Advances in Clinical and Experimental Medicine
2016, vol. 25, nr 2, March-April, p. 361–368
doi: 10.17219/acem/58955
Publication type: review
Language: English
Download citation:
Clinical, Biochemical and Molecular Characteristics of the Main Types of Porphyria
1 Department of Immunogenetics of the Institute of Haematology and Transfusion Medicine, Warszawa, Poland
2 Department of Haemostasis and Metabolic Disorders of the Institute of Haematology and Transfusion Medicine, Warszawa, Poland
Abstract
Porphyrias are diverse disorders that arise from various inherited enzyme defects in the heme biosynthesis pathway, except for porphyria cutanea tarda (PCT), in which the enzyme deficiency in most cases is acquired. The biosynthetic blocks resulting from the defective enzymes are largely expressed either in the liver or bone marrow, the sites where the majority of heme is produced. Although the pathophysiologic mechanisms of the clinical manifestations of the porphyrias are not fully understood, two cardinal features prevail: skin photosensitivity and neurologic symptoms of intermittent autonomic neuropathy, acute neurovisceral attacks, and disorders of the nervous system. The primary diagnosis of the proband is based on biochemical testing, which is not always able to identify acute porphyrias, especially in asymptomatic family carriers when heme precursors and porphyrins excretion is normal, low-normal and high-reduced values of enzyme activity overlap, and hematological diseases responsible for abnormal blood cells distribution coexist. Molecular analysis of gene mutations responsible for each type of porphyria is the best diagnostic approach for symptomatic as well as presymptomatic gene carriers.
Key words
acute hepatic porphyrias, porphyria cutanea tarda, erythropoietic porphyrias
References (39)
- Puy H, Gouya L, Deybach JC: Porphyrias. Lancet 2010, 375, 924–937.
- Ponka P: Cell biology of heme. Am J Med Sci 1999, 318, 241–256.
- Nordmann Y, Puy H: Human hereditary hepatic porphyrias. Clin Chim Acta 2002, 325, 17–37.
- Floderus Y, Shoolingin-Jordan PM, Harper P: Acute intermittent porphyria in Sweden. Molecular, functional and clinical consequences of some new mutations found in the porphobilinogen deaminase gene. Clin Genet 2002, 62, 288–297.
- Mustajoki P, Koskelo P: Hereditary hepatic porphyrias in Finland. Acta Med Scand 1976, 200, 171–178.
- Parera VE, De Siervi A, Varela L, Rossetti MV, Batlle AM: Acute porphyrias in the Argentinean population: A review. Cell Mol Biol 2003, 49, 493–500.
- Meissner PN, Dailey TA, Hift RJ, Ziman M, Corrigall AV, Roberts AG, Meissner DM, Kirsh RE, Dailey HA: A R5 9W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria. Nat Genet 1996, 13, 95–97.
- Von und zu Fraunberg M, Timonen K, Mustajoko P, Kauppinen R: Clinical and biochemical charecteristics and genotype-phenotype correlation in Finnish variegate porphyria patients. Eur J Hum Gen 2002, 10, 649–657.
- Siegesmund M, Van Tuyll van Serooskerken AM, Poblete-Gutierrez P, Frank J: The acute hepatic porphyrias: current status and future challenges. Best Pract Res Clin Gastroenterol 2010, 24, 593–605.
- Elder GH: Porphyria cutanea tarda. Semin Liver Dis 1998, 18, 67–75.
- Went L, Klasen EC: Genetic aspects of erythropoietic protoporphyria. Ann Hum Genet 1984, 48, 105–117.
- Elder GH, Smith SG, Smyth SJ: Laboratory investigation of the porphyrias. Ann Clin Biochem 1990, 27, 395–412.
- Wahlin S, Floderus Y, Stal P, Harper P: Erythropoietic protoporphyria in Sweden: demographic, clinical, biochemical and genetic characteristics. J Intern Med 2011, 269, 278–288.
- Marko PB, Miljković J, Gorenjak M, Povalej P, Kansky A: Erytropoietic protoporphyria patients in Slovenia. Acta Dermatovenerol Alp Panonica Adriat 2007, 16, 99–102.
- Kauppinen R, Mustajoki P: Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors and associated diseases. Medicine (Baltimore) 1992, 71, 1–13.
- Sassa S: Modern diagnosis and management of the porphyrias. Brit J Haematol 2006, 135, 281–292.
- Elder GH: Hepatic porphyrias in children. J Inherit Metab Dis 1997, 20, 237–246.
- Brancaleoni V, Granata F, Colancecco A, Tavazzi D, Cappellini HD, Di Pierro E: Seven novel genetic mutations within the 5’UTR and the housekeeping promoter of HMBS gene responsible for the non-erythroid form of acute intermittent porphyria. Blood Cells Mol Dis 2012, 49, 147–151.
- Human Gene Mutation Database (Cardiff; www.hgmd.cf.ac.uk), (accessed 31/03/2015).
- Schulenburg-Brand D, Katugampola R, Anstey AV, Badminton MN: The cutaneous porphyrias. Dermatol Clin 2014, 32, 369–384.
- Kostrzewska E, Gregor A: Increased activity of porphobilinogen deaminase in erythrocytes during attacks of acute intermittent porphyria. Ann Clin Res 1986, 18, 195–198.
- Deybach JC, de Verneuil H, Nordmann Y: The inherited enzymatic defect in porphyria variegata. Hum Genet 1981, 58, 425–428.
- Deybach JC, Puy H, Robreau AM, Lamoril J, Da Silva V, Grandchamp B, Nordmann Y: Mutations in the protoporphyrinogen oxidase gene in patients with variegate porphyria. Hum Mol Genet 1996, 5, 407–410.
- Poh-Fitzpatrik MB: A plasma porphyrin fluorescence marker for variegate porphyria. Arch Dermatol 1980, 116, 543–547.
- Bissell DM, Wang B, Cimino T, Lai J: Hereditary Coproporphyria. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, Adam MP, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle 2012.
- Grandchamp B, Nordmann Y: Decreased lymphocyte coproporphyrinogen III oxidase activity in hereditary coproporpyhria. Biochem Biophys Res Commun 1977, 74, 1089–1095.
- Martasek P: Hereditary coroporphyria. Semin in Liver Disease 1998, 18, 25–32.
- Inoue R, Akagi R: Co-synthesis of human delta-aminolevulinate dehydratase (ALAD) mutants with the wild-type enzyme in cell-free system – critical importance of conformation on enzyme activity. J Clin Biochem Nutr 2008, 43, 143–153.
- Gross U, Sassa S, Jacob K, Deybach JC, Nordmann Y, Frank M, Doss MO: 5-Aminolevulinic acid dehydratase deficiency porphyria: A twenty-year clinical and biochemical follow-up. Clin Chem 1998, 44, 1892–1896.
- Balwani M, Desnick RJ: The porphyrias: advances in diagnosis and treatment. Blood 2012, 120, 4496–4504.
- Darwich E, Herrero C: New developments in erythropoietic porphyrias. Actas Dermosifiliogr 2013, 104, 212–219.
- Tahara T, Yamamoto M, Akagi R Harigae H, Taketani S: The low expression allele (IVS3-48C) of ferrochelatase gene leads to low enzyme activity associated with erythropoietic protoporphyria. Int J Hematol 2010, 92, 769–771.
- Desnick RJ, Astrin KH: Congenital erythropoietic porphyria: advances in pathogenesis and treatment. Brit J Haematol 2002, 117, 779–795.
- Ged C, Moreau-Gaudry F, Richard E, Robert-Richard E, de Verneuil H: Congenital erythropoietic porphyria: mutation update and correlations between genotype and phenotype. Cell Mol Biol 2009, 55, 53–60.
- Ventura P, Cappellini MD, Biolcati G, Guida CC, Rocch E,and Gruppo Italiano Porfiria (GrIP): A challenging diagnosis for potential fatal diseases: Recommendations for diagnosing acute porphyrias. Eur J Intern Med 2014, 25, 497–505.
- Wathley SD, Badminton M: Role of genetic testing in the management of patients with inherited porphyria and their familiers. Ann Cli Biochem 2013, 50, 204–216.
- Szlendak U, Lipniacka A, Bianketti J, Podolak-Dawidziak M, Bykowska K: Porphobilinogen deaminase gene mutations in Polish patients with non-erythroid acute intermittent porphyria. Adv Clin Exp Med 2015, 24, 63–68.
- Di Pierro E, Brancaleoni V, Besana V, Cappellini MD: Multiplex ligation-dependent probe amplification: a novel approach for genetic diagnosis of porphyria. J Hum Genet 2009, 54, 479–487.
- Whatley SD, Mason NC, Woolf JR, Newcombe RG, Elder GH, Badminton MN: Diagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX or PPOX gene. Clin Chem 2009, 55, 1406–1414.