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Hubert De Verneuil - One of the best experts on this subject based on the ideXlab platform.
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therapeutic potential of proteasome inhibitors in Congenital Erythropoietic Porphyria
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Jeanmarc Blouin, Hubert De Verneuil, Cécile Ged, Ana Lain, Magalie Lalanne, Pierre Costet, Yann Duchartre, Oscar Millet, Emmanuel RichardAbstract:Congenital Erythropoietic Porphyria (CEP) is a rare autosomal recessive disorder characterized by uroporphyrinogen III synthase (UROS) deficiency resulting in massive porphyrin accumulation in blood cells, which is responsible for hemolytic anemia and skin photosensitivity. Among the missense mutations actually described up to now in CEP patients, the C73R and the P248Q mutations lead to a profound UROS deficiency and are usually associated with a severe clinical phenotype. We previously demonstrated that the UROSC73R mutant protein conserves intrinsic enzymatic activity but triggers premature degradation in cellular systems that could be prevented by proteasome inhibitors. We show evidence that the reduced kinetic stability of the UROSP248Q mutant is also responsible for increased protein turnover in human erythroid cells. Through the analysis of EGFP-tagged versions of UROS enzyme, we demonstrate that both UROSC73R and UROSP248Q are equally destabilized in mammalian cells and targeted to the proteasomal pathway for degradation. We show that a treatment with proteasomal inhibitors, but not with lysosomal inhibitors, could rescue the expression of both EGFP-UROS mutants. Finally, in CEP mice (UrosP248Q/P248Q) treated with bortezomib (Velcade), a clinically approved proteasome inhibitor, we observed reduced porphyrin accumulation in circulating RBCs and urine, as well as reversion of skin photosensitivity on bortezomib treatment. These results of medical importance pave the way for pharmacologic treatment of CEP disease by preventing certain enzymatically active UROS mutants from early degradation by using proteasome inhibitors or chemical chaperones.
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Successful match-unrelated donor bone marrow transplantation for Congenital Erythropoietic Porphyria (Günther disease)
European Journal of Pediatrics, 2005Co-Authors: Sophie Dupuis-girod, Jean-charles Deybach, Cécile Ged, Véronique Akkari, Claire Galambrun, Kamila Kebaïli, Alain Claudy, Lucette Geburher, Noël Philippe, Hubert De VerneuilAbstract:Congenital Erythropoietic Porphyria (CEP; Günther disease; OMIM 263700) is a rare autosomal recessive disorder caused by a deficiency of uroporphyrinogen III synthase (UROS). The deficiency of this enzyme is associated with lifelong overproduction of series I porphyrins which circulate and are deposited in many tissues, causing light-sensitisation and severe damage to skin beginning in childhood. Blistering and scarring of exposed areas may lead to mutilating deformities. We describe two cases: a 4-year-old boy and his first cousin who were cured of CEP by matched unrelated donor bone marrow transplants. Both are alive and disease-free 3 and 2 years post-transplant, respectively. Cutaneous lesions improved dramatically. The correction of the enzyme deficiency was confirmed by measuring erythrocyte UROS activity and urinary porphyrin excretion. Chimerism was complete for both children. Both patients were homoallelic for a novel mutation of the UROS gene, the missense mutation A69T. Conclusion: Considering the severity of the disease, if HLA-matched sibling donor is not available, haematopoietic stem cell transplantation using a matched unrelated donor should be strongly considered for treating Congenital Erythropoietic Porphyria since this is currently the only known curative therapy.
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A novel point mutation in Congenital Erythropoietic Porphyria in two members of Japanese family
Human Genetics, 1996Co-Authors: Ken Tanigawa, Noboru Takamura, Shunichi Yamashita, M. Bensidhoum, Hiroyuki Namba, Hubert De VerneuilAbstract:The molecular basis of the uroporphyrinogen III synthase (UROIIIS) deficiency was investigated in two members of a Japanese family. This defect in heme biosynthesis is responsible for a rare autosomal recessive disease: Congenital Erythropoietic Porphyria (CEP) or Günther's disease. The first patient was homoallelic for a novel missense mutation: a T to C transition of nucleotide 634 that predicted a serine to proline substitution at residue 212 (S212P). The second patient appeared heteroallelic, carrying the same missense mutation and a nonsense mutation: a C to T change at nucleotide 745, resulting in a premature stop at codon 249, instead of a glutamine (Q249X). The corresponding mutated proteins were expressed in Escherichia coli and no residual activity was observed. A family study was also performed to determine the carrier status.
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Correction of Congenital Erythropoietic Porphyria by bone marrow transplantation
The Journal of pediatrics, 1996Co-Authors: Caroline Thomas, Hubert De Verneuil, Yves Nordmann, Cécile Ged, Isabelle Pellier, Alain Fischer, Stéphane BlancheAbstract:Congenital Erythropoietic Porphyria (Gunther disease) is a rare metabolic disorder caused by uroporphyrinogen III synthetase deficiency. We report the case of a 2-year-old girl with a severe form of this disease who received HLA-identical bone marrow transplantation from her heterozygous sister. Two transplantations were necessary to obtain full hematopoietic chimerism. Correction of the enzyme deficiency was confirmed by measuring erythrocyte uroporphyrinogen III synthetase activity. The patient's clinical condition improved dramatically, and she is well 1 year after the second transplantation, with no further treatment. Although long-term efficacy remains to be confirmed, we conclude that allogeneic bone marrow transplantation can cure patients with Congenital Erythropoietic Porphyria.
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heterogeneity of mutations in the uroporphyrinogen iii synthase gene in Congenital Erythropoietic Porphyria
Human Genetics, 1992Co-Authors: Samia Boulechfar, Jean-charles Deybach, Bernard Grandchamp, Y. Nordmann, Vasco Da Silva, Hubert De VerneuilAbstract:Congenital Erythropoietic Porphyria (CEP) or Gunther's disease is an inborn error of heme biosynthesis transmitted as an autosomal recessive trait and characterized by a profound deficiency of uroporphyrinogen III synthase (UROIIIS) activity. We have previously described two missense mutations in the UROIIIS gene, confirming that the primary defect responsible for CEP is a structural alteration of this gene. We have extended our work to 5 additional unrelated families. Two new point mutations, a deletion and an insertion have been found in the messenger RNA. Our study shows that a molecular heterogeneity of the mutations exists in Gunther's disease. One mutation (C73R), however, appears to be more frequent than the others. Finally, the different normal and mutated proteins have been expressed in Escherichia coli to determine the consequence of the mutations on the enzyme activity.
Cécile Ged - One of the best experts on this subject based on the ideXlab platform.
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Phlebotomy as an efficient long-term treatment of Congenital Erythropoietic Porphyria
Haematologica, 2020Co-Authors: Arienne Mirmiran, Cécile Ged, Antoine Poli, Caroline Schmitt, Thibaud Lefebvre, Hana Manceau, Raed Daher, Boualem Moulouel, Katell Peoc'h, Sylvie SimoninAbstract:Congenital Erythropoietic Porphyria (CEP) is a rare autosomal recessive disease caused by impaired activity of uroporphyrinogen III synthase, the fourth enzyme of the heme biosynthetic pathway. Massive accumulation of porphyrins in red blood cells is responsible for hemolysis and porphyrin deposition in the skin, inducing severe bullous lesions and progressive photomutilation. Treatment options are scarce, relying mainly on supportive measures and, for severe cases, on bone marrow transplantation. In CEP, gain-of-function mutations in ALAS2 can represent an aggravating factor, and iron restriction can improve disease symptoms. Herein, we present the first case of a CEP patient significantly improved by iron deficiency induced by iterative phlebotomies for almost two years. We observed discontinuation of hemolysis and a marked decrease in plasma and urine porphyrins. The patient reported a major improvement in photosensitivity. No adverse effects were observed. The characterization of 3 CEP siblings in a consanguineous family with contrasting phenotypes modulated by iron availability highlights the importance of iron metabolism in the disease. Erythroid cultures were performed, demonstrating the role of iron in the rate of porphyrin production. Thus, we propose phlebotomy as an efficient, accessible, inexpensive and well-tolerated treatment for CEP.
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therapeutic potential of proteasome inhibitors in Congenital Erythropoietic Porphyria
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Jeanmarc Blouin, Hubert De Verneuil, Cécile Ged, Ana Lain, Magalie Lalanne, Pierre Costet, Yann Duchartre, Oscar Millet, Emmanuel RichardAbstract:Congenital Erythropoietic Porphyria (CEP) is a rare autosomal recessive disorder characterized by uroporphyrinogen III synthase (UROS) deficiency resulting in massive porphyrin accumulation in blood cells, which is responsible for hemolytic anemia and skin photosensitivity. Among the missense mutations actually described up to now in CEP patients, the C73R and the P248Q mutations lead to a profound UROS deficiency and are usually associated with a severe clinical phenotype. We previously demonstrated that the UROSC73R mutant protein conserves intrinsic enzymatic activity but triggers premature degradation in cellular systems that could be prevented by proteasome inhibitors. We show evidence that the reduced kinetic stability of the UROSP248Q mutant is also responsible for increased protein turnover in human erythroid cells. Through the analysis of EGFP-tagged versions of UROS enzyme, we demonstrate that both UROSC73R and UROSP248Q are equally destabilized in mammalian cells and targeted to the proteasomal pathway for degradation. We show that a treatment with proteasomal inhibitors, but not with lysosomal inhibitors, could rescue the expression of both EGFP-UROS mutants. Finally, in CEP mice (UrosP248Q/P248Q) treated with bortezomib (Velcade), a clinically approved proteasome inhibitor, we observed reduced porphyrin accumulation in circulating RBCs and urine, as well as reversion of skin photosensitivity on bortezomib treatment. These results of medical importance pave the way for pharmacologic treatment of CEP disease by preventing certain enzymatically active UROS mutants from early degradation by using proteasome inhibitors or chemical chaperones.
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Report of a novel Indian case of Congenital Erythropoietic Porphyria and overview of therapeutic options.
Journal of pediatric hematology oncology, 2013Co-Authors: Meenu Pandey, Cécile Ged, Sharmila B. Mukherjee, Bijoy Patra, Seema Kapoor, Satinder Aneja, Anju SethAbstract:Congenital Erythropoietic Porphyria is a rare disorder of heme biosynthesis, resulting from decreased enzymatic activity of uroporphyrinogen III synthase. Clinical manifestations are heterogenous, of variable severity, and with occasional phenotypic-genotypic correlation. A 14-month-old boy developed fever, extensive dermatitis, and reddish colored urine. Anemia, erythrodontia, hepatosplenomegaly, and massive urinary elimination of predominantly type I porphyrins was suggestive of Congenital Erythropoietic Porphyria. Although hemolysis remained mild and compensated, facial and digital mutilation developed indicative of moderate clinical phenotype. Mutational analysis revealed compound heterozygosity of mutant alleles, including a novel mutation (p.Pro190Leu). The child received supportive management and underwent facial reconstruction successfully.
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Congenital Erythropoietic Porphyria: mutation update and correlations between genotype and phenotype.
Cellular and molecular biology (Noisy-le-Grand France), 2009Co-Authors: Cécile Ged, François Moreau-gaudry, Emmanuel Richard, Elodie Robert-richard, H. De VerneuilAbstract:High quality genotype/phenotype analysis is a difficult issue in rare genetic diseases such as Congenital Erythropoietic Porphyria (CEP) or Gunther's disease, a heme biosynthesis defect due to uroporphyrinogen III synthase deficiency. The historical background and the main phenotypic features of the disease are depicted together with an update of published mutants and genotype/phenotype correlations. General rules concerning the prediction of disease severity are drawn as a guide for patient management and therapeutic choices. The phenotypic heterogeneity of the disease is presented in relation with a likely influence of modifying factors, either genetic or acquired.
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A knock-in mouse model of Congenital Erythropoietic Porphyria.
Genomics, 2005Co-Authors: Cécile Ged, Pierre Dubus, M. Mendez, E. Robert, Magalie Lalanne, Isabelle Lamrissi-garcia, Pierre Costet, Jean-yves Daniel, Frédéric Mazurier, François Moreau-gaudryAbstract:Abstract Congenital Erythropoietic Porphyria (CEP) is a recessive autosomal disorder characterized by a deficiency in uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthetic pathway. The severity of the disease, the lack of specific treatment except for allogeneic bone marrow transplantation, and the knowledge of the molecular lesions are strong arguments for gene therapy. An animal model of CEP has been designed to evaluate the feasibility of retroviral gene transfer in hematopoietic stem cells. We have previously demonstrated that the knockout of the Uros gene is lethal in mice (Urosdel model). This work describes the achievement of a knock-in model, which reproduces a mutation of the UROS gene responsible for a severe UROS deficiency in humans (P248Q missense mutant). Homozygous mice display erythrodontia, moderate photosensitivity, hepatosplenomegaly, and hemolytic anemia. Uroporphyrin (99% type I isomer) accumulates in urine. Total porphyrins are increased in erythrocytes and feces, while Uros enzymatic activity is below 1% of the normal level in the different tissues analyzed. These pathological findings closely mimic the CEP disease in humans and demonstrate that the Urosmut248 mouse represents a suitable model of the human disease for pathophysiological, pharmaceutical, and therapeutic purposes.
Jean-charles Deybach - One of the best experts on this subject based on the ideXlab platform.
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Successful match-unrelated donor bone marrow transplantation for Congenital Erythropoietic Porphyria (Günther disease)
European Journal of Pediatrics, 2005Co-Authors: Sophie Dupuis-girod, Jean-charles Deybach, Cécile Ged, Véronique Akkari, Claire Galambrun, Kamila Kebaïli, Alain Claudy, Lucette Geburher, Noël Philippe, Hubert De VerneuilAbstract:Congenital Erythropoietic Porphyria (CEP; Günther disease; OMIM 263700) is a rare autosomal recessive disorder caused by a deficiency of uroporphyrinogen III synthase (UROS). The deficiency of this enzyme is associated with lifelong overproduction of series I porphyrins which circulate and are deposited in many tissues, causing light-sensitisation and severe damage to skin beginning in childhood. Blistering and scarring of exposed areas may lead to mutilating deformities. We describe two cases: a 4-year-old boy and his first cousin who were cured of CEP by matched unrelated donor bone marrow transplants. Both are alive and disease-free 3 and 2 years post-transplant, respectively. Cutaneous lesions improved dramatically. The correction of the enzyme deficiency was confirmed by measuring erythrocyte UROS activity and urinary porphyrin excretion. Chimerism was complete for both children. Both patients were homoallelic for a novel mutation of the UROS gene, the missense mutation A69T. Conclusion: Considering the severity of the disease, if HLA-matched sibling donor is not available, haematopoietic stem cell transplantation using a matched unrelated donor should be strongly considered for treating Congenital Erythropoietic Porphyria since this is currently the only known curative therapy.
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heterogeneity of mutations in the uroporphyrinogen iii synthase gene in Congenital Erythropoietic Porphyria
Human Genetics, 1992Co-Authors: Samia Boulechfar, Jean-charles Deybach, Bernard Grandchamp, Y. Nordmann, Vasco Da Silva, Hubert De VerneuilAbstract:Congenital Erythropoietic Porphyria (CEP) or Gunther's disease is an inborn error of heme biosynthesis transmitted as an autosomal recessive trait and characterized by a profound deficiency of uroporphyrinogen III synthase (UROIIIS) activity. We have previously described two missense mutations in the UROIIIS gene, confirming that the primary defect responsible for CEP is a structural alteration of this gene. We have extended our work to 5 additional unrelated families. Two new point mutations, a deletion and an insertion have been found in the messenger RNA. Our study shows that a molecular heterogeneity of the mutations exists in Gunther's disease. One mutation (C73R), however, appears to be more frequent than the others. Finally, the different normal and mutated proteins have been expressed in Escherichia coli to determine the consequence of the mutations on the enzyme activity.
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Coexistent hereditary coproPorphyria and Congenital Erythropoietic Porphyria (Günther disease)
Journal of Inherited Metabolic Disease, 1990Co-Authors: Yves Nordmann, Dor Amram, L. N. Phung, Jean-charles Deybach, D. LesbrosAbstract:We present data on one patient with an inheritance pattern for two Porphyrias. From her mother she inherited the trait of hereditary coproPorphyria; from both parents she inherited the trait of Congenital Erythropoietic Porphyria (Günther disease). Enzyme studies confirmed this new type of dual Porphyria.
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point mutations in the uroporphyrinogen iii synthase gene in Congenital Erythropoietic Porphyria gunther s disease
Blood, 1990Co-Authors: Jean-charles Deybach, Hubert De Verneuil, Bernard Grandchamp, Samia Boulechfar, Yves NordmannAbstract:Congenital Erythropoietic Porphyria (Gunther's disease) is a rare disorder of heme biosynthesis inherited in an autosomal recessive fashion. The molecular abnormality responsible for the characteristic defect in uroporphyrinogen III synthase activity was investigated in two patients. For the first patient, complementary DNA was specifically amplified using the polymerase chain reaction and subsequently cloned and sequenced. Data obtained revealed the coexistence of two distinct point mutations: a T to C change in codon 73 (arginine in place of a cysteine) and a C to T change in codon 53 (leucine in place of a proline). The second case was studied by hybridization with allele specific oligonucleotides and was found to be homozygous for the same mutation in codon 53. These are the first mutations to be recognized in the uroporphyrinogen III synthase gene from Congenital Erythropoietic Porphyria patients.
Yves Nordmann - One of the best experts on this subject based on the ideXlab platform.
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Correction of Congenital Erythropoietic Porphyria by bone marrow transplantation
The Journal of pediatrics, 1996Co-Authors: Caroline Thomas, Hubert De Verneuil, Yves Nordmann, Cécile Ged, Isabelle Pellier, Alain Fischer, Stéphane BlancheAbstract:Congenital Erythropoietic Porphyria (Gunther disease) is a rare metabolic disorder caused by uroporphyrinogen III synthetase deficiency. We report the case of a 2-year-old girl with a severe form of this disease who received HLA-identical bone marrow transplantation from her heterozygous sister. Two transplantations were necessary to obtain full hematopoietic chimerism. Correction of the enzyme deficiency was confirmed by measuring erythrocyte uroporphyrinogen III synthetase activity. The patient's clinical condition improved dramatically, and she is well 1 year after the second transplantation, with no further treatment. Although long-term efficacy remains to be confirmed, we conclude that allogeneic bone marrow transplantation can cure patients with Congenital Erythropoietic Porphyria.
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Coexistent hereditary coproPorphyria and Congenital Erythropoietic Porphyria (Günther disease)
Journal of Inherited Metabolic Disease, 1990Co-Authors: Yves Nordmann, Dor Amram, L. N. Phung, Jean-charles Deybach, D. LesbrosAbstract:We present data on one patient with an inheritance pattern for two Porphyrias. From her mother she inherited the trait of hereditary coproPorphyria; from both parents she inherited the trait of Congenital Erythropoietic Porphyria (Günther disease). Enzyme studies confirmed this new type of dual Porphyria.
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point mutations in the uroporphyrinogen iii synthase gene in Congenital Erythropoietic Porphyria gunther s disease
Blood, 1990Co-Authors: Jean-charles Deybach, Hubert De Verneuil, Bernard Grandchamp, Samia Boulechfar, Yves NordmannAbstract:Congenital Erythropoietic Porphyria (Gunther's disease) is a rare disorder of heme biosynthesis inherited in an autosomal recessive fashion. The molecular abnormality responsible for the characteristic defect in uroporphyrinogen III synthase activity was investigated in two patients. For the first patient, complementary DNA was specifically amplified using the polymerase chain reaction and subsequently cloned and sequenced. Data obtained revealed the coexistence of two distinct point mutations: a T to C change in codon 73 (arginine in place of a cysteine) and a C to T change in codon 53 (leucine in place of a proline). The second case was studied by hybridization with allele specific oligonucleotides and was found to be homozygous for the same mutation in codon 53. These are the first mutations to be recognized in the uroporphyrinogen III synthase gene from Congenital Erythropoietic Porphyria patients.
Robert J. Desnick - One of the best experts on this subject based on the ideXlab platform.
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Congenital Erythropoietic Porphyria: Recent advances.
Molecular Genetics and Metabolism, 2018Co-Authors: Angelika Erwin, Robert J. DesnickAbstract:Congenital Erythropoietic Porphyria (CEP) is a rare autosomal recessive disorder characterized by photosensitivity and by hematologic abnormalities in affected individuals. CEP is caused by mutations in the uroporphyrinogen synthase (UROS) gene. In three reported cases, CEP has been associated with a specific X-linked GATA1 mutation. Disease-causing mutations in either gene result in absent or markedly reduced UROS enzymatic activity. This in turn leads to the accumulation of the non-physiologic and photoreactive porphyrinogens, uroporphyrinogen I and coproporphyrinogen I, which damage erythrocytes and elicit a phototoxic reaction upon light exposure. The clinical spectrum of CEP depends on the level of residual UROS activity, which is determined by the underlying pathogenic loss-of-function UROS mutations. Disease severity ranges from non-immune hydrops fetalis in utero to late-onset disease with only mild cutaneous involvement. The clinical characteristics of CEP include exquisite photosensitivity to visible light resulting in bullous vesicular lesions which, when infected lead to progressive photomutilation of sun-exposed areas such as the face and hands. In addition, patients have erythrodontia (brownish discoloration of teeth) and can develop corneal scarring. Chronic transfusion-dependent hemolytic anemia is common and leads to bone marrow hyperplasia, which further increases porphyrin production. Management of CEP consists of strict avoidance of exposure to visible light with sun-protective clothing, sunglasses, and car and home window filters. Adequate care of ruptured vesicles and use of topical antibiotics is indicated to prevent superinfections and osteolysis. In patients with symptomatic hemolytic anemia, frequent erythrocyte cell transfusions may be necessary to suppress hematopoiesis and decrease marrow production of the phototoxic porphyrins. In severe transfection-dependent cases, bone marrow or hematopoietic stem cell transplantation has been performed, which is curative. Therapeutic approaches including gene therapy, proteasome inhibition, and pharmacologic chaperones are under investigation.
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Congenital Erythropoietic Porphyria
2016Co-Authors: Angelika Erwin, Manisha Balwani, Robert J. DesnickAbstract:Clinical characteristics Congenital Erythropoietic Porphyria (CEP) is characterized in most individuals by severe cutaneous photosensitivity with blistering and increased friability of the skin over light-exposed areas. Onset in most affected individuals occurs at birth or early infancy. The first manifestation is often pink to dark red discoloration of the urine. Hemolytic anemia is common and can range from mild to severe, with some affected individuals requiring chronic blood transfusions. Porphyrin deposition may lead to corneal ulcers and scarring, reddish-brown discoloration of the teeth (erythrodontia), and mild bone loss and/or expansion of the bone marrow. The phenotypic spectrum, however, is broad and ranges from non-immune hydrops fetalis in utero to late-onset disease with only mild cutaneous manifestations in adulthood. Diagnosis/testing The diagnosis of CEP is supported by the biochemical findings of markedly decreased uroporphyrinogen (URO)-synthase activity in erythrocytes and/or markedly increased levels of urinary uroporphyrin I and coproporphyrin I isomers. The diagnosis is confirmed most commonly by identification of biallelic UROS pathogenic variants or on rare occasion by the identification of a hemizygous pathogenic variant in the X-linked gene GATA1. Management Treatment of manifestations: There is no FDA-approved treatment for CEP or specific treatment for the photosensitivity. The only effective management is prevention of blistering by avoidance of sun and light exposure, including the long-wave ultraviolet light that passes through window glass or is emitted from artificial light sources. Therefore, the use of protective clothing, wraparound sunglasses, protective window films, reddish incandescent bulbs, filtering screens for fluorescent lights, and opaque sunscreens containing zinc oxide or titanium oxide is recommended. Wound care is necessary to prevent infection of opened blisters; surgical intervention may be necessary; blood transfusions are necessary when hemolysis is significant. Bone marrow transplantation (BMT) is the only cure for CEP and should be considered in children with severe cutaneous and hematologic involvement. Prevention of primary manifestations: Strict avoidance of sunlight and other long-wave UV light exposure. Prevention of secondary complications: Vitamin D supplementation, immunization for hepatitis A and B. Surveillance: Monitor hematologic indices to assess hemolysis every six months. In those receiving transfusions: monitor for hemolysis more frequently and for iron overload. Monitor hepatic function and vitamin D 25-OH every six to twelve months in all patients. Agents/circumstances to avoid: Avoidance of sunlight and UV light (see Treatment of manifestations). In those with hepatic dysfunction: avoid drugs that may induce cholestasis. Evaluation of relatives at risk: Presymptomatic diagnosis is warranted in relatives at risk for initiation of early intervention (no phototherapy, strict sun protection) and future monitoring for signs of hemolytic anemia. Pregnancy management: Protective filters for artificial lights should be used in the delivery/operating room to prevent phototoxic damage to the mother during delivery. Other: Neither beta-carotene nor phototherapy with narrow-band ultraviolet B radiation has been beneficial. Genetic counseling CEP caused by biallelic UROS pathogenic variants is inherited in an autosomal recessive (AR) manner. CEP caused by a GATA1 pathogenic variant is inherited in an X-linked (XL) manner.
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Treatment of severe Congenital Erythropoietic Porphyria by bone marrow transplantation
Journal of the American Academy of Dermatology, 2001Co-Authors: Frederick A. Harada, Robert J. Desnick, Tor Shwayder, Henry W. LimAbstract:Abstract Congenital Erythropoietic Porphyria (CEP), which is the result of a deficiency of uroporphyrinogen (URO) III synthase activity, is the most disfiguring Porphyria in humans. Various methods of treatment have been used to treat CEP with varying success, including erythrocyte transfusion, hydroxyurea, and splenectomy. The only treatment that corrects the enzymatic defect resulting in a cure is bone marrow/stem cell transplantation, which has been reported previously in only 5 patients worldwide. We describe the first patient with CEP who underwent successful bone marrow transplantation performed in the United States and review the therapeutic options in the management of this challenging type of Porphyria. (J Am Acad Dermatol 2001;45:279-82.)
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Congenital Erythropoietic Porphyria successfully treated by allogeneic bone marrow transplantation
Blood, 1998Co-Authors: Ilhan Tezcan, Kenneth H. Astrin, Aytemiz Gurgey, Murat Tuncer, Mualla Cetin, C Oner, Sevgi Yetgin, F Ersoy, Gerardo I Aizencang, Robert J. DesnickAbstract:The long-term biochemical and clinical effectiveness of allogenic bone marrow transplantation (BMT) was shown in a severely affected, transfusion-dependent 18-month-old female with Congenital Erythropoietic Porphyria (CEP), an autosomal recessive inborn error of heme biosynthesis resulting from mutations in the uroporphyrinogen III synthase (URO-synthase) gene. Three years post-BMT, the recipient had normal hemoglobin, markedly reduced urinary porphyrin excretion, and no cutaneous lesions with unlimited exposure to sunlight. The patient was homoallelic for a novel URO-synthase missense mutation, G188R, that expressed less than 5% of mean normal activity in Escherichia coli, consistent with her transfusion dependency. Because the clinical severity of CEP is highly variable, ranging from nonimmune hydrops fetalis to milder, later onset forms with only cutaneous lesions, the importance of genotyping newly diagnosed infants to select severely affected patients for BMT is emphasized. In addition, the long-term effectiveness of BMT in this patient provides the rationale for future hematopoietic stem cell gene therapy in severely affected patients with CEP.
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Molecular Genetics of Congenital Erythropoietic Porphyria
Seminars in liver disease, 1998Co-Authors: Robert J. Desnick, Ian A. Glass, Constanza Solis, Kenneth H. AstrinAbstract:Congenital Erythropoietic Porphyria (CEP), an autosomal recessive inborn error of heme biosynthesis, results from the markedly deficient activity of the cytosolic enzyme, uroporphyrinogen III synthase (URO-synthase). The accumulation of the nonphysiological and pathogenic porphyrin isomers, uroporphyrin I and coproporphyrin I, leads to the clinical manifestations of CEP. Disease severity in unrelated patients is markedly heterogeneous, ranging from fetal demise or severe transfusion dependency throughout life to milder adult cases with only cutaneous photosensitivity. To date, 18 mutations causing CEP have been described in the URO-synthase gene, including single base substitutions, insertions and deletions, and splicing defects. Most mutations have been identified in one or a few unrelated families with the exception of C73R, L4F, and T228M which occurred in about 33%, 8%, and 7% of the mutant alleles studied, respectively. Prokaryotic expression of the mutant URO-synthase alleles identified those with significant residual activity, thereby permitting genotype/phenotype predictions for severe to milder phenotypes of this clinically heterogeneous disease. As successful bone marrow transplantation in severely affected patients has proven curative, current efforts are underway to develop hematopoietic stem cell gene therapy for CEP.