme biosynthesis and one of the responsible genes for congenital SA, was not affected, its protein expression was noticeably decreased by ABCB7 knockdown, indicating that compromised transport of ISC from mitochondria to the cytosol may result in decreased ALAS2 translation by the binding of IRP1 to the iron-responsive element located in the 5'-UTR of ALAS2 mRNA.We are currently conducting detailed biological analyses to elucidate the causative link between defects in ISC metabolism due to ABCB7 defects and RS formation. Conclusion: We have first demonstrated the emergence of RS by ABCB7 depletion in human erythroblasts. Further characterization of the established SA model would aid in the clarification of its molecular etiology and the establishment of novel therapeutic strategies. Furthermore, our results may lead to a better understanding of the role of ISC in affecting cerebellar symptoms. Disclosures Fukuhara: Gilead: Research Funding; Nippon Shinkyaku: Honoraria; Zenyaku: Honoraria; AbbVie: Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Mundi: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Bayer: Research Funding; Celgene Corporation: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria, Research Funding; Janssen Pharma: Honoraria; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Solasia Pharma: Research Funding. Onishi:Novartis Pharma: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen Pharmaceutical K.K.: Honoraria; MSD: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku: Honoraria; Pfizer Japan Inc.: Honoraria; Kyowa-Hakko Kirin: Honoraria; Celgene: Honoraria. Yokoyama:Astellas: Other: Travel expenses.
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Fujiwara, Tohru, Ryoyu Niikuni, Koji Okamoto, Yoko Okitsu, Noriko Fukuhara, Yasushi Onishi, Kenichi Ishizawa, et al. "Exploring the Potential Usefulness of 5-Aminolevulinic Acid for X-Linked Sideroblastic Anemia." Blood 124, no. 21 (December 6, 2014): 215. http://dx.doi.org/10.1182/blood.v124.21.215.215.
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Abstract (Backgroun d) Congenital sideroblastic anemia (CSA) is an inherited disease; it is a microcytic type of anemia characterized by bone marrow sideroblasts with excess iron deposition in the mitochondria. The most common form of CSA is XLSA (X-linked sideroblastic anemia), which is attributed to mutations in the X-linked gene ALAS2 (erythroid-specific 5-aminolevulinate synthase). ALAS2 encodes the first and rate-limiting enzyme involved in heme biosynthesis in erythroid cells, which utilizes glycine and acetyl-coenzyme A to form 5-aminolevulinic acid (ALA) and also requires pyridoxal 5'-phosphate (PLP, vitamin B6) as a cofactor. Based on the evidence that half of the XLSA cases were unresponsive to PLP (Ohba et al. Ann Hematol 2013), ALA supplementation could emerge as an alternative therapeutic strategy to restore heme synthesis in CSA caused by ALAS2 defects. As a preclinical study, we focused our study on the effect of ALA on human erythroid cells. Furthermore, we investigated the molecular mechanism by which ALA is transported into erythroid cells. (Method ) Human K562 erythroid cells as well as human induced pluripotent stem-derived erythroid progenitor (HiDEP) cells (Kurita et al. PLoS ONE 2013) were used for the analysis. We investigated the effects of ALA (0.01, 0.1, and 0.5 mM for 72 h) on heme content, hemoglobinization, and erythroid-related gene expression. Heme content was determined fluorometrically at 400 nm (excitation) and 662 nm (emission). Small interfering RNA (siRNA)-mediated knockdown of ALAS2 was conducted using Amaxa Nucleofector™ (Amaxa Biosystems, Koln, Germany). For transcription profiling, Human Oligo chip 25K (Toray, Tokyo, Japan) was used for control and ALAS2 siRNA-treated HiDEP cells. Gamma-aminobutyric acid (GABA) (Sigma, St. Louis, MO, USA) was used at concentrations of 10 and 20 mM. (Results) First, we demonstrated that ALA treatment resulted in significant dose-dependent accumulation of heme in K562 cells. Concomitantly, the treatment substantially induces erythroid differentiation as assessed using hemoglobin (benzidine) staining. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis confirmed significant upregulation of heme-regulated genes such as the globin genes (HBA and HBG) and the heme oxygenase 1 (HMOX1) gene in K562 cells. To investigate the mechanism by which ALA was transported into erythroid cells, we conducted quantitative RT-PCR analysis for previously reported ALA transporters, including SLC15A1, SLC15A2, SLC36A1, and SLC6A13 (Frølund et al. Br J Pharmacol 2010; Ahlin et al. Drug Metab Dispos 2009; Moretti et al. Br J Cancer 2002). The analysis revealed that SLC36A1 was abundantly expressed in K562 and HiDEP cells. Thus, GABA was added to K562 cells to competitively inhibit SLC36A1-mediated transport (Frølund et al. Br J Pharmacol 2010). GABA treatment significantly impeded the ALA-mediated increase in the number of hemoglobinized cells. Next, siRNA-mediated knockdown of ALAS2 in HiDEP cells resulted in a significant decrease in the expression of globin genes as well as HMOX1; however, ringed sideroblasts were not observed. Microarray analysis revealed >2-fold up- and down-regulation of 38 and 68 genes caused by ALAS2 knockdown, respectively. The downregulated gene ensemble included globins (HBZ, HBG, HBE, HBD, and HBM) as well as genes involved in iron metabolism (ferritin heavy chain 1: FTH1, transferrin receptor: TFRC and glutaredoxin-1: GLRX5). Gene ontology analysis revealed significant enrichment of cellular iron ion homeostasis (p = 0.000076), cell division (p = 0.00062), DNA repair (p = 0.0006) and translation (p = 0.018), implying that heme was involved in various biological processes in erythroid cells. Interestingly, ALA treatment significantly improved the consequences of ALAS2 knockdown-mediated downregulation of HBA, HBG, and HMOX1. (Conclusion) ALA appears to enter into erythroid cells mainly by SLC36A1 and utilized to generate heme precursor. Thus,ALA may represent a novel therapeutic option for CSA, particularly for cases harboring ALAS2 mutations. Disclosures Fujiwara: Chugai Pharmaceutical, CO., LTD.: Research Funding.