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The Journal of Biological Chemistry Mar 2022Heme is a critical biomolecule that is synthesized in vivo by several organisms such as plants, animals, and bacteria. Reflecting the importance of this molecule,... (Review)
Review
Heme is a critical biomolecule that is synthesized in vivo by several organisms such as plants, animals, and bacteria. Reflecting the importance of this molecule, defects in heme biosynthesis underlie several blood disorders in humans. Aminolevulinic acid synthase (ALAS) initiates heme biosynthesis in α-proteobacteria and nonplant eukaryotes. Debilitating and painful diseases such as X-linked sideroblastic anemia and X-linked protoporphyria can result from one of more than 91 genetic mutations in the human erythroid-specific enzyme ALAS2. This review will focus on recent structure-based insights into human ALAS2 function in health and how it dysfunctions in disease. We will also discuss how certain genetic mutations potentially result in disease-causing structural perturbations. Furthermore, we use thermodynamic and structural information to hypothesize how the mutations affect the human ALAS2 structure and categorize some of the unique human ALAS2 mutations that do not respond to typical treatments, that have paradoxical in vitro activity, or that are highly intolerable to changes. Finally, we will examine where future structure-based insights into the family of ALA synthases are needed to develop additional enzyme therapeutics.
Topics: 5-Aminolevulinate Synthetase; Aminolevulinic Acid; Anemia, Sideroblastic; Animals; Genetic Diseases, X-Linked; Heme; Humans; Structure-Activity Relationship
PubMed: 35093382
DOI: 10.1016/j.jbc.2022.101643 -
Journal of Hepatology Jun 2023Living donor liver transplantation (LDLT) is recognised as an alternative treatment modality to reduce waiting list mortality and expand the donor pool. Over recent... (Review)
Review
Living donor liver transplantation (LDLT) is recognised as an alternative treatment modality to reduce waiting list mortality and expand the donor pool. Over recent decades, there have been an increasing number of reports on the use of LT and specifically LDLT for familial hereditary liver diseases. There are marginal indications and contraindications that should be considered for a living donor in paediatric parental LDLT. No mortality or morbidity related to recurrence of metabolic diseases has been observed with heterozygous donors, except for certain relevant cases, such as ornithine transcarbamylase deficiency, protein C deficiency, hypercholesterolemia, protoporphyria, and Alagille syndrome, while donor human leukocyte antigen homozygosity also poses a risk. It is not always essential to perform preoperative genetic assays for possible heterozygous carriers; however, genetic and enzymatic assays must hereafter be included in the parental donor selection criteria in the aforementioned circumstances.
Topics: Child; Humans; Living Donors; Liver Transplantation; Siblings; Heterozygote; Liver Diseases; Treatment Outcome
PubMed: 37208102
DOI: 10.1016/j.jhep.2022.10.013 -
Experimental Dermatology Jul 2023Severe skin pain when exposed to long wave ultraviolet radiation or visible light is the main symptom of erythropoietic protoporphyria (EPP). Treatment options for EPP... (Review)
Review
Severe skin pain when exposed to long wave ultraviolet radiation or visible light is the main symptom of erythropoietic protoporphyria (EPP). Treatment options for EPP are inadequate and new treatments are needed but hampered by the lack of valid efficacy outcomes. Phototesting with well-defined illumination of the skin can be performed reliably. We aimed to provide an overview of phototest procedures used to evaluate EPP treatments. Systematic searches of Embase, MEDLINE and the Cochrane Library were performed. Searches identified 11 studies using photosensitivity as efficacy outcome. The studies used eight different phototest protocols. Illuminations were performed with a filtered high-pressure mercury arc, or a xenon arc lamp equipped with monochromator or filters. Some used broadband, others narrowband illumination. In all protocols phototests were performed on the hands or the back. Endpoints were minimal dose required to induce either first symptom of discomfort, erythema, urticaria or intolerable pain. Other endpoints were change in erythema intensity or diameter of any type of flare after exposure compared to before. In conclusion, protocols displayed extensive variability in illumination set-up and evaluation of phototest reactions. Implementation of a standardized phototest method will allow more consistent and reliable outcome evaluation in future therapeutic research of protoporphyric photosensitivity.
Topics: Humans; Protoporphyria, Erythropoietic; Ultraviolet Rays; Photosensitivity Disorders; Skin; Erythema
PubMed: 37052136
DOI: 10.1111/exd.14809 -
The British Journal of Dermatology May 2020The photodermatoses affect large proportions of the population but their impact on quality of life (QoL) and psychological health has not been reviewed. Several tools... (Review)
Review
BACKGROUND
The photodermatoses affect large proportions of the population but their impact on quality of life (QoL) and psychological health has not been reviewed. Several tools are available to evaluate QoL and psychological impacts.
OBJECTIVES
To systematically review current literature to identify tools used to assess QoL and psychological impacts in patients with photodermatoses, and to summarize the reported findings.
METHODS
A systematic search of PubMed, OVID Medline, PsycInfo and CINAHL was performed for articles investigating QoL and/or psychological impact in patients with photodermatoses, published between 1960 and September 2018.
RESULTS
Twenty studies were included: 19 incorporated QoL assessment while three evaluated psychological morbidity. Six QoL tools were found to be used: Dermatology Life Quality Index (DLQI), Children's DLQI, Family DLQI, Skindex (16- and 29-item versions), Erythropoietic Protoporphyria Quality of Life (EPP-QoL) and EuroQol. Between 31% and 39% of photosensitive patients reported a very large impact on QoL (DLQI > 10). Employment and education, social and leisure activities, and clothing choices were particularly affected. Only one tool was specifically designed for a photodermatosis (EPP-QoL). Four tools were used to evaluate psychological impact: the Hospital Anxiety and Depression Scale, Fear of Negative Evaluation, brief COPE and Illness Perception Questionnaire-Revised. Levels of anxiety and depression were approximately double British population data. Patients with facial involvement, female gender and younger age at onset showed more psychological morbidity.
CONCLUSIONS
Several tools have been used to assess QoL in the photodermatoses, and confirm substantial impact on QoL. Development of specific, validated QoL measures would address their unique impacts. Research delineating their psychological comorbidity is sparse and requires further exploration. What's already known about this topic? The photodermatoses negatively impact quality of life (QoL) and cause psychological distress, but no reviews of this area appear in the literature. What does this study add? Few studies have explored the psychological and social impacts of the photodermatoses. There are no fully validated QoL tools specific to the photodermatoses. Around one-third of adult and child patients with photosensitivity experience very or extremely large impact on QoL, with particular effect on clothing choices, employment and social and leisure activities. Studies suggest anxiety and depression levels in these patients are around double those in the U.K. general population. More attention is required on these 'hidden' conditions.
Topics: Adult; Anxiety; Anxiety Disorders; Child; Female; Humans; Photosensitivity Disorders; Quality of Life; Surveys and Questionnaires
PubMed: 31278744
DOI: 10.1111/bjd.18326 -
Molecular Genetics and Metabolism... Dec 2022The use of iron supplementation for anemia in erythropoietic protoporphyria (EPP) is controversial with both benefit and deterioration reported in single case reports....
The use of iron supplementation for anemia in erythropoietic protoporphyria (EPP) is controversial with both benefit and deterioration reported in single case reports. There is no systematic study to evaluate the benefits or risks of iron supplementation in these patients. We assessed the potential efficacy of oral iron therapy in decreasing erythrocyte protoporphyrin (ePPIX) levels in patients with EPP or X-linked protoporphyria (XLP) and low ferritin in an open-label, single-arm, interventional study. Sixteen patients (≥18 years) with EPP or XLP confirmed by biochemical and/or genetic testing, and serum ferritin ≤30 ng/mL were enrolled. Baseline testing included iron studies, normal hepatic function, and elevated plasma porphyrins and ePPIX levels. Oral ferrous sulfate 325 mg twice daily was administered for 12 months. The primary efficacy outcome was the relative difference in total ePPIX level between baseline and 12 months after starting treatment with iron. Secondary measures included improvement in serum ferritin, plasma porphyrins, and clinical symptoms. Thirteen patients had EPP (8 females, 5 males) and 3 had XLP (all females) and the mean age of participants was 38.8 years (SD 14.5). Ten patients completed all study visits limiting interpretation of results. In EPP patients, a transient increase in ePPIX levels was observed at 3 months in 9 of 12 (75%) patients. Iron was discontinued in 2 of these patients after meeting the protocol stopping rule of a 35% increase in ePPIX. Seven patients withdrew before study end. Ferritin levels increased on iron replacement indicating an improvement in iron status. A decrease in ePPIX was seen in both XLP patients who completed the study (relative difference of 0.67 and 0.5 respectively). No substantial changes in ePPIX were seen in EPP patients at the end of the study ( = 8; median relative difference: -0.21 (IQR: -0.44, 0.05). The most common side effects of iron treatment were gastrointestinal symptoms. Hepatic function remained normal throughout the study. Our study showed that oral iron therapy repletes iron stores and transiently increases ePPIX in some EPP patients, perhaps due to a transient increase in erythropoiesis, and may decrease ePPIX in XLP patients. Further studies are needed to better define the role of iron repletion in EPP. Trial registration: NCT02979249.
PubMed: 36406817
DOI: 10.1016/j.ymgmr.2022.100939 -
Wideochirurgia I Inne Techniki... Jun 2022Erythropoietic protoporphyria is a hereditary defect in heme synthesis, causing protoporphyrin deposition and phototoxic reactions after exposure to light, especially at...
Erythropoietic protoporphyria is a hereditary defect in heme synthesis, causing protoporphyrin deposition and phototoxic reactions after exposure to light, especially at a wavelength of about 400 nm. Sensitivity to light may cause postoperative complications. Therefore, in open surgery protective filters are employed on surgical luminaires. The dangers of laparoscopy are little understood and the intensity of the light used can be high. To protect against phototoxic injury, we inserted an OG 530 filter in the video track. This filter blocks wavelengths below 470 nm. Three cholecystectomies and one sigmoidectomies were performed laparoscopically. The procedures were uneventful, and the patients suffered no adverse reactions, including phototoxic symptoms. The filter had a moderate influence on color perception and caused no significant restrictions on working conditions. We consider that it is appropriate to develop a relevant design to meet the suitable requirements for a durable filter holder in the laparoscopic video track.
PubMed: 35707342
DOI: 10.5114/wiitm.2022.115003 -
Frontiers in Physiology 2022
PubMed: 36117690
DOI: 10.3389/fphys.2022.993287 -
The New England Journal of Medicine Jun 2023
Topics: Humans; Protoporphyria, Erythropoietic; Erythropoiesis
PubMed: 37379150
DOI: 10.1056/NEJMc2305601 -
The New England Journal of Medicine Jun 2023
Topics: Humans; Protoporphyria, Erythropoietic; Erythropoiesis
PubMed: 37379149
DOI: 10.1056/NEJMc2305601 -
Expert Review of Clinical Pharmacology Feb 2021: In erythropoietic protoporphyria (EPP), an inherited disorder of heme biosynthesis, accumulation of protoporphyrin IX results in acute phototoxicity. EPP patients... (Review)
Review
: In erythropoietic protoporphyria (EPP), an inherited disorder of heme biosynthesis, accumulation of protoporphyrin IX results in acute phototoxicity. EPP patients experience severe burning pain after light exposure, which results in a markedly reduced quality of life. Afamelanotide is the first effective approved medical treatment for EPP, acting on melanocortin-1 receptors. This article aims to review afamelanotide.: This review summarizes the chemical properties, pharmacokinetics, safety, preclinical and clinical data on afamelanotide in EPP, and post-marketing surveillance. PubMed search, manufacturers' websites, and relevant articles used for approval by authorities were used for the literature search.: Afamelanotide is an α-melanocyte-stimulating hormone analog. It can activate eumelanogenesis without exposure to UV radiation. Clinical studies in EPP showed that afamelanotide treatment significantly increased exposure to sunlight and QoL. In our clinical experience afamelanotide treatment is much more effective in clinical practice than demonstrated in clinical trials and should be made available for all EPP patients meeting inclusion criteria. The 60-day interval period was not based on effectiveness studies, and therefore for some of the patients the maximum of four implants per year with the 60-day interval is insufficient. Afamelanotide is well tolerated; common adverse events were headache, fatigue, and nausea.
Topics: Animals; Dermatitis, Phototoxic; Dermatologic Agents; Humans; Pain; Protoporphyria, Erythropoietic; Quality of Life; Sunlight; alpha-MSH
PubMed: 33507118
DOI: 10.1080/17512433.2021.1879638