Hostname: page-component-77c89778f8-swr86 Total loading time: 0 Render date: 2024-07-17T09:48:22.826Z Has data issue: false hasContentIssue false
  • English
  • Français

Emerging therapies for acute intermittent porphyria

Published online by Cambridge University Press:  02 November 2016

Antonio Fontanellas ,
Matías A. Ávila  and
Pedro Berraondo
Antonio Fontanellas*
Affiliation:
Hepatology Area, Centre for Applied Medical Research, University of Navarra, Spain Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain CIBEREHD, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain
Matías A. Ávila
Affiliation:
Hepatology Area, Centre for Applied Medical Research, University of Navarra, Spain Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain CIBEREHD, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain
Pedro Berraondo
Affiliation:
Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain Immunology Area, Centre for Applied Medical Research, University of Navarra, Spain
*
*Corresponding author:Antonio Fontanellas, PhD, Hepatology Area, Center for Applied Medical Research, Avda. Pio XII, 55–31008 Pamplona, Spain. E-mail: afontanellas@unav.es
Get access Rights & Permissions [Opens in a new window]

Abstract

Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disease caused by hepatic deficiency of hydroxymethylbilane synthase (HMBS), the third enzyme of the heme synthesis pathway. The dominant clinical feature is acute neurovisceral attack associated with high production of potentially neurotoxic porphyrin precursors due to increased hepatic heme consumption. Current Standard of Care is based on a down-regulation of hepatic heme synthesis using heme therapy. Recurrent hyper-activation of the hepatic heme synthesis pathway affects about 5% of patients and can be associated with neurological and metabolic manifestations and long-term complications including chronic kidney disease and increased risk of hepatocellular carcinoma. Prophylactic heme infusion is an effective strategy in some of these patients, but it induces tolerance and its frequent application may be associated with thromboembolic disease and hepatic siderosis. Orthotopic liver transplantation is the only curative treatment in patients with recurrent acute attacks. Emerging therapies including replacement enzyme therapy or gene therapies (HMBS-gene transfer and ALAS1-gene expression inhibition) are being developed to improve quality of life, reduce the significant morbidity associated with current therapies and prevent late complications such as hepatocellular cancer or kidney failure in HMBS mutation carriers with long-standing high production of noxious heme precursors. Herein, we provide a critical digest of the recent literature on the topic and a summary of recently developed approaches to AIP treatment and their clinical implications.

Type
Invited Review
Information
Expert Reviews in Molecular Medicine , Volume 18 , 2016 , e17
Copyright
Copyright © Cambridge University Press 2016 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Puy, H., Gouya, L. and Deybach, J.C. (2010) Porphyrias. Lancet 375, 924-937 Google Scholar
2. Harper, P. and Sardh, E. (2014) Management of acute intermittent porphyria. Expert Opinion on Orphan Drugs 2, 349-368. http://dx.doi.org/10.1517/21678707.2014.891456 Google Scholar
3. Kauppinen, R. (2005) Porphyrias. Lancet 365, 241-252 CrossRefGoogle ScholarPubMed
4. Meyer, U.A., Schuurmans, M.M. and Lindberg, R.L. (1998) Acute porphyrias: pathogenesis of neurological manifestations. Seminars in Liver Disease 18, 43-52 Google Scholar
5. Kauppinen, R. and Mustajoki, P. (1992) Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases. Medicine (Baltimore) 71, 1-13 CrossRefGoogle ScholarPubMed
6. Elder, G. et al. (2013) The incidence of inherited porphyrias in Europe. Journal of Inherited Metabolic Disease 36, 849-857 Google Scholar
7. Nordmann, Y. et al. (1997) Acute intermittent porphyria: prevalence of mutations in the porphobilinogen deaminase gene in blood donors in France. Journal of Internal Medicine 242, 213-217 Google Scholar
8. von und zu Fraunberg, M. et al. (2005) Clinical and biochemical characteristics and genotype-phenotype correlation in 143 Finnish and Russian patients with acute intermittent porphyria. Medicine (Baltimore) 84, 35-47 Google Scholar
9. Marsden, J.T. et al. (2015) Audit of the use of regular Haem Arginate infusions in patients with acute porphyria to prevent recurrent symptoms. JIMD Reports 22, 57-65 Google Scholar
10. Bonkovsky, H.L. et al. (2014) Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. American Journal of Medicine 127, 1233-1241 Google Scholar
11. Aarsand, A.K., Petersen, P.H. and Sandberg, S. (2006) Estimation and application of biological variation of urinary delta-aminolevulinic acid and porphobilinogen in healthy individuals and in patients with acute intermittent porphyria. Clinical Chemistry 52, 650-656 Google Scholar
12. Ajioka, R.S., Phillips, J.D. and Kushner, J.P. (2006) Biosynthesis of heme in mammals. Biochimica et Biophysica Acta 1763, 723-736 Google Scholar
13. Anderson, K.E. et al. (2005) Recommendations for the diagnosis and treatment of the acute porphyrias. Annals of Internal Medicine 142, 439-450 Google Scholar
14. Handschin, C. et al. (2005) Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha. Cell 122, 505-515 Google Scholar
15. Anderson, K.E. et al. (1990) A gonadotropin releasing hormone analogue prevents cyclical attacks of porphyria. Archives of Internal Medicine 150, 1469-1474 Google Scholar
16. Stein, P.E. et al. (2012) Acute intermittent porphyria: fatal complications of treatment. Clinical Medicine 12, 293-294 Google Scholar
17. Willandt, B. et al. (2015) Liver Fibrosis Associated with Iron Accumulation Due to Long-Term Heme-Arginate Treatment in Acute Intermittent Porphyria: A Case Series. JIMD RepGoogle Scholar
18. Goetsch, C.A. and Bissell, D.M. (1986) Instability of hematin used in the treatment of acute hepatic porphyria. New England Journal of Medicine 315, 235-238 Google Scholar
19. Doberer, D. et al. (2010) Haem arginate infusion stimulates haem oxygenase-1 expression in healthy subjects. British Journal of Pharmacology 161, 1751-1762 CrossRefGoogle ScholarPubMed
20. Yoshida, T. et al. (1988) Human heme oxygenase cDNA and induction of its mRNA by hemin. European Journal of Biochemistry 171, 457-461 Google Scholar
21. Dover, S.B. et al. (1993) Tin protoporphyrin prolongs the biochemical remission produced by heme arginate in acute hepatic porphyria. Gastroenterology 105, 500-506 Google Scholar
22. Herrero, C. et al. (2015) Acute intermittent porphyria: long-term follow up of 35 patients. Medicina Clinica 145, 332-337 Google Scholar
23. Dowman, J.K. et al. (2012) Liver transplantation for acute intermittent porphyria is complicated by a high rate of hepatic artery thrombosis. Liver Transplantation 18, 195-200 Google Scholar
24. Soonawalla, Z.F. et al. (2004) Liver transplantation as a cure for acute intermittent porphyria. Lancet 363, 705-706 Google Scholar
25. Yasuda, M. et al. (2015) Liver transplantation for acute intermittent porphyria: biochemical and pathologic studies of the explanted liver. Molecular Medicine 21, 487-495 Google Scholar
26. Junge, N. et al. (2015) Adeno-associated virus vector-based gene therapy for monogenetic metabolic diseases of the liver. Journal of Pediatric Gastroenterology and Nutrition 60, 433-440 Google Scholar
27. Pallet, N. et al. (2015) High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria. Kidney International 88, 386-395 Google Scholar
28. Unzu, C. et al. (2012) Renal failure affects the enzymatic activities of the three first steps in hepatic heme biosynthesis in the acute intermittent porphyria mouse. PLoS ONE 7, e32978 Google Scholar
29. Sardh, E. et al. (2009) Porphyrin precursors and porphyrins in three patients with acute intermittent porphyria and end-stage renal disease under different therapy regimes. Cellular and Molecular Biology (Noisy-Le-Grand) 55, 66-71 Google Scholar
30. Wahlin, S. et al. (2010) Combined liver and kidney transplantation in acute intermittent porphyria. Transplant International 23, e18-e21 Google Scholar
31. Bruix, J., Gores, G.J. and Mazzaferro, V. (2014) Hepatocellular carcinoma: clinical frontiers and perspectives. Gut 63, 844-855 Google Scholar
32. Sardh, E. et al. (2013) High risk of primary liver cancer in a cohort of 179 patients with Acute Hepatic Porphyria. Journal of Inherited Metabolic Disease 36, 1063-1071 Google Scholar
33. Andant, C. et al. (2000) Hepatocellular carcinoma in patients with acute hepatic porphyria: frequency of occurrence and related factors. Journal of Hepatology 32, 933-939 Google Scholar
34. Innala, E. and Andersson, C. (2011) Screening for hepatocellular carcinoma in acute intermittent porphyria: a 15-year follow-up in northern Sweden. Journal of Internal Medicine 269, 538-545 Google Scholar
35. Stewart, M.F. (2012) Review of hepatocellular cancer, hypertension and renal impairment as late complications of acute porphyria and recommendations for patient follow-up. Journal of Clinical Pathology 65, 976-980 Google Scholar
36. Bjersing, L., Andersson, C. and Lithner, F. (1996) Hepatocellular carcinoma in patients from northern Sweden with acute intermittent porphyria: morphology and mutations. “Cancer Epidemiology, Biomarkers & Prevention” 5, 393-397 Google Scholar
37. Andersson, C., Bjersing, L. and Lithner, F. (1996) The epidemiology of hepatocellular carcinoma in patients with acute intermittent porphyria. Journal of Internal Medicine 240, 195-201 Google Scholar
38. Deybach, J.C. and Puy, H. (2011) Hepatocellular carcinoma without cirrhosis: think acute hepatic porphyrias and vice versa. Journal of Internal Medicine 269, 521-524 Google Scholar
39. Takaki, A. and Yamamoto, K. (2015) Control of oxidative stress in hepatocellular carcinoma: Helpful or harmful? World Journal of Hepatology 7, 968-979 Google Scholar
40. Urtasun, R., Berasain, C. and Avila, M.A. (2015) Oxidative stress mechanisms in Hepatocarcinogenesis. In Studies on Hepatic Disorders, Oxidative Stress in Applied Basic Research and Clinical Practice (Albano, E. and Parola, M. eds), Humana Press, Heidelberg, New York, Dordrecht, London, 449-477Google Scholar
41. Monteiro, H.P. et al. (1986) Generation of active oxygen species during coupled autoxidation of oxyhemoglobin and delta-aminolevulinic acid. Biochimica et Biophysica Acta 881, 100-106 Google Scholar
42. Onuki, J. et al. (2004) Mitochondrial and nuclear DNA damage induced by 5-aminolevulinic acid. Archives of Biochemistry and Biophysics 432, 178-187 CrossRefGoogle Scholar
43. Onuki, J. et al. (2002) Is 5-aminolevulinic acid involved in the hepatocellular carcinogenesis of acute intermittent porphyria? Cellular and Molecular Biology (Noisy-Le-Grand) 48, 17-26 Google Scholar
44. Hermes-Lima, M. (1995) How do Ca2+ and 5-aminolevulinic acid-derived oxyradicals promote injury to isolated mitochondria? Free Radical Biology & Medicine 19, 381-390 Google Scholar
45. Hermes-Lima, M. et al. (1991) Damage to rat liver mitochondria promoted by delta-aminolevulinic acid-generated reactive oxygen species: connections with acute intermittent porphyria and lead-poisoning. Biochimica et Biophysica Acta 1056, 57-63 Google Scholar
46. Laafi, J. et al. (2014) Pro-oxidant effect of ALA is implicated in mitochondrial dysfunction of HepG2 cells. Biochimie 106, 157-166 Google Scholar
47. Homedan, C. et al. (2014) Acute intermittent porphyria causes hepatic mitochondrial energetic failure in a mouse model. International Journal of Biochemistry & Cell Biology 51, 93-101 Google Scholar
48. Heilmann, E. et al. (1976) Special clinical, light and electron microscopic aspects of acute intermittent porphyria. Annals of Clinical Research 8(Suppl 17), 213-216 Google Scholar
49. Lithner, F. and Wetterberg, L. (1984) Hepatocellular carcinoma in patients with acute intermittent porphyria. Acta Medica Scandinavica 215, 271-274 Google Scholar
50. Karim, Z. et al. (2015) Porphyrias: a 2015 update. Clinics and Research in Hepatology and Gastroenterology 39, 412-425 Google Scholar
51. Lee, J.M. et al. (2012) Hemin, an iron-binding porphyrin, inhibits HIF-1alpha induction through its binding with heat shock protein 90. International Journal of Cancer 130, 716-727 Google Scholar
52. Batlle, A.M. (1993) Porphyrins, porphyrias, cancer and photodynamic therapy--a model for carcinogenesis. “Journal of Photochemistry and Photobiology. B, Biology” 20, 5-22 CrossRefGoogle ScholarPubMed
53. Schneider-Yin, X. et al. (2015) Biallelic inactivation of protoporphyrinogen oxidase and hydroxymethylbilane synthase is associated with liver cancer in acute porphyrias. Journal of Hepatology 62, 734-738 Google Scholar
54. Lamb, J.R. et al. (2011) Predictive genes in adjacent normal tissue are preferentially altered by sCNV during tumorigenesis in liver cancer and may rate limiting. PLoS ONE 6, e20090 Google Scholar
55. Roessler, S. et al. (2010) A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients. Cancer Research 70, 10202-10212 Google Scholar
56. Schulze, K. et al. (2015) Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nature Genetics 47, 505-511 CrossRefGoogle ScholarPubMed
57. Brady, R.O. et al. (1973) Replacement therapy for inherited enzyme deficiency. Use of purified ceramidetrihexosidase in Fabry's disease. New England Journal of Medicine 289, 9-14 Google Scholar
58. Kornfeld, S. (1990) Lysosomal enzyme targeting. Biochemical Society Transactions 18, 367-374 Google Scholar
59. Somaraju, U.R. and Solis-Moya, A. (2015) Pancreatic enzyme replacement therapy for people with cystic fibrosis (Review). Paediatric Respiratory Reviews 16, 108-109 Google Scholar
60. Shemesh, E. et al. (2015) Enzyme replacement and substrate reduction therapy for Gaucher disease. Cochrane Database of Systematic Reviews 3, CD010324 Google Scholar
61. Johansson, A. et al. (2003) Biochemical characterization of porphobilinogen deaminase-deficient mice during phenobarbital induction of heme synthesis and the effect of enzyme replacement. Molecular Medicine 9, 193-199 Google Scholar
62. Sardh, E. et al. (2007) Safety, pharmacokinetics and pharmocodynamics of recombinant human porphobilinogen deaminase in healthy subjects and asymptomatic carriers of the acute intermittent porphyria gene who have increased porphyrin precursor excretion. Clinical Pharmacokinetics 46, 335-349 Google Scholar
63. Andersson, C. et al. Randomized clinical trial of recombinant human porphobilinogen deaminase (rhPBGD) in acute attacks of porphyria. This study was presented as an oral presentation at the Porphyrins and Porphyrias International Meeting. Rotterdam, The Netherlands; April 29–May 3, 2007. Session s06-5, page 45Google Scholar
64. Cardiff., T.H.G.M.D.a.t.I.o.M.G.i. http://www.hgmd.cf.ac.uk/ac/index.php. [Accessed 21 October 2015].Google Scholar
65. Yasuda, M. et al. (2010) AAV8-mediated gene therapy prevents induced biochemical attacks of acute intermittent porphyria and improves neuromotor function. Molecular Therapy 18, 17-22 Google Scholar
66. Unzu, C. et al. (2011) Sustained enzymatic correction by rAAV-mediated liver gene therapy protects against induced motor neuropathy in acute porphyria mice. Molecular Therapy 19, 243-250 Google Scholar
67. Unzu, C. et al. (2015) Helper-dependent adenovirus achieve more efficient and persistent liver transgene expression in non-human primates under immunosuppression. Gene Therapy 22, 856-865 Google Scholar
68. Paneda, A. et al. (2013) Safety and liver transduction efficacy of rAAV5-cohPBGD in nonhuman primates: a potential therapy for acute intermittent porphyria. Human Gene Therapy 24, 1007-1017 Google Scholar
69. Unzu, C. et al. (2010) Porphobilinogen deaminase over-expression in hepatocytes, but not in erythrocytes, prevents accumulation of toxic porphyrin precursors in a mouse model of acute intermittent porphyria. Journal of Hepatology 52, 417-424 Google Scholar
70. Nathwani, A.C. et al. (2011) Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. New England Journal of Medicine 365, 2357-2365 CrossRefGoogle ScholarPubMed
71. Nathwani, A.C. et al. (2014) Long-term safety and efficacy of factor IX gene therapy in hemophilia B. New England Journal of Medicine 371, 1994-2004 Google Scholar
72. Bryant, L.M. et al. (2013) Lessons learned from the clinical development and market authorization of Glybera. Human Gene Therapy Clinical Development 24, 55-64 Google Scholar
73. AIPgene AIPgene Website. https://www.aipgene.org [Accessed 5 August 2016]Google Scholar
74. D'Avola, D. et al. (2014) Phase 1 clinical trial of liver directed gene therapy with rAAV5-PBGD in acute intermittent porphyria: preliminary safety data. Journal of Hepatology 60(Suppl 1), s58 CrossRefGoogle Scholar
75. D'Avola, D. et al. (2014) Phase 1 clinical trial of liver directed gene therapy with rAAV5/2-PBGD in acute intermittent porphyria: safety data. Human Gene Therapy 25, A1-A121 Google Scholar
76. D'Avola, D. et al. (2016) Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. Journal of Hepatology 65, 776-783 Google Scholar
77. Arruda, V.R. et al. (2001) Lack of germline transmission of vector sequences following systemic administration of recombinant AAV-2 vector in males. Molecular Therapy 4, 586-592 Google Scholar
78. Manno, C.S. et al. (2006) Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Natural Medicines 12, 342-347 Google Scholar
79. Paneda, A. et al. (2009) Effect of adeno-associated virus serotype and genomic structure on liver transduction and biodistribution in mice of both genders. Human Gene Therapy 20, 908-917 Google Scholar
80. Couto, L., Parker, A. and Gordon, J.W. (2004) Direct exposure of mouse spermatozoa to very high concentrations of a serotype-2 adeno-associated virus gene therapy vector fails to lead to germ cell transduction. Human Gene Therapy 15, 287-291 CrossRefGoogle ScholarPubMed
81. Nault, J.C. et al. (2015) Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nature Genetics 47, 1187-1193 Google Scholar
82. Unzu, C. et al. (2012) Transient and intensive pharmacological immunosuppression fails to improve AAV-based liver gene transfer in non-human primates. Journal of Translational Medicine 10, 122 Google Scholar
83. Mingozzi, F. and High, K.A. (2007) Immune responses to AAV in clinical trials. Current Gene Therapy 7, 316-324 Google Scholar
84. Boutin, S. et al. (2010) Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. Human Gene Therapy 21, 704-712 Google Scholar
85. Davidoff, A.M. et al. (2005) Comparison of the ability of adeno-associated viral vectors pseudotyped with serotype 2, 5, and 8 capsid proteins to mediate efficient transduction of the liver in murine and nonhuman primate models. Molecular Therapy 11, 875-888 Google Scholar
86. youris Youris Website. http://www.youris.com/Health/Genetics/Gene-Correction-For-A-Rare-Disease.kl [Accessed 5 August 2016]Google Scholar
87. Podvinec, M. et al. (2004) Identification of the xenosensors regulating human 5-aminolevulinate synthase. Proceedings of the National Academy of Sciences of the United States of America 101, 9127-9132 Google Scholar
88. Fontanellas, A. and Unzu, C. (2015) Nucleic acid constructs and expression vectors for gene therapy of acute porphyrias and other diseases. In International patent application number: PCT/EP2015/070204Google Scholar
89. Borzio, M. et al. (1998) Hepatocyte proliferation rate is a powerful parameter for predicting hepatocellular carcinoma development in liver cirrhosis. Molecular Pathology 51, 96-101 Google Scholar
90. Barone, G.W. et al. (2001) The tolerability of newer immunosuppressive medications in a patient with acute intermittent porphyria. Journal of Clinical Pharmacology 41, 113-115 Google Scholar
91. Vicari-Christensen, M. et al. (2009) Tacrolimus: review of pharmacokinetics, pharmacodynamics, and pharmacogenetics to facilitate practitioners’ understanding and offer strategies for educating patients and promoting adherence. Progress in Transplantation 19, 277-284 Google Scholar
92. Wavamunno, M.D. and Chapman, J.R. (2008) Individualization of immunosuppression: concepts and rationale. Current Opinion in Organ Transplantation 13, 604-608 Google Scholar
93. NAPOS. The Drug Database for Acute Porphyria. In, http://www.drugs-porphyria.org [Accessed 5 August 2016]Google Scholar
94. Vallazza, B. et al. (2015) Recombinant messenger RNA technology and its application in cancer immunotherapy, transcript replacement therapies, pluripotent stem cell induction, and beyond. Wiley Interdisciplinary Reviews RNA 6, 471-499 Google Scholar
95. Yasuda, M. et al. (2014) RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice. Proceedings of the National Academy of Sciences of the United States of America 111, 7777-7782 Google Scholar
96. Alnylam. Alnylam Pharmaceuticals. In http://www.businesswire.com/news/home/20150915005532/en/ [Accessed 5 August 2016]Google Scholar
97. Yin, Z. et al. (2014) Hepatocyte transplantation ameliorates the metabolic abnormality in a mouse model of acute intermittent porphyria. Cell Transplantation 23, 1153-1162 Google Scholar
98. Fogh, J. and Andersson, C. (2002) Process for purification of recombinant porphobilinogen deaminase. In International patent application number: PCT/DK02/00452Google Scholar
99. Johansson, A., Moller, C. and Harper, P. (2003) Correction of the biochemical defect in porphobilinogen deaminase deficient cells by non-viral gene delivery. Molecular and Cellular Biochemistry 250, 65-71 Google Scholar
100. Johansson, A. et al. (2004) Non-viral delivery of the porphobilinogen deaminase cDNA into a mouse model of acute intermittent porphyria. Molecular Genetics and Metabolism 82, 20-26 Google Scholar
101. Johansson, A. et al. (2004) Adenoviral-mediated expression of porphobilinogen deaminase in liver restores the metabolic defect in a mouse model of acute intermittent porphyria. Molecular Therapy 10, 337-343 Google Scholar
102. Fontanellas, A. et al. (2009) Porphobilinogen deaminase gene therapy. In International patent application number: PCT/NL2009/050584, Date of filing: 29.09.2009Google Scholar
103. Wahlin, S. et al. (2011) Hepatocyte transplantation ameliorates the metabolic abnormality in a mouse model of acute intermittent porphyria. Presented at the International Porphyrins and Porphyrias Meeting (10–14 April 2011; Cardiff, U.K.)Google Scholar
104. Sardh, E. et al. (2011) Insulin downregulates ALAS1 expression in human hepatocytes. Presented at the International Porphyrins and Porphyrias Meeting (10–14 April 2011; Cardiff, U.K.)Google Scholar
105. Bustad, H.J. et al. (2013) Searching for Pharmacological Chaperones Aiding to Stabilize Hydroxymethylbilane Synthase. Presented at the Annual Assembly SSCC/Congress Porphyrins and porphyrias (May 16–18, 2013; Lucerne, Switzerland)Google Scholar