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Frontiers in Physiology 2022
PubMed: 36117690
DOI: 10.3389/fphys.2022.993287 -
JAMA Dermatology Feb 2023Erythropoietic protoporphyria (EPP) is a rare and underdiagnosed genetic disease characterized by painful sensitivity to light. A better understanding and...
IMPORTANCE
Erythropoietic protoporphyria (EPP) is a rare and underdiagnosed genetic disease characterized by painful sensitivity to light. A better understanding and characterization of its light-induced cutaneous symptoms may aid in the identification of EPP in patients.
OBJECTIVES
To describe the cutaneous symptoms of erythropoietic protoporphyria (EPP) and to determine if these symptoms are associated with the degree of light sensitivity.
DESIGN, SETTING, AND PARTICIPANTS
This was a cross-sectional study of adolescent and adult (≥15 years) patients with EPP across the US conducted by a single academic hospital via a remotely administered survey, measurements of light sensitivity by light dosimetry and by text message symptom assessments. Data analyses were conducted from November 2020 to April 2022.
EXPOSURES
Sunlight exposure.
MAIN OUTCOMES AND MEASURES
Self-reported symptoms and association with measured light sensitivity.
RESULTS
The study sample consisted of 35 patients with EPP (mean [SD] age, 39.1 (15.5) years; 21 [60%] female; 14 [40%] male; 35 [100%] White individuals). The patients' median [range] skin tone was 3.0 (1.0-8.0), based on self-reporting from 1 (lightest) to 12 (darkest). A total of 24 participants completed the light dosimeter measurements. Phototoxic reactions were characterized by pain (97%; 34 patients), burning (97%; 34), tingling (97%; 34), pruritus (83%; 29), allodynia (89%; 31), improvement of symptoms with cold (89%; 31), achiness (24%; 12), fatigue (46%; 16), mild swelling (83%; 29), severe swelling (63%; 22), erythema (51%; 18), petechiae (40%; 14), skin cracking (43%; 15), scabbing (46%; 16), scarring (66%; 23), and other chronic skin changes (40%; 14). Patients with EPP reported that their hands, feet, and face were most sensitive to light and that their shoulders and legs were least sensitive; 25.7% (9 patient) reported no chronic skin changes, and 5.7% (2 patients) reported never having had any visible symptoms. None of these findings varied with the degree of light sensitivity except that lower overall light sensitivity was associated with lower ranked sensitivity of the neck and arms.
CONCLUSIONS AND RELEVANCE
The findings of this cross-sectional study suggest that patients with EPP have distinctive cutaneous symptoms that may aid in identification of this underdiagnosed disease. Characteristic EPP symptoms include light-induced cutaneous burning pain and occasional swelling, particularly over the hands, with a prodrome of pruritus and paresthesias. Minimal skin changes or the absence of visible skin changes during reactions to light, including lack of erythema, do not exclude an EPP diagnosis nor suggest low EPP disease burden.
Topics: Adult; Adolescent; Humans; Male; Female; Protoporphyria, Erythropoietic; Photophobia; Cross-Sectional Studies; Erythema; Pruritus; Paresthesia
PubMed: 36630131
DOI: 10.1001/jamadermatol.2022.5850 -
The New England Journal of Medicine Jul 2015Erythropoietic protoporphyria is a severe photodermatosis that is associated with acute phototoxicity. Patients with this condition have excruciating pain and a markedly... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Erythropoietic protoporphyria is a severe photodermatosis that is associated with acute phototoxicity. Patients with this condition have excruciating pain and a markedly reduced quality of life. We evaluated the safety and efficacy of an α-melanocyte-stimulating hormone analogue, afamelanotide, to decrease pain and improve quality of life.
METHODS
We conducted two multicenter, randomized, double-blind, placebo-controlled trials of subcutaneous implants containing 16 mg of afamelanotide. Patients in the European Union (74 patients) and the United States (94 patients) were randomly assigned, in a 1:1 ratio, to receive a subcutaneous implant containing either afamelanotide or placebo every 60 days (a total of five implants in the European Union study and three in the U.S study). The type and duration of sun exposure, number and severity of phototoxic reactions, and adverse events were recorded over the respective 180-day and 270-day study periods. Quality of life was assessed with the use of validated questionnaires. A subgroup of U.S. patients underwent photoprovocation testing. The primary efficacy end point was the number of hours of direct exposure to sunlight without pain.
RESULTS
In the U.S. study, the duration of pain-free time after 6 months was longer in the afamelanotide group (median, 69.4 hours, vs. 40.8 hours in the placebo group; P=0.04). In the European Union study, the duration of pain-free time after 9 months was also longer in the afamelanotide group than in the placebo group (median, 6.0 hours vs. 0.8 hours; P=0.005), and the number of phototoxic reactions was lower in the the afamelanotide group (77 vs. 146, P=0.04). In both trials, quality of life improved with afamelanotide therapy. Adverse events were mostly mild; serious adverse events were not thought to be related to the study drug.
CONCLUSIONS
Afamelanotide had an acceptable side-effect and adverse-event profile and was associated with an increased duration of sun exposure without pain and improved quality of life in patients with erythropoietic protoporphyria. (Funded by Clinuvel Pharmaceuticals and others; ClinicalTrials.gov numbers, NCT01605136 and NCT00979745.).
Topics: Adult; Double-Blind Method; Drug Implants; Humans; Middle Aged; Pain; Protoporphyria, Erythropoietic; Sunlight; alpha-MSH
PubMed: 26132941
DOI: 10.1056/NEJMoa1411481 -
Photodiagnosis and Photodynamic Therapy Jun 2024Protoporphyrin IX (PPIX) is the final precursor of heme, forming heme when iron is inserted. Individuals with erythropoietic protoporphyrias (EPP) have accumulation of... (Review)
Review
BACKGROUND
Protoporphyrin IX (PPIX) is the final precursor of heme, forming heme when iron is inserted. Individuals with erythropoietic protoporphyrias (EPP) have accumulation of PPIX, causing photosensitivity and increased liver disease risk. Many also have iron deficiency and anemia. We investigated outcomes of oral iron supplements in individuals with EPP.
METHODS
A systematic review identified literature on oral iron supplements in EPP patients. Subsequently, we administered iron supplements to EPP patients with iron deficiency. The primary outcome was impact on PPIX level. Secondary outcomes were adverse events and relative differences in hemoglobin and iron parameters.
RESULTS
The systematic review found 13 case reports and one uncontrolled clinical trial with uncertain results. From our department 10 patients with EPP and iron deficiency took daily dosages of 330 mg of ferrous fumarate for two months. Five of our patients had anemia at baseline. After 2 months of supplementation seven patients had increased PPIX level compared to baseline, two had decrease, one remained unchanged. The administration of iron led to a rise in ferritin, and in four of the anemic patients also to an improvement in blood hemoglobin. A small transiently elevation in plasma alanine transaminase concentration was observed during supplementation.
CONCLUSIONS
Overall, iron supplementation in EPP patients replenished iron stores and elevated erythrocyte PPIX and plasma alanine transaminase. For anemic patients, there was some degree of normalization of the hemoglobin level. If iron therapy is needed for EPP patients, monitoring of photosensitivity, PPIX, hemoglobin, and plasma liver enzymes is advisable.
Topics: Humans; Protoporphyria, Erythropoietic; Protoporphyrins; Dietary Supplements; Male; Female; Adult; Iron; Anemia, Iron-Deficiency; Middle Aged; Treatment Outcome
PubMed: 38734198
DOI: 10.1016/j.pdpdt.2024.104211 -
The Journal of Investigative Dermatology Apr 2015
Topics: Anti-Inflammatory Agents; Europe; Humans; Porphyrins; Protoporphyria, Erythropoietic; Receptor, Melanocortin, Type 1; Skin Pigmentation; alpha-MSH
PubMed: 25785940
DOI: 10.1038/jid.2015.16 -
Antioxidants (Basel, Switzerland) Jul 2019Due to their potential health-promoting effects, carotenoids have drawn both scientific and public attention in recent years. The primary source of carotenoids in the... (Review)
Review
Due to their potential health-promoting effects, carotenoids have drawn both scientific and public attention in recent years. The primary source of carotenoids in the human skin is diet, mainly fruits, vegetables, and marine product, but they may originate from supplementation and topical application, too. In the skin, they accumulate mostly in the epidermis and act as a protective barrier to various environmental influences. Namely, the skin is exposed to numerous environmental factors, including ultraviolet radiation (UVR), air pollution, and smoking, that cause oxidative stress within the skin with consequent premature (extrinsic) aging. UVR, as the most prominent environmental factor, may cause additional detrimental skin effects, such as sunburn, DNA damage, and skin cancer. Therefore, photoprotection is the first line intervention in the prevention of premature aging and skin cancer. Numerous studies have demonstrated that carotenoids, particularly β-carotene, lycopene, lutein, and astaxanthin, have photoprotective effects, not only through direct light-absorbing properties, but also through their antioxidant effects (scavenging reactive oxygen species), as well as by regulation of UV light-induced gene expression, modulation of stress-dependent signaling, and/or suppression of cellular and tissue responses like inflammation. Interventional studies in humans with carotenoid-rich diet have shown its photoprotective effects on the skin (mostly by decreasing the sensitivity to UVR-induced erythema) and its beneficial effects in prevention and improvement of skin aging (improved skin elasticity and hydration, skin texture, wrinkles, and age spots). Furthermore, carotenoids may be helpful in the prevention and treatment of some photodermatoses, including erythropoietic protoporphyria (EPP), porphyria cutanea tarda (PCT) and polymorphous light eruption (PMLE). Although UVR is recognized as the main etiopathogenetic factor in the development of non-melanoma skin cancer (NMSC) and melanoma, and the photoprotective effects of carotenoids are certain, available studies still could not undoubtedly confirm the protective role of carotenoids in skin photocarcinogenesis.
PubMed: 31370257
DOI: 10.3390/antiox8080259 -
The Application of Clinical Genetics 2016Erythropoietic protoporphyria (EPP) and the phenotypically similar disease X-linked protoporphyria (XLPP) are inherited cutaneous porphyrias characterized clinically by... (Review)
Review
Erythropoietic protoporphyria (EPP) and the phenotypically similar disease X-linked protoporphyria (XLPP) are inherited cutaneous porphyrias characterized clinically by acute non-blistering photosensitivity, intolerance to sunlight, and significantly reduced quality of life. They are due to marked overproduction of protoporphyrin (PP) chiefly by erythroblasts and reticulocytes. In EPP, the underlying genetic defect is in the ferrochelatase gene, which encodes the final enzyme in the heme synthetic pathway. In XLPP, the genetic defect is a gain-of-function mutation, usually a four-base deletion, in the gene that encodes the enzyme 5-aminolevulinic acid synthase-2, the first and rate-controlling enzyme of heme synthesis in developing red blood cells. The excess PP causes acute and painful photosensitivity, being activated by light in the long ultraviolet to blue spectrum (380-420 nm, the Soret band). Although several treatments have been proposed, presently no very effective treatment exists for EPP or XLPP. Afamelanotide (Scenesse) is a first-in-class synthetic analog of α-melanocyte stimulating hormone. Afamelanotide mimics the naturally occurring hormone to increase skin pigmentation by increasing melanin production in melanocytes, resulting in increased sunlight tolerance in those with EPP/XLPP. Afamelanotide is currently approved for use in the European Union and Switzerland, and it is under review in the United States by the Food and Drug Administration for use in patients with EPP/XLPP. This paper provides a review of the clinical characteristics and current therapies for EPP/XLPP. We discuss the pharmacology, clinical efficacy, safety, and tolerability of afamelanotide and summarize the results of several key Phase II and III clinical trials. These data indicate that afamelanotide is a promising therapy for those with these debilitating diseases.
PubMed: 28003770
DOI: 10.2147/TACG.S122030 -
Pharmaceuticals (Basel, Switzerland) Dec 2023Erythropoietic protoporphyria (EPP) is a genetic disorder stemming from reduced ferrochelatase expression, the final enzyme in the pathway of heme biosynthesis. A... (Review)
Review
Erythropoietic protoporphyria (EPP) is a genetic disorder stemming from reduced ferrochelatase expression, the final enzyme in the pathway of heme biosynthesis. A closely related condition, X-linked protoporphyria (XLP), bears similar clinical features although it arises from the heightened activity of δ-aminolevulinic acid synthase 2 (ALAS2), the first and normally rate-controlling enzyme in heme biosynthesis in developing red blood cells. Both of these abnormalities result in the buildup of protoporphyrin IX, leading to excruciating light sensitivity and, in a minority of cases, potentially fatal liver complications. Traditionally, managing EPP and XLP involved sun avoidance. However, the emergence of innovative therapies, such as dersimelagon, is reshaping the therapeutic landscape for these conditions. In this review, we summarize salient features of the properties of dersimelagon, shedding light on its potential role in advancing our understanding of treatment options for EPP and XLP.
PubMed: 38256864
DOI: 10.3390/ph17010031 -
Iron misregulation and neurodegenerative disease in mouse models that lack iron regulatory proteins.Neurobiology of Disease Sep 2015Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are two cytosolic proteins that maintain cellular iron homeostasis by binding to RNA stem loops known as iron responsive... (Review)
Review
Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are two cytosolic proteins that maintain cellular iron homeostasis by binding to RNA stem loops known as iron responsive elements (IREs) that are found in the untranslated regions of target mRNAs that encode proteins involved in iron metabolism. IRPs modify the expression of iron metabolism genes, and global and tissue-specific knockout mice have been made to evaluate the physiological significance of these iron regulatory proteins (Irps). Here, we will discuss the results of the studies that have been performed with mice engineered to lack the expression of one or both Irps and made in different strains using different methodologies. Both Irp1 and Irp2 knockout mice are viable, but the double knockout (Irp1(-/-)Irp2(-/-)) mice die before birth, indicating that these Irps play a crucial role in maintaining iron homeostasis. Irp1(-/-) mice develop polycythemia and pulmonary hypertension, and when these mice are challenged with a low iron diet, they die early of abdominal hemorrhages, suggesting that Irp1 plays an essential role in erythropoiesis and in the pulmonary and cardiovascular systems. Irp2(-/-) mice develop microcytic anemia, erythropoietic protoporphyria and a progressive neurological disorder, indicating that Irp2 has important functions in the nervous system and erythropoietic homeostasis. Several excellent review articles have recently been published on Irp knockout mice that mainly focus on Irp1(-/-) mice (referenced in the introduction). In this review, we will briefly describe the phenotypes and physiological implications of Irp1(-/-) mice and discuss the phenotypes observed for Irp2(-/-) mice in detail with a particular emphasis on the neurological problems of these mice.
Topics: Animals; Disease Models, Animal; Humans; Iron Metabolism Disorders; Iron-Regulatory Proteins; Mice; Mice, Transgenic; Neurodegenerative Diseases
PubMed: 25771171
DOI: 10.1016/j.nbd.2015.02.026 -
Metabolites Nov 2014Heme, like chlorophyll, is a primordial molecule and is one of the fundamental pigments of life. Disorders of normal heme synthesis may cause human diseases, including... (Review)
Review
Heme, like chlorophyll, is a primordial molecule and is one of the fundamental pigments of life. Disorders of normal heme synthesis may cause human diseases, including certain anemias (X-linked sideroblastic anemias) and porphyrias. Porphyrias are classified as hepatic and erythropoietic porphyrias based on the organ system in which heme precursors (5-aminolevulinic acid (ALA), porphobilinogen and porphyrins) are chiefly overproduced. The hepatic porphyrias are further subdivided into acute porphyrias and chronic hepatic porphyrias. The acute porphyrias include acute intermittent, hereditary copro-, variegate and ALA dehydratase deficiency porphyria. Chronic hepatic porphyrias include porphyria cutanea tarda and hepatoerythropoietic porphyria. The erythropoietic porphyrias include congenital erythropoietic porphyria (Gűnther's disease) and erythropoietic protoporphyria. In this review, we summarize the key features of normal heme synthesis and its differing regulation in liver versus bone marrow. In both organs, principal regulation is exerted at the level of the first and rate-controlling enzyme, but by different molecules (heme in the liver and iron in the bone marrow). We also describe salient clinical, laboratory and genetic features of the eight types of porphyria.
PubMed: 25372274
DOI: 10.3390/metabo4040977