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Herbert L. Bonkovsky - One of the best experts on this subject based on the ideXlab platform.
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International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the Porphyrias
Genetics in Medicine, 2019Co-Authors: Brenden Chen, Herbert L. Bonkovsky, Michael Norman Badminton, Aasne K. Aarsand, Sharon Whatley, Karl E. Anderson, D. Montgomery Bissell, Maria D. Cappellini, Ylva Floderus, Edith C. H. FriesemaAbstract:With the advent of precision and genomic medicine, a critical issue is whether a disease gene variant is pathogenic or benign. Such is the case for the three autosomal dominant acute hepatic Porphyrias (AHPs), including acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, each resulting from the half-normal enzymatic activities of hydroxymethylbilane synthase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase, respectively. To date, there is no public database that documents the likely pathogenicity of variants causing the Porphyrias, and more specifically, the AHPs with biochemically and clinically verified information. Therefore, an international collaborative with the European Porphyria Network and the National Institutes of Health/National Center for Advancing Translational Sciences/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NCATS/NIDDK)-sponsored Porphyrias Consortium of porphyria diagnostic experts is establishing an online database that will collate biochemical and clinical evidence verifying the pathogenicity of the published and newly identified variants in the AHP-causing genes. The overall goal of the International Porphyria Molecular Diagnostic Collaborative is to determine the pathogenic and benign variants for all eight Porphyrias. Here we describe the overall objectives and the initial efforts to validate pathogenic and benign variants in the respective heme biosynthetic genes causing the AHPs.
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pathogenesis and clinical features of the acute hepatic Porphyrias ahps
Molecular Genetics and Metabolism, 2019Co-Authors: Herbert L. Bonkovsky, Natalia Dixon, Sean RudnickAbstract:Abstract The acute hepatic Porphyrias include four disorders: acute intermittent porphyria [AIP], hereditary coproporphyria [HCP], variegate porphyria [VP], and the rare porphyria due to severe deficiency of ALA dehydratase [ADP]. In the USA, AIP is the most severe and most often symptomatic. AIP, HCP, and VP are due to autosomal dominant genetic abnormalities, in which missense, nonsense, or other mutations of genes of normal hepatic heme biosynthesis, in concert with other environmental, nutritional, hormonal and genetic factors, may lead to a critical deficiency of heme, the end-product of the pathway, in a small but critical ‘regulatory pool’ within hepatocytes. This deficiency leads to de-repression of the first and normally rate-controlling enzyme of the heme synthetic pathway, delta- or 5-aminolevulinic acid [ALA] synthase-1, and thus to marked up-regulation of this key enzyme and to marked hepatic overproduction of ALA. In addition, except for ADP, there is marked overproduction as well of porphobilinogen [PBG], the intermediate immediately downstream of ALA in the synthetic chain, and, especially in HCP and VP, also porphyrinogens and porphyrins farther down the pathway. The major clinical features of the acute Porphyrias are attacks of severe neuropathic-type pain. Pain is felt first and foremost in the abdomen but may also occur in the back, chest, and extremities. Attacks are more common in women than in men [ratio of about 4:1], often accompanied by nausea, vomiting, constipation, tachycardia, and arterial hypertension. Hyponatremia may also occur. Some patients also describe chronic symptoms of pain, anxiety, insomnia, and others.
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porphyrin induced protein oxidation and aggregation as a mechanism of porphyria associated cell injury
Cellular and molecular gastroenterology and hepatology, 2019Co-Authors: Dhiman Maitra, Herbert L. Bonkovsky, Juliana Bragazzi Cunha, Jared S Elenbaas, Jordan A Shavit, Bishr M OmaryAbstract:Abstract Genetic Porphyrias comprise eight diseases caused by defects in the heme biosynthetic pathway that lead to accumulation of heme precursors. Consequences of porphyria include photosensitivity, liver damage and increased risk of hepatocellular carcinoma, and neurovisceral involvement, including seizures. Fluorescent porphyrins that include protoporphyrin-IX, uroporphyrin and coproporphyrin, are photo-reactive; they absorb light energy and are excited to high-energy singlet and triplet states. Decay of the porphyrin excited to ground state releases energy and generates singlet oxygen. Porphyrin-induced oxidative stress is thought to be the major mechanism of porphyrin-mediated tissue damage. Although this explains the acute photosensitivity in most Porphyrias, light-induced porphyrin-mediated oxidative stress does not account for the effect of porphyrins on internal organs. Recent findings demonstrate the unique role of fluorescent porphyrins in causing subcellular compartment-selective protein aggregation. Porphyrin-mediated protein aggregation associates with nuclear deformation, cytoplasmic vacuole formation and endoplasmic reticulum dilation. Porphyrin-triggered proteotoxicity is compounded by inhibition of the proteasome due to aggregation of some of its subunits. The ensuing disruption in proteostasis also manifests in cell cycle arrest coupled with aggregation of cell proliferation-related proteins, including PCNA, cdk4 and cyclin B1. Porphyrins bind to native proteins and, in presence of light and oxygen, oxidize several amino acids, particularly methionine. Noncovalent interaction of oxidized proteins with porphyrins leads to formation of protein aggregates. In internal organs, particularly the liver, light-independent porphyrin-mediated protein aggregation occurs after secondary triggers of oxidative stress. Thus, porphyrin-induced protein aggregation provides a novel mechanism for external and internal tissue damage in Porphyrias that involve fluorescent porphyrin accumulation.
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clinically important features of porphyrin and heme metabolism and the Porphyrias
Metabolites, 2014Co-Authors: Siddesh Besur, Paul Schmeltzer, Herbert L. BonkovskyAbstract:Heme, like chlorophyll, is a primordial molecule and is one of the fundamental pigments of life. Disorders of normal heme synthesis may cause human diseases, including certain anemias (X-linked sideroblastic anemias) and Porphyrias. Porphyrias are classified as hepatic and erythropoietic Porphyrias based on the organ system in which heme precursors (5-aminolevulinic acid (ALA), porphobilinogen and porphyrins) are chiefly overproduced. The hepatic Porphyrias are further subdivided into acute Porphyrias and chronic hepatic Porphyrias. The acute Porphyrias include acute intermittent, hereditary copro-, variegate and ALA dehydratase deficiency porphyria. Chronic hepatic Porphyrias include porphyria cutanea tarda and hepatoerythropoietic porphyria. The erythropoietic Porphyrias include congenital erythropoietic porphyria (Gűnther’s disease) and erythropoietic protoporphyria. In this review, we summarize the key features of normal heme synthesis and its differing regulation in liver versus bone marrow. In both organs, principal regulation is exerted at the level of the first and rate-controlling enzyme, but by different molecules (heme in the liver and iron in the bone marrow). We also describe salient clinical, laboratory and genetic features of the eight types of porphyria.
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porphyrin and heme metabolism and the Porphyrias
Comprehensive Physiology, 2013Co-Authors: Herbert L. Bonkovsky, Tarun Narang, Ting Li, Manish ThaparAbstract:Porphyrins and metalloporphyrins are the key pigments of life on earth as we know it, because they include chlorophyll (a magnesium-containing metalloporphyrin) and heme (iron protoporphyrin). In eukaryotes, porphyrins and heme are synthesized by a multistep pathway that involves eight enzymes. The first and rate-controlling step is the formation of delta-aminolevulinic acid (ALA) from glycine plus succinyl CoA, catalyzed by ALA synthase. Intermediate steps occur in the cytoplasm, with formation of the monopyrrole porphobilinogen and the tetrapyrroles hydroxymethylbilane and a series of porphyrinogens, which are serially decarboxylated. Heme is utilized chiefly for the formation of hemoglobin in erythrocytes, myoglobin in muscle cells, cytochromes P-450 and mitochondrial cytochromes, and other hemoproteins in hepatocytes. The rate-controlling step of heme breakdown is catalyzed by heme oxygenase (HMOX), of which there are two isoforms, called HMOX1 and HMOX2. HMOX breaks down heme to form biliverdin, carbon monoxide, and iron. The Porphyrias are a group of disorders, mainly inherited, in which there are defects in normal porphyrin and heme synthesis. The cardinal clinical features are cutaneous (due to the skin-damaging effects of excess deposited porphyrins) or neurovisceral attacks of pain, sometimes with weakness, delirium, seizures, and the like (probably due mainly to neurotoxic effects of ALA). The treatment of choice for the acute hepatic Porphyrias is intravenous heme therapy, which repletes a critical regulatory heme pool in hepatocytes and leads to downregulation of hepatic ALA synthase, which is a biochemical hallmark of all forms of acute porphyria in relapse. © 2013 American Physiological Society. Compr Physiol 3:365-401, 2013.
Donald C. Greenway - One of the best experts on this subject based on the ideXlab platform.
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Plasma Porphyrins in the Porphyrias
2015Co-Authors: Thomas J. Hindmarsh, Linda Oliveras, Donald C. GreenwayAbstract:Background: As an aid in the diagnosis and manage-ment of porphyria we have developed a method to fractionate and quantify plasma porphyrins and have evaluated its use in various Porphyrias. Methods: We used HPLC with fluorometric detection to measure plasma concentrations of uroporphyrin I an
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Plasma Porphyrins in the Porphyrias
Clinical Chemistry, 1999Co-Authors: J. Thomas Hindmarsh, Linda Oliveras, Donald C. GreenwayAbstract:Background: As an aid in the diagnosis and management of porphyria we have developed a method to fractionate and quantify plasma porphyrins and have evaluated its use in various Porphyrias. Methods: We used HPLC with fluorometric detection to measure plasma concentrations of uroporphyrin I and III, heptacarboxyl III, hexacarboxyl III, pentacarboxyl III, and coproporphyrin I and III. We studied 245 healthy subjects, 32 patients with classical porphyria cutanea tarda (PCT), 12 patients with PCT of renal failure, 13 patients with renal failure, 8 patients with pseudoporphyria of renal failure, 3 patients with acute intermittent porphyria, 5 patients with variegate porphyria, 5 patients with hereditary coproporphyria, and 4 patients with erythropoietic protoporphyria. Results: Between-run CVs were 5.4–13%. The recoveries of porphyrins added to plasma were 71–114% except for protoporphyrin, which could not be reliably measured with this technique. Plasma porphyrin patterns clearly identified PCT, and its clinical sensitivity equaled that of urine porphyrin fractionation. The patterns also allowed differentiation of PCT of renal failure from pseudoporphyria of renal failure. Conclusions: The assay of plasma porphyrins identifies patients with PCT and appears particularly useful for differentiating PCT of renal failure from pseudoporphyria of renal failure.
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Biochemical differentiation of the Porphyrias.
Clinical Biochemistry, 1999Co-Authors: J. Thomas Hindmarsh, Linda Oliveras, Donald C. GreenwayAbstract:Abstract Objectives: To differentiate the Porphyrias by clinical and biochemical methods. Design and methods: We describe levels of blood, urine, and fecal porphyrins and their precursors in the Porphyrias and present an algorithm for their biochemical differentiation. Diagnoses were established using clinical and biochemical data. Porphyrin analyses were performed by high performance liquid chromatography. Results and conclusions: Plasma and urine porphyrin patterns were useful for diagnosis of porphyria cutanea tarda, but not the acute Porphyrias. Erythropoietic protoporphyria was confirmed by erythrocyte protoporphyrin assay and erythrocyte fluorescence. Acute intermittent porphyria was diagnosed by increases in urine delta-aminolevulinic acid and porphobilinogen and confirmed by reduced erythrocyte porphobilinogen deaminase activity and normal or near-normal stool porphyrins. Variegate porphyria and hereditary coproporphyria were diagnosed by their characteristic stool porphyrin patterns. This appears to be the most convenient diagnostic approach until molecular abnormalities become more extensively defined and more widely available.
Manish Thapar - One of the best experts on this subject based on the ideXlab platform.
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Liver transplantation in the management of porphyria
Hepatology, 2014Co-Authors: Ashwani K. Singal, Manish Thapar, Charles J. Parker, Christine Bowden, Lawrence Liu, Brendan M. McguireAbstract:Porphyrias are a group of eight metabolic disorders, each resulting from a mutation that affects an enzyme of the heme biosynthetic pathway. Porphyrias are classified as hepatic or erythropoietic, depending upon the site where the gene defect is predominantly expressed. Clinical phenotypes are classified as follows: (1) acute Porphyrias with neurovisceral symptoms: acute intermittent porphyria; delta amino-levulinic acid hydratase deficiency porphyria; hereditary coproporphyria; and variegate porphyria and (2) cutaneous Porphyrias with skin blistering and photosensitivity: porphyria cutanea tarda; congenital erythropoietic porphyria; hepatoerythropoietic porphyria and both erythropoietic protoPorphyrias: autosomal dominant and X-linked. Liver transplantation (LT) may be needed for recurrent and/or life-threatening acute attack in acute intermittent porphyria or acute liver failure or end-stage chronic liver disease in erythropoietic protoporphyria. LT in acute intermittent porphyria is curative. Erythropoietic protoporphyria patients needing LT should be considered for bone marrow transplantation to achieve cure. Conclusion: This article provides an overview of porphyria with diagnostic approaches and management strategies for specific Porphyrias and recommendations for LT with indications, pretransplant evaluation, and posttransplant management. (Hepatology 2014;60:1082–1089)
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porphyrin and heme metabolism and the Porphyrias
Comprehensive Physiology, 2013Co-Authors: Herbert L. Bonkovsky, Tarun Narang, Ting Li, Manish ThaparAbstract:Porphyrins and metalloporphyrins are the key pigments of life on earth as we know it, because they include chlorophyll (a magnesium-containing metalloporphyrin) and heme (iron protoporphyrin). In eukaryotes, porphyrins and heme are synthesized by a multistep pathway that involves eight enzymes. The first and rate-controlling step is the formation of delta-aminolevulinic acid (ALA) from glycine plus succinyl CoA, catalyzed by ALA synthase. Intermediate steps occur in the cytoplasm, with formation of the monopyrrole porphobilinogen and the tetrapyrroles hydroxymethylbilane and a series of porphyrinogens, which are serially decarboxylated. Heme is utilized chiefly for the formation of hemoglobin in erythrocytes, myoglobin in muscle cells, cytochromes P-450 and mitochondrial cytochromes, and other hemoproteins in hepatocytes. The rate-controlling step of heme breakdown is catalyzed by heme oxygenase (HMOX), of which there are two isoforms, called HMOX1 and HMOX2. HMOX breaks down heme to form biliverdin, carbon monoxide, and iron. The Porphyrias are a group of disorders, mainly inherited, in which there are defects in normal porphyrin and heme synthesis. The cardinal clinical features are cutaneous (due to the skin-damaging effects of excess deposited porphyrins) or neurovisceral attacks of pain, sometimes with weakness, delirium, seizures, and the like (probably due mainly to neurotoxic effects of ALA). The treatment of choice for the acute hepatic Porphyrias is intravenous heme therapy, which repletes a critical regulatory heme pool in hepatocytes and leads to downregulation of hepatic ALA synthase, which is a biochemical hallmark of all forms of acute porphyria in relapse. © 2013 American Physiological Society. Compr Physiol 3:365-401, 2013.
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porphyrin and heme metabolism and the Porphyrias
Comprehensive Physiology, 2013Co-Authors: Herbert L. Bonkovsky, Tarun Narang, Juntao Guo, Weihong Hou, Manish ThaparAbstract:Porphyrins and metalloporphyrins are the key pigments of life on earth as we know it, because they include chlorophyll (a magnesium-containing metalloporphyrin) and heme (iron protoporphyrin). In eukaryotes, porphyrins and heme are synthesized by a multistep pathway that involves eight enzymes. The first and rate-controlling step is the formation of delta-aminolevulinic acid (ALA) from glycine plus succinyl CoA, catalyzed by ALA synthase. Intermediate steps occur in the cytoplasm, with formation of the monopyrrole porphobilinogen and the tetrapyrroles hydroxymethylbilane and a series of porphyrinogens, which are serially decarboxylated. Heme is utilized chiefly for the formation of hemoglobin in erythrocytes, myoglobin in muscle cells, cytochromes P-450 and mitochondrial cytochromes, and other hemoproteins in hepatocytes. The rate-controlling step of heme breakdown is catalyzed by heme oxygenase (HMOX), of which there are two isoforms, called HMOX1 and HMOX2. HMOX breaks down heme to form biliverdin, carbon monoxide, and iron. The Porphyrias are a group of disorders, mainly inherited, in which there are defects in normal porphyrin and heme synthesis. The cardinal clinical features are cutaneous (due to the skin-damaging effects of excess deposited porphyrins) or neurovisceral attacks of pain, sometimes with weakness, delirium, seizures, and the like (probably due mainly to neurotoxic effects of ALA). The treatment of choice for the acute hepatic Porphyrias is intravenous heme therapy, which repletes a critical regulatory heme pool in hepatocytes and leads to downregulation of hepatic ALA synthase, which is a biochemical hallmark of all forms of acute porphyria in relapse.
Elisabeth I Minder - One of the best experts on this subject based on the ideXlab platform.
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Original article SWISS MED WKLY 20 09; 139 ( 13–14) : 198–206 · www.smw.ch
2015Co-Authors: Peer Reviewed Article, Xiaoye Schneider-yin, Juergen Harms, Elisabeth I MinderAbstract:Background: The Porphyrias, a group of seven metabolic disorders in the haem biosynthesis, can be classified into acute and non-acute Porphyrias. A common symptom of acute Porphyrias is severe acute abdominal pain, whereas cutaneous photo-sensitivity can occur in both acute and non-acute Porphyrias. All Porphyrias, except for sporadic porphyria cutanea tarda (sPCT), are hereditary disorders caused by mutations in the respective genes.We present porphyria cases documented in our porphyria centre during the past 15 years. Methods: Diagnosis was based on clinical symptoms and biochemical analyses. Mutation analysis was performed in patients/families with a confirmed hereditary porphyria
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Porphyria in Switzerland, 15 years experience.
Swiss medical weekly, 2009Co-Authors: Xiaoye Schneider-yin, Juergen Harms, Elisabeth I MinderAbstract:The Porphyrias, a group of seven metabolic disorders in the haem biosynthesis, can be classified into acute and non-acute Porphyrias. A common symptom of acute Porphyrias is severe acute abdominal pain, whereas cutaneous photosensitivity can occur in both acute and non-acute Porphyrias. All Porphyrias, except for sporadic porphyria cutanea tarda (sPCT), are hereditary disorders caused by mutations in the respective genes. We present porphyria cases documented in our porphyria centre during the past 15 years. Diagnosis was based on clinical symptoms and biochemical analyses. Mutation analysis was performed in patients/families with a confirmed hereditary porphyria. As the porphyria specialist centre of Switzerland, we perform the specialized analyses required for the diagnosis of all types of Porphyrias, and give advice to patients, physicians and other laboratories. We therefore estimated that our data cover 80-90% of all diagnosed Swiss cases. A total of 217 patients from 170 families were diagnosed including, 111 acute intermittent porphyria, 45 erythropoietic protoporphyria, 30 variegate porphyria, 21 sPCT, five congenital erythropoietic porphyria, four hereditary coproporphyria and one hepatoerythropoietic porphyria patient. Systematic monitoring of the patients would allow early detection of the potential life-threatening complications such as hepatocellular carcinoma and renal insufficiency in acute Porphyrias, and liver failure in EPP. Seventy-five percent of all families underwent genetic testing. Identification of pre-symptomatic mutation carriers so that these individuals and their physicians can be consulted with safety on drug use and other preventive measures, is important in managing acute Porphyrias. The unique phenomenon of founder mutations in the Swiss population is also discussed.
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Porphyria in Switzerland, 15 years experience.
Swiss Medical Weekly, 2009Co-Authors: Xiaoye Schneider-yin, Juergen Harms, Elisabeth I MinderAbstract:BACKGROUND The Porphyrias, a group of seven metabolic disorders in the haem biosynthesis, can be classified into acute and non-acute Porphyrias. A common symptom of acute Porphyrias is severe acute abdominal pain, whereas cutaneous photosensitivity can occur in both acute and non-acute Porphyrias. All Porphyrias, except for sporadic porphyria cutanea tarda (sPCT), are hereditary disorders caused by mutations in the respective genes. We present porphyria cases documented in our porphyria centre during the past 15 years. METHODS Diagnosis was based on clinical symptoms and biochemical analyses. Mutation analysis was performed in patients/families with a confirmed hereditary porphyria. RESULTS AND CONCLUSIONS As the porphyria specialist centre of Switzerland, we perform the specialized analyses required for the diagnosis of all types of Porphyrias, and give advice to patients, physicians and other laboratories. We therefore estimated that our data cover 80-90% of all diagnosed Swiss cases. A total of 217 patients from 170 families were diagnosed including, 111 acute intermittent porphyria, 45 erythropoietic protoporphyria, 30 variegate porphyria, 21 sPCT, five congenital erythropoietic porphyria, four hereditary coproporphyria and one hepatoerythropoietic porphyria patient. Systematic monitoring of the patients would allow early detection of the potential life-threatening complications such as hepatocellular carcinoma and renal insufficiency in acute Porphyrias, and liver failure in EPP. Seventy-five percent of all families underwent genetic testing. Identification of pre-symptomatic mutation carriers so that these individuals and their physicians can be consulted with safety on drug use and other preventive measures, is important in managing acute Porphyrias. The unique phenomenon of founder mutations in the Swiss population is also discussed.
Shigeru Sassa - One of the best experts on this subject based on the ideXlab platform.
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Gene-environmental interactions: Lessons from porphyria
Environmental Health and Preventive Medicine, 2003Co-Authors: Shigeru SassaAbstract:The Porphyrias are uncommon, complex, and fascinating metabolic conditions, caused by deficiencies in the activities of the enzymes of the heme biosynthetic pathway. Two cardinal symptoms of the Porphyrias are cutaneous photosensitivity and neurologic disturbances. Molecular analysis of gene defects has shown that there are multiple and heterogeneous mutations in each porphyria. Patients with symptomatic porphyria can suffer greatly, and, in rare cases, may die. While congenital Porphyrias are inherited, other forms of porphyria occur as acquired diseases. In addition, not all gene carriers of inherited Porphyrias develop clinical disease and there is a significant interplay between the gene defect and acquired or environmental factors. The variable response of Porphyrias to acquired factors may, likely reflect genetic polymorphisms in drug metabolism. The lessons from acute hepatic porphyria, such as acute intermittent porphyria, are very useful in clarifying the complex nature of the clinical expression of metabolic disorders.
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Late-onset Porphyrias: what are they?
Cellular and molecular biology (Noisy-le-Grand France), 2002Co-Authors: Shigeru Sassa, Reiko Akagi, Chiaki Nishitani, Hideo Harigae, Kazumichi FuruyamaAbstract:Porphyrias are inherited disorders of heme biosynthesis. ALA dehydratase porphyria (ADP) and congenital erythropoietic porphyria (CEP) are autosomal recessive Porphyrias, and are typically expressed at birth or in childhood. However, a few cases of late-onset recessive Porphyrias have been reported. Recently we encountered a late-onset ADP patient who developed symptoms of acute porphyria when he was 63 years old. This was accompanied by polycythemia vera. It was concluded that he developed the porphyria because an abnormal ALAD allele was clonally expanded by polycythemia vera. Upon reviewing the literature, a few cases of late-onset CEP were found to be also associated with hematologic abnormalities suggestive of myelodysplastic syndrome (MDS), another clonal disorder. These findings suggest that these late-onset Porphyrias may be heterozygous for their gene defects, but clinical expression may be elicited if there is a loss of heterozygosity, either by a clonal expansion of the porphyric allele or by a loss of function mutation in the other allele.
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Hematologic aspects of the Porphyrias.
International journal of hematology, 2000Co-Authors: Shigeru SassaAbstract:The Porphyrias are disorders that can be inherited and acquired, in which the activities of the enzymes of the heme biosynthetic pathway are partially or almost totally deficient. There are 8 enzymes involved in the synthesis of heme, and, with the exception of the first enzyme, an enzymatic defect at every step leads to tissue accumulation and excessive excretion of porphyrins and/or their precursors, such as delta-aminolevulinic acid and porphobilinogen. Whereas heme, the final product of the biosynthetic pathway, is biologically important, porphyrins and their precursors are not only useless but also toxic. Porphyrias can be classified as either photosensitive or neurologic, depending on the type of symptoms, but some Porphyrias cause both photosensitive and neurologic symptoms. Alternatively, they can be classified either hepatic or erythropoietic, depending on the principal site of expression of the specific enzymatic defect. The tissue-specific expression of Porphyrias is largely due to the tissue-specific control of heme pathway gene expression, particularly at the level of delta-aminolevulinate synthase, the first and the rate-limiting enzyme of heme biosynthesis. In this chapter, hematologic aspects of the erythropoietic Porphyrias will be described. The 3 major erythropoietic Porphyrias are congenital erythropoietic porphyria (CEP), hepatoerythropoietic porphyria (HEP) and erythropoietic protoporphyria (EPP).