1,085 results on '"Diamond–Blackfan anemia"'
Search Results
2. Investigation of the Genetics of Hematologic Diseases
- Author
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Boston Children's Hospital, University of Memphis, Monroe Carell Jr. Children's Hospital at Vanderbilt, Baylor College of Medicine, Children's Hospital of Philadelphia, and Dana-Farber Cancer Institute
- Published
- 2024
3. The Paradox of Ribosomal Insufficiency Coupled with Increased Cancer: Shifting the Perspective from the Cancer Cell to the Microenvironment.
- Author
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D'Andrea, Giacomo, Deroma, Giorgia, Miluzio, Annarita, and Biffo, Stefano
- Subjects
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TUMOR risk factors , *PROTEIN metabolism , *CELL proliferation , *IMMUNOTHERAPY , *LYMPHOCYTES , *CYTOPLASM , *TUMORS , *CARCINOGENESIS , *APLASTIC anemia , *NEUTROPENIA ,TUMOR genetics - Abstract
Simple Summary: Ribosomes are essential for the life of all cells. A reduction in the production of ribosomes always leads to a delay in cell cycle progression and to impaired growth, at least at the cellular level. We define ribosomopathies as a number of inherited monogenic diseases characterized by the partial loss of ribosomal factors. Not surprisingly, ribosomopathies show multi-organ signs and reduced cellular fitness. Strikingly, cancer is also a common comorbidity of ribosomopathies. The reconciliation of reduced growth with increased cancer risk poses an interpretative challenge. However, if we consider cancer as a systemic disease in which tumor cells thrive in a favorable microenvironment, we may find the right answers. Ribosomopathies are defined as inherited diseases in which ribosomal factors are mutated. In general, they present multiorgan symptoms. In spite of the fact that in cellular models, ribosomal insufficiency leads to a reduced rate of oncogenic transformation, patients affected by ribosomopathies present a paradoxical increase in cancer incidence. Several hypotheses that explain this paradox have been formulated, mostly on the assumption that altered ribosomes in a stem cell induce compensatory changes that lead to a cancer cell. For instance, the lack of a specific ribosomal protein can lead to the generation of an abnormal ribosome, an oncoribosome, that itself leads to altered translation and increased tumorigenesis. Alternatively, the presence of ribosomal stress may induce compensatory proliferation that in turns selects the loss of tumor suppressors such as p53. However, modern views on cancer have shifted the focus from the cancer cell to the tumor microenvironment. In particular, it is evident that human lymphocytes are able to eliminate mutant cells and contribute to the maintenance of cancer-free tissues. Indeed, many tumors develop in conditions of reduced immune surveillance. In this review, we summarize the current evidence and attempt to explain cancer and ribosomopathies from the perspective of the microenvironment. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
4. Associated Congenital Abnormalities and Physical Phenotype in Patients with Diamond–Blackfan Anemia May Be Overlooked.
- Author
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Soltanova, Gulare, Oral, Nihan Avcu, Gümrük, Fatma, Şimşek Kiper, Pelin Özlem, and Ünal, Şule
- Subjects
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PHYSICAL diagnosis , *CROSS-sectional method , *STATISTICAL significance , *ULTRASONIC imaging , *DESCRIPTIVE statistics , *APLASTIC anemia , *DATA analysis software , *MULTIPLE human abnormalities , *GENETIC testing , *PHENOTYPES , *ECHOCARDIOGRAPHY , *DISEASE complications ,ULTRASONIC imaging of the abdomen - Abstract
Objective: Diamond–Blackfan anemia (DBA) is a rare and inherited form of erythroid aplasia, characterized by severe macrocytic anemia, congenital malformations, and predisposition to cancer. The purpose of this study is to determine the congenital abnormalities and dysmorphological features of DBA patients in a cross-sectional manner. Materials and Methods: The study group included patients who had diagnosis of DBA between 1983 and 2017. Dysmorphological examinations of the patients were performed by an experienced dysmorphologist and also echocardiography and abdominal ultrasonography were performed in order to figure out cardiac and urogenital abnormalities. Results: A total of 45 patients were examined in this study. Dysmorphological examination, echocardiography, and abdominal ultrasonography revealed the rate of congenital abnormalities as high as 88.7%. In consideration of the congenital abnormalities, the most common findings were craniofacial, followed by skeletal abnormalities. Conclusion: The rate of anomalies was found higher in our series of patients than that have been previously reported, most probably due to the evaluations being performed by a dysmorphologist in our cohort and not only depending on patient records or hematologists’ physical examination. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
5. Towards a Cure for Diamond–Blackfan Anemia: Views on Gene Therapy.
- Author
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Vale, Matilde, Prochazka, Jan, and Sedlacek, Radislav
- Subjects
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GENE therapy , *HEMATOPOIETIC stem cell transplantation , *ANEMIA , *ERYTHROCYTES , *RIBOSOMAL proteins - Abstract
Diamond–Blackfan anemia (DBA) is a rare genetic disorder affecting the bone marrow's ability to produce red blood cells, leading to severe anemia and various physical abnormalities. Approximately 75% of DBA cases involve heterozygous mutations in ribosomal protein (RP) genes, classifying it as a ribosomopathy, with RPS19 being the most frequently mutated gene. Non-RP mutations, such as in GATA1, have also been identified. Current treatments include glucocorticosteroids, blood transfusions, and hematopoietic stem cell transplantation (HSCT), with HSCT being the only curative option, albeit with challenges like donor availability and immunological complications. Gene therapy, particularly using lentiviral vectors and CRISPR/Cas9 technology, emerges as a promising alternative. This review explores the potential of gene therapy, focusing on lentiviral vectors and CRISPR/Cas9 technology in combination with non-integrating lentiviral vectors, as a curative solution for DBA. It highlights the transformative advancements in the treatment landscape of DBA, offering hope for individuals affected by this condition. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
6. T-Cell Depleted Alternative Donor Bone Marrow Transplant for Sickle Cell Disease (SCD) and Other Anemias
- Author
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Paul Szabolcs, Chief, Division of Blood and Marrow Transplantation and Cellular Therapy
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- 2023
7. Probable digenic inheritance of Diamond–Blackfan anemia.
- Author
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Furuta, Yutaka, Tinker, Rory J, Gulsevin, Alican, Neumann, Serena M., Hamid, Rizwan, Cogan, Joy D., Rives, Lynette, Liu, Qi, Chen, Hua‐Chang, Joos, Karen M., and Phillips, John A.
- Abstract
A 26‐year‐old female proband with a clinical diagnosis and consistent phenotype of Diamond–Blackfan anemia (DBA, OMIM 105650) without an identified genotype was referred to the Undiagnosed Diseases Network. DBA is classically associated with monoallelic variants that have an autosomal‐dominant or ‐recessive mode of inheritance. Intriguingly, her case was solved by a detection of a digenic interaction between non‐allelic RPS19 and RPL27 variants. This was confirmed with a machine learning structural model, co‐segregation analysis, and RNA sequencing. This is the first report of DBA caused by a digenic effect of two non‐allelic variants demonstrated by machine learning structural model. This case suggests that atypical phenotypic presentations of DBA may be caused by digenic inheritance in some individuals. We also conclude that a machine learning structural model can be useful in detecting digenic models of possible interactions between products encoded by alleles of different genes inherited from non‐affected carrier parents that can result in DBA with an unrealized 25% recurrence risk. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
8. Inherited bone marrow failure syndromes: phenotype as a tool for early diagnostic suspicion at a major reference center in Mexico.
- Author
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Leal-Anaya, Paula, Kimball, Tamara N., Lucia Yanez-Felix, Ana, Fiesco-Roa, Moisés Ó., García-de Teresa, Benilde, Monsiváis, Angélica, Juárez-Velázquez, Rocío, Lieberman, Esther, Villarroel, Camilo, Yokoyama, Emiy, Fernández-Hernández, Liliana, Rivera-Osorio, Anet, Sosa, David, Ortiz Sandoval, Maria Magdalena, López-Santiago, Norma, Frías, Sara, del Castillo, Victoria, and Rodríguez, Alfredo
- Abstract
Introduction: The inherited bone marrow failure syndromes (IBMFSs) are a group of rare disorders characterized by bone marrow failure (BMF), physical abnormalities, and an increased risk of neoplasia. The National Institute of Pediatrics (INP) is a major medical institution in Mexico, where patients with BMF receive a complete approach that includes paraclinical tests. Readily recognizable features, such as the hematological and distinctive physical phenotypes, identified by clinical dysmorphologists, remain crucial for the diagnosis and management of these patients, particularly in circumstances where next-generation sequencing (NGS) is not easily available. Here, we describe a group of Mexican patients with a high clinical suspicion of an IBMFS. Methods: We performed a systematic retrospective analysis of the medical records of patients who had a high IBMFS suspicion at our institution from January 2018 to July 2021. An initial assessment included first ruling out acquired causes of BMF by the Hematology Department and referral of the patient to the Department of Human Genetics for physical examination to search for specific phenotypes suggesting an IBMFS. Patients with high suspicion of having an IBMFS were classified into two main groups: 1) specific IBMFS, including dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome (SDS), thrombocytopenia with absent radii (TAR), and severe congenital neutropenia (SCN); 2) undefined IBMFS (UI). Results: We established a high suspicion of having an IBMFS in 48 patients. At initial evaluation, the most common hematologic features were bicytopenia (20%) and aplastic anemia (16%); three patients received hematopoietic stem cell transplantation. Among patients with a suspicion of an IBMFS, the most common physical abnormality was minor craniofacial features in 83% of patients and neurodevelopmental disorders in 52%. The specific suspicions that we built were DBA (31%), SDS (18%), DC (14%), TAR (4%), and SCN (4%), whereas 27% of cases remained as undefined IBMFS. SDS, TAR, and SCN were more commonly suspected at an earlier age (<1 year), followed by DBA (2 years) and DC (5 years). Conclusions: Thorough examination of reported clinical data allowed us to highly suspect a specific IBMFS in approximately 70% of patients; however, an important number of patients remained with suspicion of an undefined IBMFS. Implementation of NGS and telomere length measurement are forthcoming measures to improve IBMFS diagnosis in Mexico. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
9. Phase I/II Pilot Study of Mixed Chimerism to Treat Hemoglobinopathies
- Author
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Duke University
- Published
- 2023
10. Human Placental-Derived Stem Cell Transplantation (HPDSC)
- Published
- 2022
11. The Diverse Genomic Landscape of Diamond–Blackfan Anemia: Two Novel Variants and a Mini-Review.
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Pelagiadis, Iordanis, Kyriakidis, Ioannis, Katzilakis, Nikolaos, Kosmeri, Chrysoula, Veltra, Danai, Sofocleous, Christalena, Glentis, Stavros, Kattamis, Antonis, Makis, Alexandros, and Stiakaki, Eftichia
- Subjects
GENETIC mutation ,APLASTIC anemia ,GENOMICS ,GENE expression profiling ,TRANSCRIPTION factors ,TUMORS ,PHENOTYPES - Abstract
Diamond–Blackfan anemia (DBA) is a ribosomopathy characterized by bone marrow erythroid hypoplasia, which typically presents with severe anemia within the first months of life. DBA is typically attributed to a heterozygous mutation in a ribosomal protein (RP) gene along with a defect in the ribosomal RNA (rRNA) maturation or levels. Besides classic DBA, DBA-like disease has been described with variations in 16 genes (primarily in GATA1, followed by ADA2 alias CECR1, HEATR3, and TSR2). To date, more than a thousand variants have been reported in RP genes. Splice variants represent 6% of identifiable genetic defects in DBA, while their prevalence is 14.3% when focusing on pathogenic and likely pathogenic (P/LP) variants, thus highlighting the impact of such alterations in RP translation and, subsequently, in ribosome levels. We hereby present two cases with novel pathogenic splice variants in RPS17 and RPS26. Associations of DBA-related variants with specific phenotypic features and malignancies and the molecular consequences of pathogenic variations for each DBA-related gene are discussed. The determinants of the spontaneous remission, cancer development, variable expression of the same variants between families, and selectivity of RP defects towards the erythroid lineage remain to be elucidated. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
12. A De Novo Frameshift Mutation in RPL5 with Classical Phenotype Abnormalities and Worsening Anemia Diagnosed in a Young Adult—A Case Report and Review of the Literature.
- Author
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Dorenkamp, Moritz, Porret, Naomi, Diepold, Miriam, and Rovó, Alicia
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LITERATURE reviews ,FRAMESHIFT mutation ,YOUNG adults ,RED blood cell transfusion ,ANEMIA - Abstract
Diamond–Blackfan anemia (DBA) is a congenital bone marrow failure syndrome associated with malformations. DBA is related to defective ribosome biogenesis, which impairs erythropoiesis, causing hyporegenerative macrocytic anemia. The disease has an autosomal dominant inheritance and is commonly diagnosed in the first year of life, requiring continuous treatment. We present the case of a young woman who, at the age of 21, developed severe symptomatic anemia. Although, due to malformations, a congenital syndrome had been suspected since birth, a confirmation diagnosis was not made until the patient was referred to our center for an evaluation of her anemia. In her neonatal medical history, she presented with anemia that required red blood cell transfusions, but afterwards remained with a stable, mild, asymptomatic anemia throughout her childhood and adolescence. Her family history was otherwise unremarkable. To explain the symptomatic anemia, vitamin deficiencies, autoimmune diseases, bleeding causes, and myeloid and lymphoid neoplasms were investigated and ruled out. A molecular investigation showed the RPL5 gene variant c.392dup, p.(Asn131Lysfs*6), confirming the diagnosis of DBA. All family members have normal blood values and none harbored the mutation. Here, we will discuss the unusual evolution of this case and revisit the literature. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
13. Identification of novel mutations in patients with Diamond‐Blackfan anemia and literature review of RPS10 and RPS26 mutations.
- Author
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Li, Jing, Su, Yongfeng, Chen, Long, Lin, Yani, and Ru, Kun
- Subjects
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APLASTIC anemia treatment , *STEROID drugs , *GENETIC mutation , *SEQUENCE analysis , *APLASTIC anemia , *RETROSPECTIVE studies , *TREATMENT effectiveness , *RESEARCH funding , *GENOTYPES , *RED blood cell transfusion , *RIBOSOMAL proteins , *SYMPTOMS - Abstract
Introduction: Diamond‐Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome characterized by erythroid aplasia, physical malformation, and cancer predisposition. Twenty ribosomal protein genes and three non‐ribosomal protein genes have been identified associated with DBA. Methods: To investigate the presence of novel mutations and gain a deeper understanding of the molecular mechanisms of disease, targeted next‐generation sequencing was performed in 12 patients with clinically suspected DBA. Literatures were retrieved with complete clinical information published in English by November 2022. The clinical features, treatment, and RPS10/RPS26 mutations were analyzed. Results: Among the 12 patients, 11 mutations were identified and 5 of them were novel (RPS19, p.W52S; RPS10, p.P106Qfs*11; RPS26, p.R28*; RPL5, p.R35*; RPL11, p.T44Lfs*40). Including 2 patients in this study, 13 patients with RPS10 mutations and 38 patients with RPS26 mutations were reported from 4 and 6 countries, respectively. The incidences of physical malformation in patients with RPS10 and RPS26 mutations (22% and 36%, respectively) were lower than the overall incidence in DBA patients (~50%). Patients with RPS26 mutations had a worse response rate of steroid therapy than RPS10 (47% vs. 87.5%), but preferred RBC transfusions (67% vs. 44%, p = 0.0253). Conclusion: Our findings add to the DBA pathogenic variant database and demonstrate the clinical presentations of the DBA patients with RPS10/RPS26 mutations. It shows that next‐generation sequencing is a powerful tool for the diagnosis of genetic diseases such as DBA. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
14. p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes.
- Author
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Rakotopare, Jeanne and Toledo, Franck
- Subjects
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TELOMERES , *P53 antioncogene , *BONE marrow , *FANCONI'S anemia , *RIBOSOMAL DNA , *DNA damage , *BRAIN abnormalities - Abstract
Mice with a constitutive increase in p53 activity exhibited features of dyskeratosis congenita (DC), a bone marrow failure syndrome (BMFS) caused by defective telomere maintenance. Further studies confirmed, in humans and mice, that germline mutations affecting TP53 or its regulator MDM4 may cause short telomeres and alter hematopoiesis, but also revealed features of Diamond–Blackfan anemia (DBA) or Fanconi anemia (FA), two BMFSs, respectively, caused by defects in ribosomal function or DNA repair. p53 downregulates several genes mutated in DC, either by binding to promoter sequences (DKC1) or indirectly via the DREAM repressor complex (RTEL1, DCLRE1B), and the p53-DREAM pathway represses 22 additional telomere-related genes. Interestingly, mutations in any DC-causal gene will cause telomere dysfunction and subsequent p53 activation to further promote the repression of p53-DREAM targets. Similarly, ribosomal dysfunction and DNA lesions cause p53 activation, and p53-DREAM targets include the DBA-causal gene TSR2, at least 9 FA-causal genes, and 38 other genes affecting ribosomes or the FA pathway. Furthermore, patients with BMFSs may exhibit brain abnormalities, and p53-DREAM represses 16 genes mutated in microcephaly or cerebellar hypoplasia. In sum, positive feedback loops and the repertoire of p53-DREAM targets likely contribute to partial phenotypic overlaps between BMFSs of distinct molecular origins. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
15. Inherited bone marrow failure syndromes: phenotype as a tool for early diagnostic suspicion at a major reference center in Mexico
- Author
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Paula Leal-Anaya, Tamara N. Kimball, Ana Lucia Yanez-Felix, Moisés Ó. Fiesco-Roa, Benilde García-de Teresa, Angélica Monsiváis, Rocío Juárez-Velázquez, Esther Lieberman, Camilo Villarroel, Emiy Yokoyama, Liliana Fernández-Hernández, Anet Rivera-Osorio, David Sosa, Maria Magdalena Ortiz Sandoval, Norma López-Santiago, Sara Frías, Victoria del Castillo, and Alfredo Rodríguez
- Subjects
inherited bone marrow failure syndrome ,dyskeratosis congenita ,Diamond–Blackfan anemia ,Shwachman–Diamond syndrome ,thrombocytopenia with absent radii ,severe congenital neutropenia ,Genetics ,QH426-470 - Abstract
Introduction: The inherited bone marrow failure syndromes (IBMFSs) are a group of rare disorders characterized by bone marrow failure (BMF), physical abnormalities, and an increased risk of neoplasia. The National Institute of Pediatrics (INP) is a major medical institution in Mexico, where patients with BMF receive a complete approach that includes paraclinical tests. Readily recognizable features, such as the hematological and distinctive physical phenotypes, identified by clinical dysmorphologists, remain crucial for the diagnosis and management of these patients, particularly in circumstances where next-generation sequencing (NGS) is not easily available. Here, we describe a group of Mexican patients with a high clinical suspicion of an IBMFS.Methods: We performed a systematic retrospective analysis of the medical records of patients who had a high IBMFS suspicion at our institution from January 2018 to July 2021. An initial assessment included first ruling out acquired causes of BMF by the Hematology Department and referral of the patient to the Department of Human Genetics for physical examination to search for specific phenotypes suggesting an IBMFS. Patients with high suspicion of having an IBMFS were classified into two main groups: 1) specific IBMFS, including dyskeratosis congenita (DC), Diamond–Blackfan anemia (DBA), Shwachman–Diamond syndrome (SDS), thrombocytopenia with absent radii (TAR), and severe congenital neutropenia (SCN); 2) undefined IBMFS (UI).Results: We established a high suspicion of having an IBMFS in 48 patients. At initial evaluation, the most common hematologic features were bicytopenia (20%) and aplastic anemia (16%); three patients received hematopoietic stem cell transplantation. Among patients with a suspicion of an IBMFS, the most common physical abnormality was minor craniofacial features in 83% of patients and neurodevelopmental disorders in 52%. The specific suspicions that we built were DBA (31%), SDS (18%), DC (14%), TAR (4%), and SCN (4%), whereas 27% of cases remained as undefined IBMFS. SDS, TAR, and SCN were more commonly suspected at an earlier age (
- Published
- 2024
- Full Text
- View/download PDF
16. The Paradox of Ribosomal Insufficiency Coupled with Increased Cancer: Shifting the Perspective from the Cancer Cell to the Microenvironment
- Author
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Giacomo D’Andrea, Giorgia Deroma, Annarita Miluzio, and Stefano Biffo
- Subjects
SBDS protein ,acute myeloid leukemia ,neutropenia ,Diamond–Blackfan anemia ,CD4+ ,CD8+ ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Ribosomopathies are defined as inherited diseases in which ribosomal factors are mutated. In general, they present multiorgan symptoms. In spite of the fact that in cellular models, ribosomal insufficiency leads to a reduced rate of oncogenic transformation, patients affected by ribosomopathies present a paradoxical increase in cancer incidence. Several hypotheses that explain this paradox have been formulated, mostly on the assumption that altered ribosomes in a stem cell induce compensatory changes that lead to a cancer cell. For instance, the lack of a specific ribosomal protein can lead to the generation of an abnormal ribosome, an oncoribosome, that itself leads to altered translation and increased tumorigenesis. Alternatively, the presence of ribosomal stress may induce compensatory proliferation that in turns selects the loss of tumor suppressors such as p53. However, modern views on cancer have shifted the focus from the cancer cell to the tumor microenvironment. In particular, it is evident that human lymphocytes are able to eliminate mutant cells and contribute to the maintenance of cancer-free tissues. Indeed, many tumors develop in conditions of reduced immune surveillance. In this review, we summarize the current evidence and attempt to explain cancer and ribosomopathies from the perspective of the microenvironment.
- Published
- 2024
- Full Text
- View/download PDF
17. Towards a Cure for Diamond–Blackfan Anemia: Views on Gene Therapy
- Author
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Matilde Vale, Jan Prochazka, and Radislav Sedlacek
- Subjects
Diamond–Blackfan anemia ,ribosomopathy ,ribosomal protein genes ,rare genetic disorder ,hematopoietic stem cell transplantation ,gene therapy ,Cytology ,QH573-671 - Abstract
Diamond–Blackfan anemia (DBA) is a rare genetic disorder affecting the bone marrow’s ability to produce red blood cells, leading to severe anemia and various physical abnormalities. Approximately 75% of DBA cases involve heterozygous mutations in ribosomal protein (RP) genes, classifying it as a ribosomopathy, with RPS19 being the most frequently mutated gene. Non-RP mutations, such as in GATA1, have also been identified. Current treatments include glucocorticosteroids, blood transfusions, and hematopoietic stem cell transplantation (HSCT), with HSCT being the only curative option, albeit with challenges like donor availability and immunological complications. Gene therapy, particularly using lentiviral vectors and CRISPR/Cas9 technology, emerges as a promising alternative. This review explores the potential of gene therapy, focusing on lentiviral vectors and CRISPR/Cas9 technology in combination with non-integrating lentiviral vectors, as a curative solution for DBA. It highlights the transformative advancements in the treatment landscape of DBA, offering hope for individuals affected by this condition.
- Published
- 2024
- Full Text
- View/download PDF
18. Pure Red Cell Aplasia Encountered in a Tertiary Care Hematology Laboratory: A Series of Nine Distinctive Cases
- Author
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Mansi Kala, Kunal Das, Avriti Baveja, Manish Raturi, Meghali Dhebane, Sohaib Ahmad, and Mansi Mehrotra
- Subjects
diamond-blackfan anemia ,red cell transfusion ,erythroblasts ,severe anemia ,Medicine - Abstract
Pure red cell aplasia (PRCA) is characterized by severe anemia with reticulocytopenia and bone marrow erythroblastopenia. The early erythroblasts are markedly decreased; however, in rare instances, they may be normal or raised in number. There are varied etiologies, namely congenital or acquired and primary or secondary. The congenital PRCA is known as “Diamond-Blackfan anemia.” Thymomas, autoimmune disease, lymphomas, infections, and drugs also may be familiar associates. However, the etiologies of PRCA are numerous, and many diseases/infections can be associated with PRCA. The diagnosis rests on clinical suspicion and appropriate laboratory workup. We evaluated nine cases of red cell aplasia, having severe anemia with reticulocytopenia. Nearly half of the cases showed adequate erythroid (> 5% of the differential count) but with a maturation arrest. The adequacy of the erythroid could confuse the hematologist and may even delay the diagnosis. Hence, it is empirical that PRCA could be considered a differential in every case of severe anemia with reticulocytopenia, even in the presence of adequate erythroid precursors in the bone marrow.
- Published
- 2023
- Full Text
- View/download PDF
19. Hematopoietic cell transplantation and gene therapy for Diamond-Blackfan anemia: state of the art and science
- Author
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Senthil Velan Bhoopalan, Shruthi Suryaprakash, Akshay Sharma, and Marcin W. Wlodarski
- Subjects
Diamond-Blackfan anemia ,DBA ,anemia ,HCT ,HSCT ,gene therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Diamond-Blackfan anemia (DBA) is one of the most common inherited causes of bone marrow failure in children. DBA typically presents with isolated erythroid hypoplasia and anemia in infants. Congenital anomalies are seen in 50% of the patients. Over time, many patients experience panhematopoietic defects resulting in immunodeficiency and multilineage hematopoietic cytopenias. Additionally, DBA is associated with increased risk of myelodysplastic syndrome, acute myeloid leukemia and solid organ cancers. As a prototypical ribosomopathy, DBA is caused by heterozygous loss-of-function mutations or deletions in over 20 ribosomal protein genes, with RPS19 being involved in 25% of patients. Corticosteroids are the only effective initial pharmacotherapy offered to transfusion-dependent patients aged 1 year or older. However, despite good initial response, only ~20-30% remain steroid-responsive while the majority of the remaining patients will require life-long red blood cell transfusions. Despite continuous chelation, iron overload and related toxicities pose a significant morbidity problem. Allogeneic hematopoietic cell transplantation (HCT) performed to completely replace the dysfunctional hematopoietic stem and progenitor cells is a curative option associated with potentially uncontrollable risks. Advances in HLA-typing, conditioning regimens, infection management, and graft-versus-host-disease prophylaxis have led to improved transplant outcomes in DBA patients, though survival is suboptimal for adolescents and adults with long transfusion-history and patients lacking well-matched donors. Additionally, many patients lack a suitable donor. To address this gap and to mitigate the risk of graft-versus-host disease, several groups are working towards developing autologous genetic therapies to provide another curative option for DBA patients across the whole age spectrum. In this review, we summarize the results of HCT studies and review advances and potential future directions in hematopoietic stem cell-based therapies for DBA.
- Published
- 2023
- Full Text
- View/download PDF
20. Pure Red Cell Aplasia Encountered in a Tertiary Care Hematology Laboratory: A Series of Nine Distinctive Cases.
- Author
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Kala, Mansi, Das, Kunal, Baveja, Avriti, Raturi, Manish, Dhebane, Meghali, Ahmad, Sohaib, and Mehrotra, Mansi
- Subjects
- *
PURE red cell aplasia , *HEMATOLOGY , *TERTIARY care , *BONE marrow , *ERYTHROCYTES , *DELAYED diagnosis , *PATHOLOGICAL laboratories - Abstract
Pure red cell aplasia (PRCA) is characterized by severe anemia with reticulocytopenia and bone marrow erythroblastopenia. The early erythroblasts are markedly decreased; however, in rare instances, they may be normal or raised in number. There are varied etiologies, namely congenital or acquired and primary or secondary. The congenital PRCA is known as "Diamond-Blackfan anemia." Thymomas, autoimmune disease, lymphomas, infections, and drugs also may be familiar associates. However, the etiologies of PRCA are numerous, and many diseases/infections can be associated with PRCA. The diagnosis rests on clinical suspicion and appropriate laboratory workup. We evaluated nine cases of red cell aplasia, having severe anemia with reticulocytopenia. Nearly half of the cases showed adequate erythroid (> 5% of the differential count) but with a maturation arrest. The adequacy of the erythroid could confuse the hematologist and may even delay the diagnosis. Hence, it is empirical that PRCA could be considered a differential in every case of severe anemia with reticulocytopenia, even in the presence of adequate erythroid precursors in the bone marrow. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
21. Molecular etiology of defective nuclear and mitochondrial ribosome biogenesis: Clinical phenotypes and therapy.
- Author
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Jerome, Maria Sona, Nanjappa, Dechamma Pandyanda, Chakraborty, Anirban, and Chakrabarty, Sanjiban
- Subjects
- *
RIBOSOMES , *ORGANELLE formation , *MITOCHONDRIA formation , *TUMOR suppressor proteins , *MITOCHONDRIA , *PHENOTYPES , *P53 antioncogene , *GENETIC translation - Abstract
Ribosomopathies are rare congenital disorders associated with defective ribosome biogenesis due to pathogenic variations in genes that encode proteins related to ribosome function and biogenesis. Defects in ribosome biogenesis result in a nucleolar stress response involving the TP53 tumor suppressor protein and impaired protein synthesis leading to a deregulated translational output. Despite the accepted notion that ribosomes are omnipresent and essential for all cells, most ribosomopathies show tissue-specific phenotypes affecting blood cells, hair, spleen, or skin. On the other hand, defects in mitochondrial ribosome biogenesis are associated with a range of clinical manifestations affecting more than one organ. Intriguingly, the deregulated ribosomal function is also a feature in several human malignancies with a selective upregulation or downregulation of specific ribosome components. Here, we highlight the clinical conditions associated with defective ribosome biogenesis in the nucleus and mitochondria with a description of the affected genes and the implicated pathways, along with a note on the treatment strategies currently available for these disorders. • Ribosomopathies are rare congenital disorders associated with defective ribosome biogenesis in the nucleus and mitochondria. • Most ribosomopathies show tissue-specific phenotypes affecting blood cells, hair, spleen, or skin. • Mitochondrial ribosomopathies are associated with heterogeneous clinical manifestations affecting multiple organs. • Clinical diagnosis and developing therapeutic strategies for ribosomopathies are of paramount importance. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
22. De novo intronic GATA1 mutation leads to diamond-blackfan anemia like disease.
- Author
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Shan Liu, Kunlin Pei, Lu Chen, Jing Wu, Qiuling Chen, Jinyan Zhang, Hui Zhang, and Chengyi Wang
- Subjects
ANEMIA ,GENETIC mutation ,ERYTHROPOIESIS - Abstract
GATA1 is required for normal erythropoiesis. Exonic/intronic GATA1 mutations causes Diamond-Blackfan Anemia (DBA)-like disease. Herein, we present a case of a 5-year-old boy with anemia of unknown etiology. Whole-exome sequencing revealed a de novo GATA1 c.220 + 1G>C mutation. The reporter gene assay revealed that such mutations did not affect on GATA1 transcriptional activity. The normal transcription of GATA1 was disturbed, as evidenced by increased expression of the shorter GATA1 isoform. RDDS prediction analysis revealed that abnormal GATA1 splicing might be the underlying mechanism disrupting GATA1 transcription, thereby impairing erythropoiesis. Prednisone treatment significantly improved erythropoiesis, evidenced by increased hemoglobin and reticulocyte counts. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
23. Unusual Association of Diamond–Blackfan Anemia and Severe Sinus Bradycardia in a Six-Month-Old White Infant: A Case Report and Literature Review.
- Author
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Moisa, Stefana Maria, Spoiala, Elena-Lia, Trandafir, Laura Mihaela, Butnariu, Lacramioara Ionela, Miron, Ingrith-Crenguta, Ciobanu, Antonela, Mocanu, Adriana, Ivanov, Anca, Ciongradi, Carmen Iulia, Sarbu, Ioan, Ciubara, Anamaria, Rusu, Carmen Daniela, Luca, Alina Costina, and Burlacu, Alexandru
- Subjects
ARRHYTHMIA ,BRADYCARDIA ,LEFT ventricular hypertrophy ,PATENT foramen ovale ,CENTRAL venous catheters ,ANEMIA - Abstract
Diamond–Blackfan anemia is a rare (6–7 million live births), inherited condition manifesting as severe anemia due to the impaired bone marrow production of red blood cells. We present the unusual case of a six month old infant with a de novo mutation of the RPS19 gene causing Diamond–Blackfan anemia who additionally suffers from severe sinus bradycardia. The infant was diagnosed with this condition at the age of four months; at the age of 6 months, she presents with severe anemia causing hypoxia which, in turn, caused severe dyspnea and polypnea, which had mixed causes (hypoxic and infectious) as the child was febrile. After correction of the overlapping diarrhea, metabolic acidosis, and severe anemia (hemoglobin < 3 g/dL), she developed severe persistent sinus bradycardia immediately after mild sedation (before central venous catheter insertion), not attributable to any of the more frequent causes, with a heart rate as low as 49 beats/min on 24 h Holter monitoring, less than the first percentile for age, but with a regular QT interval and no arrhythmia. The echocardiogram was unremarkable, showing a small interatrial communication (patent foramen ovale with left-to-right shunting), mild left ventricular hypertrophy, normal systolic and diastolic function, and mild tricuspid regurgitation. After red cell transfusion and appropriate antibiotic and supportive treatment, the child's general condition improved dramatically but the sinus bradycardia persisted. We consider this a case of well-tolerated sinus bradycardia and foresee a good cardiologic prognosis, while the hematologic prognosis remains determined by future corticoid response, treatment-related complications and risk of leukemia. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
24. Splice‐site variant in the RPS7 5′‐UTR leads to a decrease in the mRNA level and development of Diamond‐Blackfan anemia.
- Author
-
Skorodumova, Liubov O., Davydenko, Ksenia A., Filatova, Alexandra Y., Skoblov, Mikhail Yu, Kulemin, Nikolay A., Khadzhieva, Maryam B., Zakharova, Elena S., Gordeeva, Veronika D., Smetanina, Nataliya S., Fedyushkina, Irina V., Anastasevich, Lyudmila A., and Larin, Sergey S.
- Subjects
- *
PURE red cell aplasia , *GENE expression , *DNA copy number variations , *ANEMIA , *RIBOSOMAL proteins - Abstract
Diamond‐Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by erythroid aplasia. Pathogenic variants in ribosomal protein (RP) genes, GATA1, TSR2, and EPO, are considered to be the etiology of DBA. Variants in 5′‐untranslated regions (UTRs) of these genes are poorly studied and can complicate the variant interpretation. We investigated the functional consequences NM_001011.4:c.‐19 + 1G > T variant in the donor splice‐site of the RPS7 5′‐UTR. This variant was found in a family where two sons with DBA were carriers. Father, who also had this variant, developed myelodysplastic syndrome, which caused his death. Search for candidate causal variants and copy number variations in DBA‐associated genes left RPS7 variant as the best candidate. Trio whole exome sequencing analysis revealed no pathogenic variants in other genes. Functional analysis using luciferase expression system revealed that this variant leads to disruption of splicing. Also, a decrease in the levels of mRNA and protein expression was detected. In conclusion, the established consequences of 5′‐UTR splice‐site variant c.‐19 + 1G > T in the RPS7 gene provide evidence that it is likely pathogenic. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
25. The Diverse Genomic Landscape of Diamond–Blackfan Anemia: Two Novel Variants and a Mini-Review
- Author
-
Iordanis Pelagiadis, Ioannis Kyriakidis, Nikolaos Katzilakis, Chrysoula Kosmeri, Danai Veltra, Christalena Sofocleous, Stavros Glentis, Antonis Kattamis, Alexandros Makis, and Eftichia Stiakaki
- Subjects
Diamond–Blackfan anemia ,splicing ,splice variants ,mutation ,ribosome ,ribosomal proteins ,Pediatrics ,RJ1-570 - Abstract
Diamond–Blackfan anemia (DBA) is a ribosomopathy characterized by bone marrow erythroid hypoplasia, which typically presents with severe anemia within the first months of life. DBA is typically attributed to a heterozygous mutation in a ribosomal protein (RP) gene along with a defect in the ribosomal RNA (rRNA) maturation or levels. Besides classic DBA, DBA-like disease has been described with variations in 16 genes (primarily in GATA1, followed by ADA2 alias CECR1, HEATR3, and TSR2). To date, more than a thousand variants have been reported in RP genes. Splice variants represent 6% of identifiable genetic defects in DBA, while their prevalence is 14.3% when focusing on pathogenic and likely pathogenic (P/LP) variants, thus highlighting the impact of such alterations in RP translation and, subsequently, in ribosome levels. We hereby present two cases with novel pathogenic splice variants in RPS17 and RPS26. Associations of DBA-related variants with specific phenotypic features and malignancies and the molecular consequences of pathogenic variations for each DBA-related gene are discussed. The determinants of the spontaneous remission, cancer development, variable expression of the same variants between families, and selectivity of RP defects towards the erythroid lineage remain to be elucidated.
- Published
- 2023
- Full Text
- View/download PDF
26. A De Novo Frameshift Mutation in RPL5 with Classical Phenotype Abnormalities and Worsening Anemia Diagnosed in a Young Adult—A Case Report and Review of the Literature
- Author
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Moritz Dorenkamp, Naomi Porret, Miriam Diepold, and Alicia Rovó
- Subjects
bone marrow failure ,pure red cell aplasia ,erythroaplasia ,Diamond–Blackfan anemia ,RPL5 ,ribosomopathy ,Medicine (General) ,R5-920 - Abstract
Diamond–Blackfan anemia (DBA) is a congenital bone marrow failure syndrome associated with malformations. DBA is related to defective ribosome biogenesis, which impairs erythropoiesis, causing hyporegenerative macrocytic anemia. The disease has an autosomal dominant inheritance and is commonly diagnosed in the first year of life, requiring continuous treatment. We present the case of a young woman who, at the age of 21, developed severe symptomatic anemia. Although, due to malformations, a congenital syndrome had been suspected since birth, a confirmation diagnosis was not made until the patient was referred to our center for an evaluation of her anemia. In her neonatal medical history, she presented with anemia that required red blood cell transfusions, but afterwards remained with a stable, mild, asymptomatic anemia throughout her childhood and adolescence. Her family history was otherwise unremarkable. To explain the symptomatic anemia, vitamin deficiencies, autoimmune diseases, bleeding causes, and myeloid and lymphoid neoplasms were investigated and ruled out. A molecular investigation showed the RPL5 gene variant c.392dup, p.(Asn131Lysfs*6), confirming the diagnosis of DBA. All family members have normal blood values and none harbored the mutation. Here, we will discuss the unusual evolution of this case and revisit the literature.
- Published
- 2023
- Full Text
- View/download PDF
27. p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes
- Author
-
Jeanne Rakotopare and Franck Toledo
- Subjects
p53 ,DREAM repressor complex ,dyskeratosis congenita ,Fanconi anemia ,Diamond–Blackfan anemia ,microcephaly ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Mice with a constitutive increase in p53 activity exhibited features of dyskeratosis congenita (DC), a bone marrow failure syndrome (BMFS) caused by defective telomere maintenance. Further studies confirmed, in humans and mice, that germline mutations affecting TP53 or its regulator MDM4 may cause short telomeres and alter hematopoiesis, but also revealed features of Diamond–Blackfan anemia (DBA) or Fanconi anemia (FA), two BMFSs, respectively, caused by defects in ribosomal function or DNA repair. p53 downregulates several genes mutated in DC, either by binding to promoter sequences (DKC1) or indirectly via the DREAM repressor complex (RTEL1, DCLRE1B), and the p53-DREAM pathway represses 22 additional telomere-related genes. Interestingly, mutations in any DC-causal gene will cause telomere dysfunction and subsequent p53 activation to further promote the repression of p53-DREAM targets. Similarly, ribosomal dysfunction and DNA lesions cause p53 activation, and p53-DREAM targets include the DBA-causal gene TSR2, at least 9 FA-causal genes, and 38 other genes affecting ribosomes or the FA pathway. Furthermore, patients with BMFSs may exhibit brain abnormalities, and p53-DREAM represses 16 genes mutated in microcephaly or cerebellar hypoplasia. In sum, positive feedback loops and the repertoire of p53-DREAM targets likely contribute to partial phenotypic overlaps between BMFSs of distinct molecular origins.
- Published
- 2023
- Full Text
- View/download PDF
28. Multi-Center Study of Iron Overload: Pilot Study (MCSIO)
- Author
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University College London (UCL) Cancer Institute, Universitätsklinikum Hamburg-Eppendorf, Medical University Innsbruck, and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Published
- 2020
29. Multi-Center Study of Iron Overload: Survey Study (MCSIO) (MCSIO)
- Author
-
University College London (UCL) Cancer Institute, Universitätsklinikum Hamburg-Eppendorf, Medical University Innsbruck, and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Published
- 2020
30. CD34+ (Non-Malignant) Stem Cell Selection for Patients Receiving Allogeneic Stem Cell Transplantation
- Author
-
Diane George, Assistant Professor of Pediatrics
- Published
- 2020
31. Stem Cell Transplant for Hemoglobinopathy
- Author
-
National Marrow Donor Program
- Published
- 2020
32. Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
- Author
-
John Horan, Associate Professor
- Published
- 2019
33. 先天性纯红细胞再生障碍性贫血患儿 肥胖发生情况及影响因素分析.
- Author
-
易美慧, 万扬, 程思琪, 巩晓文, 尹梓溪, 李俊, 高洋洋, 吴超, 宗苏玉, 常丽贤, 陈玉梅, 郑荣秀, and 竺晓凡
- Subjects
CHILDHOOD obesity ,MEDICAL sciences ,BLOOD diseases ,DRUG dosage ,RIBOSOMAL proteins - Abstract
Copyright of Chinese Journal of Contemporary Pediatrics is the property of Xiangya Medical Periodical Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2022
- Full Text
- View/download PDF
34. Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
- Published
- 2019
35. Bone Marrow Failure Disorders in the Adolescent Female
- Author
-
Sasa, Ghadir S., Vlachos, Adrianna, and Srivaths, Lakshmi V., editor
- Published
- 2020
- Full Text
- View/download PDF
36. DNA Methyl Transferase 3A (DNMT3A) Mutation Presenting as Isolated Pure Red Cell Aplasia.
- Author
-
Sidda, Adarsh, Manu, Gurusidda, Alsharedi, Mohamed, Dotson, Jennifer, and Nahar, Niru
- Abstract
Pure red cell aplasia (PRCA) is a rare disorder mainly affecting the erythroid precursor cells. It presents with severe isolated reticulocytopenia with relatively normal counts in the myeloid and megakaryocytic lineages. It has been attributed to numerous congenital and acquired causes. DNA Methyl Transferase 3 Alpha (DNMT3A) mutation has been typically associated with myeloid and lymphoid malignancies. There is a scarcity of data regarding the association of DNMT3A mutation with PRCA. We report a case of a 73-year-old man who initially presented with anemia and reticulocytopenia. After a thorough evaluation and eventual bone marrow biopsy, he was diagnosed with PRCA. Further genetic testing identified a DNMT3A mutation. We are reporting this rare case to highlight the fact that DNMT3A mutation can also present as isolated PRCA in and of itself without the co-occurrence of leukemia, lymphoma, or myelodysplastic syndrome (MDS). [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
37. Patent Application Titled "Translational Activators, Including Methods of Discovery and Uses Thereof" Published Online (USPTO 20240277799).
- Subjects
PATENT applications ,INTERNET publishing ,RIBOSOMAL proteins ,GENETIC translation ,GENE expression ,NATIVE Americans - Abstract
The article discusses the online publication of a patent application titled "Translational Activators, Including Methods of Discovery and Uses Thereof" by Barna and Lantz, filed by Stanford University. Topics include the use of macrolides for treating disorders caused by insufficient global protein synthesis, specific medical conditions addressed such as Diamond-Blackfan Anemia, and methods for diagnosing and screening translational activator compounds.
- Published
- 2024
38. Research from Center for Cancer and Blood Disorders Provides New Data on Diamond Blackfan Anemia (De Novo Variant in the RPL27 Gene in a Second Infant with Diamond-Blackfan Anemia).
- Subjects
ANEMIA ,GENETIC variation ,INFANTS ,RESEARCH institutes ,BLOOD diseases - Abstract
A recent study conducted by the Center for Cancer and Blood Disorders has provided new data on Diamond Blackfan Anemia (DBA). The study focused on a 10-month-old female with DBA who presented with macrocytic anemia and reticulocytopenia. Whole exome sequencing revealed a de novo intronic variant in the RPL27 gene, which is associated with DBA. The researchers concluded that this case expands the clinical spectrum of RPL27-associated DBA and highlights the importance of reclassifying this gene as likely pathogenic. Further research is needed to assess the functional significance of this variant and its implications for genetic testing and therapeutic strategies. [Extracted from the article]
- Published
- 2024
39. Study Findings from Institute of Molecular Genetics of the Czech Academy of Sciences Update Knowledge in Gene Therapy (Towards a Cure for Diamond-Blackfan Anemia: Views on Gene Therapy).
- Abstract
A recent study conducted by the Institute of Molecular Genetics of the Czech Academy of Sciences has provided new insights into gene therapy for Diamond-Blackfan anemia (DBA), a rare genetic disorder that affects the production of red blood cells in the bone marrow. The study highlights the potential of gene therapy, particularly using lentiviral vectors and CRISPR/Cas9 technology, as a promising alternative to current treatments such as glucocorticosteroids, blood transfusions, and hematopoietic stem cell transplantation. The researchers believe that these transformative advancements in treatment offer hope for individuals affected by DBA. [Extracted from the article]
- Published
- 2024
40. Transplantation using targeted busulfan for Diamond–Blackfan anemia.
- Author
-
Kato, Shota, Nakano, Yoshiko, Hidaka, Moe, Sekiguchi, Masahiro, Watanabe, Kentaro, Fujimura, Junya, and Kato, Motohiro
- Subjects
- *
APLASTIC anemia treatment , *GANCICLOVIR , *HLA-B27 antigen , *INTRAVENOUS therapy , *BONE marrow transplantation , *APLASTIC anemia , *FERRITIN , *TREATMENT effectiveness , *BUSULFAN , *HEMATOPOIETIC stem cell transplantation , *RADIOTHERAPY , *ROUTINE diagnostic tests - Abstract
The article presents a case study of a three year old with Diamond–Blackfan anemia (DBA) who underwent allogeneic hematopoietic cell transplantation (HCT). It is reported that the patient received reduced-intensity conditioning with targeted busulfan. It is further reported that the patient achieved successful engraftment, became transfusion-independent, and showed no severe adverse events during the 12-month follow-up.
- Published
- 2023
- Full Text
- View/download PDF
41. Allo-HCT MUD for Non-malignant Red Blood Cell (RBC) Disorders: Sickle Cell, Thal, and DBA: Reduced Intensity Conditioning, Co-tx MSCs
- Author
-
University of Minnesota, University of Alabama at Birmingham, and Sandhya Kharbanda, Principle Investigator
- Published
- 2018
42. Diamond-Blackfan anemia, the archetype of ribosomopathy: How distinct is it from the other constitutional ribosomopathies?
- Author
-
Da Costa, L., Mohandas, Narla, David-NGuyen, Ludivine, Platon, Jessica, Marie, Isabelle, O'Donohue, Marie Françoise, Leblanc, Thierry, and Gleizes, Pierre-Emmanuel
- Subjects
- *
APLASTIC anemia , *ANEMIA , *BLOOD diseases , *RIBOSOMAL proteins , *RIBOSOMAL RNA - Abstract
Diamond-Blackfan anemia (DBA) was the first ribosomopathy described in humans. DBA is a congenital hypoplastic anemia, characterized by macrocytic aregenerative anemia, manifesting by differentiation blockage between the BFU-e/CFU-e developmental erythroid progenitor stages. In 50 % of the DBA cases, various malformations are noted. Strikingly, for a hematological disease with a relative erythroid tropism, DBA is due to ribosomal haploinsufficiency in 24 different ribosomal protein (RP) genes. A few other genes have been described in DBA-like disorders, but they do not fit into the classical DBA phenotype (Sankaran et al., 2012; van Dooijeweert et al., 2022; Toki et al., 2018; Kim et al., 2017 [ 1–4 ]). Haploinsufficiency in a RP gene leads to defective ribosomal RNA (rRNA) maturation, which is a hallmark of DBA. However, the mechanistic understandings of the erythroid tropism defect in DBA are still to be fully defined. Erythroid defect in DBA has been recently been linked in a non-exclusive manner to a number of mechanisms that include: 1) a defect in translation, in particular for the GATA1 erythroid gene; 2) a deficit of HSP70, the GATA1 chaperone, and 3) free heme toxicity. In addition, p53 activation in response to ribosomal stress is involved in DBA pathophysiology. The DBA phenotype may thus result from the combined contributions of various actors, which may explain the heterogenous phenotypes observed in DBA patients, even within the same family. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
43. Unusual Association of Diamond–Blackfan Anemia and Severe Sinus Bradycardia in a Six-Month-Old White Infant: A Case Report and Literature Review
- Author
-
Stefana Maria Moisa, Elena-Lia Spoiala, Laura Mihaela Trandafir, Lacramioara Ionela Butnariu, Ingrith-Crenguta Miron, Antonela Ciobanu, Adriana Mocanu, Anca Ivanov, Carmen Iulia Ciongradi, Ioan Sarbu, Anamaria Ciubara, Carmen Daniela Rusu, Alina Costina Luca, and Alexandru Burlacu
- Subjects
Diamond–Blackfan anemia ,severe persistent sinus bradycardia ,rare diseases association ,Medicine (General) ,R5-920 - Abstract
Diamond–Blackfan anemia is a rare (6–7 million live births), inherited condition manifesting as severe anemia due to the impaired bone marrow production of red blood cells. We present the unusual case of a six month old infant with a de novo mutation of the RPS19 gene causing Diamond–Blackfan anemia who additionally suffers from severe sinus bradycardia. The infant was diagnosed with this condition at the age of four months; at the age of 6 months, she presents with severe anemia causing hypoxia which, in turn, caused severe dyspnea and polypnea, which had mixed causes (hypoxic and infectious) as the child was febrile. After correction of the overlapping diarrhea, metabolic acidosis, and severe anemia (hemoglobin < 3 g/dL), she developed severe persistent sinus bradycardia immediately after mild sedation (before central venous catheter insertion), not attributable to any of the more frequent causes, with a heart rate as low as 49 beats/min on 24 h Holter monitoring, less than the first percentile for age, but with a regular QT interval and no arrhythmia. The echocardiogram was unremarkable, showing a small interatrial communication (patent foramen ovale with left-to-right shunting), mild left ventricular hypertrophy, normal systolic and diastolic function, and mild tricuspid regurgitation. After red cell transfusion and appropriate antibiotic and supportive treatment, the child’s general condition improved dramatically but the sinus bradycardia persisted. We consider this a case of well-tolerated sinus bradycardia and foresee a good cardiologic prognosis, while the hematologic prognosis remains determined by future corticoid response, treatment-related complications and risk of leukemia.
- Published
- 2023
- Full Text
- View/download PDF
44. Stem Cell Transplant for Bone Marrow Failure Syndromes
- Published
- 2017
45. Donor Umbilical Cord Blood Transplant in Treating Patients With Hematologic Cancer
- Author
-
National Cancer Institute (NCI)
- Published
- 2017
46. GATA-1 Defects in Diamond–Blackfan Anemia: Phenotypic Characterization Points to a Specific Subset of Disease.
- Author
-
van Dooijeweert, Birgit, Kia, Sima Kheradmand, Dahl, Niklas, Fenneteau, Odile, Leguit, Roos, Nieuwenhuis, Edward, van Solinge, Wouter, van Wijk, Richard, Da Costa, Lydie, and Bartels, Marije
- Subjects
- *
PURE red cell aplasia , *ANEMIA , *PHENOTYPES , *BONE marrow , *IRANIANS - Abstract
Diamond–Blackfan anemia (DBA) is one of the inherited bone marrow failure syndromes marked by erythroid hypoplasia. Underlying variants in ribosomal protein (RP) genes account for 80% of cases, thereby classifying DBA as a ribosomopathy. In addition to RP genes, extremely rare variants in non-RP genes, including GATA1, the master transcription factor in erythropoiesis, have been reported in recent years in patients with a DBA-like phenotype. Subsequently, a pivotal role for GATA-1 in DBA pathophysiology was established by studies showing the impaired translation of GATA1 mRNA downstream of the RP haploinsufficiency. Here, we report on a patient from the Dutch DBA registry, in which we found a novel hemizygous variant in GATA1 (c.220+2T>C), and an Iranian patient with a previously reported variant in the initiation codon of GATA1 (c.2T>C). Although clinical features were concordant with DBA, the bone marrow morphology in both patients was not typical for DBA, showing moderate erythropoietic activity with signs of dyserythropoiesis and dysmegakaryopoiesis. This motivated us to re-evaluate the clinical characteristics of previously reported cases, which resulted in the comprehensive characterization of 18 patients with an inherited GATA-1 defect in exon 2 that is presented in this case-series. In addition, we re-investigated the bone marrow aspirate of one of the previously published cases. Altogether, our observations suggest that DBA caused by GATA1 defects is characterized by distinct phenotypic characteristics, including dyserythropoiesis and dysmegakaryopoiesis, and therefore represents a distinct phenotype within the DBA disease spectrum, which might need specific clinical management. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
47. Functionally impaired RPL8 variants associated with Diamond–Blackfan anemia and a Diamond–Blackfan anemia‐like phenotype.
- Author
-
Lebaron, Simon, O'Donohue, Marie‐Françoise, Smith, Scott C., Engleman, Kendra L., Juusola, Jane, Safina, Nicole P., Thiffault, Isabelle, Saunders, Carol J., and Gleizes, Pierre‐Emmanuel
- Abstract
Diamond–Blackfan anemia is a rare genetic disease characterized by erythroblastopenia and a large spectrum of developmental anomalies. The vast majority of the cases genetically described are linked to heterozygous pathogenic variants in more than 20 ribosomal protein genes. Here we report an atypical clinical case of DBA associated with a missense variant in RPL8, which encodes RPL8/uL2, a protein of the 60S large ribosomal subunit. RPL8 has been previously implicated as a candidate disease gene in one patient with DBA bearing another type of missense variant; however, evidence for pathogenicity was limited to computational tools. Using functional studies in lymphoblastoid cells as well as yeast models, we show that the RPL8 variants detected in these two patients encode functionally deficient proteins that affect ribosome production and are therefore likely pathogenic. We propose to include RPL8 in the list of DBA‐associated genes. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
48. Short Stature in Patients with Diamond-Blackfan Anemia: A Cross-Sectional Study.
- Author
-
Wan, Yang, Gong, Xiaowen, Cheng, Siqi, Yin, Zixi, Gao, Yangyang, Li, Jun, Zong, Suyu, Zhang, Yingchi, Chen, Yumei, Zheng, Rongxiu, and Zhu, Xiaofan
- Abstract
Objective: To systematically describe the short stature of patients with Diamond-Blackfan anemia and to explore factors affecting the height development of patients with Diamond-Blackfan anemia.Study Design: This cross-sectional study was conducted at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, and the height, weight, and clinical data of 129 patients with Diamond-Blackfan anemia were collected from June 2020 to September 2020.Results: The median height-age-z score (HAZ) of children affected by Diamond-Blackfan anemia was -1.54 (-6.36-1.96). Short stature was found in 37.98% of the patients. Specific Diamond-Blackfan anemia growth curves were developed for weight, height, and body mass index, separately for male and female patients. Multivariable logistic regression models showed that female sex (aOR 4.92; 95% CI 1.29-18.71; P = .0195), underweight (aOR 10.41, 95% CI 1.41-76.98, P = .0217), cardiovascular malformations (aOR 216.65; 95% CI 3.29-14279.79; P = .0118), and RPL11(aOR 29.14; 95% CI 1.18-719.10; P = .0392) or RPS26 (aOR 53.49; 95% CI 1.40-2044.30; P = .0323) mutations were independent risk factors for short stature. In the subgroup of patients who were steroid-dependent, patients with a duration of steroid therapy over 2 years (OR 2.95; 95% CI 1.00-8.66; P = .0494) or maintenance dose of prednisone >0.1 mg/kg per day (OR 3.30; 95% CI 1.02-10.72; P = .0470) had a higher incidence of short stature.Conclusions: Patients with Diamond-Blackfan anemia had a high prevalence of short stature. The risk of short stature increased with age and was associated with sex, underweight, congenital malformations, and RPL11 or RPS26 mutations. The duration of steroid therapy and maintenance dose of steroid was significantly associated with the incidence of short stature in steroid-dependent patients with Diamond-Blackfan anemia. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
49. Inherited Bone Marrow Failure Syndromes
- Author
-
Karthika, K. V., Mishra, Priyanka, Pati, Hara Prasad, Saxena, Renu, editor, and Pati, Hara Prasad, editor
- Published
- 2019
- Full Text
- View/download PDF
50. Inherited Bone Marrow Failure Syndromes
- Author
-
Hamm, Jennifer D., Sorge, Caryn E., and Means Jr., Robert T., editor
- Published
- 2019
- Full Text
- View/download PDF
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