Genetic background influences hepcidin response to iron imbalance in a mouse model of hemolytic anemia (Congenital erythropoietic porphyria).

Clinical severity is heterogeneous among patients suffering from congenital erythropoietic porphyria (CEP) suggesting a modulation of the disease (UROS deficiency) by environmental factors and modifier genes. A KI model of CEP due to a missense mutation of UROS gene present in human has been developed on 3 congenic mouse strains (BALB/c, C57BL/6, and 129/Sv) in order to study the impact of genetic background on disease severity. To detect putative modifiers of disease expression in congenic mice, hematologic data, iron parameters, porphyrin content and tissue samples were collected. Regenerative hemolytic anemia, a consequence of porphyrin excess in RBCs, had various expressions: 129/Sv mice were more hemolytic, BALB/c had more regenerative response to anemia, C57BL/6 were less affected. Iron status and hemolysis level were directly related: C57BL/6 and BALB/c had moderate hemolysis and active erythropoiesis able to reduce iron overload in the liver, while, 129/Sv showed an imbalance between iron release due to hemolysis and erythroid use. The negative control of hepcidin on the ferroportin iron exporter appeared strain specific in the CEP mice models tested. Full repression of hepcidin was observed in BALB/c and 129/Sv mice, favoring parenchymal iron overload in the liver. Unchanged hepcidin levels in C57BL/6 resulted in retention of iron predominantly in reticuloendothelial tissues. These findings open the field for potential therapeutic applications in the human disease, of hepcidin agonists and iron depletion in chronic hemolytic anemia.

Acquired erythropoietic uroporphyria secondary to myelodysplastic syndrome with chromosome 3 alterations: a case report.

Congenital erythropoietic porphyria is a rare autosomal recessive disease caused by a deficiency of uroporphyrinogen III synthase, owing to mutations in UROS in chromosome 10. Occasionally, patients show a mild, late-onset disease, without germline UROS mutations, associated with haematological malignancies. We report a 65-year-old patient with photosensitivity, overexcretion of porphyrins and thrombocytopenia. Bone marrow analysis gave a diagnosis of myelodysplastic syndrome (MDS) with the presence of a derivative chromosome 3, possibly due to an inversion including 3q21 and 3q26 break points. After allogeneic stem-cell transplantation, complete remission of MDS and uroporphyria was achieved. To our knowledge, this is the first reported case of acquired erythropoietic uroporphyria associated with MDS, with chromosome 3 alterations.

Acute hepatic and erythropoietic porphyrias: from ALA synthases 1 and 2 to new molecular bases and treatments.

PURPOSE OF REVIEW: Many studies over the past decade have together identified new genes including modifier genes and new regulation and pathophysiological mechanisms in inherited inborn diseases of the heme biosynthetic pathway. A new porphyria has been characterized: X-linked protoporphyria and the perspective to have innovative treatment at very short-term became a reality. We will summarize how recent data on both ALAS1 and ALAS2 have informed our understanding of disease pathogenesis with an emphasis on how this information may contribute to new therapeutic strategies. RECENT FINDINGS: The development of clinical and biological porphyria networks improved the long-term follow up of cohorts. The ageing of patients have allowed for the identification of novel recurrently mutated genes, and highlighted long-term complications in acute hepatic porphyrias. The treatment of hepatic porphyrias by an RNAi-targeting hepatic ALAS1 is actually tested and may lead to improve the management of acute attacks.In erythropoietic porphyrias, the key role of ALAS2 as a gate keeper of the heme and subsequently hemoglobin synthesis has been demonstrated. Its implication as a modifier gene in over erythroid disorders has also been documented. SUMMARY: The knowledge of both the genetic abnormalities and the regulation of heme biosynthesis has increased over the last 5 years and open new avenues in the management of erythropoietic and acute hepatic porphyrias.

Advances in understanding the pathogenesis of congenital erythropoietic porphyria.

Congenital erythropoietic porphyria (CEP) is a rare genetic disease resulting from the remarkable deficient activity of uroporphyrinogen III synthase, the fourth enzyme of the haem biosynthetic pathway. This enzyme defect results in overproduction of the non-physiological and pathogenic porphyrin isomers, uroporphyrin I and coproporphyrin I. The predominant clinical characteristics of CEP include bullous cutaneous photosensitivity to visible light from early infancy, progressive photomutilation and chronic haemolytic anaemia. The severity of clinical manifestations is markedly heterogeneous among patients; and interdependence between disease severity and porphyrin amount in the tissues has been pointed out. A more pronounced endogenous production of porphyrins concomitant to activation of ALAS2, the first and rate-limiting of the haem synthesis enzymes in erythroid cells, has also been reported. CEP is inherited as autosomal recessive or X-linked trait due to mutations in UROS or GATA1 genes; however an involvement of other causative or modifier genes cannot be ruled out.

[Erythropoietic porphyrias]. / Erytropoieettiset porfyriat.

Erythropoietic, i.e., myelogenous porphyrias include erythropoietic protoporphyria and the very rare congenital protoporphyria and X-linked protoporphyria. Of these, in Finland only erythropoietic protoporphyria has been diagnosed, in which pain and swelling in the skin upon sunlight exposure are the most typical symptoms. A high protoporphyrin level in erythrocytes and a typical peak in the plasma porphyrin spectrum lead to diagnosis.

Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria.

Congenital erythropoietic porphyria (CEP), an autosomal recessive disorder, is due to mutations of uroporphyrinogen III synthase (UROS). Deficiency of UROS results in excess uroporphyrin I, which causes photosensitization. We evaluated a 3-year-old boy with CEP. A hypochromic, microcytic anemia was present from birth, and platelet counts averaged 70 x 10(9)/L (70,000/microL). Erythrocyte UROS activity was 21% of controls. Red cell morphology and globin chain labeling studies were compatible with beta-thalassemia. Hb electrophoresis revealed 36.3% A, 2.4% A(2), 59.5% F, and 1.8% of an unidentified peak. No UROS or alpha- and beta-globin mutations were found in the child or the parents. The molecular basis of the phenotype proved to be a mutation of GATA1, an X-linked transcription factor common to globin genes and heme biosynthetic enzymes in erythrocytes. A mutation at codon 216 in the child and on one allele of his mother changed arginine to tryptophan (R216W). This is the first report of a human porphyria due to a mutation in a trans-acting factor and the first association of CEP with thalassemia and thrombocytopenia. The Hb F level of 59.5% suggests a role for GATA-1 in globin switching. A bone marrow allograft corrected both the porphyria and the thalassemia.

[Clinical manifestations of porphyrin metabolism disorders]. / Klinicheskie proiavleniia narushenii porfirinovogo obmena.

AIM: To characterize patients with various nosological unities [symbol: see text] of porphyria in accordance with their age, clinical symptoms, provoking factors, therapy and outcome. MATERIAL AND METHODS: Patients with acute intermittent porphyria (43), hereditary coproporphyria (8), variegate porphyria (3), porphyria cutanea tarda (7), hepatoerythropoietic porphyria (1), and hereditary erythropoietic porphyria (2) were studied. One patient was suspected of porphyria caused by deficiency of delta-aminolevulenic acid dehydrogenase. RESULTS: The patients were from the CIS. The overwhelming majority of them were young and middle-aged subjects. Rapid development of the disease and severe neurological symptoms were predominantly observed in patients with acute forms of porphyria. CONCLUSION: Early diagnosis of porphyrin metabolism disorders makes it possible to decrease abruptly the number of cases leading to severe complications, disability, and fatal outcome. The use of inexpensive methods of screening of porphyrin metabolism disorders provides a promising approach to solving this problem. These methods should be used in municipal hospitals. In addition, asymptomatic carriers of defective gene should be revealed at the preclinical stage using various methods of molecular genetic assay.

An unusual case of purpuric erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is the most common of the erythropoietic porphyrias. Recent advances in diagnostic laboratory tests have led to the discovery of a number of previously undiagnosed cases. We describe a case of EPP presenting late with a purpuric eruption and discuss the pathogenesis and significance of purpura in EPP.

Erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is an inherited inborn error of porphyrin metabolism caused by decreased activity of the enzyme ferrochelatase, the terminal enzyme of the haem biosynthetic pathway, which catalyses the insertion of iron into protoporphyrin to form haem. EPP is characterized clinically by photosensitivity to visible light commencing in childhood, and biochemically by elevated red cell protoporphyrin levels. Although the majority of papers and reviews have classified EPP as an autosomal dominant disorder, the inheritance has now been shown to be more complex, and both autosomal dominant and recessive patterns of inheritance have been demonstrated using ferrochelatase activity. Further molecular studies should clarify the exact mode of inheritance. It seems likely that in the majority of families a defective allele from the apparently normal parent will be required for disease expression, but another possibility is autosomal dominant inheritance with low clinical penetrance. Exposure to bright sunlight, for as little as a few minutes in the worst affected patients, causes burning pain in exposed skin, which may be so severe and persistent that it prevents sleep for several nights. Patients usually attempt to relieve the pain by cold water or cold compresses. Apart from sun avoidance, the mainstay of prophylactic treatment has been beta-carotene. Although the published evidence for the effectiveness of beta-carotene is impressive, no controlled trials using adequate doses have been performed to unequivocally confirm its usefulness. The most serious complication of EPP is acute hepatic failure, which is due to accumulation of protoporphyrin in the liver. If jaundice develops, a rapidly fatal outcome often follows, unless liver transplantation is undertaken. Regular monitoring of liver function and red cell porphyrin levels is advisable, but this does not always identify patients before serious liver damage has occurred. Even when patients are identified at an early stage in the development of liver disease the therapeutic options available to prevent further damage are limited, and have not been fully evaluated. The gene for ferrochelatase has been cloned, sequenced and mapped to the long arm of chromosome 18. As mutations continue to be identified, phenotype/genotype correlations should become apparent, and it may eventually be possible to identify those patients at risk of developing hepatic failure. In addition, as the basic enzymatic defect in EPP is at the level of the bone marrow stem cells, which are the target cells of choice in the development of retroviral-mediated gene transfer, definitive treatment of EPP by gene therapy is a distinct hope for the future.(ABSTRACT TRUNCATED AT 400 WORDS)