RARE DISEASE
Congenital erythropoietic porphyria
Congenital erythropoietic porphyria
Congenital erythropoietic porphyria
Synonyms: CEP, Günther disease
Synonyms: CEP, Günther disease
Synonyms: CEP, Günther disease
Drug discovery
3
drugs
With orphan designations
Overview
Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder caused by uroporphyrinogen III synthase (UROS) deficiency, leading to toxic accumulation of type I porphyrins. Clinical features include severe photosensitivity with blistering skin lesions, erythrodontia, hemolytic anemia, splenomegaly, and potential skeletal abnormalities. Diagnosis involves elevated uroporphyrin I in urine/erythrocytes and genetic confirmation. Management focuses on photoprotection, hematologic support, and advanced therapies like hematopoietic stem cell transplantation [1][4][6][10].
Burden
High morbidity: Photomutilation, chronic anemia, infections, and osteolytic complications [4][6][10]
Reduced life expectancy (median 40-60 years) in severe cases, with significant psychosocial impacts [7][11][14]
Requires multidisciplinary care (dermatology, hematology, genetics) and lifelong monitoring [6][10][16]
Therapies
First-line: Strict sunlight avoidance, protective clothing/window films [4][14]
Hematologic: Transfusions, splenectomy, hydroxyurea; hematopoietic stem cell transplantation for severe cases [8][9][13]
Emerging: Proteasome inhibitors (bortezomib), gene therapy, and iron depletion via phlebotomy/deferasirox [3][13][19]
Categories: rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare renal diseases, rare skin diseases
Research Papers
140 drug discovery papers about Congenital erythropoietic porphyria, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
140 drug discovery papers about Congenital erythropoietic porphyria, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-03-12 | Hematopoietic stem cell transplantation for erythropoietic porphyria-induced acute liver failure: a case report and literature review.
Protoporphyrias are rare genetic disorders in heme biosynthesis, causing protoporphyrin IX accumulation with progressive liver injury. Liver transplantation has traditionally treated protoporphyria-induced liver injury but does not correct the underlying hematopoietic defect. We present a 16-year-old male with painful cutaneous photosensitivity who developed cholestatic liver dysfunction and severe abdominal pain. After plasmapheresis, red blood cell (RBC) transfusions, and intravenous hemin, he had transient improvement and subsequently underwent hematopoietic stem cell transplantation (HSCT) without liver transplantation, which normalized his protoporphyrin levels, liver function, and symptoms. This case underscores HSCT as a disease-modifying therapy that may prevent liver transplantation when performed before irreversible hepatic damage.
2025-12-31 | Congenital Erythropoietic Porphyria with Persistent Severe Biochemical Abnormalities and a Non-Mutilating Clinical Course: A Case Report
Congenital erythropoietic porphyria (CEP), also known as Günther disease, is a rare autosomal recessive porphyria caused by deficiency of uroporphyrinogen III synthase, leading to accumulation of phototoxic type I porphyrins. CEP classically presents in infancy with severe photosensitivity, blistering, scarring, and hemolytic anemia; however, significant phenotypic variability has increasingly been recognized. We report 32-year-old women diagnosed with CEP in early infancy who demonstrated persistently and profoundly elevated erythrocyte porphyrin levels over more than a decade yet followed a relatively non-mutilating clinical course. Genetic testing identified a low penetrance intronic UROS variant typically associated with erythropoietic protoporphyria, underscoring diagnostic challenges and genotype-phenotype discordance. The patient experienced marked improvement in photosensitivity and burning pain after initiation of afamelanotide, without need for transfusion therapy or stem cell transplantation. This case highlights the heterogeneity of CEP, the importance of long-term biochemical follow up, and the potential role of afamelanotide in improving quality of life for selected patients with CEP.
2025-12-30 | New pharmacotherapies for the erythropoietic protoporphyrias: an analysis of trial protocols from a patient perspective.
The erythropoietic protoporphyrias (EPP) are a group of ultra-rare (1:100.000) inborn errors of the heme biosynthesis characterised by painful phototoxic reactions in tissue exposed to visible light. Afamelanotide is the only approved treatment for EPP and effectively prevents phototoxic reactions and improves the quality of life of the patients. In the past years, several new potential treatment options for EPP have been identified, some of which are currently under investigation in clinical trials. While these developments could improve patient care, it is important to know how safety and efficacy of drug candidates compare to the existing treatment, i.e. afamelanotide. We identified pharmacotherapies (leaving out, for example, topical applications such as sunscreens or supplements such as iron) which are currently (that is, within the last 5 years) evaluated for EPP from clinical trial registries and investigated whether the trial designs allow a comparison of their treatment effects with each other and with afamelanotide. Therefore, we analysed the clinical trial protocols with emphasis on their trial designs, efficacy outcome measures, inclusion and exclusion criteria, safety aspects and, if available, published results. Our search in the clinical trials registries retrieved 29 trials that included patients with EPP. From these, we identified 16 clinical trials evaluating afamelanotide and three new pharmacotherapies, i.e., dersimelagon, bitopertin and cimetidine. Safety and efficacy of all new pharmacotherapies are currently being investigated against placebo-control groups or against baseline. Because of differences in the outcome measures and included patient populations, the results of the trials cannot be directly compared. Moreover, methodically challenging aspects and ethical issues were identified in some of the trial protocols. Efficacy and safety of currently investigated treatments for EPP are not directly comparable. We wrote this manuscript as a call to action to Principal Investigators, Ethical Review Boards, Regulatory Authorities and the sponsors of trials because we are convinced that trials directly assessing new pharmacotherapies against afamelanotide would be the more informative, and methodological and ethically sounder trial design. Not applicable. The online version contains supplementary material available at 10.1186/s13023-025-04170-9.
2025-09-17 | Rbm38 deficiency impairs erythroid heme biosynthesis and induces porphyria via reduced ferrochelatase expression.
RNA splicing and processing are critical for erythropoiesis, because dysregulation of RNA splicing ultimately disrupts protein synthesis. The RNA-binding protein Rbm38 is highly expressed during terminal erythropoiesis. Although in vitro studies have implicated Rbm38 as a key regulator of erythroid differentiation, the landscape of RNA splicing regulated by Rbm38 and its role in terminal erythropoiesis in vivo have not been fully elucidated. Here, we generated whole-body and conditional knockout mouse models for Rbm38 and found that mature red blood cell (RBC) production was impaired in the bone marrow of Rbm38-deficient mice. Rbm38-/- RBCs exhibited reduced hemoglobin content and increased susceptibility to oxidative stress-induced hemolysis. These mutant mice also developed microcytic hypochromic anemia, along with dysregulated iron homeostasis. Additionally, they exhibited decreased mitochondrial heme biosynthesis and accumulation of free protoporphyrin IX (PPIX) in erythrocytes and feces, resembling human erythropoietic protoporphyria (EPP). Mechanistically, Rbm38 regulates the incorporation of ferrous iron (Fe2+) into PPIX to form heme by modulating alternative splicing, messenger RNA decay, and translation of the porphyrin metabolic enzyme gene Ferrochelatase (Fech). Importantly, enforced expression of Fech largely restored erythroid differentiation defects and ameliorated anemia in Rbm38-/- transplants. We further demonstrated that genetic variants in the human RBM38 gene locus influence PPIX levels in erythrocytes from healthy cohorts. Our findings demonstrate that Rbm38 governs terminal erythropoiesis by orchestrating RNA splicing, stability, and translation during heme biosynthesis.
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.
2026-03-12 | Hematopoietic stem cell transplantation for erythropoietic porphyria-induced acute liver failure: a case report and literature review.
Protoporphyrias are rare genetic disorders in heme biosynthesis, causing protoporphyrin IX accumulation with progressive liver injury. Liver transplantation has traditionally treated protoporphyria-induced liver injury but does not correct the underlying hematopoietic defect. We present a 16-year-old male with painful cutaneous photosensitivity who developed cholestatic liver dysfunction and severe abdominal pain. After plasmapheresis, red blood cell (RBC) transfusions, and intravenous hemin, he had transient improvement and subsequently underwent hematopoietic stem cell transplantation (HSCT) without liver transplantation, which normalized his protoporphyrin levels, liver function, and symptoms. This case underscores HSCT as a disease-modifying therapy that may prevent liver transplantation when performed before irreversible hepatic damage.
2025-12-31 | Congenital Erythropoietic Porphyria with Persistent Severe Biochemical Abnormalities and a Non-Mutilating Clinical Course: A Case Report
Congenital erythropoietic porphyria (CEP), also known as Günther disease, is a rare autosomal recessive porphyria caused by deficiency of uroporphyrinogen III synthase, leading to accumulation of phototoxic type I porphyrins. CEP classically presents in infancy with severe photosensitivity, blistering, scarring, and hemolytic anemia; however, significant phenotypic variability has increasingly been recognized. We report 32-year-old women diagnosed with CEP in early infancy who demonstrated persistently and profoundly elevated erythrocyte porphyrin levels over more than a decade yet followed a relatively non-mutilating clinical course. Genetic testing identified a low penetrance intronic UROS variant typically associated with erythropoietic protoporphyria, underscoring diagnostic challenges and genotype-phenotype discordance. The patient experienced marked improvement in photosensitivity and burning pain after initiation of afamelanotide, without need for transfusion therapy or stem cell transplantation. This case highlights the heterogeneity of CEP, the importance of long-term biochemical follow up, and the potential role of afamelanotide in improving quality of life for selected patients with CEP.
2025-12-30 | New pharmacotherapies for the erythropoietic protoporphyrias: an analysis of trial protocols from a patient perspective.
The erythropoietic protoporphyrias (EPP) are a group of ultra-rare (1:100.000) inborn errors of the heme biosynthesis characterised by painful phototoxic reactions in tissue exposed to visible light. Afamelanotide is the only approved treatment for EPP and effectively prevents phototoxic reactions and improves the quality of life of the patients. In the past years, several new potential treatment options for EPP have been identified, some of which are currently under investigation in clinical trials. While these developments could improve patient care, it is important to know how safety and efficacy of drug candidates compare to the existing treatment, i.e. afamelanotide. We identified pharmacotherapies (leaving out, for example, topical applications such as sunscreens or supplements such as iron) which are currently (that is, within the last 5 years) evaluated for EPP from clinical trial registries and investigated whether the trial designs allow a comparison of their treatment effects with each other and with afamelanotide. Therefore, we analysed the clinical trial protocols with emphasis on their trial designs, efficacy outcome measures, inclusion and exclusion criteria, safety aspects and, if available, published results. Our search in the clinical trials registries retrieved 29 trials that included patients with EPP. From these, we identified 16 clinical trials evaluating afamelanotide and three new pharmacotherapies, i.e., dersimelagon, bitopertin and cimetidine. Safety and efficacy of all new pharmacotherapies are currently being investigated against placebo-control groups or against baseline. Because of differences in the outcome measures and included patient populations, the results of the trials cannot be directly compared. Moreover, methodically challenging aspects and ethical issues were identified in some of the trial protocols. Efficacy and safety of currently investigated treatments for EPP are not directly comparable. We wrote this manuscript as a call to action to Principal Investigators, Ethical Review Boards, Regulatory Authorities and the sponsors of trials because we are convinced that trials directly assessing new pharmacotherapies against afamelanotide would be the more informative, and methodological and ethically sounder trial design. Not applicable. The online version contains supplementary material available at 10.1186/s13023-025-04170-9.
2025-09-17 | Rbm38 deficiency impairs erythroid heme biosynthesis and induces porphyria via reduced ferrochelatase expression.
RNA splicing and processing are critical for erythropoiesis, because dysregulation of RNA splicing ultimately disrupts protein synthesis. The RNA-binding protein Rbm38 is highly expressed during terminal erythropoiesis. Although in vitro studies have implicated Rbm38 as a key regulator of erythroid differentiation, the landscape of RNA splicing regulated by Rbm38 and its role in terminal erythropoiesis in vivo have not been fully elucidated. Here, we generated whole-body and conditional knockout mouse models for Rbm38 and found that mature red blood cell (RBC) production was impaired in the bone marrow of Rbm38-deficient mice. Rbm38-/- RBCs exhibited reduced hemoglobin content and increased susceptibility to oxidative stress-induced hemolysis. These mutant mice also developed microcytic hypochromic anemia, along with dysregulated iron homeostasis. Additionally, they exhibited decreased mitochondrial heme biosynthesis and accumulation of free protoporphyrin IX (PPIX) in erythrocytes and feces, resembling human erythropoietic protoporphyria (EPP). Mechanistically, Rbm38 regulates the incorporation of ferrous iron (Fe2+) into PPIX to form heme by modulating alternative splicing, messenger RNA decay, and translation of the porphyrin metabolic enzyme gene Ferrochelatase (Fech). Importantly, enforced expression of Fech largely restored erythroid differentiation defects and ameliorated anemia in Rbm38-/- transplants. We further demonstrated that genetic variants in the human RBM38 gene locus influence PPIX levels in erythrocytes from healthy cohorts. Our findings demonstrate that Rbm38 governs terminal erythropoiesis by orchestrating RNA splicing, stability, and translation during heme biosynthesis.
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Drug Discovery Landscape
3 orphan drug designations for Congenital erythropoietic porphyria.
3 orphan drug designations for Congenital erythropoietic porphyria.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Ciclopirox | small molecules | FDA | 2018-04-17 | — | Atlas Molecular Pharma S.L. |
Ciclopirox | small molecules | EMA | 2018-01-17 | — | Atlas Molecular Pharma S.L. |
[Nle4, D-Phe7]-alpha-melanocyte stimulating hormone | peptides | EMA | 2008-05-08 | — | Clinuvel Europe Limited |
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