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Frontiers in Physiology 2022Partial deficiency of the last enzyme of the heme biosynthetic pathway, namely, ferrochelatase (FECH), is responsible for erythropoietic protoporphyria (EPP) in humans....
Partial deficiency of the last enzyme of the heme biosynthetic pathway, namely, ferrochelatase (FECH), is responsible for erythropoietic protoporphyria (EPP) in humans. This disorder is characterized by painful skin photosensitivity, due to excessive protoporphyrin IX (PPIX) production in erythrocytes. Although several papers report the presence of iron deficiency anemia in about 50% of EPP patients, there is still no a conclusive explanation of the why this occurs. In the present work, we explored hematological indices and iron status in 20 unrelated Italian EPP patients in order to propose a new hypothesis. Our data show that microcytosis is present in EPP patients also in the absence of anemia and iron deficiency with a link between PPIX accumulation and reduced MCV, probably indicating an indirect condition of heme deficiency. Patients studied had a downward shift of iron parameters due to increased hepcidin concentrations only in a state of repleted iron stores. Interestingly, hemoglobin synthesis was not limited by iron supply except in cases with further iron loss, in which concomitantly increased soluble transferrin (Tf) receptor (sTfR) levels were detected. The mechanisms involved in the iron uptake downregulation in EPP remain unclear, and the role of PPIX accumulation in microcytosis.
PubMed: 35309058
DOI: 10.3389/fphys.2022.841050 -
Diagnostics (Basel, Switzerland) May 2022The World Health Organization (WHO) describes "health" as a state of physical, mental, and social well-being and not merely the absence of disease or infirmity.... (Review)
Review
The World Health Organization (WHO) describes "health" as a state of physical, mental, and social well-being and not merely the absence of disease or infirmity. Therefore, a biopsychosocial approach should be considered as an integral part of patients' management. In this review, we summarize the available data starting from 1986 on the biological, psychological, and social aspects of porphyrias in order to provide a useful tool for clinicians about the missing knowledge within this field. Porphyrias are a group of rare metabolic disorders affecting the heme biosynthetic pathway and can be categorized into hepatic and erythropoietic. Here, a total of 20 articles reporting the psychological and the quality of life (QoL) data of porphyria patients affected by acute hepatic porphyrias (AHPs), Porphyria Cutanea Tarda (PCT), and Erythropoietic Protoporphyria (EPP) were analyzed. These 13 articles include reported quantitative methods using questionnaires, while the reaming articles employed qualitative descriptive approaches through direct interviews with patients by psychology professionals. We conclude that the use of questionnaires limits the complete description of all areas of a patient's life compared to a direct interview with specialists. However, only a combined use of these methods could be the best approach for the correct disorder management.
PubMed: 35626348
DOI: 10.3390/diagnostics12051193 -
Hematology, Transfusion and Cell Therapy 2018Hemoglobin is an essential biological component of human physiology and its production in red blood cells relies upon proper biosynthesis of heme and globin protein.... (Review)
Review
Hemoglobin is an essential biological component of human physiology and its production in red blood cells relies upon proper biosynthesis of heme and globin protein. Disruption in the synthesis of these precursors accounts for a number of human blood disorders found in patients. Mutations in genes encoding heme biosynthesis enzymes are associated with a broad class of metabolic disorders called porphyrias. In particular, one subtype - erythropoietic protoporphyria - is caused by the accumulation of protoporphyrin IX. Erythropoietic protoporphyria patients suffer from photosensitivity and a higher risk of liver failure, which is the principle cause of morbidity and mortality. Approximately 90% of these patients carry loss-of-function mutations in the enzyme ferrochelatase (), while 5% of cases are associated with activating mutations in the C-terminus of . Recent work has begun to uncover novel mechanisms of heme regulation that may account for the remaining 5% of cases with previously unknown genetic basis. One erythropoietic protoporphyria family has been identified with inherited mutations in the AAA+ protease ClpXP that regulates activity. In this review article, recent findings on the role of ClpXP as both an activating unfoldase and degrading protease and its impact on heme synthesis will be discussed. This review will also highlight the role of ClpX dysfunction in erythropoietic protoporphyria.
PubMed: 30057992
DOI: 10.1016/j.htct.2018.03.001 -
The Journal of Pediatrics Nov 2018Erythropoietic protoporphyria is a photodermatosis presenting in childhood with severe pain on sun exposure. The diagnosis is often delayed because of the lack of... (Review)
Review
Erythropoietic protoporphyria is a photodermatosis presenting in childhood with severe pain on sun exposure. The diagnosis is often delayed because of the lack of awareness among pediatricians. We describe the diagnostic odyssey of 2 children presenting with symptoms of erythropoietic protoporphyria and report results of a survey of 129 affected individuals.
Topics: Child, Preschool; Delayed Diagnosis; Diagnosis, Differential; Female; Humans; Hypersensitivity; Male; Photosensitivity Disorders; Prognosis; Protective Clothing; Protoporphyria, Erythropoietic; Recurrence; Risk Assessment; Severity of Illness Index; Sunlight
PubMed: 30041937
DOI: 10.1016/j.jpeds.2018.06.001 -
Molecular Genetics and Metabolism Nov 20195-Aminolevulinate (ALA) synthase (ALAS), a homodimeric pyridoxal-5'-phosphate (PLP)-dependent enzyme, catalyzes the first step of heme biosynthesis in metazoa, fungi and... (Review)
Review
5-Aminolevulinate (ALA) synthase (ALAS), a homodimeric pyridoxal-5'-phosphate (PLP)-dependent enzyme, catalyzes the first step of heme biosynthesis in metazoa, fungi and α-proteobacteria. In this review, we focus on the advances made in unraveling the mechanism of the ALAS-catalyzed reaction during the past decade. The interplay between the PLP cofactor and the protein moiety determines and modulates the multi-intermediate reaction cycle of ALAS, which involves the decarboxylative condensation of two substrates, glycine and succinyl-CoA. Substrate binding and catalysis are rapid, and product (ALA) release dominates the overall ALAS kinetic mechanism. Interconversion between a catalytically incompetent, open conformation and a catalytically competent, closed conformation is linked to ALAS catalysis. Reversion to the open conformation, coincident with ALA dissociation, defines the slowest step of the reaction cycle. These findings were further substantiated by introducing seven mutations in the16-amino acid loop that gates the active site, yielding an ALAS variant with a greatly increased rate of catalytic turnover and heightened specificity constants for both substrates. Recently, molecular dynamics (MD) simulation analysis of various dimeric ALAS forms revealed that the seven active site loop mutations caused the proteins to adopt different conformations. In particular, the emergence of a β-strand in the mutated loop, which interacted with two preexisting β-strands to form an anti-parallel three-stranded β-sheet, conferred the murine heptavariant with a more stable open conformation and prompted faster product release than wild-type mALAS2. Moreover, the dynamics of the mALAS2 active site loop anti-correlated with that of the 35 amino acid C-terminal sequence. This led us to propose that this C-terminal extension, which is absent in prokaryotic ALASs, finely tunes mammalian ALAS activity. Based on the above results, we extend our previous proposal to include that discovery of a ligand inducing the mammalian C-terminal extension to fold offers a good prospect for the development of a new drug for X-linked protoporphyria and/or other porphyrias associated with enhanced ALAS activity and/or porphyrin accumulation.
Topics: 5-Aminolevulinate Synthetase; Biosynthetic Pathways; Catalysis; Heme; Humans; Kinetics; Molecular Dynamics Simulation; Protein Conformation; Pyridoxal Phosphate; Substrate Specificity
PubMed: 31345668
DOI: 10.1016/j.ymgme.2019.06.003 -
Hepatology (Baltimore, Md.) Sep 2014Porphyrias are a group of eight metabolic disorders, each resulting from a mutation that affects an enzyme of the heme biosynthetic pathway. Porphyrias are classified as... (Review)
Review
UNLABELLED
Porphyrias are a group of eight metabolic disorders, each resulting from a mutation that affects an enzyme of the heme biosynthetic pathway. Porphyrias are classified as hepatic or erythropoietic, depending upon the site where the gene defect is predominantly expressed. Clinical phenotypes are classified as follows: (1) acute porphyrias with neurovisceral symptoms: acute intermittent porphyria; delta amino-levulinic acid hydratase deficiency porphyria; hereditary coproporphyria; and variegate porphyria and (2) cutaneous porphyrias with skin blistering and photosensitivity: porphyria cutanea tarda; congenital erythropoietic porphyria; hepatoerythropoietic porphyria and both erythropoietic protoporphyrias: autosomal dominant and X-linked. Liver transplantation (LT) may be needed for recurrent and/or life-threatening acute attack in acute intermittent porphyria or acute liver failure or end-stage chronic liver disease in erythropoietic protoporphyria. LT in acute intermittent porphyria is curative. Erythropoietic protoporphyria patients needing LT should be considered for bone marrow transplantation to achieve cure.
CONCLUSION
This article provides an overview of porphyria with diagnostic approaches and management strategies for specific porphyrias and recommendations for LT with indications, pretransplant evaluation, and posttransplant management.
Topics: Humans; Liver Transplantation; Porphyrias
PubMed: 24700519
DOI: 10.1002/hep.27086 -
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 -
Genes & Genomics 2017The main purpose of present review is to describe and organize autosomal recessive disorders (arachnomelia, syndactylism, osteopetrosis, dwarfism, crooked tail syndrome,... (Review)
Review
The main purpose of present review is to describe and organize autosomal recessive disorders (arachnomelia, syndactylism, osteopetrosis, dwarfism, crooked tail syndrome, muscular hyperplasia, glycogen storage disease, protoporphyria), which occur among beef cattle, and methods that can be applied to detect these defects. Prevalence of adverse alleles in beef breeds happens due to human activity-selections of favorable features, e.g. developed muscle tissue. Unfortunately, carriers of autosomal recessive diseases are often characterized by these attributes. Fast and effective identification of individuals, that may carry faulty genes, can prevent economical losses.
PubMed: 28458779
DOI: 10.1007/s13258-017-0525-8 -
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 -
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