Center Francais des Porphyries
Center Francais des Porphyries
Guyon L.,Lille University Hospital Center |
Farine M.-O.,Lille University Hospital Center |
Lesage J.C.,University of Lille Nord de France |
Gevaert A.-M.,Lille University Hospital Center |
And 4 more authors.
Photodiagnosis and photodynamic therapy | Year: 2014
CONTEXT: While photodynamic therapy (PDT) is a promising treatment for peritoneal carcinomatosis, its use is often limited because of the toxicity of photosensitizers. In this study, safety of PDT with hexaminoevulinate (HAL), a second generation photosensitizer, is assessed.METHODS: PDT of the peritoneal cavity was performed in a rat model of peritoneal carcinomatosis. Rats were treated according to different protocols: with full or half HAL dose, after intraperitoneal or oral administration of HAL, 4 or 8h after its injection, using red or green light, after protection of the liver or cooling of the abdominal wall. Toxicity was assessed by blood tests quantifying hematocrit, liver and muscular enzymes and by pathological examination of abdominal and intrathoracic organs after treatment. The results were analyzed in the light of quantification of fluorescence and protoporphyrin IX (PPIX) content of the same organs.RESULTS: PDT with HAL induced rhabdomyolysis, intestinal necrosis and liver function test anomalies, leading to death in 2 out of 34 rats. The liver and the intestine contained high levels of PPIX (3-5 times more than tumor nodules).CONCLUSION: HAL PDT lacked specificity. However, the strategy associating diagnosis, treatment and evaluation of the results in one single procedure was effective and should be tested with other photosensitizers. Copyright © 2014 Elsevier B.V. All rights reserved.
Martelli A.,Institute Of Genetique Et Of Biologie Moleculaire Et Cellulaire Igbmc |
Martelli A.,French Institute of Health and Medical Research |
Martelli A.,French National Center for Scientific Research |
Martelli A.,University of Strasbourg |
And 23 more authors.
Cell Metabolism | Year: 2015
Summary Mitochondrial iron accumulation is a hallmark of diseases associated with impaired iron-sulfur cluster (Fe-S) biogenesis, such as Friedreich ataxia linked to frataxin (FXN) deficiency. The pathophysiological relevance of the mitochondrial iron loading and the underlying mechanisms are unknown. Using a mouse model of hepatic FXN deficiency in combination with mice deficient for iron regulatory protein 1 (IRP1), a key regulator of cellular iron metabolism, we show that IRP1 activation in conditions of Fe-S deficiency increases the available cytosolic labile iron pool. Surprisingly, our data indicate that IRP1 activation sustains mitochondrial iron supply and function rather than driving detrimental iron overload. Mitochondrial iron accumulation is shown to depend on mitochondrial dysfunction and heme-dependent upregulation of the mitochondrial iron importer mitoferrin-2. Our results uncover an unexpected protective role of IRP1 in pathological conditions associated with altered Fe-S metabolism. © 2015 Elsevier Inc.
Gelot P.,Nantes University Hospital Center |
Dutartre H.,Nantes University Hospital Center |
Khammari A.,Nantes University Hospital Center |
Khammari A.,French Institute of Health and Medical Research |
And 9 more authors.
Experimental Dermatology | Year: 2013
Vemurafenib is a new-targeted therapy approved for the treatment of patients with V600E BRAF-mutant metastatic melanoma. Among the cutaneous adverse events reported, the photosensitivity is frequently experienced. We aimed to characterize more deeply the mechanism leading to this photosensitivity as well as the corresponding UV spectrum. Phototests showed that the phototoxicity was UVA-dependent since from normal value prior to vemurafenib treatment, the UVA-minimal erythema dose decreased in 17 of 18 patients (94.4%) while the minimal erythema dose remained unchanged. Furthermore, a vemurafenib-induced erythema appeared quickly during the UVA exposure contrarily to what is observed with a conventional drug-induced phototoxicity showing an erythema 12-24 h after the phototesting. Vitamin PP concentration decreased, and porphyrin level significantly increased after 2 months of vemurafenib. Our study confirms the high risk of vemurafenib-induced photosensitivity and indicates that it is possibly vitamin PP- and porphyrin dependent. © 2013 John Wiley & Sons A/S.
Galy B.,European Molecular Biology Laboratory |
Ferring-Appel D.,European Molecular Biology Laboratory |
Sauer S.W.,University of Heidelberg |
Kaden S.,German Cancer Research Center |
And 7 more authors.
Cell Metabolism | Year: 2010
Mitochondria supply cells with ATP, heme, and iron sulfur clusters (ISC), and mitochondrial energy metabolism involves both heme-and ISC-dependent enzymes. Here, we show that mitochondrial iron supply and function require iron regulatory proteins (IRP), cytosolic RNA-binding proteins that control mRNA translation and stability. Mice lacking both IRP1 and IRP2 in their hepatocytes suffer from mitochondrial iron deficiency and dysfunction associated with alterations of the ISC and heme biosynthetic pathways, leading to liver failure and death. These results uncoveramajor roleofthe IRPsincell biology: to ensure adequate iron supply to the mitochondrion for proper function of this critical organelle. © 2010 Elsevier Inc.
Elder G.,University of Wales |
Harper P.,University of Stockholm |
Badminton M.,University of Wales |
Sandberg S.,University of Bergen |
Deybach J.-C.,Center Francais des Porphyries
Journal of Inherited Metabolic Disease | Year: 2013
Retrospective estimates of the prevalence of porphyrias have been reported but there has been no large scale prospective study of their incidence. The European Porphyria Network collected information prospectively over a 3 year period about the number of newly diagnosed symptomatic patients with an inherited porphyria (335 patients from 11 countries). Prevalence was calculated from the incidence and mean disease duration. The incidence of hepato-cellular carcinoma (HCC) in acute hepatic porphyria and the prevalence of patients with recurrent acute attacks of porphyria were also investigated. The incidence of symptomatic acute intermittent porphyria (AIP) was similar in all countries (0.13 per million per year; 95 % CI: 0.10 - 0.14) except Sweden (0.51; 95 % CI: 0.28-0.86). The incidence ratio for symptomatic AIP: variegate porphyria: hereditary coproporphyria was 1.00:0.62: 0.15. The prevalence of AIP (5.4 per million; 95 % CI: 4.5-6.3) was about half that previously reported. The prevalence of erythropoietic protoporphyria (EPP) was less uniform between countries and, in some countries, exceeded previous estimates. Fourteen new cases of HCC (11 from Sweden) were reported in patients with acute porphyria. Sixty seven patients (3 VP; 64 AIP: 53 females, 11 males) with recurrent attacks of acute porphyria were identified. The estimated percentage of patients with AIP that will develop recurrent acute attacks was 3-5 %. In conclusion, the prevalence of symptomatic acute porphyria may be decreasing, possibly due to improved management, whereas the prevalence of EPP may be increasing due to improved diagnosis and its greater recognition as a cause of photosensitivity. © 2012 SSIEM and Springer Science+Business Media Dordrecht.
Puy H.,Center Francais des Porphyries |
Puy H.,Institute National Of La Sante |
Gouya L.,Center Francais des Porphyries |
Gouya L.,Institute National Of La Sante |
And 3 more authors.
The Lancet | Year: 2010
Hereditary porphyrias are a group of eight metabolic disorders of the haem biosynthesis pathway that are characterised by acute neurovisceral symptoms, skin lesions, or both. Every porphyria is caused by abnormal function of a separate enzymatic step, resulting in a specific accumulation of haem precursors. Seven porphyrias are the result of a partial enzyme deficiency, and a gain of function mechanism has been characterised in a new porphyria. Acute porphyrias present with acute attacks, typically consisting of severe abdominal pain, nausea, constipation, confusion, and seizure, and can be life-threatening. Cutaneous porphyrias present with either acute painful photosensitivity or skin fragility and blisters. Rare recessive porphyrias usually manifest in early childhood with either severe cutaneous photosensitivity and chronic haemolysis or chronic neurological symptoms with or without photosensitivity. Porphyrias are still underdiagnosed, but when they are suspected, and dependent on clinical presentation, simple first-line tests can be used to establish the diagnosis in all symptomatic patients. Diagnosis is essential to enable specific treatments to be started as soon as possible. Screening of families to identify presymptomatic carriers is crucial to decrease risk of overt disease of acute porphyrias through counselling about avoidance of potential precipitants. © 2010 Elsevier Ltd. All rights reserved.
Tchernitchko D.,University Paris Diderot |
Tchernitchko D.,Center Francais des Porphyries |
Robreau A.M.,Center Francais des Porphyries |
Lefebvre T.,University Paris Diderot |
And 6 more authors.
British Journal of Dermatology | Year: 2012
Summary Background Porphyria cutanea tarda (PCT), the most frequent type of porphyria, results from decreased uroporphyrinogen decarboxylase (UROD) activity. Two forms of PCT have been described: a familial form (fPCT) characterized by the inherited decrease of UROD activity in all tissues and a sporadic form (sPCT) characterized by decreased UROD activity in the liver. Cytochrome P450 CYP1A2 plays a major role in triggering experimental uroporphyria in rodents. It has been suggested that the highly inducible -163A/A genotype of the CYP1A2 gene could confer a heightened risk of PCT in patients. Objectives To examine the impact of CYP1A2 polymorphisms on the clinical course of PCT. Methods We performed an extensive CYP1A2 gene analysis in 96 (48 fPCT and 48 sPCT) unrelated French caucasian patients with PCT and in 99 healthy volunteers of similar ethnic origin. Results We did not observe any difference in CYP1A2 allele distribution, including a novel and rare CYP1A2 c.1063C>T (p.R355W) single nucleotide polymorphism. In addition, we compared the frequency of the -163A highly inducible allele both in patients with symptomatic fPCT (n = 48) and in asymptomatic UROD gene mutations carrier relatives (n = 54). This variant was not over-represented in patients with PCT vs. either healthy volunteers or asymptomatic UROD gene mutation carriers. Conclusions The CYP1A2 genotype does not appear to be a major susceptibility factor in the development of fPCT or sPCT in the French population. © 2011 British Association of Dermatologists.
PubMed | Center francais des porphyries and University Paris Diderot
Type: Journal Article | Journal: La Revue de medecine interne | Year: 2016
The hereditary porphyrias comprise a group of eight metabolic disorders of the haem biosynthesis pathway characterised by acute neurovisceral symptoms, skin lesions or both. Each porphyria is caused by abnormal function of a separate enzymatic step resulting in a specific accumulation of haem precursors. Seven porphyrias are the consequence of a partial enzyme deficiency while a gain of function mechanism has been recently characterised in a novel porphyria. Acute porphyrias present with severe abdominal pain, nausea, constipation, confusion and seizure, which may be life threatening. Cutaneous porphyrias can be present with either acute painful photosensitivity or skin fragility and blisters. Rare recessive porphyrias usually manifest in early childhood with either severe chronic neurological symptoms or chronic haemolysis and severe cutaneous photosensitivity. Porphyrias are still underdiagnosed, but once they are suspected, and depending on the clinical presentation, a specific and simple front line test allows the diagnosis in all symptomatic patients. Diagnosis is essential to institute as soon as possible a specific treatment. Screening families to identify presymptomatic carriers is crucial to prevent chronic complications and overt disease by counselling on avoiding potential precipitants.
PubMed | French Institute of Health and Medical Research, AP HP, Rennes University Hospital Center, University Paris Diderot and Center Francais des Porphyries
Type: Journal Article | Journal: Gastroenterology | Year: 2016
Hereditary hemochromatosis is a heterogeneous group of genetic disorders characterized by parenchymal iron overload. It is caused by defective expression of liver hepcidin, the main regulator of iron homeostasis. Iron stimulates the gene encoding hepcidin (HAMP) via the bone morphogenetic protein (BMP)6 signaling to SMAD. Although several genetic factors have been found to cause late-onset hemochromatosis, many patients have unexplained signs of iron overload. We investigated BMP6 function in these individuals.We sequenced the BMP6 gene in 70 consecutive patients with a moderate increase in serum ferritin and liver iron levels who did not carry genetic variants associated with hemochromatosis. We searched for BMP6 mutations in relatives of 5 probands and in 200 healthy individuals (controls), as well as in 2 other independent cohorts of hyperferritinemia patients. We measured serum levels of hepcidin by liquid chromatography-tandem mass spectrometry and analyzed BMP6 in liver biopsy specimens from patients by immunohistochemistry. The functions of mutant and normal BMP6 were assessed in transfected cells using immunofluorescence, real-time quantitative polymerase chain reaction, and immunoblot analyses.We identified 3 heterozygous missense mutations in BMP6 (p.Pro95Ser, p.Leu96Pro, and p.Gln113Glu) in 6 unrelated patients with unexplained iron overload (9% of our cohort). These mutations were detected in less than 1% of controls. p.Leu96Pro also was found in 2 patients from the additional cohorts. Family studies indicated dominant transmission. Serum levels of hepcidin were inappropriately low in patients. A low level of BMP6, compared with controls, was found in a biopsy specimen from 1 patient. In cell lines, the mutated residues in the BMP6 propeptide resulted in defective secretion of BMP6; reduced signaling via SMAD1, SMAD5, and SMAD8; and loss of hepcidin production.We identified 3 heterozygous missense mutations in BMP6 in patients with unexplained iron overload. These mutations lead to loss of signaling to SMAD proteins and reduced hepcidin production. These mutations might increase susceptibility to mild-to-moderate late-onset iron overload.
PubMed | French Institute of Health and Medical Research and Center Francais des Porphyries
Type: | Journal: Journal of the American Society of Nephrology : JASN | Year: 2016
CKD occurs in most patients with acute intermittent porphyria (AIP). During AIP, -aminolevulinic acid (ALA) accumulates and promotes tubular cell death and tubulointerstitial damage. The human peptide transporter 2 (PEPT2) expressed by proximal tubular cells mediates the reabsorption of ALA, and variants of PEPT2 have different affinities for ALA. We tested the hypothesis that PEPT2 genotypes affect the severity and prognosis of porphyria-associated kidney disease. We analyzed data from 122 individuals with AIP who were followed from 2003 to 2013 and genotyped for PEPT2 At last follow-up, carriers of the PEPT2*1*1 genotype (higher affinity variant) exhibited worse renal function than carriers of the lower affinity variants PEPT2*1/*2 and PEPT2*2/*2 (meanSD eGFR: 54.419.1, 66.623.8, and 78.119.9 ml/min per 1.73 m