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Karl E. Anderson - One of the best experts on this subject based on the ideXlab platform.

  • Porphyria cutanea tarda and Hepatoerythropoietic Porphyria identification of 19 novel uroporphyrinogen iii decarboxylase mutations
    Molecular Genetics and Metabolism, 2019
    Co-Authors: Yedidyah Weiss, Karl E. Anderson, Brenden Chen, Makiko Yasuda, Irina Nazarenko, Robert J Desnick
    Abstract:

    Porphyria Cutanea Tarda (PCT) is a cutaneous Porphyria that results from the hepatic inhibition of the heme biosynthetic enzyme uroporphyrinogen decarboxylase (UROD), and can occur either in the absence or presence of an inherited heterozygous UROD mutation (PCT subtypes 1 and 2, respectively). A heterozygous UROD mutation causes half-normal levels of UROD activity systemically, which is a susceptibility factor but is not sufficient alone to cause type 2 PCT. In both Types 1 and 2 PCT, the cutaneous manifestations are precipitated by additional factors that lead to generation of an inhibitor that more profoundly reduces hepatic UROD activity. PCT is an iron-related disorder, and many of its known susceptibility factors, which include infections (e.g. hepatitis C virus, HIV), high alcohol consumption, smoking, estrogens, and genetic traits (e.g. hemochromatosis mutations) can increase hepatic iron accumulation. Hepatoerythropoietic Porphyria (HEP) is a rare autosomal recessive disease that results from homozygosity or compound heterozygosity for UROD mutations and often causes infantile or childhood onset of both erythropoietic and cutaneous manifestations. During the 11-year period from 01/01/2007 through 12/31/2017, the Mount Sinai Porphyrias Diagnostic Laboratory provided molecular diagnostic testing for 387 unrelated patients with PCT and four unrelated patients with HEP. Of the 387 unrelated individuals tested for Type 2 PCT, 79 (20%) were heterozygous for UROD mutations. Among 26 family members of mutation-positive PCT patients, eight (31%) had the respective family mutation. Additionally, of the four unrelated HEP patients referred for UROD mutation analyses, all had homozygosity or compound heterozygosity for UROD mutations, and all eight asymptomatic family members were heterozygotes for UROD mutations. Of the UROD mutations identified, 19 were novel, including nine missense, two nonsense, one consensus splice-site, and seven insertions and deletions. These results expand the molecular heterogeneity of PCT and HEP by adding a total of 19 novel UROD mutations. Moreover, the results document the usefulness of molecular testing to confirm a genetic susceptibility trait in Type 2 PCT, confirm a diagnosis in HEP, and identify heterozygous family members.

  • Porphyria diagnostics part 1 a brief overview of the Porphyrias
    Current protocols in human genetics, 2015
    Co-Authors: Vaithamanithimudumbai Sadagopa Ramanujam, Karl E. Anderson
    Abstract:

    Porphyria diseases are a group of metabolic disorders caused by abnormal functioning of heme biosynthesis enzymes and characterized by excessive accumulation and excretion of porphyrins and their precursors. Precisely which of these chemicals builds up depends on the type of Porphyria. Porphyria is not a single disease but a group of nine disorders: acute intermittent Porphyria (AIP), hereditary coproPorphyria (HCP), variegate Porphyria (VP), δ-aminolevulinic acid dehydratase deficiency Porphyria (ADP), Porphyria cutanea tarda (PCT), Hepatoerythropoietic Porphyria (HEP), congenital erythropoietic Porphyria (CEP), erythropoietic protoPorphyria (EPP), and X-linked protoPorphyria (XLP). Each Porphyria results from overproduction of heme precursors secondary to partial deficiency or, in XLP, increased activity of one of the enzymes of heme biosynthesis. Taken together, all forms of Porphyria afflict fewer than 200,000 people in the United States. Based on European studies, the most common Porphyria, PCT, has a prevalence of 1 in 10,000, the most common acute Porphyria, AlP, has a prevalence of ∼1 in 20,000, and the most common erythropoietic Porphyria, EPP, is estimated at 1 in 50,000 to 75,000. CEP is extremely rare, with prevalence estimates of 1 in 1,000,000 or less. Only six cases of ADP are documented. The current Porphyria literature is very exhaustive and a brief overview of Porphyria diseases is essential in order for the reader to better appreciate the relevance of this area of research prior to undertaking biochemical diagnostics procedures. This unit summarizes the current knowledge on the classification, clinical features, etiology, pathogenesis, and genetics of Porphyria diseases.

  • Current Protocols in Human Genetics - Porphyria Diagnostics—Part 1: A Brief Overview of the Porphyrias
    Current Protocols in Human Genetics, 2015
    Co-Authors: Vaithamanithi‐mudumbai Sadagopa Ramanujam, Karl E. Anderson
    Abstract:

    Porphyria diseases are a group of metabolic disorders caused by abnormal functioning of heme biosynthesis enzymes and characterized by excessive accumulation and excretion of porphyrins and their precursors. Precisely which of these chemicals builds up depends on the type of Porphyria. Porphyria is not a single disease but a group of nine disorders: acute intermittent Porphyria (AIP), hereditary coproPorphyria (HCP), variegate Porphyria (VP), δ-aminolevulinic acid dehydratase deficiency Porphyria (ADP), Porphyria cutanea tarda (PCT), Hepatoerythropoietic Porphyria (HEP), congenital erythropoietic Porphyria (CEP), erythropoietic protoPorphyria (EPP), and X-linked protoPorphyria (XLP). Each Porphyria results from overproduction of heme precursors secondary to partial deficiency or, in XLP, increased activity of one of the enzymes of heme biosynthesis. Taken together, all forms of Porphyria afflict fewer than 200,000 people in the United States. Based on European studies, the most common Porphyria, PCT, has a prevalence of 1 in 10,000, the most common acute Porphyria, AlP, has a prevalence of ∼1 in 20,000, and the most common erythropoietic Porphyria, EPP, is estimated at 1 in 50,000 to 75,000. CEP is extremely rare, with prevalence estimates of 1 in 1,000,000 or less. Only six cases of ADP are documented. The current Porphyria literature is very exhaustive and a brief overview of Porphyria diseases is essential in order for the reader to better appreciate the relevance of this area of research prior to undertaking biochemical diagnostics procedures. This unit summarizes the current knowledge on the classification, clinical features, etiology, pathogenesis, and genetics of Porphyria diseases.

Elisabeth I Minder - One of the best experts on this subject based on the ideXlab platform.

  • Porphyria in Switzerland, 15 years experience.
    Swiss medical weekly, 2009
    Co-Authors: Xiaoye Schneider-yin, Juergen Harms, Elisabeth I Minder
    Abstract:

    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.

  • Porphyria in Switzerland, 15 years experience.
    Swiss Medical Weekly, 2009
    Co-Authors: Xiaoye Schneider-yin, Juergen Harms, Elisabeth I Minder
    Abstract:

    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.

G.h. Elder - One of the best experts on this subject based on the ideXlab platform.

  • Hepatoerythropoietic Porphyria a missense mutation in the urod gene is associated with mild disease and an unusual porphyrin excretion pattern
    British Journal of Dermatology, 2004
    Co-Authors: D K B Armstrong, Andrew G. Roberts, P C Sharpe, C R Chambers, Sharon D Whatley, G.h. Elder
    Abstract:

    Hepatoerythropoietic Porphyria (HEP) is an uncommon inherited cutaneous Porphyria, related to Porphyria cutanea tarda, that results from severe uroporphyrinogen decarboxylase (UROD) deficiency. It is characterized clinically by the onset in early childhood of severe lesions on sun-exposed skin. We describe a man aged 38 years with an unusually mild form of the disease that started in his early teens. Our data confirm that homozygosity for the F46L mutation in the UROD gene causes a mild form of HEP and show that this genotype may be associated with a unique urinary porphyrin excretion pattern in which pentacarboxylic porphyrin predominates.

  • Hepatic Porphyrias in children
    Journal of Inherited Metabolic Disease, 1997
    Co-Authors: G.h. Elder
    Abstract:

    Clinically overt hepatic Porphyria is uncommon in children. The autosomal dominant acute hepatic Porphyrias, acute intermittent Porphyria (AIP), variegate Porphyria (VP) and hereditary coproPorphyria (HCP), are rarely present before puberty. Identification of asymptomatic children who have inherited these disorders is an important aspect of the management of the disease in their families and requires either enzymatic or DNA methods. Homozygous variants of AIP, VP and HCP usually present in early childhood and have phenotypes of variable severity. Mutational analysis is currently elucidating the relationship between these disorders and their autosomal dominant counterparts. 5-Aminolaevulinate dehydratase deficiency Porphyria is a rare, autosomal recessive acute Porphyria that may present at any age. Two cutaneous hepatic Porphyrias are seen in children. Porphyria cutanea tarda (PCT), although mainly an adult disease, has been reported in young children with the autosomal dominant (type II) form of the disorder. Hepatoerythropoietic Porphyria usually develops before the age of 2 years; patients are homo- or heteroallelic for uroporphyrinogen decarboxylase mutations, at least one of which is known to cause type II PCT.

  • Uroporphyrinogen decarboxylase
    Journal of Bioenergetics and Biomembranes, 1995
    Co-Authors: G.h. Elder, A. G. Roberts
    Abstract:

    Uroporphyrinogen decarboxylase (EC 4.1.1.37) catalyzes the decarboxylation of uroporphyrinogen III to coproporphyrinogen III. The amino acid sequences, kinetic properties, and physicochemical characteristics of enzymes from different sources (mammals, yeast, bacteria) are similar, but little is known about the structure/function relationships of uroporphyrinogen decarboxylases. Halogenated and other aromatic hydrocarbons cause hepatic uroPorphyria by decreasing hepatic uroporphyrinogen decarboxylase activity. Two related human Porphyrias, Porphyria cutanea tarda and Hepatoerythropoietic Porphyria, also result from deficiency of this enzyme. The roles of inherited and acquired factors, including iron, in the pathogenesis of human and experimental uroPorphyrias are reviewed.

Shigeru Sassa - One of the best experts on this subject based on the ideXlab platform.

  • Hematologic aspects of the Porphyrias.
    International journal of hematology, 2000
    Co-Authors: Shigeru Sassa
    Abstract:

    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).

  • A zebrafish model for Hepatoerythropoietic Porphyria
    Nature Genetics, 1998
    Co-Authors: Han Wang, Qiaoming Long, Scott D. Marty, Shigeru Sassa
    Abstract:

    Defects in the enzymes involved in the haem biosynthetic pathway can lead to a group of human diseases known as the Porphyrias. yquem ( yqe ^ tp61 ) is a zebrafish mutant with a photosensitive Porphyria syndrome. Here we show that the porphyric phenotype is due to an inherited homozygous mutation in the gene encoding uroporphyrinogen decarboxylase (UROD); a homozygous deficiency of this enzyme causes Hepatoerythropoietic Porphyria (HEP) in humans. The zebrafish mutant represents the first genetically 'accurate' animal model of HEP, and should be useful for studying the pathogenesis of UROD deficiency and evaluating gene therapy vectors. We rescued the mutant phenotype by transient and germline expression of the wild-type allele.

Hubert Verneuil - One of the best experts on this subject based on the ideXlab platform.

  • erythropoietic Porphyrias animal models and update in gene based therapies
    Current Gene Therapy, 2008
    Co-Authors: Emmanuel Richard, Cecile Ged, Francois Moreaugaudry, Elodie Robertrichard, Hubert Verneuil
    Abstract:

    The inherited Porphyrias are inborn errors of haem biosynthesis, each resulting from the deficient activity of a specific enzyme of the haem biosynthetic pathway. Porphyrias are divided into erythropoietic and hepatic according to the predominant porphyrin-accumulating tissue. Three different erythropoietic Porphyrias (EP) have been described: erythropoietic protoPorphyria (EPP, MIM 177000) the most frequent, congenital erythropoietic Porphyria (CEP, MIM 263700), and the very rare Hepatoerythropoietic Porphyria (HEP, MIM 176100). Bone marrow transplantation is considered as the only curative treatment for severe cases of erythropoietic Porphyria (especially CEP), if donors are available. Some EPP patients who undergo liver failure may require hepatic transplantation. Murine models of EPP and CEP have been developed and mimic most of the human disease features. These models allow a better understanding of the pathophysiological mechanisms involved in EP as well as the development of new therapeutic strategies. The restoration of deficient enzymatic activity in the bone marrow compartment following gene therapy has been extensively studied. Murine oncoretroviral, and recently, lentiviral vectors have been successfully used to transduce hematopoietic stem cells, allowing full metabolic and phenotypic correction of both EPP and CEP mice. In CEP, a selective survival advantage of corrected cells was demonstrated in mice, reinforcing the arguments for a gene therapy approach in the human disease. These successful results form the basis for gene therapy clinical trials in severe forms of erythropoietic Porphyrias.

  • correction of uroporphyrinogen decarboxylase deficiency Hepatoerythropoietic Porphyria in epstein barr virus transformed b cell lines by retrovirus mediated gene transfer fluorescence based selection of transduced cells
    Blood, 1999
    Co-Authors: Antonio Fontanellas, Cecile Ged, Frederic Mazurier, Francois Moreaugaudry, Francis Belloc, Hubert Verneuil
    Abstract:

    Hepatoerythropoietic Porphyria (HEP) is an inherited metabolic disorder characterized by the accumulation of porphyrins resulting from a deficiency in uroporphyrinogen decarboxylase (UROD). This autosomal recessive disorder is severe, starting early in infancy with no specific treatment. Gene therapy would represent a great therapeutic improvement. Because hematopoietic cells are the target for somatic gene therapy in this Porphyria, Epstein-Barr virus-transformed B-cell lines from patients with HEP provide a model system for the disease. Thus, retrovirus-mediated expression of UROD was used to restore enzymatic activity in B-cell lines from 3 HEP patients. The potential of gene therapy for the metabolic correction of the disease was demonstrated by a reduction of porphyrin accumulation to the normal level in deficient transduced cells. Mixed culture experiments demonstrated that there is no metabolic cross-correction of deficient cells by normal cells. However, the observation of cellular expansion in vitro and in vivo in immunodeficient mice suggested that genetically corrected cells have a competitive advantage. Finally, to facilitate future human gene therapy trials, we have developed a selection system based on the expression of the therapeutic gene. Genetically corrected cells are easily separated from deficient ones by the absence of fluorescence when illuminated under UV light.

  • Characterization of a new mutation (R292G) and a deletion at the human uroporphyrinogen decarboxylase locus in two patients with Hepatoerythropoietic Porphyria.
    Human Genetics, 1992
    Co-Authors: Hubert Verneuil, Bernard Grandchamp, Francine Bourgeois, Felix W. M. De Rooij, Peter D. Siersema, J. H. P. Wilson, Yves Nordmann
    Abstract:

    A deficiency in the activity of uroporphyrinogen decarboxylase (UROD), the fifth enzyme of the haem biosynthetic pathway, is found in familial Porphyria cutanea tarda (F-PCT) and Hepatoerythropoietic Porphyria (HEP). A new mutation (R292G) and a deletion have been found in a pedigree with two HEP patients (two sisters). The R292G mutation was not detected in 13 unrelated affected patients with F-PCT, so it appears to be uncommon. The possibility that the arginine 292 may participate at the active site of the enzyme is discussed. A summary of the 7 mutations/deletions found in the UROD gene with their frequency is presented.