RARE DISEASE
Congenital dyserythropoietic anemia type I
Congenital dyserythropoietic anemia type I
Congenital dyserythropoietic anemia type I
Synonyms: CDA I, CDA type 1, CDA type I, Congenital dyserythropoietic anemia type 1
Synonyms: CDA I, CDA type 1, CDA type I, Congenital dyserythropoietic anemia type 1
Synonyms: CDA I, CDA type 1, CDA type I, Congenital dyserythropoietic anemia type 1
Drug discovery
0
drugs
With orphan designations
Overview
Congenital Dyserythropoietic Anemia Type I (CDA I) is a rare autosomal recessive disorder characterized by ineffective erythropoiesis, macrocytic anemia, and iron overload due to biallelic mutations in CDAN1 or C15ORF41. Clinical features include jaundice, splenomegaly, skeletal anomalies (e.g., syndactyly), and complications like cholelithiasis or organ damage from chronic iron accumulation. Diagnosis relies on bone marrow findings (e.g., erythroid hyperplasia, bi-/multinucleated erythroblasts, "Swiss cheese" chromatin) and genetic testing. Therapeutic strategies include interferon-alpha (for CDAN1 mutations), iron chelation, transfusions, and stem cell transplantation in severe cases [1][4][9][11].
Burden
Chronic anemia increases fatigue, reduces quality of life, and necessitates lifelong monitoring [1][5].
Iron overload drives complications (e.g., cirrhosis, heart failure) [1][11], with potential fatal outcomes if untreated [4].
Management challenges include genetic heterogeneity and variable treatment responsiveness [8][12].
Therapies
Categories: rare genetic diseases, rare hematological diseases
Research Papers
70 drug discovery papers about Congenital dyserythropoietic anemia type I, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
70 drug discovery papers about Congenital dyserythropoietic anemia type I, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2025-09-26 | Haploidentical hematopoietic stem cell transplantation for the treatment of congenital dyserythropoietic anemia combined with thalassemia: a report of two cases.
Congenital dyserythropoietic anemia (CDA) represents a heterogeneous group of rare hereditary disorders characterized by ineffective erythropoiesis and often presents with clinical features that overlap with thalassemia. Hematopoietic stem cell transplantation (HSCT) remains the only definitive curative intervention for CDA; however, the application of haploidentical HSCT in this context is limited and presents considerable challenges. Herein, we report two pediatric cases of CDA coexisting with thalassemia who underwent haploidentical related donor HSCT utilizing a novel conditioning regimen comprising three alkylating agents. Graft-versus-host disease (GVHD) prophylaxis was achieved using. posttransplant cyclophosphamide and anti-thymocyte globulin. Both patients attained sustained engraftment, transfusion independence, and remained free from severe transplant-related complications. These cases illustrate the feasibility and therapeutic potential of haploidentical HSCT for CDA, even in. the presence of concomitant thalassemia.
2022-06-14 | Hematopoietic Cell Transplantation for Congenital Dyserythropoietic Anemia: A Report from the Pediatric Transplant and Cellular Therapy Consortium.
Hematopoietic cell transplantation (HCT) is the sole curative option for congenital dyserythropoietic anemia (CDA), a rare type of hemolytic anemia characterized by anemia, ineffective erythropoiesis, and secondary hemochromatosis. In this retrospective multicenter study, we report the outcomes of children with CDA who underwent HCT at participating Pediatric Transplantation and Cellular Therapy Consortium centers. Clinical information on HCT and associated outcomes was collected retrospectively using a common questionnaire. Data were analyzed using descriptive statistics and appropriate analysis. Eighteen patients with CDA who underwent allogeneic HCT between 2002 and 2020 were identified. The majority of patients (n = 13) had CDA type II, and the remainder had either CDA type I (n = 2) or CDA of unknown type (n = 3). Mutations were identified in 7 patients (39%), including SEC23B in 5, GATA1 in 1, and abnormality of chromosome 20 in 1. Thirteen patients had evidence of iron overload pre-HCT and received chelation therapy for a median duration of 10 months (range, 2 months to 17 years) pre-HCT. The median age at the time of HCT was 5.5 years (range, 0.7 to 26 years). Donors were HLA-matched (sibling, 4; unrelated, 10) and mismatched (haploidentical, 1; unrelated, 3). Graft sources were bone marrow in 15 patients, umbilical cord blood in 2 patients, or both in 1 patient. Conditioning included busulfan-based myeloablative (67%), fludarabine-based reduced-intensity (27%), or nonmyeloablative (6%) regimens. Five patients developed veno-occlusive disease, and 4 had viral reactivation. The cumulative incidence of acute graft-versus-host disease (GVHD) was 33%, and that of chronic GVHD was 22%. Four patients (22%) experienced graft failure; all engrafted following either a second HCT (n = 2) or third HCT (n = 2) but sustained considerable morbidities (3 GVHD, 1 death, 2 viral reactivation). With a median follow-up of 3.2 years (range, 0.6 to 14 years)), the 2-year overall survival, event-free survival (EFS), and GVHD-free EFS were 88% (95% confidence interval [CI], 73% to 100%), 65% (95% CI, 45% to 92%), and 60% (95% CI, 40% to 88%), respectively. Univariate analysis did not identify any patient- or transplantation-related variables impacting outcomes. Our study indicates that HCT can be curative for patients with CDA. Strategies such as aggressive chelation, use of preconditioning therapy, and early HCT in the presence of a suitable donor before comorbidities occur are needed to improve engraftment without increasing the risk for toxicity and mortality.
2017-04-24 | An Unusual Hydrops Fetalis Associated with Compound Heterozygosity for Krüppel-like Factor 1 mutations.
Hydrops fetalis is commonly due to Hb Bart's (γ4) disease in South East Asia. Here, we report an unusual case of hydrops fetalis due to congenital dyserythropoietic anemia (CDA) associated with compound heterozygosity for Krüppel-like factor 1 (KLF1) gene mutations. Fetal cardiomegaly was first detected on routine mid-trimester scan in a pregnant woman with normal mean corpuscular volume (MCV) and Rhesus positive status. The fetus subsequently developed hydrops fetalis, and cordocentesis showed severe fetal anemia with a hemoglobin (Hb) level of 3.4 g/dL. Common causes of fetal anemia including Hb Bart's disease, parvovirus infection, and red cell antibodies were excluded. In view of the marked increase in erythroblasts at various stages of erythropoiesis, the diagnosis of CDA was suspected. We screened the couple for previously reported KLF1 gene mutations, showing that the mother was heterozygous for the c.525_526insCGGCGCC, p.Gly176Argfs*179 mutation, and her husband heterozygous for c.1012C>A, p.Pro338Thr mutation. The fetus was a compound heterozygote for these two KLF1 mutations. After counseling, repeated intrauterine transfusions were given at 27, 29, and 34 weeks' gestation; the hydrops fetalis was resolved. The baby was delivered at 34 weeks' gestation and required monthly blood transfusions but was otherwise thriving. Bone marrow aspiration at 10 months of age showed the features of ineffective erythropoiesis, compatible with CDA. In conclusion, hydrops fetalis can rarely be due to CDA associated with a compound heterozygous mutation for KLF1 gene mutations, and be managed by repeated intrauterine transfusions. Our present report adds to the wide clinical spectrum of KLF1 mutations.
2012-08-08 | Unrelated hematopoietic stem cell transplantation in a patient with congenital dyserythropoietic anemia and iron overload.
CDA is a heterogeneous group of disorders that result in morphologically abnormal erythroid maturation and ineffective erythropoiesis. Curative therapy for CDA focuses on the use of HSCT using fully matched sibling donors. This is the first report of a Type II CDA patient with severe iron overload who was successfully treated with HSCT using a HLA-matched unrelated donor after aggressive chelation therapy. Given the challenges of HSCT in any patient with CDA and severe iron overload, the role of novel approaches to iron chelation and HSCT is discussed.
2002-12-04 | Transfusion-dependent congenital dyserythropoietic anemia type I successfully treated with allogeneic stem cell transplantation.
Until recently, therapy for patients with severe congenital dyserythropoietic anemia (CDA) has been limited to blood transfusions and chelation therapy. Three children with transfusion-dependent CDA type I underwent allogeneic stem cell transplantation (SCT) from matched sibling donors. Conditioning was with cyclophosphamide 50 mg/kg/day for 4 days, busulphan 4 mg/kg/day for 4 days, and antithymocyte globulin (ATG) 30 mg/kg for four doses pre-SCT. All patients engrafted and are alive, and transfusion independent. To our knowledge, this is the first report of successful SCT in the management of CDA type I.
small molecules
2026-02-23 | A Pharmacogenomic Basis for Tolerance of 5-Fluorouracil Following Early, Severe Toxicity from Capecitabine in a CDA Ultrarapid Metabolizer Colon Cancer Patient: A Case Report.
Capecitabine is an oral prodrug that is converted to 5-FU via three enzyme-catalysed steps: carboxylesterase (CES), cytidine deaminase (CDA), and thymidine phosphorylase (TYMS). Approximately 80-90% of 5-FU, whether from capecitabine or direct administration, is quickly inactivated by dihydropyrimidine dehydrogenase (DPD), encoded by DPYD. Preemptive testing for four pathogenic DPYD variants that reduce DPD activity is advised; however, currently, no evidence for CES, CDA, or TYMS has necessitated a similar recommendation despite polymorphisms in these genes potentially causing treatment toxicity. The current preemptive testing guidelines for 5-FU and capecitabine are similar. A 74-year-old black woman with a caecal adenocarcinoma diagnosis of pT4bG1N0M0 was prescribed adjuvant oxaliplatin and capecitabine post-hemicolectomy. On day 16 of the first cycle, she presented with severe gastrointestinal, myelosuppressive, hand and foot side effects and enterocolitis infection. She underwent a pharmacogenomic workup with whole-exome sequencing and was noted to be genetically DPD non-deficient (DPYD *1/*9A). She was found to express CDA rs3215400 (c.-33delC) and CDA rs1048977, both of which are associated with an increased risk of toxicity from capecitabine. CDA rs3215400 has been specifically described as an ultrametabolizer variant with an observation to increase enzyme activity by 3-7 fold and the occurrence of adverse drug events in capecitabine. After recovery and follow-up, she continued to receive 5-FU, leucovorin, and oxaliplatin therapy which she tolerated well and completed six months of therapy. This case shows that the severe adverse effects of capecitabine therapy in a patient with a CDA ultrametabolizer profile can be successfully switched to 5-FU-based therapy at a normal dose and tolerate this alternative fluoropyrimidine.
2026-01-12 | Use of Post-Transplant Cyclophosphamide in Matched Related and Unrelated Donor Hematopoietic Stem Cell Transplant for Benign Hematological Disorders.
Introduction of Post-Transplant Cyclophosphamide (PTCy) based immunosuppression in Haploidentical Hematopoietic Stem Cell Transplants (HSCT) has shown to reduce the incidence of Graft vs. Host Disease (GVHD). However, data on its use in HLA matched settings is lacking. We describe our experience using PTCY in pediatric patients undergoing matched donor HSCT. We retrospectively analysed data of 16 patients who underwent HLA-matched HSCT using PTCy from March 2022-July 2024 at our institute. Sixteen patients of median age-6 years (Range:1-17 years) were analysed. Indications of transplant were Thalassemia in 10, severe aplastic anemia in 5 and Congenital dyserythropoietic anemia in 1. Conditioning regimes used were Rabbit ATG-Thio-Flu-Cy-2 Gy TBI in 8 and Rabbit ATG-Thio-Treo-Flu-2 Gy TBI in 3 which was preceded by two cycles of pre-transplant immunosuppression (PTIS); Rabbit ATG-Flu-Cy-4 Gy TBI in 5 patients of aplastic anemia. PTCy, Mycophenolate mofetil and cyclosporine were used as GVHD prophylaxis. One patient had primary and another had CMV induced secondary graft failure. Three patients had grade I-II acute GVHD at median 32days post HSCT (Range: 28-140days). None of the patients had chronic GVHD. CMV reactivation occurred in 8 patients at a median + 21 days (Range: 14-35 days). Median follow up duration post HSCT was 473days (Range:85-808 days). 1 year- Event-free and 1 year-overall survival rates were 81.25% and 93.7% respectively. PTCy-based approach appears to be promising in matched related and unrelated donor transplants for benign hematological disorders.
2025-12-19 | STING and VDAC inhibitors attenuate inflammation and ineffective erythropoiesis caused by an altered metabolome in the Nan (EKLF/E339D) mouse model of neonatal anemia.
Erythroid Krüppel-like factor (EKLF/KLF1) is an essential transcriptional regulator of all aspects of erythropoiesis. The mouse neonatal anemia ( Nan ) mutation is driven by a semi-dominant mutation in one allele of the EKLF second Zn-finger at position E339D. RNA-seq analysis of Nan/+ erythroid cells showed that expression of numerous enzymes associated with metabolic pathways are changed as a result. We assessed and analyzed the effects of this dysregulation by mass spectrometry of embryonic and adult material. Our results show that mono-allelic expression of Nan-EKLF has profound impacts on erythroid cell metabolism: levels of amino acids, nucleotides, and metabolites are altered, more energy is needed for survival and proliferation, and glucose is taken up more rapidly. As a result, mitochondrial morphology is distorted, leading to VDAC1 oligomerization and mtDNA release to the cytosol. This activates the cGAS-STING signaling pathway and induces a type-I IFN response that drives inflammation. Use of STING or VDAC inhibitors alleviates these conditions both ex vivo and in vivo . Mechanistically, treatment restores normal erythroid cell divisions and differentiation, and decreases inflammatory pathways in the bone marrow. Our findings are likely directly relevant to the dyserythropoiesis observed in CDA type IV patients that carry a similar mutation.
2025-05-24 | Angioid streaks and optic disc drusen in a patient with congenital dyserythropoietic anaemia.
A man in his 60s with dry eye symptoms was noted to have angioid streaks under the peripapillary retina. Congenital dyserythropoietic anaemia was the major health issue throughout his life, requiring venesection for iron overload, but no transfusions for many years. Close inspection of the eyes with optical coherence tomography also detected small subclinical optic disc drusen, which have not been reported in association with congenital dyserythropoietic anaemia. Together, optic disc drusen and angioid streaks represent an ectopic calcification phenotype in the eye and can be seen in the more common inherited condition of pseudoxanthoma elasticum or other inherited haemolytic anaemias such as sickle cell or thalassaemia. These associations highlight the role of pyrophosphate as a physiological inhibitor of calcification, and deficiencies of serum pyrophosphate lead to excessive and ectopic calcification. This raises intriguing hypotheses for the treatment of optic disc drusen, angioid streaks and other conditions of ectopic calcification.
2022-02-02 | An IDH1-vitamin C crosstalk drives human erythroid development by inhibiting pro-oxidant mitochondrial metabolism.
The metabolic changes controlling the stepwise differentiation of hematopoietic stem and progenitor cells (HSPCs) to mature erythrocytes are poorly understood. Here, we show that HSPC development to an erythroid-committed proerythroblast results in augmented glutaminolysis, generating alpha-ketoglutarate (αKG) and driving mitochondrial oxidative phosphorylation (OXPHOS). However, sequential late-stage erythropoiesis is dependent on decreasing αKG-driven OXPHOS, and we find that isocitrate dehydrogenase 1 (IDH1) plays a central role in this process. IDH1 downregulation augments mitochondrial oxidation of αKG and inhibits reticulocyte generation. Furthermore, IDH1 knockdown results in the generation of multinucleated erythroblasts, a morphological abnormality characteristic of myelodysplastic syndrome and congenital dyserythropoietic anemia. We identify vitamin C homeostasis as a critical regulator of ineffective erythropoiesis; oxidized ascorbate increases mitochondrial superoxide and significantly exacerbates the abnormal erythroblast phenotype of IDH1-downregulated progenitors, whereas vitamin C, scavenging reactive oxygen species (ROS) and reprogramming mitochondrial metabolism, rescues erythropoiesis. Thus, an IDH1-vitamin C crosstalk controls terminal steps of human erythroid differentiation.
proteins
2026-01-28 | Using Patient Feedback to Improve Treatment Outcomes for Patients with Congenital Dyserythropoietic Anaemia Type I Receiving Interferon Therapy.
Congenital dyserythropoietic anaemia type-I (CDA-I) is a rare autosomal recessive disease characterised by ineffective erythropoiesis, haemolysis and non-haematological developmental abnormalities. Its treatment is multifactorial, including the management of anaemia, iron overload and prevention of osteoporosis. The only treatment specific to CDA-I is subcutaneous interferon alpha (IFNα) 2A. This study presents the first summary of all published cases of CDA-I patients (n = 33) treated with IFNα and categorises their outcome. We also present new unpublished cases (n = 7). Overall, we find that IFNα administration causes a statistically significant mean increase in haemoglobin of 30.7 g/L (p < 0.001). However, we note that previous studies do not assess the impact of IFNα therapy on providing symptomatic benefit to patients with CDA-I, or the weight of side effects on their quality of life. We collaborate directly with patients through the organisation Congenital Anaemia Network to establish patient preferences regarding IFNα treatment. We propose a classification framework for the use of IFNα in CDA-I that includes patient-reported outcome measures in addition to grading response according to changes in Hb levels. We believe that the use of this framework will aid standardisation in measuring response to therapy, improve clinical practice and assist in future research.
2025-07-11 | Ropeginterferon alfa-2b as a promising alternative to conventional interferon in CDA type 1: a case report of two siblings.
Congenital dyserythropoietic anemia type I (CDA-I) is a rare hereditary anemia caused by CDAN1 or C15orf41 mutations, with CDAN1-related cases responding to interferon-alpha (IFN-α) therapy. However, traditional IFN-α requires frequent injections and often causes flu-like symptoms, which can hinder long-term adherence. Here, we present the first documented use of ropeginterferon alfa-2b, a next-generation pegylated interferon, in two patients with CDA-I. Both patients, who were previously transfusion dependent, achieved transfusion independence and improved hemoglobin levels after transitioning from recombinant IFN-α to ropeginterferon alfa-2b with biweekly dosing. This treatment preserved efficacy while minimizing adverse effects and the injection burden. Our findings suggest that ropeginterferon alfa-2b may serve as a more tolerable and effective long-term treatment. Further prospective large-scale studies are needed to validate its broader clinical applicability.
2023-10-01 | EP21.11: A rare non‐immune cause of fetal anemia
A 29-year-old primigravida with low chance trisomy screening was seen in Fetal Medicine at 23 weeks of gestation with a pericardial effusion. The head and circumference were gestation appropriate but all the long bones, whilst normally calcified and straight were ≤ 5th centile. The structurally normal heart was enlarged with a pericardial effusion but good contractility. The hyperdynamic fetal circulation resulted in a peak systolic velocity in the middle cerebral artery >1.5MoMs. Infection screening was negative and an amniocentesis was performed. Fetal blood sampling at 23 weeks revealed a hemoglobin of 2.4g/l. A fetal transfusion of 33mls was given to raise this to 11.3g/l. Results showed a normal CGH array, no evidence of mevalonic aciduria and a negative Kleihauer. Given ongoing fetal anemia concerns a second transfusion was performed at 24 weeks, with further transfusions needed at 28 and 34 weeks of gestation. Whole-exome sequencing showed that both parents were carriers of CDAN1 gene variants. The baby was a compound heterozygote, consistent with a diagnosis of congenital dyserythropoietic anemia type 1. Delivery at 37 weeks of gestation resulted in a liveborn baby, needing phototherapy and subsequently required fortnightly transfusions with chelation. Pegylated interferon α2a was successfully started at one year of age to reduce transfusion frequency. MRI and neurological assessments showed no abnormalities. Congenital dyserythropoietic anemia type 1 is a rare autosomal recessive disorder characterised by ineffective erythropoiesis resulting in moderate-to-severe macrocytic anemia presenting occasionally in utero. More commonly it presents with intrauterine growth restriction and distal limb anomalies (4-14%). Most affected individuals have life-long moderate anemia, usually accompanied by jaundice and splenomegaly. Secondary hemochromatosis develops with age as a result of increased iron absorption even in those who are not transfused.
2023-04-20 | Ineffective erythropoiesis and its treatment.
The erythroid marrow and circulating red blood cells (RBCs) are the key components of the human erythron. Abnormalities of the erythron that are responsible for anemia can be separated into 3 major categories: erythroid hypoproliferation, ineffective erythropoiesis, and peripheral hemolysis. Ineffective erythropoiesis is characterized by erythropoietin-driven expansion of early-stage erythroid precursors, associated with apoptosis of late-stage precursors. This mechanism is primarily responsible for anemia in inherited disorders like β-thalassemia, inherited sideroblastic anemias, and congenital dyserythropoietic anemias, as well as in acquired conditions like some subtypes of myelodysplastic syndrome (MDS). The inherited anemias that are due to ineffective erythropoiesis are also defined as iron-loading anemias because of the associated parenchymal iron loading caused by the release of erythroid factors that suppress hepcidin production. Novel treatments specifically targeting ineffective erythropoiesis are being developed. Iron restriction through enhancement of hepcidin activity or inhibition of ferroportin function has been shown to reduce ineffective erythropoiesis in murine models of β-thalassemia. Luspatercept is a transforming growth factor-β ligand trap that inhibits SMAD2/3 signaling. Based on preclinical and clinical studies, this compound is now approved for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions. Luspatercept is also approved for the treatment of transfusion-dependent anemia in patients with MDS with ring sideroblasts, most of whom carry a somatic SF3B1 mutation. While the long-term effectiveness and safety of luspatercept need to be evaluated in β-thalassemia and MDS, defining the molecular mechanisms of ineffective erythropoiesis in different disorders might allow the discovery of new effective compounds.
2021-07-02 | Congenital dyserythropoietic anemia type I: First report from the Congenital Dyserythropoietic Anemia Registry of North America (CDAR).
Congenital dyserythropoietic anemias (CDAs) are characterized by ineffective erythropoiesis and distinctive erythroblast abnormalities; the diagnosis is often missed or delayed due to significant phenotypic heterogeneity. We established the CDA Registry of North America (CDAR) to study the natural history of CDA and create a biorepository to investigate the pathobiology of this heterogeneous disease. Seven of 47 patients enrolled so far in CDAR have CDA-I due to biallelic CDAN1 mutations. They all presented with perinatal anemia and required transfusions during infancy. Anemia spontaneously improved during infancy in three patients; two became transfusion-independent rapidly after starting interferon-α2; and two remain transfusion-dependent at last follow-up at ages 5 and 30 y.o. One of the transfusion-dependent patients underwent splenectomy at 11 y.o due to misdiagnosis and returned to medical attention at 27 y.o with severe hemolytic anemia and pulmonary hypertension. All patients developed iron overload even without transfusions; four were treated with chelation. Genetic testing allowed for more rapid and accurate diagnosis; the median age of confirmed diagnosis in our cohort was 3 y.o compared to 17.3 y.o historically. In conclusion, CDAR provides an organized research network for multidisciplinary clinical and research collaboration to conduct natural history and biologic studies in CDA.
gene therapies
2026-09-03 | Murine model for Congenital Dyserythropoietic Anemia Type I.
Congenital Dyserythropoietic Anemia type I (CDA-I) is an autosomal recessive disease characterized by anemia due to ineffective erythropoiesis and results primarily from mutations in CDAN1, which encodes CODANIN1. Research efforts to understand the CDA-I pathogenesis have been impeded by the embryonic lethality of germline Cdan1 deleted mice as well as mice deleted for Cdan1 in the erythroid compartment, using the constitutively active EpoR-Cre allele. To study the function of CODANIN1 in adult erythropoiesis, we generated mice with inducible erythroid-specific biallelic Cdan1 deletion using the Gata1-CreERT2 allele. Following tamoxifen administration to adult mice, Cdan1 is excised, resulting in features of CDA-I, including anemia, impaired erythroid differentiation, disturbances in erythroblast cell cycle progression, and the finding of 'spongy' heterochromatin in bone marrow erythroblasts. These findings confirm a critical role for CODANIN1 in effective adult erythropoiesis and demonstrate the successful generation of an inducible CDA-I mouse model, which serves as a valuable platform for testing novel therapies for this orphan disease.
2026-07-15 | Red lines and green lights: Gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
Gene therapy is revolutionizing treatment paradigms for inherited haematological and immunological conditions. Recent successes, including the United States Food and Drug Administration (FDA) approval of gene therapy products for sickle cell disease and beta-thalassaemia, highlight the translational path of gene therapies for erythroid-specific disorders. In contrast, gene therapy development for other inherited erythroid disorders remains largely preclinical. Here, we examine the emerging landscape of gene therapies for inherited non-haemoglobinopathy erythroid disorders, focusing on the status of gene therapies for Diamond-Blackfan anaemia (DBA), pyruvate kinase deficiency (PKD), X-linked sideroblastic anaemia (XLSA), congenital erythropoietic porphyria (CEP) and congenital dyserythropoietic anaemia (CDA). We discuss the latest cellular engineering approaches being applied to developing therapies for these erythroid disorders and evolving strategies for conditioning and engraftment of modified cells. Despite the rarity of these disorders individually, several convergent biological and translational themes have emerged. Leveraging shared insights across diseases may accelerate clinical translation and broaden the curative potential of gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
2025-02-13 | Hereditary disorders of ineffective erythropoiesis.
Under steady state conditions, humans must produce ∼2 million red blood cells per second to sustain normal red blood cell counts and hemoglobin levels. Ineffective erythropoiesis, also termed dyserythropoiesis, is a process by which erythroid precursors die or fail to efficiently differentiate in the bone marrow. Ineffective erythropoiesis is characterized by expanded bone marrow erythropoiesis and increased erythroferrone production by bone marrow erythroblasts, with the latter resulting in reduced hepcidin production and increased iron absorption. Ineffective erythropoiesis may result from acquired and congenital conditions. Inherited causes of ineffective erythropoiesis include β-thalassemia, sideroblastic anemias, pyruvate kinase deficiency, and congenital dyserythropoietic anemias. This manuscript reviews the definition and evidence for ineffective erythropoiesis and describes the most common hereditary disorders of dyserythropoiesis.
2022-04-21 | The congenital dyserythropoieitic anemias: genetics and pathophysiology.
The congenital dyserythropoietic anemias (CDA) are hereditary disorders characterized by ineffective erythropoiesis. This review evaluates newly developed CDA disease models, the latest advances in understanding the pathogenesis of the CDAs, and recently identified CDA genes. Mice exhibiting features of CDAI were recently generated, demonstrating that Codanin-1 (encoded by Cdan1) is essential for primitive erythropoiesis. Additionally, Codanin-1 was found to physically interact with CDIN1, suggesting that mutations in CDAN1 and CDIN1 result in CDAI via a common mechanism. Recent advances in CDAII (which results from SEC23B mutations) have also been made. SEC23B was found to functionally overlap with its paralogous protein, SEC23A, likely explaining the absence of CDAII in SEC23B-deficient mice. In contrast, mice with erythroid-specific deletion of 3 or 4 of the Sec23 alleles exhibited features of CDAII. Increased SEC23A expression rescued the CDAII erythroid defect, suggesting a novel therapeutic strategy for the disease. Additional recent advances included the identification of new CDA genes, RACGAP1 and VPS4A, in CDAIII and a syndromic CDA type, respectively. Establishing cellular and animal models of CDA is expected to result in improved understanding of the pathogenesis of these disorders, which may ultimately lead to the development of new therapies.
2014-04-11 | Intrauterine therapy in a fetus with congenital dyserythropoietic anaemia type I
"Intrauterine therapy in a fetus with congenital dyserythropoietic anaemia type I." Journal of Obstetrics and Gynaecology, 34(4), pp. 352–353
cell therapies
2025-09-26 | Haploidentical hematopoietic stem cell transplantation for the treatment of congenital dyserythropoietic anemia combined with thalassemia: a report of two cases.
Congenital dyserythropoietic anemia (CDA) represents a heterogeneous group of rare hereditary disorders characterized by ineffective erythropoiesis and often presents with clinical features that overlap with thalassemia. Hematopoietic stem cell transplantation (HSCT) remains the only definitive curative intervention for CDA; however, the application of haploidentical HSCT in this context is limited and presents considerable challenges. Herein, we report two pediatric cases of CDA coexisting with thalassemia who underwent haploidentical related donor HSCT utilizing a novel conditioning regimen comprising three alkylating agents. Graft-versus-host disease (GVHD) prophylaxis was achieved using. posttransplant cyclophosphamide and anti-thymocyte globulin. Both patients attained sustained engraftment, transfusion independence, and remained free from severe transplant-related complications. These cases illustrate the feasibility and therapeutic potential of haploidentical HSCT for CDA, even in. the presence of concomitant thalassemia.
2022-06-14 | Hematopoietic Cell Transplantation for Congenital Dyserythropoietic Anemia: A Report from the Pediatric Transplant and Cellular Therapy Consortium.
Hematopoietic cell transplantation (HCT) is the sole curative option for congenital dyserythropoietic anemia (CDA), a rare type of hemolytic anemia characterized by anemia, ineffective erythropoiesis, and secondary hemochromatosis. In this retrospective multicenter study, we report the outcomes of children with CDA who underwent HCT at participating Pediatric Transplantation and Cellular Therapy Consortium centers. Clinical information on HCT and associated outcomes was collected retrospectively using a common questionnaire. Data were analyzed using descriptive statistics and appropriate analysis. Eighteen patients with CDA who underwent allogeneic HCT between 2002 and 2020 were identified. The majority of patients (n = 13) had CDA type II, and the remainder had either CDA type I (n = 2) or CDA of unknown type (n = 3). Mutations were identified in 7 patients (39%), including SEC23B in 5, GATA1 in 1, and abnormality of chromosome 20 in 1. Thirteen patients had evidence of iron overload pre-HCT and received chelation therapy for a median duration of 10 months (range, 2 months to 17 years) pre-HCT. The median age at the time of HCT was 5.5 years (range, 0.7 to 26 years). Donors were HLA-matched (sibling, 4; unrelated, 10) and mismatched (haploidentical, 1; unrelated, 3). Graft sources were bone marrow in 15 patients, umbilical cord blood in 2 patients, or both in 1 patient. Conditioning included busulfan-based myeloablative (67%), fludarabine-based reduced-intensity (27%), or nonmyeloablative (6%) regimens. Five patients developed veno-occlusive disease, and 4 had viral reactivation. The cumulative incidence of acute graft-versus-host disease (GVHD) was 33%, and that of chronic GVHD was 22%. Four patients (22%) experienced graft failure; all engrafted following either a second HCT (n = 2) or third HCT (n = 2) but sustained considerable morbidities (3 GVHD, 1 death, 2 viral reactivation). With a median follow-up of 3.2 years (range, 0.6 to 14 years)), the 2-year overall survival, event-free survival (EFS), and GVHD-free EFS were 88% (95% confidence interval [CI], 73% to 100%), 65% (95% CI, 45% to 92%), and 60% (95% CI, 40% to 88%), respectively. Univariate analysis did not identify any patient- or transplantation-related variables impacting outcomes. Our study indicates that HCT can be curative for patients with CDA. Strategies such as aggressive chelation, use of preconditioning therapy, and early HCT in the presence of a suitable donor before comorbidities occur are needed to improve engraftment without increasing the risk for toxicity and mortality.
2017-04-24 | An Unusual Hydrops Fetalis Associated with Compound Heterozygosity for Krüppel-like Factor 1 mutations.
Hydrops fetalis is commonly due to Hb Bart's (γ4) disease in South East Asia. Here, we report an unusual case of hydrops fetalis due to congenital dyserythropoietic anemia (CDA) associated with compound heterozygosity for Krüppel-like factor 1 (KLF1) gene mutations. Fetal cardiomegaly was first detected on routine mid-trimester scan in a pregnant woman with normal mean corpuscular volume (MCV) and Rhesus positive status. The fetus subsequently developed hydrops fetalis, and cordocentesis showed severe fetal anemia with a hemoglobin (Hb) level of 3.4 g/dL. Common causes of fetal anemia including Hb Bart's disease, parvovirus infection, and red cell antibodies were excluded. In view of the marked increase in erythroblasts at various stages of erythropoiesis, the diagnosis of CDA was suspected. We screened the couple for previously reported KLF1 gene mutations, showing that the mother was heterozygous for the c.525_526insCGGCGCC, p.Gly176Argfs*179 mutation, and her husband heterozygous for c.1012C>A, p.Pro338Thr mutation. The fetus was a compound heterozygote for these two KLF1 mutations. After counseling, repeated intrauterine transfusions were given at 27, 29, and 34 weeks' gestation; the hydrops fetalis was resolved. The baby was delivered at 34 weeks' gestation and required monthly blood transfusions but was otherwise thriving. Bone marrow aspiration at 10 months of age showed the features of ineffective erythropoiesis, compatible with CDA. In conclusion, hydrops fetalis can rarely be due to CDA associated with a compound heterozygous mutation for KLF1 gene mutations, and be managed by repeated intrauterine transfusions. Our present report adds to the wide clinical spectrum of KLF1 mutations.
2012-08-08 | Unrelated hematopoietic stem cell transplantation in a patient with congenital dyserythropoietic anemia and iron overload.
CDA is a heterogeneous group of disorders that result in morphologically abnormal erythroid maturation and ineffective erythropoiesis. Curative therapy for CDA focuses on the use of HSCT using fully matched sibling donors. This is the first report of a Type II CDA patient with severe iron overload who was successfully treated with HSCT using a HLA-matched unrelated donor after aggressive chelation therapy. Given the challenges of HSCT in any patient with CDA and severe iron overload, the role of novel approaches to iron chelation and HSCT is discussed.
2002-12-04 | Transfusion-dependent congenital dyserythropoietic anemia type I successfully treated with allogeneic stem cell transplantation.
Until recently, therapy for patients with severe congenital dyserythropoietic anemia (CDA) has been limited to blood transfusions and chelation therapy. Three children with transfusion-dependent CDA type I underwent allogeneic stem cell transplantation (SCT) from matched sibling donors. Conditioning was with cyclophosphamide 50 mg/kg/day for 4 days, busulphan 4 mg/kg/day for 4 days, and antithymocyte globulin (ATG) 30 mg/kg for four doses pre-SCT. All patients engrafted and are alive, and transfusion independent. To our knowledge, this is the first report of successful SCT in the management of CDA type I.
small molecules
2026-02-23 | A Pharmacogenomic Basis for Tolerance of 5-Fluorouracil Following Early, Severe Toxicity from Capecitabine in a CDA Ultrarapid Metabolizer Colon Cancer Patient: A Case Report.
Capecitabine is an oral prodrug that is converted to 5-FU via three enzyme-catalysed steps: carboxylesterase (CES), cytidine deaminase (CDA), and thymidine phosphorylase (TYMS). Approximately 80-90% of 5-FU, whether from capecitabine or direct administration, is quickly inactivated by dihydropyrimidine dehydrogenase (DPD), encoded by DPYD. Preemptive testing for four pathogenic DPYD variants that reduce DPD activity is advised; however, currently, no evidence for CES, CDA, or TYMS has necessitated a similar recommendation despite polymorphisms in these genes potentially causing treatment toxicity. The current preemptive testing guidelines for 5-FU and capecitabine are similar. A 74-year-old black woman with a caecal adenocarcinoma diagnosis of pT4bG1N0M0 was prescribed adjuvant oxaliplatin and capecitabine post-hemicolectomy. On day 16 of the first cycle, she presented with severe gastrointestinal, myelosuppressive, hand and foot side effects and enterocolitis infection. She underwent a pharmacogenomic workup with whole-exome sequencing and was noted to be genetically DPD non-deficient (DPYD *1/*9A). She was found to express CDA rs3215400 (c.-33delC) and CDA rs1048977, both of which are associated with an increased risk of toxicity from capecitabine. CDA rs3215400 has been specifically described as an ultrametabolizer variant with an observation to increase enzyme activity by 3-7 fold and the occurrence of adverse drug events in capecitabine. After recovery and follow-up, she continued to receive 5-FU, leucovorin, and oxaliplatin therapy which she tolerated well and completed six months of therapy. This case shows that the severe adverse effects of capecitabine therapy in a patient with a CDA ultrametabolizer profile can be successfully switched to 5-FU-based therapy at a normal dose and tolerate this alternative fluoropyrimidine.
2026-01-12 | Use of Post-Transplant Cyclophosphamide in Matched Related and Unrelated Donor Hematopoietic Stem Cell Transplant for Benign Hematological Disorders.
Introduction of Post-Transplant Cyclophosphamide (PTCy) based immunosuppression in Haploidentical Hematopoietic Stem Cell Transplants (HSCT) has shown to reduce the incidence of Graft vs. Host Disease (GVHD). However, data on its use in HLA matched settings is lacking. We describe our experience using PTCY in pediatric patients undergoing matched donor HSCT. We retrospectively analysed data of 16 patients who underwent HLA-matched HSCT using PTCy from March 2022-July 2024 at our institute. Sixteen patients of median age-6 years (Range:1-17 years) were analysed. Indications of transplant were Thalassemia in 10, severe aplastic anemia in 5 and Congenital dyserythropoietic anemia in 1. Conditioning regimes used were Rabbit ATG-Thio-Flu-Cy-2 Gy TBI in 8 and Rabbit ATG-Thio-Treo-Flu-2 Gy TBI in 3 which was preceded by two cycles of pre-transplant immunosuppression (PTIS); Rabbit ATG-Flu-Cy-4 Gy TBI in 5 patients of aplastic anemia. PTCy, Mycophenolate mofetil and cyclosporine were used as GVHD prophylaxis. One patient had primary and another had CMV induced secondary graft failure. Three patients had grade I-II acute GVHD at median 32days post HSCT (Range: 28-140days). None of the patients had chronic GVHD. CMV reactivation occurred in 8 patients at a median + 21 days (Range: 14-35 days). Median follow up duration post HSCT was 473days (Range:85-808 days). 1 year- Event-free and 1 year-overall survival rates were 81.25% and 93.7% respectively. PTCy-based approach appears to be promising in matched related and unrelated donor transplants for benign hematological disorders.
2025-12-19 | STING and VDAC inhibitors attenuate inflammation and ineffective erythropoiesis caused by an altered metabolome in the Nan (EKLF/E339D) mouse model of neonatal anemia.
Erythroid Krüppel-like factor (EKLF/KLF1) is an essential transcriptional regulator of all aspects of erythropoiesis. The mouse neonatal anemia ( Nan ) mutation is driven by a semi-dominant mutation in one allele of the EKLF second Zn-finger at position E339D. RNA-seq analysis of Nan/+ erythroid cells showed that expression of numerous enzymes associated with metabolic pathways are changed as a result. We assessed and analyzed the effects of this dysregulation by mass spectrometry of embryonic and adult material. Our results show that mono-allelic expression of Nan-EKLF has profound impacts on erythroid cell metabolism: levels of amino acids, nucleotides, and metabolites are altered, more energy is needed for survival and proliferation, and glucose is taken up more rapidly. As a result, mitochondrial morphology is distorted, leading to VDAC1 oligomerization and mtDNA release to the cytosol. This activates the cGAS-STING signaling pathway and induces a type-I IFN response that drives inflammation. Use of STING or VDAC inhibitors alleviates these conditions both ex vivo and in vivo . Mechanistically, treatment restores normal erythroid cell divisions and differentiation, and decreases inflammatory pathways in the bone marrow. Our findings are likely directly relevant to the dyserythropoiesis observed in CDA type IV patients that carry a similar mutation.
2025-05-24 | Angioid streaks and optic disc drusen in a patient with congenital dyserythropoietic anaemia.
A man in his 60s with dry eye symptoms was noted to have angioid streaks under the peripapillary retina. Congenital dyserythropoietic anaemia was the major health issue throughout his life, requiring venesection for iron overload, but no transfusions for many years. Close inspection of the eyes with optical coherence tomography also detected small subclinical optic disc drusen, which have not been reported in association with congenital dyserythropoietic anaemia. Together, optic disc drusen and angioid streaks represent an ectopic calcification phenotype in the eye and can be seen in the more common inherited condition of pseudoxanthoma elasticum or other inherited haemolytic anaemias such as sickle cell or thalassaemia. These associations highlight the role of pyrophosphate as a physiological inhibitor of calcification, and deficiencies of serum pyrophosphate lead to excessive and ectopic calcification. This raises intriguing hypotheses for the treatment of optic disc drusen, angioid streaks and other conditions of ectopic calcification.
2022-02-02 | An IDH1-vitamin C crosstalk drives human erythroid development by inhibiting pro-oxidant mitochondrial metabolism.
The metabolic changes controlling the stepwise differentiation of hematopoietic stem and progenitor cells (HSPCs) to mature erythrocytes are poorly understood. Here, we show that HSPC development to an erythroid-committed proerythroblast results in augmented glutaminolysis, generating alpha-ketoglutarate (αKG) and driving mitochondrial oxidative phosphorylation (OXPHOS). However, sequential late-stage erythropoiesis is dependent on decreasing αKG-driven OXPHOS, and we find that isocitrate dehydrogenase 1 (IDH1) plays a central role in this process. IDH1 downregulation augments mitochondrial oxidation of αKG and inhibits reticulocyte generation. Furthermore, IDH1 knockdown results in the generation of multinucleated erythroblasts, a morphological abnormality characteristic of myelodysplastic syndrome and congenital dyserythropoietic anemia. We identify vitamin C homeostasis as a critical regulator of ineffective erythropoiesis; oxidized ascorbate increases mitochondrial superoxide and significantly exacerbates the abnormal erythroblast phenotype of IDH1-downregulated progenitors, whereas vitamin C, scavenging reactive oxygen species (ROS) and reprogramming mitochondrial metabolism, rescues erythropoiesis. Thus, an IDH1-vitamin C crosstalk controls terminal steps of human erythroid differentiation.
proteins
2026-01-28 | Using Patient Feedback to Improve Treatment Outcomes for Patients with Congenital Dyserythropoietic Anaemia Type I Receiving Interferon Therapy.
Congenital dyserythropoietic anaemia type-I (CDA-I) is a rare autosomal recessive disease characterised by ineffective erythropoiesis, haemolysis and non-haematological developmental abnormalities. Its treatment is multifactorial, including the management of anaemia, iron overload and prevention of osteoporosis. The only treatment specific to CDA-I is subcutaneous interferon alpha (IFNα) 2A. This study presents the first summary of all published cases of CDA-I patients (n = 33) treated with IFNα and categorises their outcome. We also present new unpublished cases (n = 7). Overall, we find that IFNα administration causes a statistically significant mean increase in haemoglobin of 30.7 g/L (p < 0.001). However, we note that previous studies do not assess the impact of IFNα therapy on providing symptomatic benefit to patients with CDA-I, or the weight of side effects on their quality of life. We collaborate directly with patients through the organisation Congenital Anaemia Network to establish patient preferences regarding IFNα treatment. We propose a classification framework for the use of IFNα in CDA-I that includes patient-reported outcome measures in addition to grading response according to changes in Hb levels. We believe that the use of this framework will aid standardisation in measuring response to therapy, improve clinical practice and assist in future research.
2025-07-11 | Ropeginterferon alfa-2b as a promising alternative to conventional interferon in CDA type 1: a case report of two siblings.
Congenital dyserythropoietic anemia type I (CDA-I) is a rare hereditary anemia caused by CDAN1 or C15orf41 mutations, with CDAN1-related cases responding to interferon-alpha (IFN-α) therapy. However, traditional IFN-α requires frequent injections and often causes flu-like symptoms, which can hinder long-term adherence. Here, we present the first documented use of ropeginterferon alfa-2b, a next-generation pegylated interferon, in two patients with CDA-I. Both patients, who were previously transfusion dependent, achieved transfusion independence and improved hemoglobin levels after transitioning from recombinant IFN-α to ropeginterferon alfa-2b with biweekly dosing. This treatment preserved efficacy while minimizing adverse effects and the injection burden. Our findings suggest that ropeginterferon alfa-2b may serve as a more tolerable and effective long-term treatment. Further prospective large-scale studies are needed to validate its broader clinical applicability.
2023-10-01 | EP21.11: A rare non‐immune cause of fetal anemia
A 29-year-old primigravida with low chance trisomy screening was seen in Fetal Medicine at 23 weeks of gestation with a pericardial effusion. The head and circumference were gestation appropriate but all the long bones, whilst normally calcified and straight were ≤ 5th centile. The structurally normal heart was enlarged with a pericardial effusion but good contractility. The hyperdynamic fetal circulation resulted in a peak systolic velocity in the middle cerebral artery >1.5MoMs. Infection screening was negative and an amniocentesis was performed. Fetal blood sampling at 23 weeks revealed a hemoglobin of 2.4g/l. A fetal transfusion of 33mls was given to raise this to 11.3g/l. Results showed a normal CGH array, no evidence of mevalonic aciduria and a negative Kleihauer. Given ongoing fetal anemia concerns a second transfusion was performed at 24 weeks, with further transfusions needed at 28 and 34 weeks of gestation. Whole-exome sequencing showed that both parents were carriers of CDAN1 gene variants. The baby was a compound heterozygote, consistent with a diagnosis of congenital dyserythropoietic anemia type 1. Delivery at 37 weeks of gestation resulted in a liveborn baby, needing phototherapy and subsequently required fortnightly transfusions with chelation. Pegylated interferon α2a was successfully started at one year of age to reduce transfusion frequency. MRI and neurological assessments showed no abnormalities. Congenital dyserythropoietic anemia type 1 is a rare autosomal recessive disorder characterised by ineffective erythropoiesis resulting in moderate-to-severe macrocytic anemia presenting occasionally in utero. More commonly it presents with intrauterine growth restriction and distal limb anomalies (4-14%). Most affected individuals have life-long moderate anemia, usually accompanied by jaundice and splenomegaly. Secondary hemochromatosis develops with age as a result of increased iron absorption even in those who are not transfused.
2023-04-20 | Ineffective erythropoiesis and its treatment.
The erythroid marrow and circulating red blood cells (RBCs) are the key components of the human erythron. Abnormalities of the erythron that are responsible for anemia can be separated into 3 major categories: erythroid hypoproliferation, ineffective erythropoiesis, and peripheral hemolysis. Ineffective erythropoiesis is characterized by erythropoietin-driven expansion of early-stage erythroid precursors, associated with apoptosis of late-stage precursors. This mechanism is primarily responsible for anemia in inherited disorders like β-thalassemia, inherited sideroblastic anemias, and congenital dyserythropoietic anemias, as well as in acquired conditions like some subtypes of myelodysplastic syndrome (MDS). The inherited anemias that are due to ineffective erythropoiesis are also defined as iron-loading anemias because of the associated parenchymal iron loading caused by the release of erythroid factors that suppress hepcidin production. Novel treatments specifically targeting ineffective erythropoiesis are being developed. Iron restriction through enhancement of hepcidin activity or inhibition of ferroportin function has been shown to reduce ineffective erythropoiesis in murine models of β-thalassemia. Luspatercept is a transforming growth factor-β ligand trap that inhibits SMAD2/3 signaling. Based on preclinical and clinical studies, this compound is now approved for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions. Luspatercept is also approved for the treatment of transfusion-dependent anemia in patients with MDS with ring sideroblasts, most of whom carry a somatic SF3B1 mutation. While the long-term effectiveness and safety of luspatercept need to be evaluated in β-thalassemia and MDS, defining the molecular mechanisms of ineffective erythropoiesis in different disorders might allow the discovery of new effective compounds.
2021-07-02 | Congenital dyserythropoietic anemia type I: First report from the Congenital Dyserythropoietic Anemia Registry of North America (CDAR).
Congenital dyserythropoietic anemias (CDAs) are characterized by ineffective erythropoiesis and distinctive erythroblast abnormalities; the diagnosis is often missed or delayed due to significant phenotypic heterogeneity. We established the CDA Registry of North America (CDAR) to study the natural history of CDA and create a biorepository to investigate the pathobiology of this heterogeneous disease. Seven of 47 patients enrolled so far in CDAR have CDA-I due to biallelic CDAN1 mutations. They all presented with perinatal anemia and required transfusions during infancy. Anemia spontaneously improved during infancy in three patients; two became transfusion-independent rapidly after starting interferon-α2; and two remain transfusion-dependent at last follow-up at ages 5 and 30 y.o. One of the transfusion-dependent patients underwent splenectomy at 11 y.o due to misdiagnosis and returned to medical attention at 27 y.o with severe hemolytic anemia and pulmonary hypertension. All patients developed iron overload even without transfusions; four were treated with chelation. Genetic testing allowed for more rapid and accurate diagnosis; the median age of confirmed diagnosis in our cohort was 3 y.o compared to 17.3 y.o historically. In conclusion, CDAR provides an organized research network for multidisciplinary clinical and research collaboration to conduct natural history and biologic studies in CDA.
gene therapies
2026-09-03 | Murine model for Congenital Dyserythropoietic Anemia Type I.
Congenital Dyserythropoietic Anemia type I (CDA-I) is an autosomal recessive disease characterized by anemia due to ineffective erythropoiesis and results primarily from mutations in CDAN1, which encodes CODANIN1. Research efforts to understand the CDA-I pathogenesis have been impeded by the embryonic lethality of germline Cdan1 deleted mice as well as mice deleted for Cdan1 in the erythroid compartment, using the constitutively active EpoR-Cre allele. To study the function of CODANIN1 in adult erythropoiesis, we generated mice with inducible erythroid-specific biallelic Cdan1 deletion using the Gata1-CreERT2 allele. Following tamoxifen administration to adult mice, Cdan1 is excised, resulting in features of CDA-I, including anemia, impaired erythroid differentiation, disturbances in erythroblast cell cycle progression, and the finding of 'spongy' heterochromatin in bone marrow erythroblasts. These findings confirm a critical role for CODANIN1 in effective adult erythropoiesis and demonstrate the successful generation of an inducible CDA-I mouse model, which serves as a valuable platform for testing novel therapies for this orphan disease.
2026-07-15 | Red lines and green lights: Gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
Gene therapy is revolutionizing treatment paradigms for inherited haematological and immunological conditions. Recent successes, including the United States Food and Drug Administration (FDA) approval of gene therapy products for sickle cell disease and beta-thalassaemia, highlight the translational path of gene therapies for erythroid-specific disorders. In contrast, gene therapy development for other inherited erythroid disorders remains largely preclinical. Here, we examine the emerging landscape of gene therapies for inherited non-haemoglobinopathy erythroid disorders, focusing on the status of gene therapies for Diamond-Blackfan anaemia (DBA), pyruvate kinase deficiency (PKD), X-linked sideroblastic anaemia (XLSA), congenital erythropoietic porphyria (CEP) and congenital dyserythropoietic anaemia (CDA). We discuss the latest cellular engineering approaches being applied to developing therapies for these erythroid disorders and evolving strategies for conditioning and engraftment of modified cells. Despite the rarity of these disorders individually, several convergent biological and translational themes have emerged. Leveraging shared insights across diseases may accelerate clinical translation and broaden the curative potential of gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
2025-02-13 | Hereditary disorders of ineffective erythropoiesis.
Under steady state conditions, humans must produce ∼2 million red blood cells per second to sustain normal red blood cell counts and hemoglobin levels. Ineffective erythropoiesis, also termed dyserythropoiesis, is a process by which erythroid precursors die or fail to efficiently differentiate in the bone marrow. Ineffective erythropoiesis is characterized by expanded bone marrow erythropoiesis and increased erythroferrone production by bone marrow erythroblasts, with the latter resulting in reduced hepcidin production and increased iron absorption. Ineffective erythropoiesis may result from acquired and congenital conditions. Inherited causes of ineffective erythropoiesis include β-thalassemia, sideroblastic anemias, pyruvate kinase deficiency, and congenital dyserythropoietic anemias. This manuscript reviews the definition and evidence for ineffective erythropoiesis and describes the most common hereditary disorders of dyserythropoiesis.
2022-04-21 | The congenital dyserythropoieitic anemias: genetics and pathophysiology.
The congenital dyserythropoietic anemias (CDA) are hereditary disorders characterized by ineffective erythropoiesis. This review evaluates newly developed CDA disease models, the latest advances in understanding the pathogenesis of the CDAs, and recently identified CDA genes. Mice exhibiting features of CDAI were recently generated, demonstrating that Codanin-1 (encoded by Cdan1) is essential for primitive erythropoiesis. Additionally, Codanin-1 was found to physically interact with CDIN1, suggesting that mutations in CDAN1 and CDIN1 result in CDAI via a common mechanism. Recent advances in CDAII (which results from SEC23B mutations) have also been made. SEC23B was found to functionally overlap with its paralogous protein, SEC23A, likely explaining the absence of CDAII in SEC23B-deficient mice. In contrast, mice with erythroid-specific deletion of 3 or 4 of the Sec23 alleles exhibited features of CDAII. Increased SEC23A expression rescued the CDAII erythroid defect, suggesting a novel therapeutic strategy for the disease. Additional recent advances included the identification of new CDA genes, RACGAP1 and VPS4A, in CDAIII and a syndromic CDA type, respectively. Establishing cellular and animal models of CDA is expected to result in improved understanding of the pathogenesis of these disorders, which may ultimately lead to the development of new therapies.
2014-04-11 | Intrauterine therapy in a fetus with congenital dyserythropoietic anaemia type I
"Intrauterine therapy in a fetus with congenital dyserythropoietic anaemia type I." Journal of Obstetrics and Gynaecology, 34(4), pp. 352–353
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