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1.
Mol Genet Metab ; 128(3): 164-177, 2019 11.
Article in English | MEDLINE | ID: mdl-31326287

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.


Subject(s)
Heme/biosynthesis , Porphyrias/genetics , Animals , Biosynthetic Pathways , Environment , Humans , Liver/physiopathology , Mice , Mutation , Porphobilinogen Synthase/deficiency , Porphyria, Acute Intermittent , Porphyrias/classification , Porphyrias/congenital , Porphyrias, Hepatic , Uroporphyrinogen Decarboxylase/metabolism
2.
J Coll Physicians Surg Pak ; 29(6): S23-S25, 2019 Jun.
Article in English | MEDLINE | ID: mdl-31142411

ABSTRACT

Congenital erythropoietic porphyria, also called Gunther's disease, is a very rare genetic autosomal recessive diseaseaffecting less than 1 per 1,000,000 children. Pathogenesis involves genetic mutation encoding uroporphyrinogen-III cosynthase which leads to accumulation of porphyrin in many tissues, leading to extreme skin photosensitivity, red cell lysis, splenomegaly and reduced life expectancy. Herein, we report a 12-year mentally challenged girl with multiple blisters and scars on sun exposed sites since birth. She had hepatomegaly, erythrodontia, severe anaemia with haemolytic blood picture and mildly elevated liver enzymes. Skin biopsy showed deposition of amorphous eosinophilic porphyrins in the dermis, thus confirming a diagnosis of congenital erythropoietic porphyria.


Subject(s)
Anemia, Hemolytic/diagnosis , Intellectual Disability , Photosensitivity Disorders/diagnosis , Porphyria, Erythropoietic/diagnosis , Porphyrias/congenital , Biopsy , Child , Female , Hepatomegaly , Humans , Photosensitivity Disorders/metabolism , Photosensitivity Disorders/pathology , Porphyria, Erythropoietic/complications , Porphyria, Erythropoietic/metabolism , Porphyrias/metabolism , Porphyrias/pathology
5.
Dermatol. rev. mex ; 37(6): 510-2, nov.-dic. 1993. ilus
Article in Spanish | LILACS | ID: lil-135190

ABSTRACT

Se informa el caso de porfiria eritropoyética congénita en una niña; las alteraciones se presentaron en piel, dientes y orina; presentó además como problema asociado sordera. En los exámenes realizados hubo aumento de coproporfirinas y uroporfirinas en orina así como la presencia de porfirinas en haces


Subject(s)
Humans , Female , Child, Preschool , Photosensitivity Disorders/diagnosis , Porphyrias/diagnosis , Clinical Laboratory Techniques/statistics & numerical data , Photosensitivity Disorders/physiopathology , Porphyrias/congenital , Porphyrias/physiopathology
6.
Arch Dermatol ; 128(9): 1243-8, 1992 Sep.
Article in English | MEDLINE | ID: mdl-1519940

ABSTRACT

BACKGROUND AND DESIGN: Congenital erythropoietic porphyria, an inborn error of heme biosynthesis, results from the deficient activity of the enzyme uroporphyrinogen III synthase. The clinical manifestations in unrelated patients with this autosomal recessive disorder are remarkedly variable, ranging from mild cutaneous involvement to severe transfusion-dependent hemolytic anemia. Biochemical and molecular studies were undertaken to investigate the nature of the unusually mild phenotype in a 15-year-old boy with only cutaneous manifestations. RESULTS: The proband's levels of total porphyrins, urinary uroporphyrin I, and erythrocyte coproporphyrin I were elevated, but not as dramatically as in other patients with this porphyria. Interestingly, the erythrocyte uroporphyrinogen III synthase activity in the proband was about 21% of the normal mean, indicating the presence of significant residual activity. In cultured lymphoblasts from the proband, his father, and mother, the enzymatic activities were 10%, 70%, and 50% of the normal mean, respectively. Molecular analyses revealed that the proband was heteroallelic for two uroporphyrinogen III synthase missense mutations: the C73R allele inherited from his mother and the A66V allele transmitted by his father. The A66V allele encoded residual enzymatic activity in vitro while the C73R allele did not. CONCLUSIONS: The A66V allele accounted for the proband's low levels of porphyrin accumulation and mild clinical manifestations. Such genotype-phenotype correlations should provide understanding of the remarkable clinical variability in other patients with this inherited porphyria.


Subject(s)
Porphyrias/congenital , Porphyrias/genetics , Skin Diseases/congenital , Skin Diseases/genetics , Uroporphyrinogen III Synthetase/genetics , Uroporphyrins/biosynthesis , Adolescent , Arginine/genetics , Erythropoiesis , Humans , Male , Mutation , Pedigree , Porphyrias/diagnosis , Porphyrias/enzymology , Skin Diseases/diagnosis , Skin Diseases/enzymology , Valine/genetics
8.
J Clin Invest ; 89(2): 693-700, 1992 Feb.
Article in English | MEDLINE | ID: mdl-1737856

ABSTRACT

Congenital erythropoietic porphyria (CEP), an inborn error of heme biosynthesis, results from the deficient activity of uroporphyrinogen III synthase (URO-synthase). This autosomal recessive disorder is heterogeneous; patients with severe disease are often transfusion dependent, while milder patients primarily have cutaneous involvement. To investigate this phenotypic heterogeneity, exonic point mutations in the URO-synthase gene were identified in unrelated CEP patients. Four missense mutations were identified: (a) an A to G transition of nucleotide (nt) 184 that predicted a Thr to Ala substitution at residue 62 (designated T62A); (b) a C to T transition of nt 197 that encoded an Ala to Val replacement at residue 66 (A66V); (c) a T to C transition of nt 217 that predicted a Cys to Arg substitution at residue 73 (C73R); and (d) a C to T transition of nt 683 that resulted in a Thr to Met replacement at residue 228 (T228M). In addition, a G to A transition of nt 27 that did not change the encoded amino acid (A9A) was detected in an African patient. The T62A, C73R, and T228M alleles did not express detectable enzymatic activity, while the A66V allele expressed residual, but unstable activity. The C73R allele was present in eight of 21 unrelated CEP patients (21% of CEP alleles). In three patients, identification of both alleles permitted genotype-phenotype correlations; the A66V/C73R, T228M/C73R, and C73R/C73R genotypes had mild, moderately severe, and severe disease, respectively. These findings provide the first genotype-phenotype correlations and permit molecular heterozygote detection in this inherited porphyria.


Subject(s)
Erythropoiesis , Exons , Mutation , Porphyrias/genetics , Uroporphyrinogen III Synthetase/genetics , Adolescent , Adult , Base Sequence , Child , Female , Humans , Infant , Male , Middle Aged , Molecular Sequence Data , Polymerase Chain Reaction , Porphyrias/congenital
10.
Hum Genet ; 88(3): 320-4, 1992 Jan.
Article in English | MEDLINE | ID: mdl-1733834

ABSTRACT

Congenital erythropoietic porphyria (CEP) or Günther's disease is an inborn error of heme biosynthesis transmitted as an autosomal recessive trait and characterized by a profound deficiency of uroporphyrinogen III synthase (UROIIIS) activity. We have previously described two missense mutations in the UROIIIS gene, confirming that the primary defect responsible for CEP is a structural alteration of this gene. We have extended our work to 5 additional unrelated families. Two new point mutations, a deletion and an insertion have been found in the messenger RNA. Our study shows that a molecular heterogeneity of the mutations exists in Günther's disease. One mutation (C73R), however, appears to be more frequent than the others. Finally, the different normal and mutated proteins have been expressed in Escherichia coli to determine the consequence of the mutations on the enzyme activity.


Subject(s)
Mutation , Porphyrias/genetics , Uroporphyrinogen III Synthetase/genetics , Amino Acid Sequence , Base Sequence , Chromosome Deletion , DNA/genetics , Escherichia coli/enzymology , Genetic Vectors , Humans , Molecular Sequence Data , Nucleic Acid Hybridization , Polymerase Chain Reaction , Porphyrias/congenital
11.
Vet Rec ; 129(18): 403-7, 1991 Nov 02.
Article in English | MEDLINE | ID: mdl-1767483

ABSTRACT

Three blonde d'Aquitaine calves (one male and two females) about four months old, exhibited skin lesions just after birth, the site and nature of which suggested photosensitisation. Their porphyrin metabolism indicated a marked decrease in the activity of lymphocytic ferrochelatase, leading to a diagnosis of congenital erythrocytic protoporphyria. The associated nervous disorders of the 'recurrent epileptiform seizure' type are discussed in the light of complementary histological and biochemical tests.


Subject(s)
Cattle Diseases/congenital , Erythrocytes/chemistry , Porphyrias/veterinary , Protoporphyrins/blood , Animals , Breeding , Cattle , Cattle Diseases/blood , Feces/chemistry , Female , Ferrochelatase/blood , Liver/pathology , Male , Porphyrias/blood , Porphyrias/congenital , Protoporphyrins/analysis
12.
Tijdschr Diergeneeskd ; 116(15-16): 773-6, 1991 Aug 15.
Article in Dutch | MEDLINE | ID: mdl-1926095

ABSTRACT

The case of a male calf affected with bovine congenital porphyria is reported in the present paper. The diagnosis was based on the specific and pathognomonic symptoms: lesions of the pale parts of the skin due to photosensitization, brownish discolouration of the teeth and urine, overall wasting and retardation of growth. The diagnosis was verified by analysis of the blood and urine: in the blood we found a high concentration of protoporphyrins (269 micrograms/l) and a rather low cell count (19 per cent), in the urine high concentrations of uro- and coproporphyrins (3340 and 2550 micrograms/l respectively) were determined. As there is no effective treatment for this disease, it was advised to keep the animal indoors and fatten it. The farmer did not follow this advice. The calf died within a few months.


Subject(s)
Cattle Diseases/congenital , Porphyrias/veterinary , Animals , Cattle , Coproporphyrins/urine , Diagnosis, Differential , Male , Porphyrias/congenital , Porphyrias/diagnosis , Protoporphyrins/blood , Uroporphyrins/urine
13.
J Chromatogr ; 550(1-2): 603-7, 1991 Jul 26.
Article in English | MEDLINE | ID: mdl-1774232

ABSTRACT

A reversed-phase high-performance liquid chromatographic method is described for the determination of hydroxy and peroxy acid derivatives of uroporphyrin in the plasma of patients with congenital erythropoietic porphyria. The porphyrins were extracted from the plasma with 20% trichloroacetic acid-dimethyl sulphoxide (1:1, v/v). The supernatant after centrifugation was chromatographed on a Hypersil-ODS column by gradient elution with 9% (v/v) acetonitrile in 1 M ammonium acetate buffer (pH 5.16) (solvent A) and 10% (v/v) acetonitrile in methanol (solvent B) as the gradient mixture. The method was also suitable for the preparative isolation of the porphyrins.


Subject(s)
Chromatography, High Pressure Liquid/methods , Hydroxy Acids/blood , Porphyrias/blood , Uroporphyrins/blood , Humans , Porphyrias/congenital
14.
Lancet ; 337(8756): 1510-1, 1991 Jun 22.
Article in English | MEDLINE | ID: mdl-1675371

ABSTRACT

Congenital erythropoietic porphyria, a disorder of haem synthesis, is caused by uroporphyrinogen III synthase deficiency in bone-marrow normoblasts. Uroporphyrins and coproporphyrins accumulate and cause oxidative damage to cells exposed to sunlight. Uroporphyrin overproduction was greatly reduced and skin changes reversed in a girl who received a bone-marrow graft from an HLA-identical sibling at 10 years of age. The patient died 11 months after transplantation because of severe progressive pneumonitis and encephalopathy associated with cytomegalovirus infection, but the encouraging response up to 8 months after engraftment indicates a possible benefit of bone-marrow transplantation in the treatment of this rare but usually fatal inherited disease.


Subject(s)
Bone Marrow Transplantation , Erythroid Precursor Cells/transplantation , Porphyria, Erythropoietic , Porphyrias/surgery , Bone Marrow Transplantation/adverse effects , Child , Coproporphyrins/urine , Cytomegalovirus Infections/etiology , Erythroid Precursor Cells/enzymology , Female , Humans , Male , Porphyrias/congenital , Porphyrias/metabolism , Prognosis , Uroporphyrins/urine
15.
Biomed Chromatogr ; 5(2): 53-6, 1991 Mar.
Article in English | MEDLINE | ID: mdl-1868257

ABSTRACT

A new porphyrin, peroxyacetic acid uroporphyrin I, has been isolated from the urine of patients with congenital erythropoietic porphyria by reversed phase high performance liquid chromatography. The porphyrin was characterized by high resolution mass spectrometry and by typical chemical reactions of a peroxyacid.


Subject(s)
Porphyrias/urine , Uroporphyrins/urine , Chromatography, High Pressure Liquid/methods , Humans , Mass Spectrometry/methods , Molecular Structure , Porphyrias/congenital , Uroporphyrins/isolation & purification
17.
Bone ; 12(2): 89-92, 1991.
Article in English | MEDLINE | ID: mdl-2064845

ABSTRACT

Congenital erythropoietic porphyria (CEP) is a rare disorder of heme biosynthesis that results in the production of large quantities of photoactive porphyrins. The clinical syndrome is dominated by extreme photosensitivity with mutilation of light exposed extremities and hemolytic anemia. Bone disease has been occasionally noted, but is not well characterised. We describe a man with CEP who developed bone pain and spinal crush fractures at the age of 22. Skeletal radiographs revealed features typical of other severe hemolytic anemias, but in addition there was loss of the terminal phalanges of the hand as a result of photomutilation. Spinal bone density (assessed by DPA) was reduced and at the hip bone density was at the lower limit of normal. The metacarpal cortical bone density was 2.9 standard deviations below normal. Biochemical and histological studies accelerated bone turnover. Although the serum 250H vitamin D concentration was very low (because of light avoidance) there was no evidence that the bone disease was a consequence of this. Treatment for one year with clodronate and a high transfusion regime was associated with small reductions in serum alkaline phosphatase and urine hydroxyproline excretion, but there was no improvement in bone mineral density. We conclude that CEP has a distinctive osteodystrophy comprising osteolysis of light-exposed extremities and a high turnover type of osteoporosis. Privational vitamin D deficiency may also occur. The effect upon bone of the new therapies for CEP should be considered.


Subject(s)
Bone Diseases, Metabolic/complications , Porphyria, Erythropoietic , Porphyrias/congenital , Alkaline Phosphatase/blood , Bone Density , Bone Diseases, Metabolic/metabolism , Bone Diseases, Metabolic/pathology , Humans , Infant , Male , Porphyrias/complications , Porphyrias/metabolism
19.
Methods Find Exp Clin Pharmacol ; 12(9): 645-8, 1990 Nov.
Article in English | MEDLINE | ID: mdl-2084460

ABSTRACT

Non-absorbable sorbents that bind porphyrins in the gastrointestinal tract may be useful in the treatment of porphyrias whose manifestations result from porphyrin excess. To test this, we assessed the effect of oral charcoal on porphyrin economy in a patient with a probable congenital erythropoietic porphyria. Treatment with a superactivated charcoal (Super Char), 25 g three times daily, was associated with a precipitous drop in erythrocyte porphyrin (from 21.4 +/- 2.9 [SD] to 7.4 +/- 0.4 nmole/ml; p less than 0.025) and plasma porphyrin (from 1.56 +/- 0.24 to 0.70 +/- 0.08 nmole/ml; p less than 0.01). Urinary porphyrin excretion appeared to rise, from 103 +/- 45 to 160 +/- 30 mumole/d, but the change was not statistically significant. Constipation appeared to limit compliance with the charcoal regimen by the end of the study period. Nonetheless, superactivated charcoal may be a useful therapy in this disfiguring porphyria.


Subject(s)
Charcoal/therapeutic use , Porphyrias/drug therapy , Porphyrins/blood , Skin Diseases/drug therapy , Adolescent , Charcoal/adverse effects , Constipation/chemically induced , Humans , Male , Porphyrias/congenital , Porphyrins/urine , Skin Diseases/congenital
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