Clinical, Biochemical, and Genetic Characterization of North American Patients With Erythropoietic Protoporphyria and X-linked Protoporphyria | Genetics and Genomics | JAMA Dermatology | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 34.239.150.57. Please contact the publisher to request reinstatement.
1.
Anderson  KE, Sassa  S, Bishop  DF, Desnick  RJ. Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias. In: Scriver  CR, Beadet  AL, Sly  WS, Valle  D, eds.  The Metabolic and Molecular Bases of Inherited Disease. Vol 2. 8th ed. New York: McGraw Hill; 2001:2991-3062.
2.
Lecha  M, Puy  H, Deybach  JC.  Erythropoietic protoporphyria.  Orphanet J Rare Dis. 2009;4(4):19-28.PubMedGoogle ScholarCrossref
3.
Bonkovsky  HL, Guo  JT, Hou  W, Li  T, Narang  T, Thapar  M.  Porphyrin and heme metabolism and the porphyrias.  Compr Physiol. 2013;3(1):365-401.PubMedGoogle Scholar
4.
Poh-Fitzpatrick  MB.  Porphyrias: photosensitivity and phototherapy.  Methods Enzymol. 2000;319:485-493.PubMedGoogle ScholarCrossref
5.
Holme  SA, Anstey  AV, Finlay  AY, Elder  GH, Badminton  MN.  Erythropoietic protoporphyria in the UK: clinical features and effect on quality of life.  Br J Dermatol. 2006;155(3):574-581.PubMedGoogle ScholarCrossref
6.
Frank  J, Poblete-Gutiérrez  P.  Delayed diagnosis and diminished quality of life in erythropoietic protoporphyria: results of a cross-sectional study in Sweden.  J Intern Med. 2011;269(3):270-274.PubMedGoogle ScholarCrossref
7.
Elder  GH, Gouya  L, Whatley  SD, Puy  H, Badminton  MN, Deybach  JC.  The molecular genetics of erythropoietic protoporphyria.  Cell Mol Biol (Noisy-le-grand). 2009;55(2):118-126.PubMedGoogle Scholar
8.
Balwani  M, Bloomer  J, Desnick  R; Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network. Erythropoietic protoporphyria, autosomal recessive. In: Pagon  RA, Adam  MP, Ardinger  HH,  et al, eds.  GeneReviews. Seattle: University of Washington; 2014.
9.
Whatley  SD, Ducamp  S, Gouya  L,  et al.  C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.  Am J Hum Genet. 2008;83(3):408-414.PubMedGoogle ScholarCrossref
10.
Bishop  DF, Tchaikovskii  V, Nazarenko  I, Desnick  RJ.  Molecular expression and characterization of erythroid-specific 5-aminolevulinate synthase gain-of-function mutations causing X-linked protoporphyria.  Mol Med. 2013;19:18-25.PubMedGoogle ScholarCrossref
11.
Whatley  SD, Mason  NG, Holme  SA, Anstey  AV, Elder  GH, Badminton  MN.  Molecular epidemiology of erythropoietic protoporphyria in the UK.  Br J Dermatol. 2010;162(3):642-646.PubMedGoogle ScholarCrossref
12.
Balwani  M, Doheny  D, Bishop  DF,  et al; Porphyrias Consortium of the National Institutes of Health Rare Diseases Clinical Research Network.  Loss-of-function ferrochelatase and gain-of-function erythroid-specific 5-aminolevulinate synthase mutations causing erythropoietic protoporphyria and X-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria.  Mol Med. 2013;19:26-35.PubMedGoogle ScholarCrossref
13.
Bloomer  JR, Phillips  MJ, Davidson  DL, Klatskin  G, Bloomer.  Hepatic disease in erythropoietic protoporphyria.  Am J Med. 1975;58(6):869-882.PubMedGoogle ScholarCrossref
14.
Bloomer  JR.  The liver in protoporphyria.  Hepatology. 1988;8(2):402-407.PubMedGoogle ScholarCrossref
15.
Bloomer  JR, Weimer  MK, Bossenmaier  IC, Snover  DC, Payne  WD, Ascher  NL.  Liver transplantation in a patient with protoporphyria.  Gastroenterology. 1989;97(1):188-194.PubMedGoogle ScholarCrossref
16.
Wahlin  S, Stal  P, Adam  R,  et al; European Liver and Intestine Transplant Association.  Liver transplantation for erythropoietic protoporphyria in Europe.  Liver Transpl. 2011;17(9):1021-1026.PubMedGoogle Scholar
17.
Gou  EW, Balwani  M, Bissell  DM,  et al.  Pitfalls in erythrocyte protoporphyrin measurement for diagnosis and monitoring of protoporphyrias.  Clin Chem. 2015;61(12):1453-1456.PubMedGoogle ScholarCrossref
18.
Balwani  M, Bloomer  J, Desnick  R; Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network. X-linked protoporphyria. In: Pagon  RA, Adam  MP, Ardinger  HH,  et al, eds.  GeneReviews. Seattle: University of Washington; 2013.
19.
Wahlin  S, Floderus  Y, Stål  P, Harper  P.  Erythropoietic protoporphyria in Sweden: demographic, clinical, biochemical and genetic characteristics.  J Intern Med. 2011;269(3):278-288.PubMedGoogle ScholarCrossref
20.
Rare Diseases Clinical Research Network. The Porphyrias Consortium. https://www.rarediseasesnetwork.org/cms/porphyrias. Accessed January 26, 2017.
21.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.  JAMA. 2013;310(20):2191-2194.PubMedGoogle ScholarCrossref
22.
Goerz  G, Krieg  T, Bolsen  K, Seubert  S, Ippen  H.  Erythropoietic protoporphyria: porphyrin content of a gall-stone  [in German].  Arch Dermatol Res. 1976;256(3):283-289.PubMedGoogle ScholarCrossref
23.
Brancaleoni  V, Balwani  M, Granata  F,  et al.  X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria.  Clin Genet. 2016;89(1):20-26.PubMedGoogle ScholarCrossref
24.
Minder  EI, Schneider-Yin  X, Steurer  J, Bachmann  LM.  A systematic review of treatment options for dermal photosensitivity in erythropoietic protoporphyria.  Cell Mol Biol (Noisy-le-grand). 2009;55(1):84-97.PubMedGoogle Scholar
25.
Tu  JH, Sheu  SL, Teng  JM.  Novel treatment using cimetidine for erythropoietic protoporphyria in children.  JAMA Dermatol. 2016;152(11):1258-1261.PubMedGoogle ScholarCrossref
26.
Marcus  DL, Halbrecht  JL, Bourque  AL, Lew  G, Nadel  H, Freedman  ML.  Effect of cimetidine on δ-aminolevulinic acid synthase and microsomal heme oxygenase in rat liver.  Biochem Pharmacol. 1984;33(13):2005-2008.PubMedGoogle ScholarCrossref
27.
Langendonk  JG, Balwani  M, Anderson  KE,  et al.  Afamelanotide for erythropoietic protoporphyria.  N Engl J Med. 2015;373(1):48-59.PubMedGoogle ScholarCrossref
28.
Biolcati  G, Marchesini  E, Sorge  F, Barbieri  L, Schneider-Yin  X, Minder  EI.  Long-term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria.  Br J Dermatol. 2015;172(6):1601-1612.PubMedGoogle ScholarCrossref
29.
Butler  DF, Ginn  KF, Daniel  JF,  et al.  Bone marrow transplant for X-linked protoporphyria with severe hepatic fibrosis.  Pediatr Transplant. 2015;19(4):E106-E110.PubMedGoogle ScholarCrossref
30.
Wahlin  S, Harper  P.  The role for BMT in erythropoietic protoporphyria.  Bone Marrow Transplant. 2010;45(2):393-394.PubMedGoogle ScholarCrossref
31.
Singal  AK, Parker  C, Bowden  C, Thapar  M, Liu  L, McGuire  BM.  Liver transplantation in the management of porphyria.  Hepatology. 2014;60(3):1082-1089.PubMedGoogle ScholarCrossref
32.
McGuire  BM, Bonkovsky  HL, Carithers  RL  Jr,  et al.  Liver transplantation for erythropoietic protoporphyria liver disease.  Liver Transpl. 2005;11(12):1590-1596.PubMedGoogle ScholarCrossref
Original Investigation
August 2017

Clinical, Biochemical, and Genetic Characterization of North American Patients With Erythropoietic Protoporphyria and X-linked Protoporphyria

Author Affiliations
  • 1Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York
  • 2Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston
  • 3Department of Medicine, University of California, San Francisco
  • 4Department of Medicine, University of Alabama, Birmingham
  • 5Department of Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina
  • 6Department of Internal Medicine, University of Utah, Salt Lake City
  • 7Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York
  • 8Department of Liver Diseases and Recanti/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York
JAMA Dermatol. 2017;153(8):789-796. doi:10.1001/jamadermatol.2017.1557
Key Points

Question  What are the baseline characteristics and determinants of disease severity in patients with erythropoietic protoporphyria and X-linked protoporphyria?

Findings  In this cohort study of 226 patients, higher erythrocyte protoporphyrin levels were correlated with earlier age of symptom onset, decreased sun tolerance, and increased risk of liver dysfunction. Patients with erythropoietic protoporphyria and FECH missense mutations had lower erythrocyte protoporphyrin levels and a less severe phenotype, and male patients with X-linked protoporphyria had significantly higher erythrocyte protoporphyrin levels than did patients with erythropoietic protoporphyria.

Meaning  Erythrocyte protoporphyrin levels are a significant determinant of disease severity in patients with erythropoietic protoporphyria or X-linked protoporphyria.

Abstract

Importance  Autosomal recessive erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses presenting with variable degrees of painful phototoxicity that markedly affects quality of life. The clinical variability, determinants of severity, and genotype/phenotype correlations of these diseases are not well characterized.

Objective  To describe the baseline clinical characteristics, genotypes, and determinants of disease severity in a large patient cohort with EPP or XLP.

Design, Setting, and Participants  A prospective observational study was conducted among patients with confirmed diagnoses of EPP or XLP from November 1, 2010, to December 6, 2015, at 6 academic medical centers of the Porphyrias Consortium of the National Institutes of Health Rare Diseases Clinical Research Network. Detailed medical histories, including history of phototoxicity and treatment, were collected on standardized case report forms. Patients underwent baseline laboratory testing, total erythrocyte protoporphyrin (ePPIX) testing, and molecular genetic testing. Data were entered into a centralized database.

Main Outcomes and Measures  Results of biochemical and genetic tests were explored for association with clinical phenotype in patients with EPP or XLP.

Results  Of the 226 patients in the study (113 female and 113 male patients; mean [SD] age, 36.7 [17.0] years), 186 (82.3%) had EPP with a FECH (OMIM 612386) mutation and the common low-expression FECH allele IVS3–48T>C, and only 1 patient had 2 FECH mutations. Twenty-two patients had XLP (9.7%; 10 male and 12 female patients), and 9 patients (4.0%) had elevated ePPIX levels and symptoms consistent with protoporphyria but no detectable mutation in the FECH or ALAS2 (OMIM 301300) gene. Samples of DNA could not be obtained from 8 patients. Patients’ mean (SD) age at symptom onset was 4.4 (4.4) years. Anemia (107 [47.3%]), history of liver dysfunction (62 [27.4%]), and gallstones (53 [23.5%]) were commonly reported. Higher ePPIX levels were associated with earlier age of symptom onset (median ePPIX levels for those who developed symptoms before vs after 1 year of age, 1744 vs 1567 µg/dL; P = .02), less sun tolerance (median ePPIX levels for those reporting symptoms before vs after 10 minutes of sun exposure, 2233 vs 1524 µg/dL; P ≤ .001), and increased risk of liver dysfunction (median ePPIX levels for those with liver dysfunction vs normal liver function, 2016 vs 1510 µg/dL; P = .003). Patients with EPP and FECH missense mutations had significantly lower ePPIX levels than those with other mutations (1462 vs 1702 µg/dL; P = .01). Male patients with XLP had significantly higher ePPIX levels, on average, than did patients with EPP (3574 vs 1669 µg/dL; P < .001). Marked clinical variability was seen in female patients with XLP owing to random X-chromosomal inactivation.

Conclusions and Relevance  These data suggest that higher ePPIX levels are a major determinant of disease severity and risk of liver dysfunction in patients with EPP or XLP. These findings provide a framework for clinical monitoring and management of these disorders.

×