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Metabolites Nov 2021Erythropoietic porphyrias are caused by enzymatic dysfunctions in the heme biosynthetic pathway, resulting in porphyrins accumulation in red blood cells. The porphyrins... (Review)
Review
Erythropoietic porphyrias are caused by enzymatic dysfunctions in the heme biosynthetic pathway, resulting in porphyrins accumulation in red blood cells. The porphyrins deposition in tissues, including the skin, leads to photosensitivity that is present in all erythropoietic porphyrias. In the bone marrow, heme synthesis is mainly controlled by intracellular labile iron by post-transcriptional regulation: translation of mRNA, the first and rate-limiting enzyme of the pathway, is inhibited when iron availability is low. Moreover, it has been shown that the expression of ferrochelatase (FECH, an iron-sulfur cluster enzyme that inserts iron into protoporphyrin IX to form heme), is regulated by intracellular iron level. Accordingly, there is accumulating evidence that iron status can mitigate disease expression in patients with erythropoietic porphyrias. This article will review the available clinical data on how iron status can modify the symptoms of erythropoietic porphyrias. We will then review the modulation of heme biosynthesis pathway by iron availability in the erythron and its role in erythropoietic porphyrias physiopathology. Finally, we will summarize what is known of FECH interactions with other proteins involved in iron metabolism in the mitochondria.
PubMed: 34940556
DOI: 10.3390/metabo11120798 -
Orphanet Journal of Rare Diseases Oct 2023A new active substance called "dersimelagon" (MT-7117) is being tested as an alternative treatment option for Erythropoietic protoporphyria (EPP). At the moment,...
A new active substance called "dersimelagon" (MT-7117) is being tested as an alternative treatment option for Erythropoietic protoporphyria (EPP). At the moment, dersimelagon is being tested both in the US and in Europe in a phase III placebo-controlled RCT. However, given the availability of an already approved treatment option for EPP the use of a placebo arm is questionable from an ethics point of view. We analyze the issue and suggest that a noninferiority active-control trial without placebo is an ethically and scientifically more valid design to test the efficacy of dersimelagon as well as other EPP treatments.
Topics: Humans; Europe; Protoporphyria, Erythropoietic; Randomized Controlled Trials as Topic; United States
PubMed: 37845740
DOI: 10.1186/s13023-023-02941-w -
Clinical Chemistry Dec 2015Laboratory diagnosis of erythropoietic protoporphyria (EPP) requires a marked increase in total erythrocyte protoporphyrin (300-5000 μg/dL erythrocytes, reference...
BACKGROUND
Laboratory diagnosis of erythropoietic protoporphyria (EPP) requires a marked increase in total erythrocyte protoporphyrin (300-5000 μg/dL erythrocytes, reference interval <80 μg/dL) and a predominance (85%-100%) of metal-free protoporphyrin [normal, mostly zinc protoporphyrin (reference intervals for the zinc protoporphyrin proportion have not been established)]; plasma porphyrins are not always increased. X-linked protoporphyria (XLP) causes a similar increase in total erythrocyte protoporphyrin with a lower fraction of metal-free protoporphyrin (50%-85% of the total).
CONTENT
In studying more than 180 patients with EPP and XLP, the Porphyrias Consortium found that erythrocyte protoporphyrin concentrations for some patients were much higher (4.3- to 46.7-fold) than indicated by previous reports provided by these patients. The discrepant earlier reports, which sometimes caused the diagnosis to be missed initially, were from laboratories that measure protoporphyrin only by hematofluorometry, which is intended primarily to screen for lead poisoning. However, the instrument can calculate results on the basis of assumed hematocrits and reports results as "free" and "zinc" protoporphyrin (with different reference intervals), implying separate measurements of metal-free and zinc protoporphyrin. Such misleading reports impair diagnosis and monitoring of patients with protoporphyria.
SUMMARY
We suggest that laboratories should prioritize testing for EPP and XLP, because accurate measurement of erythrocyte total and metal-free protoporphyrin is essential for diagnosis and monitoring of these conditions, but less important for other disorders. Terms and abbreviations used in reporting erythrocyte protoporphyrin results should be accurately defined.
Topics: Adolescent; Adult; Child; Child, Preschool; Diagnosis, Differential; Erythrocytes; Female; Fluorometry; Humans; Infant; Infant, Newborn; Lead Poisoning; Male; Porphyrias; Protoporphyria, Erythropoietic; Protoporphyrins; Reagent Kits, Diagnostic; Reference Values
PubMed: 26482161
DOI: 10.1373/clinchem.2015.245456 -
Molecular Genetics and Metabolism Nov 2019Mouse models of the human porphyrias have proven useful for investigations of disease pathogenesis and to facilitate the development of new therapeutic approaches. To... (Review)
Review
Mouse models of the human porphyrias have proven useful for investigations of disease pathogenesis and to facilitate the development of new therapeutic approaches. To date, mouse models have been generated for all major porphyrias, with the exception of X-linked protoporphyria (XLP) and the ultra rare 5-aminolevulinic acid dehydratase deficient porphyria (ADP). Mouse models have been generated for the three autosomal dominant acute hepatic porphyrias, acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). The AIP mice, in particular, provide a useful investigative model as they have been shown to have acute biochemical attacks when induced with the prototypic porphyrinogenic drug, phenobarbital. In addition to providing important insights into the disease pathogenesis of the neurological impairment in AIP, these mice have been valuable for preclinical evaluation of liver-targeted gene therapy and RNAi-mediated approaches. Mice with severe HMBS deficiency, which clinically and biochemically mimic the early-onset homozygous dominant AIP (HD-AIP) patients, have been generated and were used to elucidate the striking phenotypic differences between AIP and HD-AIP. Mice modeling the hepatocutaneous porphyria, porphyria cutanea tarda (PCT), made possible the identification of the iron-dependent inhibitory mechanism of uroporphyrinogen decarboxylase (UROD) that leads to symptomatic PCT. Mouse models for the two autosomal recessive erythropoietic porphyrias, congenital erythropoietic porphyria (CEP) and erythropoeitic protoporphyria (EPP), recapitulate many of the clinical and biochemical features of the severe human diseases and have been particularly useful for evaluation of bone marrow transplantation and hematopoietic stem cell (HSC)-based gene therapy approaches. The EPP mice have also provided valuable insights into the underlying pathogenesis of EPP-induced liver damage and anemia.
Topics: Anemia; Animals; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Genetic Therapy; Humans; Liver; Mice; Phenobarbital; Porphobilinogen Synthase; Porphyrias; Porphyrias, Hepatic; Protoporphyria, Erythropoietic
PubMed: 30737139
DOI: 10.1016/j.ymgme.2019.01.007 -
Proceedings of the Royal Society of... Nov 1973
Topics: Blister; Carotenoids; Child; Erythropoiesis; Female; Humans; Porphyrias; Scalp; Sunlight
PubMed: 4777021
DOI: No ID Found -
Biochimica Et Biophysica Acta Nov 2011Pyridoxal-5'-phosphate (PLP) is an obligatory cofactor for the homodimeric mitochondrial enzyme 5-aminolevulinate synthase (ALAS), which controls metabolic flux into the... (Review)
Review
Pyridoxal-5'-phosphate (PLP) is an obligatory cofactor for the homodimeric mitochondrial enzyme 5-aminolevulinate synthase (ALAS), which controls metabolic flux into the porphyrin biosynthetic pathway in animals, fungi, and the α-subclass of proteobacteria. Recent work has provided an explanation for how this enzyme can utilize PLP to catalyze the mechanistically unusual cleavage of not one but two substrate amino acid α-carbon bonds, without violating the theory of stereoelectronic control of PLP reaction-type specificity. Ironically, the complex chemistry is kinetically insignificant, and it is the movement of an active site loop that defines k(cat) and ultimately, the rate of porphyrin biosynthesis. The kinetic behavior of the enzyme is consistent with an equilibrium ordered induced-fit mechanism wherein glycine must bind first and a portion of the intrinsic binding energy with succinyl-Coenzyme A is then utilized to perturb the enzyme conformational equilibrium towards a closed state wherein catalysis occurs. Return to the open conformation, coincident with ALA dissociation, is the slowest step of the reaction cycle. A diverse variety of loop mutations have been associated with hyperactivity, suggesting the enzyme has evolved to be purposefully slow, perhaps as a means to allow for rapid up-regulation of activity in response to an as yet undiscovered allosteric type effector. Recently it was discovered that human erythroid ALAS mutations can be associated with two very different diseases. Mutations that down-regulate activity can lead to X-linked sideroblastic anemia, which is characterized by abnormally high iron levels in mitochondria, while mutations that up-regulate activity are associated with X-linked dominant protoporphyria, which in contrast is phenotypically identified by abnormally high porphyrin levels. This article is part of a Special Issue entitled: Pyridoxal Phosphate Enzymology.
Topics: 5-Aminolevulinate Synthetase; Heme; Humans; Kinetics; Models, Molecular; Protein Conformation
PubMed: 21215825
DOI: 10.1016/j.bbapap.2010.12.015 -
The Tohoku Journal of Experimental... Oct 2023Erythropoietic protoporphyria (EPP) is a very rare disease with an estimated prevalence of 1 in 200,000 individuals. Decreased ferrochelatase activity causes the... (Review)
Review
Erythropoietic protoporphyria (EPP) is a very rare disease with an estimated prevalence of 1 in 200,000 individuals. Decreased ferrochelatase activity causes the accumulation of protoporphyrin in the body, and light exposure results in the generation of active oxygen, causing photosensitivity. Liver damage has the greatest influence on the prognosis, and liver transplantation is the only treatment option for patients with decompensated liver cirrhosis. We report a case of living-donor liver transplantation for decompensated liver cirrhosis associated with EPP. The patient was a 52-year-old male who led a normal life except for mild photosensitivity. When the patient was 37-year-old, hepatic dysfunction was noticed. At 48-year-old, high erythrocyte protoporphyrin levels, skin biopsy, and genetic tests resulted in a diagnosis of EPP. The patient underwent living- donor liver transplantation because of decompensated liver cirrhosis. In the operating room and intensive care unit, a special light-shielding film was applied to all light sources to block light with harmful wavelengths during treatment. Due to the need for special measures, a lecture on patients with EPP was given before surgery to deepen understanding among all medical professionals involved in the treatment. As a result, no adverse events occurred during the perioperative period, and the patient was discharged on the 46th post-operative day. Currently, the transplanted liver is functioning extremely well, and the patient is alive 3 years post-transplant. Herein, we describe a case of living donor liver transplantation for EPP with a brief literature review.
Topics: Male; Humans; Middle Aged; Adult; Protoporphyria, Erythropoietic; Liver Transplantation; Living Donors; Protoporphyrins; Ferrochelatase; Liver Diseases; Liver Cirrhosis
PubMed: 37495523
DOI: 10.1620/tjem.2023.J061 -
Frontiers in Immunology 2021The homeostasis of tissues in a chronic disease is an essential function of the alternative pathway (AP) of the complement system (CS). However, if not controlled, it...
The homeostasis of tissues in a chronic disease is an essential function of the alternative pathway (AP) of the complement system (CS). However, if not controlled, it may also be detrimental to healthy cells with a consequent aggravation of symptoms. The protoporphyria (PP) is a rare chronic disease that causes phototoxicity in visible light with local skin pain and general malaise. In order to establish if there is a systemic involvement of the CS during sun exposure, we designed a non-invasive method with a serum collection in winter and summer from 19 PP and 13 controls to detect the levels of CS protein: Properdin, Factor H (FH), and C5. Moreover, the global radiation data were collected from the regional agency of environmental protection (ARPA). The results show growing values for every protein in patients with PP, compared to control, in both seasons, in particular in summer compared to winter. To reinforce the evidence, we have estimated the personal exposure of patients based on the global radiation data. The main factors of the AP increased over the season, confirming the involvement of the AP in relation to light exposure. The systemic response could justify the general malaise of patients after long light exposure and can be exploited to elucidate new therapeutic approaches.
Topics: Adult; Biomarkers; Complement C5; Complement Factor H; Complement Pathway, Alternative; Complement System Proteins; Disease Susceptibility; Female; Humans; Male; Middle Aged; Properdin; Protoporphyria, Erythropoietic; Seasons; Sunlight
PubMed: 33664746
DOI: 10.3389/fimmu.2021.615620 -
Skin Therapy Letter Nov 2018Afamelanotide, an α-melanocyte stimulating hormone analogue, has become an emerging therapeutic option for a variety of skin conditions previously refractory to other...
Afamelanotide, an α-melanocyte stimulating hormone analogue, has become an emerging therapeutic option for a variety of skin conditions previously refractory to other treatments. Its efficacy has been demonstrated in several dermatologic conditions, including erythropoietic protoporphyria (EPP), solar urticaria, polymorphic light eruption (PMLE), vitiligo, acne, and Hailey-Hailey disease. Its relatively low risk side effect profile makes it an attractive treatment option and also paves the way for innovative use in other disorders.
PubMed: 30517779
DOI: No ID Found -
The Journal of Investigative Dermatology Jan 2005
Review
Topics: Animals; Humans; Photosensitivity Disorders; Protoporphyria, Erythropoietic
PubMed: 15654946
DOI: 10.1111/j.0022-202X.2004.23531.x