Congenital Erythropoietic Porphyria Research Articles

Congenital erythropoietic porphyria.

Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disease due to the deficient, but not absent, activity of uroporphyrinogen III synthase (UROS), the fourth enzyme in the heme biosynthesis pathway. Biallelic variants in the UROS gene result in decreased UROS enzymatic activity and the accumulation of non-physiologic Type I porphyrins in cells and fluids. Overproduced uroporphyrins in haematopoietic cells are released into the circulation and distributed to tissues, inducing primarily hematologic and dermatologic symptoms. The clinical manifestations vary in severity ranging from non-immune hydrops fetalis in utero to mild dermatologic manifestations in adults. Here, the biochemical, molecular and clinical features of CEP as well as current and new treatment options, including the rescue of UROS enzyme activity by chaperones, are presented.

Congenital Hematological and Metabolic Disorders Causing Intrinsic Discoloration of Pediatric Dentition at Pre-Eruptive Stage

The current review assesses the literature and depicts the hematological and metabolic diseases of newborns resulting in intrinsic stains of primary dentition. The appearance of dentition is an esthetic concern to the child as well as to the caregivers. The correct diagnosis claims prime importance to the dentist as it has profound value in deciding the appropriate treatment protocol and describing it to the patient. The review describes the hematological and metabolic diseases of newborns which can affect the color of normal pediatric dentition. Erythroblastosis fetalis, icterus gravis neonatorum, congenital erythropoietic porphyria, thalassemia, sickle cell anemia, and alkaptonuria are found to have a definite impact on the intrinsic discoloration of deciduous teeth. The article is an overview of those congenital hematological and metabolic disorders and their direct and indirect effects on primary dentition at the pre-eruptive stage resulting in discoloration.

Causal effect of porphyria biomarkers on alcohol-related hepatocellular carcinoma through Mendelian Randomization.

According to some cohort studies, an association exists between acute intermittent porphyria (AIP) and liver cancer. However, establishing a definitive causal relationship between porphyria and hepatocellular carcinoma (HCC) remains challenging. Prexisting studies regarding porphyria biomarkers and alcohol-related hepatocellular carcinoma (AR-HCC) make possible an entry point. In this study, we aimed to investigate the causal relationships between biomarkers of two types of porphyria, AIP and congenital erythropoietic porphyria (CEP), and AR-HCC. Single-nucleotide polymorphisms (SNPs) associated with porphobilinogen deaminase (PBGD) and uroporphyrinogen-III synthase (UROS), along with outcome data on AR-HCC, were extracted from public genome-wide association studies (GWAS). The GWAS data were then used to explore the potential causal relationships via a two-sample Mendelian randomization (MR) analysis. The effect estimates were calculated using the random-effect inverse-variance-weighted (IVW) method. Additionally, the Cochrane's Q test, MR-Egger test, and leave-one-out analysis were conducted to detect heterogeneity and pleiotropy in the MR results. Using the IVW method as the primary causal effects model in the MR analyses, we found that both PBGD (effect estimate = 1.51; 95% CI, from 1.08 to 2.11, p = 0.016) and UROS (effect estimate = 1.53; 95% CI, from 1.08 to 2.18, p = 0.018) have a significant causal effect on AR-HCC. Our findings revealed a causal effect of both PBGD and UROS on AR-HCC, suggesting that both AIP and CEP have a causal association with AR-HCC.

Severe Perinatal Presentations of Günther's Disease: Series of 20 Cases and Perspectives.

(1) Background: Congenital erythropoietic porphyria (CEP), named Günther's disease, is a rare recessive type of porphyria, resulting from deficient uroporphyrinogen III synthase (UROS), the fourth enzyme of heme biosynthesis. The phenotype ranges from extremely severe perinatal onset, with life-threatening hemolytic anaemia, to mild or moderate cutaneous involvement in late-onset forms. This work reviewed the perinatal CEP cases recorded in France in order to analyse their various presentations and evolution. (2) Methods: Clinical and biological data were retrospectively collected through medical and published records. (3) Results: Twenty CEP cases, who presented with severe manifestations during perinatal period, were classified according to the main course of the disease: antenatal features, acute neonatal distress and postnatal diagnosis. Antenatal symptoms (seven patients) were mainly hydrops fetalis, hepatosplenomegaly, anemia, and malformations. Six of them died prematurely. Five babies showed acute neonatal distress, associated with severe anemia, thrombocytopenia, hepatosplenomegaly, liver dysfunction, and marked photosensitivity leading to diagnosis. The only two neonates who survived underwent hematopoietic stem cell transplantation (HSCT). Common features in post-natal diagnosis (eight patients) included hemolytic anemia, splenomegaly, skin sensitivity, and discoloured teeth and urine. All patients underwent HSCT, with success for six of them, but with fatal complications in two patients. The frequency of the missense variant named C73R is striking in antenatal and neonatal presentations, with 9/12 and 7/8 independent alleles, respectively. (4) Conclusions: The most recent cases in this series are remarkable, as they had a less fatal outcome than expected. Regular transfusions from the intrauterine period and early access to HSCT are the main objectives.

Congenital erythropoietic porphyria presenting with recurrent epistaxis: a case report

BackgroundCongenital erythropoietic porphyria (CEP), also known as pink tooth or Gunther disease, is a rare hereditary disorder caused by an enzyme mutation in the heme biosynthesis pathway, which leads to the accumulation of immature and non-physiological protoporphyrin rings in various tissues. CEP is characterized by sun-exposed bullous skin lesions, hemolytic anemia, red/brown urine, and teeth staining.Case presentationWe present a unique case of a 10-year-old Asian boy with CEP who presented with recurrent epistaxis, an unusual presentation for this condition. Based on clinical presentation and laboratory findings, including elevated urine uroporphyrin and coproporphyrin I and III levels, microcytic anemia, a higher red cell distribution width (RDW), and a lower platelet count, a thorough assessment and detailed workup resulted in a diagnosis of CEP. The patient underwent a successful splenectomy and recovered without any complications.ConclusionThis case report aims to raise awareness among healthcare professionals about the uncommon and atypical presentation of CEP and its management options.

Twelve-year follow-up of bone marrow transplantation in congenital erythropoietic porphyria: lessons learned from a challenging case.

The only curative treatment for congenital erythropoietic porphyria (CEP) is bone marrow transplantation (BMT), but long-term data on this therapy in CEP are scarce. We present the evolution after 12 years of a case of CEP treated with BMT. The BMT has allowed the young patient to develop adequately and to avoid devastating consequences, but mild skin symptoms along with liver and kidney damage persist.

Congenital Erythropoietic Porphyria about a succcessful evolution case

BACKGROUND: Congenital erythropoietic porphyria is an extremely rare autosomal recessive disease. Caused by a deficiency of the enzymatic activity of uroporphyrinogen synthetase III (UROS), collect accumulation of porphyrins of the type I isomer and alterations in the synthesis of the heme group, responsible for the clinical manifestations, mainly cutaneous, hematological, ophthalmic and bone. Diagnosis is based on elevated levels of type I uroporphyrinogen in urine and fecal coproporphyrinogen and clinical findings. CLINICAL CASE: This is a 31-year-old female patient who presented since childhood, multiple hyper and hypopigmented macules both on the back of the hands and on the face, slight destruction of the nasal cartilage, areas of scarring and perioral retraction, sclerodermiform changes, erythrodontia and marked retraction of the phalanges, who was diagnosed with congenital hematopoietic porphyria, who began conservative treatment, achieving an adequate evolution and clinical stability. CONCLUSIONS: It is important to know the different manifestations of this disease to show a prompt diagnosis and avoid known progression, since despite being a rare disease, it can have high morbidity in untreated patients.

P013: Congenital erythropoietic porphyria: Variable age of onset of porphyrinuria, an indicator of disease severity and correlation with genotype

P013: Congenital erythropoietic porphyria: Variable age of onset of porphyrinuria, an indicator of disease severity and correlation with genotype

Porphyrias: Uncommon disorders masquerading as common childhood diseases.

Porphyrias are a rare group of inborn errors of metabolism due to defects in the heme biosynthetic pathway. The biochemical hallmark is the overproduction of porphyrin precursors and porphyrin species. Afflicted patients present with a myriad of symptoms causing a diagnostic odyssey. Symptoms often overlap with those of common diseases and may be overlooked unless there is heightened clinical suspicion. We are reporting clinical features and diagnostic challenges in four pediatric patients having variegate porphyria, congenital erythropoietic porphyria, acute intermittent porphyria, and erythropoietic protoporphyria (EPP), who presented with diverse multisystem manifestations. This case series illustrates a logical analysis of symptoms and judicious selection of investigations and the role of genotyping in successfully diagnosing porphyrias.

Porfiria eritropoyética congénita bovina en la Estacion Experimetal de Choquenaira

We report a case of congenital erythropoietic porphyria in a 5-day-old black and white Holstein female born in Choquenaira Experimental Station of the Faculty of Agronomy of the Universidad Mayor de San Andrés. The clinical picture was characterized by the presence of pinkish brown color of the teeth (pink tooth) caused by porphyrin deposition, hempglobinuria, growth retardation. At 4 months of age. In addition to photosensitization, the most evident macroscopic changes were the reddish brown coloration of the bones and the pinkish brown color of the teeth, caused by porphyrin deposition.

Very Early Diagnosis and Management of Congenital Erythropoietic Porphyria.

Congenital erythropoietic porphyria (CEP), a rare form of porphyria, is caused by a defect in the heme biosynthesis pathway of the enzyme uroporphyrinogen III synthase (UROS). Uroporphyrinogen III synthase deficiency leads to an accumulation of nonphysiological porphyrins in bone marrow, red blood cells, skin, bones, teeth, and spleen. Consequently, the exposure to sunlight causes severe photosensitivity, long-term intravascular hemolysis, and eventually, irreversible mutilating deformities. Several supportive therapies such as strict sun avoidance, physical sunblocks, red blood cells transfusions, hydroxyurea, and splenectomy are commonly used in the management of CEP. Currently, the only available curative treatment of CEP is hematopoietic stem cell transplantation (HSCT). In this article, we present a young girl in which precocious genetic testing enabled early diagnosis and allowed curative treatment with HSCT for CEP at the age of 3 months of age, that is, the youngest reported case thus far.

EP018: Late-onset congenital erythropoietic porphyria associated with myeloid malignancy

Congenital erythropoietic porphyria (CEP, OMIM #263700) is a rare disorder of heme biosynthesis characterized biochemically by elevated excretion of type I porphyrin isomers in urine and feces. The disorder is caused by decreased uroporphyrinogen III synthase (UROS) activity, leading to an overproduction of the dead-end metabolites uro- and coproporphyrinogen I, primarily in the bone marrow, and the subsequent deposition of type I porphyrin isomers in tissues.

Aggressive Systemic Mastocytosis with a Relatively Non-aggressive Course

Background: Mastocytosis is a heterogeneous group of disorders that is characterized by excessive proliferation and pathologic accumulation of mast cells in various body tissues. The mast cells also have abnormal morphology and aberrant expression of surface receptors. Clinical Description: A 4-year-old boy was brought with a history of generalized skin lesions since birth and abdominal distension for 3 years. The diagnosis had not been established to date. General physical examination revealed severe acute malnutrition, pallor, dental staining, facial hypertrichosis, polymorphous skin lesions (cicatricial alopecia, diffuse erythema, multiple plaques of variable diameter, skin-colored nodules, and hypertrophic irregular scars), and positive Darier's sign. He also had hepatosplenomegaly. The differentials considered were congenital erythropoietic porphyria, systemic mastocytosis (SM), multifocal Langerhans cell histiocytosis, and linear immunoglobulin A bullous dermatosis. The presence of mast cells on skin biopsy and elevated serum tryptase levels led us to suspect SM and perform bone marrow studies. The diagnosis of “aggressive” SM was initially made on the application of the diagnostic criteria but revised to “smoldering” SM with the emergence of Vitamin B12 deficiency as the probable cause of pancytopenia. Management: Management was planned by a multidisciplinary team: pediatrician, dermatologist, and hematopathologist. The parents were counseled about the nature, natural history, treatment options, and prognosis of the disorder. The child was provided with nutritional rehabilitation and medication for the cutaneous symptoms (selective histamine H1 receptor inverse agonist, H2-receptor antagonist, and application of topical tacrolimus and calamine lotion). Conclusion: The prognosis varies according to subtype. Careful correlation of clinical and laboratory investigations is required when applying the diagnostic criteria for staging.

26285 A rare case of congenital erythropoietic porphyria presenting with pulse oximeter–induced blisters

Introduction: Congenital erythropoietic porphyria (CEP) is an uncommon disease. It is caused by mutations in the gene encoding the enzyme uroporphyrinogen III synthase (UROS), which lead to accumulation of porphyrins in different tissues. Main manifestations are photosensitivity, hemolytic anemia, bone resorption, ocular impairment, plus red coloration of urine and teeth. The only known curative treatment is bone marrow transplantation.

Acquired erythropoietic uroporphyria secondary to myeloid malignancy: A case report and literature review

Congenital erythropoietic porphyria (CEP) or Günther's disease is a rare autosomal recessive disease resulting from deficient uroporphyrinogen III synthase (UROS) activity, mostly due to homozygous mutations in the UROS gene, and less frequently in GATA1.1 CEP commonly presents at birth with cutaneous photosensitivity, blistering, hypo- and hyperpigmentation, severe scarring and deformities.

Porphyrien

Porphyrien werden durch Enzymdefekte der Hämbiosynthese hervorgerufen und anhand spezifischer biochemischer Muster von Porphyrinen und deren Vorläufern in Urin, Stuhl und Blut diagnostiziert. Das jeweilige Muster der akkumulierten Porphyrine, Vorläufer und Derivate ist verbunden mit der klinischen Ausprägung, die abdominale, neurologische, psychiatrische, endokrine, kardiovaskuläre Symptome, Leberschaden und/oder Lichtempfindlichkeit der Haut umfassen kann. Klinisch werden akute und nichtakute Porphyrien unterschieden. Bei symptomatischen (klinisch aktiven), akuten hepatischen Porphyrien – hierzu gehören akute intermittierende Porphyrie, Porphyria variegata, hereditäre Koproporphyrie und Doss-Porphyrie – kommt es aufgrund einer Regulationsstörung zur Kumulation der Porphyrinvorläufer 5‑Aminolävulinsäure und Porphobilinogen. Bei den nichtakuten Formen – u. a. Porphyria cutanea tarda, erythropoetische und X‑chromosomale Protoporphyrie sowie kongenitale erythropoetische Porphyrie – führen akkumulierte Porphyrine zu Lichtempfindlichkeit (Fotodermatose) und mitunter auch zu schweren Leberschäden. Zur Therapie der Porphyrien stehen sowohl bewährte und sichere als auch innovative Optionen zur Verfügung.

Metabolic Landscape of the Mouse Liver by Quantitative 31 P Nuclear Magnetic Resonance Analysis of the Phosphorome.

Background and AimsThe liver plays a central role in all metabolic processes in the body. However, precise characterization of liver metabolism is often obscured by its inherent complexity. Phosphorylated metabolites occupy a prominent position in all anabolic and catabolic pathways. Here, we develop a 31P nuclear magnetic resonance (NMR)–based method to study the liver “phosphorome” through the simultaneous identification and quantification of multiple hydrophilic and hydrophobic phosphorylated metabolites.Approach and ResultsWe applied this technique to define the metabolic landscape in livers from a mouse model of the rare disease disorder congenital erythropoietic porphyria (CEP) as well as two well‐known murine models of nonalcoholic steatohepatitis: one genetic, methionine adenosyltransferase 1A knockout mice, and the other dietary, mice fed a high‐fat choline‐deficient diet. We report alterations in the concentrations of phosphorylated metabolites that are readouts of the balance between glycolysis, gluconeogenesis, the pentose phosphate pathway, the tricarboxylic acid cycle, and oxidative phosphorylation and of phospholipid metabolism and apoptosis. Moreover, these changes correlate with the main histological features: steatosis, apoptosis, iron deposits, and fibrosis. Strikingly, treatment with the repurposed drug ciclopirox improves the phosphoromic profile of CEP mice, an effect that was mirrored by the normalization of liver histology.ConclusionsIn conclusion, these findings indicate that NMR‐based phosphoromics may be used to unravel metabolic phenotypes of liver injury and to identify the mechanism of drug action.

Improving the Pharmacological Properties of Ciclopirox for Its Use in Congenital Erythropoietic Porphyria.

Congenital erythropoietic porphyria (CEP), also known as Günther’s disease, results from a deficient activity in the fourth enzyme, uroporphyrinogen III synthase (UROIIIS), of the heme pathway. Ciclopirox (CPX) is an off-label drug, topically prescribed as an antifungal. It has been recently shown that it also acts as a pharmacological chaperone in CEP, presenting a specific activity in deleterious mutations in UROIIIS. Despite CPX is active at subtoxic concentrations, acute gastrointestinal (GI) toxicity was found due to the precipitation in the stomach of the active compound and subsequent accumulation in the intestine. To increase its systemic availability, we carried out pharmacokinetic (PK) and pharmacodynamic (PD) studies using alternative formulations for CPX. Such strategy effectively suppressed GI toxicity in WT mice and in a mouse model of the CEP disease (UROIIISP248Q/P248Q). In terms of activity, phosphorylation of CPX yielded good results in CEP cellular models but showed limited activity when administered to the CEP mouse model. These results highlight the need of a proper formulation for pharmacological chaperones used in the treatment of rare diseases.

Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models

Congenital erythropoietic porphyria (CEP) is a rare genetic disorder leading to accumulation of uro/coproporphyrin-I in tissues due to inhibition of uroporphyrinogen-III synthase. Clinical manifestations of CEP include bone fragility, severe photosensitivity and photomutilation. Currently there is no specific treatment for CEP, except bone marrow transplantation, and there is an unmet need for treating this orphan disease. Fluorescent porphyrins cause protein aggregation, which led us to hypothesize that uroporphyrin-I accumulation leads to protein aggregation and CEP-related bone phenotype. We developed a zebrafish model that phenocopies features of CEP. As in human patients, uroporphyrin-I accumulated in the bones of zebrafish, leading to impaired bone development. Furthermore, in an osteoblast-like cell line, uroporphyrin-I decreased mineralization, aggregated bone matrix proteins, activated endoplasmic reticulum stress and disrupted autophagy. Using high-throughput drug screening, we identified acitretin, a second-generation retinoid, and showed that it reduced uroporphyrin-I accumulation and its deleterious effects on bones. Our findings provide a new CEP experimental model and a potential repurposed therapeutic.

Congenital erythropoietic porphyria and its rarity in Indian siblings

Congenital erythropoietic porphyria and its rarity in Indian siblings