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Hepatoerythropoietic Porphyria and Familial Porphyria Cutanea Tarda in Spanish Patients: G281E Mutation in the Uroporphyrinogen Decarboxylase Gene

Hepatoerythropoietic Porphyria and Familial Porphyria Cutanea Tarda in Spanish Patients: G281E... Report of Cases We describe 2 new unrelated patients with familial porphyria cutanea tarda (f-PCT) who harbored a G281E mutation (GGG→GAG, codon 281) in the uroporphyrinogen decarboxylase (UROD) gene (OMIM 613521). Patient 1 was a 49-year-old woman with hyperpigmentation, hypertrichosis, and bullous skin lesions. She had been undergoing hemodialysis since 2006 and tested positive for hepatitis C virus (HCV) infection. Patient 2 was a 35-year-old man with hypertrichosis and bullae on the dorsal aspects of his hands who had undergone renal transplantation in 1997. Biochemical analyses of urine, blood, and feces by fluorimetry and high-performance liquid chromatography confirmed a PCT pattern of porphyrin excretion. Subsequent analysis of UROD activity in erythrocytes and genotyping of the UROD gene confirmed the diagnosis of f-PCT with a G281E mutation in heterozygosity. The hemochromatosis (HFE) gene and iron parameters were also studied (Table). Table View LargeDownload Characteristics of Patients With Familial Porphyria Cutanea Tarda Comment More than 100 different mutations causing f-PCT and/or hepatoerythropoietic porphyria (HEP), the homozygous form of PCT, have been identified in the UROD gene. However, only 6 of these (P62L, A80G, V134Q, E167K, G281E, and F46L) have been found to be common to both diseases.1,2 Two of the mutations, G281E and F46L, have been identified in Spanish families.2-4 In Spain, HEP cases are remarkably genetically homogeneous, with 6 of 7 patients reported being homozygous for the G281E mutation. After the molecular characterization of the first HEP cases in the 1980s,5 the G281E mutation has been found in 3 patients with f-PCT, to our knowledge.3,4,6 We report herein 2 additional patients with overt f-PCT and G281E mutation. Consequently, this mutation appears to be the most frequent of the 6 mutations reported to date being common to both HEP and f-PCT. The UROD activity of these patients was below the normal limit (<39 U/mg hemoglobin),7 about 50% of the mean in normal subjects. This suggests that the mutated allele retains virtually no residual activity in erythrocytes. Moreover, a study of Spanish patients with f-PCT6 showed that the G281E mutation led to the lowest erythrocyte UROD activity in the series. In patients with HEP who have the G281E/G281E genotype, the erythrocyte UROD residual activity was below 5% of normal, in accordance with the relatively severe clinical findings in most of these patients.3,4,7 Several cases of HEP with mutations other than G281E have been reported, showing enzyme activities around 30% of normal or a milder phenotype.8-10 Therefore, the G281E mutation may be a relatively severe mutation, if comparative UROD residual activity and clinical status are taken into account. The 2 patients described herein presented additional risks (HCV infection, iron overload, and impaired renal function) that could have triggered the expression of PCT. However, at least 1 of the previously described patients with the G281E mutation in heterozygosity presented no other known risk factor.3 In conclusion, the G281E mutation may be more penetrant than previously anticipated, being found in an increasing number of patients with f-PCT and inducing a severe phenotype in HEP, which could explain why this particular mutation was responsible for the first ever reported cases of HEP.5 Correspondence: Dr Darwich, Department of Dermatology, Hospital Clíinic, Universitat de Barcelona, C/Villarroel 170 CP, 08036 Barcelona, Spain (chevedarwich@yahoo.es). Financial Disclosure: None reported. Additional Contributions: Patricia Bassas, MD, and Jordi Carreras, MD, were the physicians in charge of the patients. References 1. Elder GH Porphyria cutanea tarda and related disorders. Kadish KMSmith KMGuilard Reds.The Porphyrin Handbook: Medical Aspects of Porphyria.14 San Diego, CA Academic Press2003;67- 92 2. Ged COzalla DHerrero C et al. Description of a new mutation in hepatoerythropoietic porphyria and prenatal exclusion of a homozygous fetus. Arch Dermatol 2002;138 (7) 957- 960PubMedGoogle Scholar 3. Roberts AGElder GHDe Salamanca REHerrero CLecha MMascaro JM A mutation (G281E) of the human uroporphyrinogen decarboxylase gene causes both hepatoerythropoietic porphyria and overt familial porphyria cutanea tarda: biochemical and genetic studies on Spanish patients. J Invest Dermatol 1995;104 (4) 500- 502PubMedGoogle ScholarCrossref 4. Moran-Jimenez MJGed CRomana M et al. Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria. Am J Hum Genet 1996;58 (4) 712- 721PubMedGoogle Scholar 5. de Verneuil HGrandchamp BBeaumont CPicat CNordmann Y Uroporphyrinogen decarboxylase structural mutant (Gly281----Glu) in a case of porphyria. Science 1986;234 (4777) 732- 734PubMedGoogle ScholarCrossref 6. Méndez MPoblete-Gutiérrez PGarcíia-Bravo M et al. Molecular heterogeneity of familial porphyria cutanea tarda in Spain: characterization of 10 novel mutations in the UROD gene. Br J Dermatol 2007;157 (3) 501- 507PubMedGoogle ScholarCrossref 7. Badenas CTo-Figueras JPhillips JDWarby CAMuñoz CHerrero C Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives. Clin Genet 2009;75 (4) 346- 353PubMedGoogle ScholarCrossref 8. Phillips JDWhitby FGStadtmueller BMEdwards CQHill CPKushner JP Two novel uroporphyrinogen decarboxylase (URO-D) mutations causing hepatoerythropoietic porphyria (HEP). Transl Res 2007;149 (2) 85- 91PubMedGoogle ScholarCrossref 9. Armstrong DKSharpe PCChambers CRWhatley SDRoberts AGElder GH Hepatoerythropoietic porphyria: a missense mutation in the UROD gene is associated with mild disease and an unusual porphyrin excretion pattern. Br J Dermatol 2004;151 (4) 920- 923PubMedGoogle ScholarCrossref 10. Meguro KFujita HIshida N et al. Molecular defects of uroporphyrinogen decarboxylase in a patient with mild hepatoerythropoietic porphyria. J Invest Dermatol 1994;102 (5) 681- 685PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Dermatology American Medical Association

Hepatoerythropoietic Porphyria and Familial Porphyria Cutanea Tarda in Spanish Patients: G281E Mutation in the Uroporphyrinogen Decarboxylase Gene

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Publisher
American Medical Association
Copyright
Copyright © 2010 American Medical Association. All Rights Reserved.
ISSN
0003-987X
eISSN
1538-3652
DOI
10.1001/archdermatol.2010.314
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Abstract

Report of Cases We describe 2 new unrelated patients with familial porphyria cutanea tarda (f-PCT) who harbored a G281E mutation (GGG→GAG, codon 281) in the uroporphyrinogen decarboxylase (UROD) gene (OMIM 613521). Patient 1 was a 49-year-old woman with hyperpigmentation, hypertrichosis, and bullous skin lesions. She had been undergoing hemodialysis since 2006 and tested positive for hepatitis C virus (HCV) infection. Patient 2 was a 35-year-old man with hypertrichosis and bullae on the dorsal aspects of his hands who had undergone renal transplantation in 1997. Biochemical analyses of urine, blood, and feces by fluorimetry and high-performance liquid chromatography confirmed a PCT pattern of porphyrin excretion. Subsequent analysis of UROD activity in erythrocytes and genotyping of the UROD gene confirmed the diagnosis of f-PCT with a G281E mutation in heterozygosity. The hemochromatosis (HFE) gene and iron parameters were also studied (Table). Table View LargeDownload Characteristics of Patients With Familial Porphyria Cutanea Tarda Comment More than 100 different mutations causing f-PCT and/or hepatoerythropoietic porphyria (HEP), the homozygous form of PCT, have been identified in the UROD gene. However, only 6 of these (P62L, A80G, V134Q, E167K, G281E, and F46L) have been found to be common to both diseases.1,2 Two of the mutations, G281E and F46L, have been identified in Spanish families.2-4 In Spain, HEP cases are remarkably genetically homogeneous, with 6 of 7 patients reported being homozygous for the G281E mutation. After the molecular characterization of the first HEP cases in the 1980s,5 the G281E mutation has been found in 3 patients with f-PCT, to our knowledge.3,4,6 We report herein 2 additional patients with overt f-PCT and G281E mutation. Consequently, this mutation appears to be the most frequent of the 6 mutations reported to date being common to both HEP and f-PCT. The UROD activity of these patients was below the normal limit (<39 U/mg hemoglobin),7 about 50% of the mean in normal subjects. This suggests that the mutated allele retains virtually no residual activity in erythrocytes. Moreover, a study of Spanish patients with f-PCT6 showed that the G281E mutation led to the lowest erythrocyte UROD activity in the series. In patients with HEP who have the G281E/G281E genotype, the erythrocyte UROD residual activity was below 5% of normal, in accordance with the relatively severe clinical findings in most of these patients.3,4,7 Several cases of HEP with mutations other than G281E have been reported, showing enzyme activities around 30% of normal or a milder phenotype.8-10 Therefore, the G281E mutation may be a relatively severe mutation, if comparative UROD residual activity and clinical status are taken into account. The 2 patients described herein presented additional risks (HCV infection, iron overload, and impaired renal function) that could have triggered the expression of PCT. However, at least 1 of the previously described patients with the G281E mutation in heterozygosity presented no other known risk factor.3 In conclusion, the G281E mutation may be more penetrant than previously anticipated, being found in an increasing number of patients with f-PCT and inducing a severe phenotype in HEP, which could explain why this particular mutation was responsible for the first ever reported cases of HEP.5 Correspondence: Dr Darwich, Department of Dermatology, Hospital Clíinic, Universitat de Barcelona, C/Villarroel 170 CP, 08036 Barcelona, Spain (chevedarwich@yahoo.es). Financial Disclosure: None reported. Additional Contributions: Patricia Bassas, MD, and Jordi Carreras, MD, were the physicians in charge of the patients. References 1. Elder GH Porphyria cutanea tarda and related disorders. Kadish KMSmith KMGuilard Reds.The Porphyrin Handbook: Medical Aspects of Porphyria.14 San Diego, CA Academic Press2003;67- 92 2. Ged COzalla DHerrero C et al. Description of a new mutation in hepatoerythropoietic porphyria and prenatal exclusion of a homozygous fetus. Arch Dermatol 2002;138 (7) 957- 960PubMedGoogle Scholar 3. Roberts AGElder GHDe Salamanca REHerrero CLecha MMascaro JM A mutation (G281E) of the human uroporphyrinogen decarboxylase gene causes both hepatoerythropoietic porphyria and overt familial porphyria cutanea tarda: biochemical and genetic studies on Spanish patients. J Invest Dermatol 1995;104 (4) 500- 502PubMedGoogle ScholarCrossref 4. Moran-Jimenez MJGed CRomana M et al. Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria. Am J Hum Genet 1996;58 (4) 712- 721PubMedGoogle Scholar 5. de Verneuil HGrandchamp BBeaumont CPicat CNordmann Y Uroporphyrinogen decarboxylase structural mutant (Gly281----Glu) in a case of porphyria. Science 1986;234 (4777) 732- 734PubMedGoogle ScholarCrossref 6. Méndez MPoblete-Gutiérrez PGarcíia-Bravo M et al. Molecular heterogeneity of familial porphyria cutanea tarda in Spain: characterization of 10 novel mutations in the UROD gene. Br J Dermatol 2007;157 (3) 501- 507PubMedGoogle ScholarCrossref 7. Badenas CTo-Figueras JPhillips JDWarby CAMuñoz CHerrero C Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives. Clin Genet 2009;75 (4) 346- 353PubMedGoogle ScholarCrossref 8. Phillips JDWhitby FGStadtmueller BMEdwards CQHill CPKushner JP Two novel uroporphyrinogen decarboxylase (URO-D) mutations causing hepatoerythropoietic porphyria (HEP). Transl Res 2007;149 (2) 85- 91PubMedGoogle ScholarCrossref 9. Armstrong DKSharpe PCChambers CRWhatley SDRoberts AGElder GH Hepatoerythropoietic porphyria: a missense mutation in the UROD gene is associated with mild disease and an unusual porphyrin excretion pattern. Br J Dermatol 2004;151 (4) 920- 923PubMedGoogle ScholarCrossref 10. Meguro KFujita HIshida N et al. Molecular defects of uroporphyrinogen decarboxylase in a patient with mild hepatoerythropoietic porphyria. J Invest Dermatol 1994;102 (5) 681- 685PubMedGoogle ScholarCrossref

Journal

Archives of DermatologyAmerican Medical Association

Published: Nov 15, 2010

Keywords: mutation,genes,hepatoerythropoietic porphyria,uroporphyrinogen decarboxylase

References