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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 identification and expression of eight novel mutations in the uroporphyrinogen iii synthase gene
British Journal of Haematology, 2002Co-Authors: Amr A Shady, Kenneth H. Astrin, Brandon R Colby, Luis F Cunha, David F Bishop, Robert J. DesnickAbstract:Summary. Mutations in the uroporphyrinogen III synthase (URO-synthase) gene cause congenital Erythropoietic Porphyria (CEP), an autosomal recessive inborn error of haem biosynthesis. Molecular analysis of the URO-synthase gene in seven unrelated CEP patients revealed eight novel mutations. These included four missense mutations (A69T, E81D, G188W and I219S), a deletion (21delG), two insertions (398insG and 672ins28) and one complex mutation (627del6ins39), as well as three previously reported mutations, C73R, T228M, and −86CA. When the four novel missense mutations were expressed in Escherichia coli, only E81D expressed significant enzymatic activity (30% of expressed wild-type activity), which was thermolabile. In addition, reverse transcription polymerase chain reaction studies demonstrated that E81D, which altered the penultimate nucleotide in exon 4, impaired splicing and caused about 85% exon 4 skipping. The identification and expression of these mutations provided genotype–phenotype correlations and further evidence of the molecular heterogeneity underlying this Erythropoietic Porphyria.
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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, Tor Shwayder, Robert J. DesnickAbstract: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.
Hubert De Verneuil - One of the best experts on this subject based on the ideXlab platform.
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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, Hubert 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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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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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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PRENATAL DIAGNOSIS IN CONGENITAL Erythropoietic Porphyria BY METABOLIC MEASUREMENT AND DNA MUTATION ANALYSIS
Prenatal diagnosis, 1996Co-Authors: Cécile Ged, François Moreau-gaudry, I. Hombrados, Laurence Taine, P. Calvas, P. Colombies, Hubert De VerneuilAbstract:Identification of uroporphyrinogen III synthase (UROIIIS) gene mutations in patients with congenital Erythropoietic Porphyria (CEP) allows fast and reliable carrier detection and prenatal diagnosis. We describe here the first case of prenatal diagnosis by concomitant measurement of uroporphyrin I in amniotic fluid and direct detection of the gene mutation. A French couple, whose first child was diagnosed with CEP, requested prenatal diagnosis at 16 weeks of gestation. Uroporphyrin I was dramatically increased in amniotic fluid and the fetus was homozygous for the C73R mutation, the most common mutation in this disease. The pregnancy was then terminated.
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Identification of Two New Mutations in Congenital Erythropoietic Porphyria
European Journal of Human Genetics, 1995Co-Authors: M. Bensidhoum, Cécile Ged, François Moreau-gaudry, I. Hombrados, R. S. Hift, P. Meissner, E. D. Sturrock, Hubert De VerneuilAbstract:Congenital Erythropoietic Porphyria (CEP) or Günther’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. Six missense mutations in the UROIIIS gene, a deletion and an insertion have already been described in CEP. This work brings further evidence for the heterogeneity in the genetic defect found in CEP. Two new mutations are described, a point mutation (V99A) and a frame-shift mutation (633insA) in the same patient who had a mild to moderate form of Günther’s disease. The mutation (V99A) had a detectable residual activity when expressed in Escherichia coli while the insertion (633insA), which introduced a premature stop, had no activity. In the patients studied in our laboratory, the mutation C73R, associated with a severe phenotype, remains the most frequently seen.
Cécile Ged - One of the best experts on this subject based on the ideXlab platform.
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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, Hubert 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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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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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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PRENATAL DIAGNOSIS IN CONGENITAL Erythropoietic Porphyria BY METABOLIC MEASUREMENT AND DNA MUTATION ANALYSIS
Prenatal diagnosis, 1996Co-Authors: Cécile Ged, François Moreau-gaudry, I. Hombrados, Laurence Taine, P. Calvas, P. Colombies, Hubert De VerneuilAbstract:Identification of uroporphyrinogen III synthase (UROIIIS) gene mutations in patients with congenital Erythropoietic Porphyria (CEP) allows fast and reliable carrier detection and prenatal diagnosis. We describe here the first case of prenatal diagnosis by concomitant measurement of uroporphyrin I in amniotic fluid and direct detection of the gene mutation. A French couple, whose first child was diagnosed with CEP, requested prenatal diagnosis at 16 weeks of gestation. Uroporphyrin I was dramatically increased in amniotic fluid and the fetus was homozygous for the C73R mutation, the most common mutation in this disease. The pregnancy was then terminated.
Kenneth H. Astrin - One of the best experts on this subject based on the ideXlab platform.
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congenital Erythropoietic Porphyria identification and expression of eight novel mutations in the uroporphyrinogen iii synthase gene
British Journal of Haematology, 2002Co-Authors: Amr A Shady, Kenneth H. Astrin, Brandon R Colby, Luis F Cunha, David F Bishop, Robert J. DesnickAbstract:Summary. Mutations in the uroporphyrinogen III synthase (URO-synthase) gene cause congenital Erythropoietic Porphyria (CEP), an autosomal recessive inborn error of haem biosynthesis. Molecular analysis of the URO-synthase gene in seven unrelated CEP patients revealed eight novel mutations. These included four missense mutations (A69T, E81D, G188W and I219S), a deletion (21delG), two insertions (398insG and 672ins28) and one complex mutation (627del6ins39), as well as three previously reported mutations, C73R, T228M, and −86CA. When the four novel missense mutations were expressed in Escherichia coli, only E81D expressed significant enzymatic activity (30% of expressed wild-type activity), which was thermolabile. In addition, reverse transcription polymerase chain reaction studies demonstrated that E81D, which altered the penultimate nucleotide in exon 4, impaired splicing and caused about 85% exon 4 skipping. The identification and expression of these mutations provided genotype–phenotype correlations and further evidence of the molecular heterogeneity underlying this Erythropoietic Porphyria.
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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.
Mukhopadhyay Somnath - One of the best experts on this subject based on the ideXlab platform.
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A Rare Case of Puberty Onset Congenital Erythropoietic Porphyria with Ophthalmological Manifestations.
Middle East African journal of ophthalmology, 2016Co-Authors: Mishra Debjani, Mukhopadhyay SomnathAbstract:A 27-year-old male patient was presented with foreign body sensation in both the eyes for 2 years duration and blisters followed by scarring and pigmentation in the photo-exposed areas of the body over the previous 12 years. His urine was reddish colored for the previous year. On examination, there was scarring, hyper-pigmentation of photo-exposed parts of the body along with resorption of the distal phalanges of fingers in both hands except the smallest digit which had onycholysis. Ocular examination indicated scleral necrosis in the interpalpebral areas in both eyes and bilateral dry eye. Hematological examination indicated a picture suggestive of hemolytic anemia. Abdominal ultrasonography indicated an enlarged spleen. These clinical features are suggestive of puberty onset congenital Erythropoietic Porphyria with ophthalmological manifestations.