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Sverre Sandberg - One of the best experts on this subject based on the ideXlab platform.
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european specialist Porphyria laboratories diagnostic strategies analytical quality clinical interpretation and reporting as assessed by an external quality assurance program
Clinical Chemistry, 2011Co-Authors: Aasne K Aarsand, Michael Norman Badminton, Jorild Haugen Villanger, Egil Stole, Jeancharles Deybach, Joanne T Marsden, Jordi Tofigueras, G H Elder, Sverre SandbergAbstract:BACKGROUND: The Porphyrias are a group of rare metabolic disorders whose diagnosis depends on identification of specific patterns of porphyrin precursor and porphyrin accumulation in urine, blood, and feces. Diagnostic tests for Porphyria are performed by specialized laboratories in many countries. Data regarding the analytical and diagnostic performance of these laboratories are scarce. METHODS: We distributed 5 sets of multispecimen samples from different Porphyria patients accompanied by clinical case histories to 18–21 European specialist Porphyria laboratories/centers as part of a European Porphyria Network organized external analytical and postanalytical quality assessment (EQA) program. The laboratories stated which analyses they would normally have performed given the case histories and reported results of all Porphyria-related analyses available, interpretative comments, and diagnoses. RESULTS: Reported diagnostic strategies initially showed considerable diversity, but the number of laboratories applying adequate diagnostic strategies increased during the study period. We found an average interlaboratory CV of 50% (range 12%–152%) for analytes in absolute concentrations. Result normalization by forming ratios to the upper reference limits did not reduce this variation. Sixty-five percent of reported results were within biological variation–based analytical quality specifications. Clinical interpretation of the obtained analytical results was accurate, and most laboratories established the correct diagnosis in all distributions. CONCLUSIONS: Based on a case-based EQA scheme, variations were apparent in analytical and diagnostic performance between European specialist Porphyria laboratories. Our findings reinforce the use of EQA schemes as an essential tool to assess both analytical and diagnostic processes and thereby to improve patient care in rare diseases.
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Excess risk of adverse pregnancy outcomes in women with Porphyria: a population-based cohort study
Journal of Inherited Metabolic Disease, 2011Co-Authors: Mette Christophersen Tollånes, Aasne Karine Aarsand, Sverre SandbergAbstract:The Porphyrias comprise a heterogeneous group of rare, primarily hereditary, metabolic diseases caused by a partial deficiency in one of the eight enzymes involved in the heme biosynthesis. Our aim was to assess whether acute or cutaneous Porphyria has been associated with excess risks of adverse pregnancy outcomes. A population-based cohort study was designed by record linkage between the Norwegian Porphyria Register, covering 70% of all known Porphyria patients in Norway, and the Medical Birth Registry of Norway, based on all births in Norway during 1967–2006. The risks of the adverse pregnancy outcomes preeclampsia, delivery by caesarean section, low birth weight, premature delivery, small for gestational age (SGA), perinatal death, and congenital malformations were compared between porphyric mothers and the rest of the population. The 200 mothers with Porphyria had 398 singletons during the study period, whereas the 1,100,391 mothers without Porphyria had 2,275,317 singletons. First-time mothers with active acute Porphyria had an excess risk of perinatal death [adjusted odds ratio (OR) 4.9, 95% confidence interval (CI) 1.5–16.0], as did mothers with the hereditable form of Porphyria cutanea tarda (PCT) (3.0, 1.2–7.7). Sporadic PCT was associated with an excess risk of SGA [adjusted relative risk (RR) 2.0, 1.2–3.4], and for first-time mothers, low birth weight (adjusted OR 3.4, 1.2–10.0) and premature delivery (3.5, 1.2–10.5) in addition. The findings suggest women with Porphyria should be monitored closely during pregnancy.
Staffan Wahlin - One of the best experts on this subject based on the ideXlab platform.
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Treatment options in acute Porphyria, Porphyria cutanea tarda, and erythropoietic protoPorphyria
Current Treatment Options in Gastroenterology, 2007Co-Authors: Pauline Harper, Staffan WahlinAbstract:The Porphyrias are a group of uncommon metabolic diseases caused by enzyme deficiencies within heme biosynthesis that lead to neurotoxic or phototoxic heme precursor accumulation. There are four acute Porphyrias characterized by neuropsy-chiatric symptoms: acute intermittent Porphyria, variegate Porphyria, hereditary coproPorphyria, and 5-aminolevulinic acid dehydratase deficiency Porphyria. Treatment includes elimination of any porphyrogenic factor and symptomatic treatment. Carbohydrate and intravenous heme administration constitute specific therapies in the disorders’ acute phase. The mainstay treatment in the cutaneous Porphyrias is avoidance of sunlight exposure. In Porphyria cutanea tarda and the two acute Porphyrias with skin manifestations, variegate Porphyria and hereditary coproPorphyria, care of the vulnerable skin is important. In Porphyria cutanea tarda, specific treatment is accomplished by a series of phlebotomies and/or by low-dose chloroquine administration. In erythropoietic protoPorphyria, light-protective beta-carotene is prescribed.
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Treatment Options in Acute Porphyria, Treatment Options in Acute Porphyria, Porphyria Cutanea Tarda, Porphyria Cutanea Tarda, and Erythropoietic ProtoPorphyria and Erythropoietic ProtoPorphyria
2007Co-Authors: Pauline Harper, Staffan WahlinAbstract:Porphyrias are inherited metabolic diseases secondary to deficiencies in the activity of specific enzymes in the heme biosynthetic pathway. With the exception of the initial enzyme, catalytic deficiency at any of the seven subsequent steps in the heme biosynthetic chain may result in accumulation of toxic heme precursors [1].Clinically, the Porphyrias are divided into two main groups: the acute Porphyrias, which present with neuropsychiatric symptoms, and the cutaneous Porphyrias, which are characterized by dermal photo-sensitivity. Two of the acute forms of Porphyria also present with photosensitivity.The autosomal dominant Porphyrias are acute intermittent Porphyria (AIP), familial Porphyria cutanea tarda (PCT), hereditary coproPorphyria (HCP), variegate Porphyria (VP), and erythropoietic protoPorphyria (EPP). Two rare forms are inherited in a recessive fashion: 5-aminolevulinic acid dehydra-tase–deficient Porphyria and congenital erythropoietic Porphyria. Two mutations for PCT cause hepatoeryth-ropoietic Porphyria.Most Porphyrias have low clinical penetrance, and symptoms are often triggered by specific endogenous or environmental porphyrogenic factors. Residual enzyme activity usually is enough to satisfy the physiologic heme demands [2••]. However, the recessive condi-tions exhibit very low residual enzyme activity and high clinical penetrance, often with manifestations from early childhood [2••]. The same is true for the extremely rare homozygous or compound heterozygous conditions of AIP, HCP, and VP.Porphyria symptoms result from the action of neu-rotoxic or phototoxic metabolites produced in the liver or bone marrow. Liver transplantation [3,4,5••] and/or bone marrow transplantation (BMT) [6,7] may be the final therapeutic alternatives.
James P Kushner - One of the best experts on this subject based on the ideXlab platform.
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cytochrome p450 induction uroporphyrinogen decarboxylase depression porphyrin accumulation and excretion and gender influence in a 3 week rat model of Porphyria cutanea tarda
Toxicology and Applied Pharmacology, 1997Co-Authors: Michael R Franklin, John D Phillips, James P KushnerAbstract:An experimental model of Porphyria cutanea tarda, consisting of depressed hepatic uroporphyrinogen decarboxylase (URO-D) activity and accumulation of highly carboxylated porphyrins in the liver, was produced in 3 weeks in Fischer 344 rats. A single administration of a polychlorinated biphenyl mixture (Aroclor 1254) to iron-loaded female rats maintained continuously on δ-aminolevulinic acid supplemented drinking water produced the porphyric state. Without iron loading, URO-D activity appeared slightly less inhibited (33% of normal vs 23% of normal) but porphyrin accumulation was dramatically less (70 vs 605 μg porphyrin/g liver). Similar treatment in male rats produced URO-D activities of 54 and 70% of normal with and without iron loading, respectively, and porphyrin concentrations of 76 and 17 μg/g. When hexachlorobenzene was substituted for Aroclor 1254 treatment in female rats, URO-D activity was 61 and 69% of normal (with and without iron loading, respectively) and liver porphyrin concentrations were 96 and 25 μg/g, respectively. Hexachlorobenzene did not produce significant porphyric effects in male rats. Aroclor 1254 induced CYP1A to a greater extent in females than in males and to a greater extent than hexachlorobenzene, which showed a greater propensity to induce CYP2B. Overall correlation between URO-D activity depression and porphyrin accumulation was highest when fitted to an exponential curve, indicating the importance of the extreme of the depression URO-D activity in evoking experimental Porphyria cutanea tarda.
Pauline Harper - One of the best experts on this subject based on the ideXlab platform.
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Treatment options in acute Porphyria, Porphyria cutanea tarda, and erythropoietic protoPorphyria
Current Treatment Options in Gastroenterology, 2007Co-Authors: Pauline Harper, Staffan WahlinAbstract:The Porphyrias are a group of uncommon metabolic diseases caused by enzyme deficiencies within heme biosynthesis that lead to neurotoxic or phototoxic heme precursor accumulation. There are four acute Porphyrias characterized by neuropsy-chiatric symptoms: acute intermittent Porphyria, variegate Porphyria, hereditary coproPorphyria, and 5-aminolevulinic acid dehydratase deficiency Porphyria. Treatment includes elimination of any porphyrogenic factor and symptomatic treatment. Carbohydrate and intravenous heme administration constitute specific therapies in the disorders’ acute phase. The mainstay treatment in the cutaneous Porphyrias is avoidance of sunlight exposure. In Porphyria cutanea tarda and the two acute Porphyrias with skin manifestations, variegate Porphyria and hereditary coproPorphyria, care of the vulnerable skin is important. In Porphyria cutanea tarda, specific treatment is accomplished by a series of phlebotomies and/or by low-dose chloroquine administration. In erythropoietic protoPorphyria, light-protective beta-carotene is prescribed.
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Treatment Options in Acute Porphyria, Treatment Options in Acute Porphyria, Porphyria Cutanea Tarda, Porphyria Cutanea Tarda, and Erythropoietic ProtoPorphyria and Erythropoietic ProtoPorphyria
2007Co-Authors: Pauline Harper, Staffan WahlinAbstract:Porphyrias are inherited metabolic diseases secondary to deficiencies in the activity of specific enzymes in the heme biosynthetic pathway. With the exception of the initial enzyme, catalytic deficiency at any of the seven subsequent steps in the heme biosynthetic chain may result in accumulation of toxic heme precursors [1].Clinically, the Porphyrias are divided into two main groups: the acute Porphyrias, which present with neuropsychiatric symptoms, and the cutaneous Porphyrias, which are characterized by dermal photo-sensitivity. Two of the acute forms of Porphyria also present with photosensitivity.The autosomal dominant Porphyrias are acute intermittent Porphyria (AIP), familial Porphyria cutanea tarda (PCT), hereditary coproPorphyria (HCP), variegate Porphyria (VP), and erythropoietic protoPorphyria (EPP). Two rare forms are inherited in a recessive fashion: 5-aminolevulinic acid dehydra-tase–deficient Porphyria and congenital erythropoietic Porphyria. Two mutations for PCT cause hepatoeryth-ropoietic Porphyria.Most Porphyrias have low clinical penetrance, and symptoms are often triggered by specific endogenous or environmental porphyrogenic factors. Residual enzyme activity usually is enough to satisfy the physiologic heme demands [2••]. However, the recessive condi-tions exhibit very low residual enzyme activity and high clinical penetrance, often with manifestations from early childhood [2••]. The same is true for the extremely rare homozygous or compound heterozygous conditions of AIP, HCP, and VP.Porphyria symptoms result from the action of neu-rotoxic or phototoxic metabolites produced in the liver or bone marrow. Liver transplantation [3,4,5••] and/or bone marrow transplantation (BMT) [6,7] may be the final therapeutic alternatives.
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Porphyria in Sweden.
Physiological Research, 2006Co-Authors: Thunell S, Floderus Y, Henrichson A, Pauline HarperAbstract:In a brief survey the work of Swedish porphyrinologists through time is presented, from the organic chemist Jakob Berzelius 1840 to the molecular biologists of today. The building up in Stockholm of a Swedish national competence centre for Porphyria is touched upon and the emergence of a computerized national register on the Porphyria gene carriers in the country described. Figures for the prevalences of the seven different forms of Porphyria diagnosed in Sweden are given. The geographical distribution of gene mutation spectra is shown for the most frequent form, acute intermittent Porphyria. The organisation at Porphyria Centre Sweden of its diagnostic and consultative services is described, as is the decentralized model for Porphyria care applied in the form of a clinical network covering the long and sparsely populated country. The ideas and activities of the Swedish Porphyria Patients' Association are presented. Its focus on protection-by-information of the Porphyria gene carrier against maltreatment in health service contacts, and against other exposures to environmental threats to his or her health, is discussed. The combined efforts of the national Porphyria centre and the patients' association have resulted in early and accurate diagnosis of most of the Porphyria gene carriers in the country. The information to the carriers and to the health service regarding the mechanisms of the diseases and the importance of avoiding exposure to disease triggering environmental factors have greatly reduced porphyric morbidity. In the case of the acute Porphyrias, by this programme and after the introduction of heme arginate in the therapy, mortality in the acute phase has become extremely rare in Sweden. In contrast, probably due to greater awareness of the high risk for liver cancer in acute Porphyrias the number of hepatoma cases diagnosed has increased. The current research activities at the Porphyria Centre which aim at finding ways to substitute the mutated gene in acute intermittent Porphyria for an undamaged one, or to substitute the enzyme deficiency by administration of exogenously produced enzyme, are mentioned, as is the work to establish a reliable drug porphyrinogenicity prediction model for evidence based drug counselling.
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Large phlebotomy in variegate Porphyria
Journal of Internal Medicine, 1997Co-Authors: Pauline Harper, T. Hybinette, S. ThunellAbstract:Harper P, Hybinette T, Thunell S (Porphyria Centre Sweden, Karolinska Institute, Stockholm and the Department of Internal Medicine, Regional Hospital Kalmar, Sweden). Large phlebotomy in variegate Porphyria (Case report). J Intern Med 1997; 242: 255–9. There are no reports on effects of large blood losses in acute hepatic Porphyria. In the present study we report the experiences of repeated large therapeutic phlebotomies in a patient with Porphyria cutanea tarda coexisting with variegate Porphyria. Neither a series of 12 phlebotomies, 300 mL each, resulting in a 17% decrease in blood haemoglobin, nor a single 400 mL phlebotomy activated the acute porphyric condition. It is concluded that the increased bone marrow metabolic throughput resulting from blood loss, in acute types of Porphyria does not overload the normoblast or leukocyte precursor haem synthetic pathways in a way which will increase porphyrin precursor excretion or trigger acute porphyric symptoms.
John D Phillips - One of the best experts on this subject based on the ideXlab platform.
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Heme biosynthesis and the Porphyrias.
Molecular Genetics and Metabolism, 2019Co-Authors: John D PhillipsAbstract:Abstract Porphyrias, is a general term for a group of metabolic diseases that are genetic in nature. In each specific Porphyria the activity of specific enzymes in the heme biosynthetic pathway is defective and leads to accumulation of pathway intermediates. Phenotypically, each disease leads to either neurologic and/or photocutaneous symptoms based on the metabolic intermediate that accumulates. In each Porphyria the distinct patterns of these substances in plasma, erythrocytes, urine and feces are the basis for diagnostically defining the metabolic defect underlying the clinical observations. Porphyrias may also be classified as either erythropoietic or hepatic, depending on the principal site of accumulation of pathway intermediates. The erythropoietic Porphyrias are congenital erythropoietic Porphyria (CEP), and erythropoietic protoPorphyria (EPP). The acute hepatic Porphyrias include ALA dehydratase deficiency Porphyria, acute intermittent Porphyria (AIP), hereditary coproPorphyria (HCP) and variegate Porphyria (VP). Porphyria cutanea tarda (PCT) is the only Porphyria that has both genetic and/or environmental factors that lead to reduced activity of uroporphyrinogen decarboxylase in the liver. Each of the 8 enzymes in the heme biosynthetic pathway have been associated with a specific Porphyria ( Table 1 ). Mutations affecting the erythroid form of ALA synthase (ALAS2) are most commonly associated with X-linked sideroblastic anemia, however, gain-of-function mutations of ALAS2 have also been associated with a variant form of EPP. This overview does not describe the full clinical spectrum of the Porphyrias, but is meant to be an overview of the biochemical steps that are required to make heme in both erythroid and non-erythroid cells.
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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, 2014Co-Authors: Makiko Yasuda, John D Phillips, Brenden Chen, Lin Gan, Senkottuvelan Kadirvel, Maria I New, Abigail Liebow, Kevin Fitzgerald, William Querbes, Robert J DesnickAbstract:The acute hepatic Porphyrias are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks. Factors that induce the expression of hepatic 5-aminolevulinic acid synthase 1 (ALAS1) result in the accumulation of the neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which recent studies indicate are primarily responsible for the acute attacks. Current treatment of these attacks involves i.v. administration of hemin, but a faster-acting, more effective, and safer therapy is needed. Here, we describe preclinical studies of liver-directed small interfering RNAs (siRNAs) targeting Alas1 (Alas1-siRNAs) in a mouse model of acute intermittent Porphyria, the most common acute hepatic Porphyria. A single i.v. dose of Alas1-siRNA prevented the phenobarbital-induced biochemical acute attacks for approximately 2 wk. Injection of Alas1-siRNA during an induced acute attack significantly decreased plasma ALA and PBG levels within 8 h, more rapidly and effectively than a single hemin infusion. Alas1-siRNA was well tolerated and a therapeutic dose did not cause hepatic heme deficiency. These studies provide proof-of-concept for the clinical development of RNA interference therapy for the prevention and treatment of the acute attacks of the acute hepatic Porphyrias.
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cytochrome p450 induction uroporphyrinogen decarboxylase depression porphyrin accumulation and excretion and gender influence in a 3 week rat model of Porphyria cutanea tarda
Toxicology and Applied Pharmacology, 1997Co-Authors: Michael R Franklin, John D Phillips, James P KushnerAbstract:An experimental model of Porphyria cutanea tarda, consisting of depressed hepatic uroporphyrinogen decarboxylase (URO-D) activity and accumulation of highly carboxylated porphyrins in the liver, was produced in 3 weeks in Fischer 344 rats. A single administration of a polychlorinated biphenyl mixture (Aroclor 1254) to iron-loaded female rats maintained continuously on δ-aminolevulinic acid supplemented drinking water produced the porphyric state. Without iron loading, URO-D activity appeared slightly less inhibited (33% of normal vs 23% of normal) but porphyrin accumulation was dramatically less (70 vs 605 μg porphyrin/g liver). Similar treatment in male rats produced URO-D activities of 54 and 70% of normal with and without iron loading, respectively, and porphyrin concentrations of 76 and 17 μg/g. When hexachlorobenzene was substituted for Aroclor 1254 treatment in female rats, URO-D activity was 61 and 69% of normal (with and without iron loading, respectively) and liver porphyrin concentrations were 96 and 25 μg/g, respectively. Hexachlorobenzene did not produce significant porphyric effects in male rats. Aroclor 1254 induced CYP1A to a greater extent in females than in males and to a greater extent than hexachlorobenzene, which showed a greater propensity to induce CYP2B. Overall correlation between URO-D activity depression and porphyrin accumulation was highest when fitted to an exponential curve, indicating the importance of the extreme of the depression URO-D activity in evoking experimental Porphyria cutanea tarda.
