Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-745bb68f8f-l4dxg Total loading time: 0 Render date: 2025-01-29T00:30:09.889Z Has data issue: false hasContentIssue false

Chapter 30 - Heme Biosynthesis and the Porphyrias in Children

from Section IV - Metabolic Liver Disease

Published online by Cambridge University Press:  19 January 2021

By
Robert J. Desnick ,
Manisha Balwani  and
Karl E. Anderson
Edited by
Frederick J. Suchy ,
Ronald J. Sokol  and
William F. Balistreri
Edited in association with
Jorge A. Bezerra ,
Cara L. Mack  and
Benjamin L. Shneider
Frederick J. Suchy
Affiliation:
University of Colorado, Children’s Hospital Colorado, Aurora
Ronald J. Sokol
Affiliation:
University of Colorado, Children’s Hospital Colorado, Aurora
William F. Balistreri
Affiliation:
Cincinnati Children’s Hospital Medical Center, Cincinnati
Jorge A. Bezerra
Affiliation:
Cincinnati Children’s Hospital Medical Center, Cincinnati
Cara L. Mack
Affiliation:
University of Colorado, Children’s Hospital Colorado, Aurora
Benjamin L. Shneider
Affiliation:
Texas Children’s Hospital, Houston
Get access

Summary

The porphyrias are metabolic disorders each resulting from the deficiency of a specific enzyme in the heme biosynthetic pathway (Figure 30.1 and Table 30.1) [1–6]. These enzyme deficiencies are inherited as autosomal dominant, autosomal recessive and X-linked traits, with the exception of porphyria cutanea tarda (PCT), which usually is sporadic. The porphyrias are classified as either hepatic or erythropoietic depending on the primary site of overproduction and accumulation of porphyrin precursors or porphyrins (Table 30.2) although some have overlapping features. The hepatic porphyrias are characterized by overproduction and initial accumulation of porphyrin precursors and/or porphyrins primarily in the liver, whereas in the erythropoietic porphyrias, overproduction and initial accumulation of the pathway intermediates occur primarily in bone marrow erythroid cells.

Type
Chapter
Information
Liver Disease in Children , pp. 530 - 547
Publisher: Cambridge University Press
Print publication year: 2021

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

Anderson, KE SS, Bishop, DF, Desnick, RJ. (2014). Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias. In Valle, D, Beaud, AL, Vogelstein, B, Kinzler, KW, Antonarakis, SE, Ballabio, A, Gibson, K, Mitchell, G (Eds.). New York, NY: McGraw-Hill. http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62638866 [last accessed June 23, 2020].Google Scholar
Anderson, KE, Bloomer, JR, Bonkovsky, HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med 2005;142:439–50.CrossRefGoogle ScholarPubMed
Bissell, DM, Anderson, KE, Bonkovsky, HL. Porphyria. N Engl J Med 2017;377:2101.CrossRefGoogle ScholarPubMed
Puy, H, Gouya, L, Deybach, JC. Porphyrias. Lancet 2010;375:924–37.CrossRefGoogle ScholarPubMed
Elder, GH. Hepatic porphyrias in children. J Inherit Metab Dis 1997;20:237–46.CrossRefGoogle ScholarPubMed
Yasuda, M, Chen, B, Desnick, RJ. Recent advances on porphyria genetics: inheritance, penetrance and molecular heterogeneity, including new modifying/causative genes. Mol Genet Metab 2019;128(3):320–31.CrossRefGoogle ScholarPubMed
Soonawalla, ZF, Orug, T, Badminton, MN, et al. Liver transplantation as a cure for acute intermittent porphyria. Lancet 2004;363:705–6.CrossRefGoogle ScholarPubMed
Yasuda, M, Erwin, AL, Liu, LU, et al. Liver transplantation for acute intermittent porphyria: biochemical and pathologic studies of the explanted liver. Mol Med 2015;21:487–95.Google Scholar
Wahlin, S, Harper, P, Sardh, E, et al. Combined liver and kidney transplantation in acute intermittent porphyria. Transpl Int 2010;23:e18–21.Google Scholar
Erwin, AL, Desnick, RJ. Congenital erythropoietic porphyria: recent advances. Mol Genet Metab 2019;128(3):288–97.CrossRefGoogle ScholarPubMed
Desnick, RJ, Astrin, KH. Congenital erythropoietic porphyria: advances in pathogenesis and treatment. Br J Haematol 2002;117:779–95.Google Scholar
Phillips, JD. Heme biosynthesis and the porphyrias. Mol Genet Metab 2019; 128(3):164–77.Google Scholar
Balwani, M, Doheny, D, Bishop, DF, et al. 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.CrossRefGoogle Scholar
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;83:408–14.CrossRefGoogle ScholarPubMed
May, BK, Dogra, SC, Sadlon, TJ, et al. Molecular regulation of heme biosynthesis in higher vertebrates. Prog Nucleic Acid Res Mol Biol 1995;51:1–51.Google Scholar
Bonkovsky, HL, Maddukuri, VC, Yazici, C, et al. Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am J Med 2014;127:1233–41.Google Scholar
Chen, B, Whatley, S, Badminton, M, et al. International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias. Genet Med 2019;21(11):2605–13.Google Scholar
Grandchamp, B, Picat, C, de Rooij, F, et al. A point mutation G–-A in exon 12 of the porphobilinogen deaminase gene results in exon skipping and is responsible for acute intermittent porphyria. Nucleic Acids Res 1989;17:6637–49.Google Scholar
Mustajoki, P, Desnick, RJ. Genetic heterogeneity in acute intermittent porphyria: characterisation and frequency of porphobilinogen deaminase mutations in Finland. Br Med J (Clin Res Ed) 1985;291:505–9.Google Scholar
Balwani, M, Naik, H, Anderson, KE, et al. Clinical, biochemical, and genetic characterization of North American patients with erythropoietic protoporphyria and X-linked protoporphyria. JAMA Dermatol 2017;153:789–96.CrossRefGoogle ScholarPubMed
Balwani, M, Wang, B, Anderson, KE, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology 2017;66:1314–22.CrossRefGoogle ScholarPubMed
Akagi, R, Kato, N, Inoue, R, et al. delta-Aminolevulinate dehydratase (ALAD) porphyria: the first case in North America with two novel ALAD mutations. Mol Genet Metab 2006;87:329–36.Google Scholar
Stenson, PD, Ball, EV, Mort, M, et al. Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat 2003;21:577–81.Google Scholar
Plewinska, M, Thunell, S, Holmberg, L, et al. delta-Aminolevulinate dehydratase deficient porphyria: identification of the molecular lesions in a severely affected homozygote. Am J Hum Genet 1991;49:167–74.Google Scholar
Astrin, KH, Bishop, DF, Wetmur, JG, et al. delta-Aminolevulinic acid dehydratase isozymes and lead toxicity. Ann N Y Acad Sci 1987;514:23–9.Google Scholar
Chen, B, Solis-Villa, C, Hakenberg, J, et al. Acute intermittent porphyria: predicted pathogenicity of HMBS variants indicates extremely low penetrance of the autosomal dominant disease. Hum Mutat 2016;37:1215–22.Google Scholar
Lenglet, H, Schmitt, C, Grange, T, et al. From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria. Hum Mol Genet 2018;27:1164–73.Google Scholar
Handschin, C, Lin, J, Rhee, J, et al. Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha. Cell 2005;122:505–15.Google Scholar
Pallet, N, Mami, I, Schmitt, C, et al. High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria. Kidney Int 2015;88:386–95.CrossRefGoogle ScholarPubMed
Tchernitchko, D, Tavernier, Q, Lamoril, J, et al. A variant of peptide transporter 2 predicts the severity of porphyria-associated kidney disease. J Am Soc Nephrol 2017;28:1924–32.Google Scholar
Dowman, JK, Gunson, BK, Mirza, DF, et al. Liver transplantation for acute intermittent porphyria is complicated by a high rate of hepatic artery thrombosis. Liver Transpl 2012;18:195–200.Google Scholar
Yasuda, M, Bishop, DF, Fowkes, M, et al. AAV8-mediated gene therapy prevents induced biochemical attacks of acute intermittent porphyria and improves neuromotor function. Mol Ther 2010;18:17–22.CrossRefGoogle ScholarPubMed
D’Avola, D, Lopez-Franco, E, Sangro, B, et al. Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J Hepatol 2016;65:776–83.CrossRefGoogle ScholarPubMed
Sardh, E, Harper, P, Balwani, M, et al. Phase 1 trial of an RNA interference therapy for acute intermittent porphyria. N Engl J Med 2019;380:549–58.Google Scholar
Llewellyn, DH, Smyth, SJ, Elder, GH, et al. Homozygous acute intermittent porphyria: compound heterozygosity for adjacent base transitions in the same codon of the porphobilinogen deaminase gene. Hum Genet 1992;89:97–8.Google Scholar
Solis, C, Martinez-Bermejo, A, Naidich, TP, et al. Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias. Arch Neurol 2004;61:1764–70.Google Scholar
Yasuda, M, Gan, L, Chen, B, et al. Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria. Hum Mol Genet 2019;28:1755–67.Google Scholar
Phillips, JD, Bergonia, HA, Reilly, CA, et al. A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proc Natl Acad Sci U S A 2007;104:5079–84.Google Scholar
Egger, NG, Goeger, DE, Payne, DA, et al. Porphyria cutanea tarda: multiplicity of risk factors including HFE mutations, hepatitis C, and inherited uroporphyrinogen decarboxylase deficiency. Dig Dis Sci 2002;47:419–26.Google Scholar
Kuhnel, A, Gross, U, Doss, MO. Hereditary coproporphyria in Germany: clinical-biochemical studies in 53 patients. Clin Biochem 2000;33:465–73.Google Scholar
Martasek, P. Hereditary coproporphyria. Semin Liver Dis 1998;18:25–32.Google Scholar
Martasek, P, Nordmann, Y, Grandchamp, B. Homozygous hereditary coproporphyria caused by an arginine to tryptophane substitution in coproporphyrinogen oxidase and common intragenic polymorphisms. Hum Mol Genet 1994;3:477–80.Google Scholar
Lee, DS, Flachsova, E, Bodnarova, M, et al. Structural basis of hereditary coproporphyria. Proc Natl Acad Sci U S A 2005;102:14232–7.Google Scholar
Schmitt, C, Gouya, L, Malonova, E, et al. Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria. Hum Mol Genet 2005;14:3089–98.Google Scholar
Hasanoglu, A, Balwani, M, Kasapkara, CS, et al. Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327 R. J Inherit Metab Dis 2011;34:225–31.CrossRefGoogle Scholar
Meissner, P, Hift, R, Corrigall, A. (2003). Variegate porphyria. In Kadish, K, Smith, K, Guilard, R (Eds.). Porphyrin Handbook, Part II (p. 93). San Diego, CA: Academic Press.Google Scholar
Poh-Fitzpatrick, MB. A plasma porphyrin fluorescence marker for variegate porphyria. Arch Dermatol 1980;116:543–7.Google Scholar
Meissner, PN, Dailey, TA, Hift, RJ, et al. A R59 W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria. Nat Genet 1996;13:95–7.Google Scholar
Solis, C, Aizencang, GI, Astrin, KH, et al. Uroporphyrinogen III synthase erythroid promoter mutations in adjacent GATA1 and CP2 elements cause congenital erythropoietic porphyria. J Clin Invest 2001;107:753–62.Google Scholar
Phillips, JD, Steensma, DP, Pulsipher, MA, et al. Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria. Blood 2007;109:2618–21.Google Scholar
Piomelli, S, Poh-Fitzpatrick, MB, Seaman, C, et al. Complete suppression of the symptoms of congenital erythropoietic porphyria by long-term treatment with high-level transfusions. N Engl J Med 1986;314:1029–31.CrossRefGoogle ScholarPubMed
Dupuis-Girod, S, Akkari, V, Ged, C, et al. Successful match-unrelated donor bone marrow transplantation for congenital erythropoietic porphyria (Gunther disease). Eur J Pediatr 2005;164:104–7.Google Scholar
Gouya, L, Martin-Schmitt, C, Robreau, AM, et al. Contribution of a common single-nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria. Am J Hum Genet 2006;78:2–14.Google Scholar
Wahlin, S, Floderus, Y, Stal, P, et al. Erythropoietic protoporphyria in Sweden: demographic, clinical, biochemical and genetic characteristics. J Intern Med 2011;269:278–88.Google Scholar
Whatley, SD, Mason, NG, Holme, SA, et al. Molecular epidemiology of erythropoietic protoporphyria in the U.K. Br J Dermatol 2010;162:642–6.Google ScholarPubMed
Meerman, L, Koopen, NR, Bloks, V, et al. Biliary fibrosis associated with altered bile composition in a mouse model of erythropoietic protoporphyria. Gastroenterology 1999;117:696–705.Google Scholar
Minder, EI, Gouya, L, Schneider-Yin, X, et al. A genotype-phenotype correlation between null-allele mutations in the ferrochelatase gene and liver complication in patients with erythropoietic protoporphyria. Cell Mol Biol (Noisy-le-grand) 2002;48:91–6.Google ScholarPubMed
Harms, J, Lautenschlager, S, Minder, CE, et al. An alpha-melanocyte-stimulating hormone analogue in erythropoietic protoporphyria. N Engl J Med 2009;360:306–7.CrossRefGoogle ScholarPubMed
Langendonk, JG, Balwani, M, Anderson, KE, et al. Afamelanotide for erythropoietic protoporphyria. N Engl J Med 2015;373:48–59.Google Scholar
McGuire, BM, Bonkovsky, HL, Carithers, RL Jr., et al. Liver transplantation for erythropoietic protoporphyria liver disease. Liver Transpl 2005;11:1590–6.Google Scholar
Fontanellas, A, Mazurier, F, Landry, M, et al. Reversion of hepatobiliary alterations by bone marrow transplantation in a murine model of erythropoietic protoporphyria. Hepatology 2000;32:73–81.CrossRefGoogle Scholar
Akagi, R, Inoue, R, Muranaka, S, et al. Dual gene defects involving delta-aminolaevulinate dehydratase and coproporphyrinogen oxidase in a porphyria patient. Br J Haematol 2006;132:237–43.Google Scholar
Harraway, JR, Florkowski, CM, Sies, C, et al. Dual porphyria with mutations in both the UROD and HMBS genes. Ann Clin Biochem 2006;43:80–2.Google Scholar
Yasuda, M, Desnick, RJ. Murine models of the human porphyrias: contributions toward understanding disease pathogenesis and the development of new therapies. Mol Genet Metab 2019;128(3):332–41.Google Scholar
Lindberg, RL, Porcher, C, Grandchamp, B, et al. Porphobilinogen deaminase deficiency in mice causes a neuropathy resembling that of human hepatic porphyria. Nat Genet 1996;12:195–9.Google Scholar
Bishop, DF, Johansson, A, Phelps, R, et al. Uroporphyrinogen III synthase knock-in mice have the human congenital erythropoietic porphyria phenotype, including the characteristic light-induced cutaneous lesions. Am J Hum Genet 2006;78:645–58.CrossRefGoogle ScholarPubMed
Bishop, DF, Clavero, S, Mohandas, N, et al. Congenital erythropoietic porphyria: characterization of murine models of the severe common (C73 R/C73 R) and later-onset genotypes. Mol Med 2011;17:748–56.Google Scholar
Tutois, S, Montagutelli, X, Da Silva, V, et al. Erythropoietic protoporphyria in the house mouse. A recessive inherited ferrochelatase deficiency with anemia, photosensitivity, and liver disease. J Clin Invest 1991;88:1730–6.Google Scholar
Lindberg, RL, Martini, R, Baumgartner, M, et al. Motor neuropathy in porphobilinogen deaminase-deficient mice imitates the peripheral neuropathy of human acute porphyria. J Clin Invest 1999;103:1127–34.Google Scholar
Phillips, JD, Jackson, LK, Bunting, M, et al. A mouse model of familial porphyria cutanea tarda. Proc Natl Acad Sci U S A 2001;98:259–64.Google Scholar
Medlock, AE, Meissner, PN, Davidson, BP, et al. A mouse model for South African (R59 W) variegate porphyria: construction and initial characterization. Cell Mol Biol (Noisy-le-grand) 2002;48:71–8.Google Scholar
Gou, E, Balwani, M, Bissell, DM, Bloomer, JR, Bonkovsky, HL, Desnick, RJ, Naik, H, Phillips, J, Singal, AK, Wang, B, Keel, S, and Anderson, KE. Pitfalls in erythrocyte protoporphyrin measurement for diagnosis and monitoring of protoporphyrias. Clinical Chemistry 2015:61(12):1453–6.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×