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Heme Metabolism and Porphyria

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A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Medical Research".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 26788

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Special Issue Editors

Dr. Elena Di Pierro

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Guest Editor

UOC General Medicine, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
Interests: porphyria; heme; metabolic disorders; homocysteine; mitochondria; genetic variants

Dr. Jasmin Barman-Aksözen

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Guest Editor

Institute of Laboratory Medicine, Municipal Hospital, 8063 Zurich, Switzerland
Interests: erythropoietic protoporphyria; heme biosynthesis; hepatic porphyrias; rare diseases; patient advocacy

Dr. Emmanuel Richard

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Guest Editor

1. Medical Science Faculty, University of Bordeaux, 33076 Bordeaux, France
2. Biotherapy of Genetic Diseases, Inflammatory disorders and Cancers, INSERM U1035, 33076 Bordeaux, France
3. Department of Biology and Pathology, Bordeaux University Hospital Center, 33000 Bordeaux, France
Interests: heme and iron metabolism disorders; porphyrias; inherited metabolic disorders; urolithiasis and inherited nephrolithiasis

Special Issue Information

Dear Colleagues,

Heme is the “pigment of life”. It is widely recognized as component of hemoglobin, which is necessary to bind oxygen in the bloodstream, but it also is an essential prosthetic group in a number of other biologically important hemoproteins. Heme production takes place in all cells of the body even though the major tissues for heme synthesis are the bone marrow by erythrocytes and the liver by hepatocytes. Its biosynthesis involves a tightly regulated eight-step enzymatic pathway that occurs partly in the mitochondria and partly in the cytosol. A defect in an enzyme of the pathway leads to accumulation of intermediates of heme synthesis causing a clinically significant outcome of a group of metabolic disorders called “porphyrias”. Current biochemical and genetic evidences do not yet fully explain the low penetrance and wide variability in clinical presentation of these rare diseases. This special issue will focus on the recent advances in heme homeostasis, mitochondrial transport and cellular trafficking as well as on the progress of clinical and translational research in pathophysiology, genetic, diagnosis and treatment for the acute hepatic and erythropoietic porphyrias. Studies presenting new biomarkers of disease severity, validation of pathogenetic variants, clinical trial results and relationship with environmental and nutritional factors will also be included.

Dr. Elena Di Pierro
Dr. Jasmin Barman-Aksözen
Dr. Emmanuel Richard
Guest Editors

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Keywords

heme transporters
heme trafficking
heme enzymes
heme synthesis regulation
animal and cellular models of porphyria
pathophysiology of porphyria
pathogenetic variants
biochemical and genetic diagnostic tests
therapy
epidemiology

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Published Papers (12 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 161 KiB

Open AccessEditorial

Editorial on the Special Issue “Heme Metabolism and Porphyria”

by Elena Di Pierro, Jasmin Barman-Aksözen and Emmanuel Richard

Life 2024, 14(5), 581; https://doi.org/10.3390/life14050581 - 30 Apr 2024

Viewed by 818

Abstract

Porphyria denotes a heterogeneous group of metabolic disorders caused by anomalies in the biosynthesis of heme, a crucial component of hemoglobin and other vital hemoproteins [...] Full article

(This article belongs to the Special Issue Heme Metabolism and Porphyria)

Research

Jump to: Editorial, Review, Other

11 pages, 265 KiB

Open AccessArticle

Severe Perinatal Presentations of Günther’s Disease: Series of 20 Cases and Perspectives

by Claire Goudet, Cécile Ged, Audrey Petit, Chloe Desage, Perrine Mahe, Aicha Salhi, Ines Harzallah, Jean-Marc Blouin, Patrick Mercie, Caroline Schmitt, Antoine Poli, Laurent Gouya, Vincent Barlogis and Emmanuel Richard

Life 2024, 14(1), 130; https://doi.org/10.3390/life14010130 - 17 Jan 2024

Cited by 2 | Viewed by 1380

Abstract

(1) Background: Congenital erythropoietic porphyria (CEP), named Günther’s disease, is a rare recessive type of porphyria, resulting from deficient uroporphyrinogen III synthase (UROS), the fourth enzyme of heme biosynthesis. The phenotype ranges from extremely severe perinatal onset, with life-threatening hemolytic anaemia, to mild or moderate cutaneous involvement in late-onset forms. This work reviewed the perinatal CEP cases recorded in France in order to analyse their various presentations and evolution. (2) Methods: Clinical and biological data were retrospectively collected through medical and published records. (3) Results: Twenty CEP cases, who presented with severe manifestations during perinatal period, were classified according to the main course of the disease: antenatal features, acute neonatal distress and postnatal diagnosis. Antenatal symptoms (seven patients) were mainly hydrops fetalis, hepatosplenomegaly, anemia, and malformations. Six of them died prematurely. Five babies showed acute neonatal distress, associated with severe anemia, thrombocytopenia, hepatosplenomegaly, liver dysfunction, and marked photosensitivity leading to diagnosis. The only two neonates who survived underwent hematopoietic stem cell transplantation (HSCT). Common features in post-natal diagnosis (eight patients) included hemolytic anemia, splenomegaly, skin sensitivity, and discoloured teeth and urine. All patients underwent HSCT, with success for six of them, but with fatal complications in two patients. The frequency of the missense variant named C73R is striking in antenatal and neonatal presentations, with 9/12 and 7/8 independent alleles, respectively. (4) Conclusions: The most recent cases in this series are remarkable, as they had a less fatal outcome than expected. Regular transfusions from the intrauterine period and early access to HSCT are the main objectives. Full article

(This article belongs to the Special Issue Heme Metabolism and Porphyria)

31 pages, 5076 KiB

Open AccessArticle

Potential Biomarkers for the Earlier Diagnosis of Kidney and Liver Damage in Acute Intermittent Porphyria

by Elin Storjord, Staffan Wahlin, Bård Ove Karlsen, Randolf I. Hardersen, Amy K. Dickey, Judith K. Ludviksen and Ole-Lars Brekke

Life 2024, 14(1), 19; https://doi.org/10.3390/life14010019 - 21 Dec 2023

Cited by 1 | Viewed by 1903

Abstract

Acute intermittent porphyria (AIP) is an inherited metabolic disorder associated with complications including kidney failure and hepatocellular carcinoma, probably caused by elevations in the porphyrin precursors porphobilinogen (PBG) and delta-aminolevulinic acid (ALA). This study explored differences in modern biomarkers for renal and hepatic damage between AIP patients and controls. Urine PBG testing, kidney injury panels, and liver injury panels, including both routine and modern biomarkers, were performed on plasma and urine samples from AIP cases and matched controls (50 and 48 matched pairs, respectively). Regarding the participants’ plasma, the AIP cases had elevated kidney injury marker-1 (KIM-1, p = 0.0002), fatty acid-binding protein-1 (FABP-1, p = 0.04), and α-glutathione S-transferase (α-GST, p = 0.001) compared to the matched controls. The AIP cases with high PBG had increased FABP-1 levels in their plasma and urine compared to those with low PBG. In the AIP cases, KIM-1 correlated positively with PBG, CXCL10, CCL2, and TCC, and the liver marker α-GST correlated positively with IL-13, CCL2, and CCL4 (all p < 0.05). In conclusion, KIM-1, FABP-1, and α-GST could represent potential early indicators of renal and hepatic damage in AIP, demonstrating associations with porphyrin precursors and inflammatory markers. Full article

(This article belongs to the Special Issue Heme Metabolism and Porphyria)

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12 pages, 1205 KiB

Open AccessArticle

Mitochondrial DNA Copy Number Drives the Penetrance of Acute Intermittent Porphyria

by Elena Di Pierro, Miriana Perrone, Milena Franco, Francesca Granata, Lorena Duca, Debora Lattuada, Giacomo De Luca and Giovanna Graziadei

Life 2023, 13(9), 1923; https://doi.org/10.3390/life13091923 - 15 Sep 2023

Cited by 4 | Viewed by 1391

Abstract

No published study has investigated the mitochondrial count in patients suffering from acute intermittent porphyria (AIP). In order to determine whether mitochondrial content can influence the pathogenesis of porphyria, we measured the mitochondrial DNA (mtDNA) copy number in the peripheral blood cells of 34 patients and 37 healthy individuals. We found that all AIP patients had a low number of mitochondria, likely as a result of a protective mechanism against an inherited heme synthesis deficiency. Furthermore, we identified a close correlation between disease penetrance and decreases in the mitochondrial content and serum levels of PERM1, a marker of mitochondrial biogenesis. In a healthy individual, mitochondrial count is usually modulated to fit its ability to respond to various environmental stressors and bioenergetic demands. In AIP patients, coincidentally, the phenotype only manifests in response to endogenous and exogenous triggers factors. Therefore, these new findings suggest that a deficiency in mitochondrial proliferation could affect the individual responsiveness to stimuli, providing a new explanation for the variability in the clinical manifestations of porphyria. However, the metabolic and/or genetic factors responsible for this impairment remain to be identified. In conclusion, both mtDNA copy number per cell and mitochondrial biogenesis seem to play a role in either inhibiting or promoting disease expression. They could serve as two novel biomarkers for porphyria. Full article

(This article belongs to the Special Issue Heme Metabolism and Porphyria)

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11 pages, 1715 KiB

Open AccessCommunication

First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria

by Adrian Belosevic, Anna-Elisabeth Minder, Morgan Gueuning, Franziska van Breemen, Gian Andri Thun, Maja P. Mattle-Greminger, Stefan Meyer, Alessandra Baumer, Elisabeth I. Minder, Xiaoye Schneider-Yin and Jasmin Barman-Aksözen

Life 2023, 13(9), 1889; https://doi.org/10.3390/life13091889 - 10 Sep 2023

Cited by 1 | Viewed by 2274

Abstract

Acute porphyrias are a group of monogenetic inborn errors of heme biosynthesis, characterized by acute and potentially life-threatening neurovisceral attacks upon exposure to certain triggering factors. Biochemical analyses can determine the type of acute porphyria, and subsequent genetic analysis allows for the identification of pathogenic variants in the specific gene, which provides information for family counselling. In 2017, a male Swiss patient was diagnosed with an acute porphyria while suffering from an acute attack. The pattern of porphyrin metabolite excretion in urine, faeces, and plasma was typical for an acute intermittent porphyria (AIP), which is caused by inherited autosomal dominant mutations in the gene for hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. However, the measurement of HMBS enzymatic activity in the erythrocytes was within the normal range and Sanger sequencing of the HMBS gene failed to detect any pathogenic variants. To explore the molecular basis of the apparent AIP in this patient, we performed third-generation long-read single-molecule sequencing (nanopore sequencing) on a PCR product spanning the entire HMBS gene, including the intronic sequences. We identified a known pathogenic variant, c.77G>A, p.(Arg26His), in exon 3 at an allelic frequency of ~22% in the patient’s blood. The absence of the pathogenic variant in the DNA of the parents and the results of additional confirmatory studies supported the presence of a de novo mosaic mutation. To our knowledge, such a mutation has not been previously described in any acute porphyria. Therefore, de novo mosaic mutations should be considered as potential causes of acute porphyrias when no pathogenic genetic variant can be identified through routine molecular diagnostics. Full article

(This article belongs to the Special Issue Heme Metabolism and Porphyria)

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15 pages, 2733 KiB

Open AccessEditor’s ChoiceArticle

Afamelanotide Is Associated with Dose-Dependent Protective Effect from Liver Damage Related to Erythropoietic Protoporphyria

by Anna-Elisabeth Minder, Xiaoye Schneider-Yin, Henryk Zulewski, Christoph E. Minder and Elisabeth I. Minder

Life 2023, 13(4), 1066; https://doi.org/10.3390/life13041066 - 21 Apr 2023

Cited by 4 | Viewed by 2508

Abstract

In animal models, melanocyte-stimulating hormones (MSHs) protect the liver from various injuries. Erythropoietic protoporphyria (EPP), a metabolic disorder, leads to the accumulation of protoporphyrin (PPIX). In addition to the most prominent symptom of incapacitating phototoxic skin reactions, 20% of EPP patients exhibit disturbed liver functioning and 4% experience terminal liver failure caused by the hepatobiliary elimination of excess PPIX. Skin symptoms are mitigated through the application of the controlled-release implant afamelanotide, an α-MSH analog, every sixty days. Recently, we showed that liver function tests (LFTs) improved during afamelanotide treatment when compared to before treatment. The present study investigated whether this effect is dose-dependent, as the evidence of dose dependency would support a beneficial influence of afamelanotide. Methods: In this retrospective observational study, we included 2933 liver-function tests, 1186 PPIX concentrations and 1659 afamelanotide implant applications in 70 EPP patients. We investigated whether the number of days since the preceding afamelanotide dose or the number of doses during the preceding 365 days had an effect on LFTs and PPIX levels. In addition, we assessed the effect of global radiation. Results: Inter-patient differences exerted the most prominent effect on PPIX and LFTs. In addition, PPIX increased significantly with an increase in the number of days since the last afamelanotide implant (p < 0.0001). ALAT and bilirubin decreased significantly with an increasing number of afamelanotide doses in the preceding 365 days (p = 0.012, p = 0.0299, respectively). Global radiation only influenced PPIX (p = 0.0113). Conclusions: These findings suggest that afamelanotide ameliorates both PPIX concentrations and LFTs in EPP in a dose-dependent manner. Full article

(This article belongs to the Special Issue Heme Metabolism and Porphyria)

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15 pages, 2022 KiB

Open AccessArticle

Proteomic Analysis of Ferrochelatase Interactome in Erythroid and Non-Erythroid Cells

by Chibuike David Obi, Harry A. Dailey, Yasaman Jami-Alahmadi, James A. Wohlschlegel and Amy E. Medlock

Life 2023, 13(2), 577; https://doi.org/10.3390/life13020577 - 18 Feb 2023

Cited by 4 | Viewed by 2731

Abstract

Heme is an essential cofactor for multiple cellular processes in most organisms. In developing erythroid cells, the demand for heme synthesis is high, but is significantly lower in non-erythroid cells. While the biosynthesis of heme in metazoans is well understood, the tissue-specific regulation of the pathway is less explored. To better understand this, we analyzed the mitochondrial heme metabolon in erythroid and non-erythroid cell lines from the perspective of ferrochelatase (FECH), the terminal enzyme in the heme biosynthetic pathway. Affinity purification of FLAG-tagged-FECH, together with mass spectrometric analysis, was carried out to identify putative protein partners in human and murine cell lines. Proteins involved in the heme biosynthetic process and mitochondrial organization were identified as the core components of the FECH interactome. Interestingly, in non-erythroid cell lines, the FECH interactome is highly enriched with proteins associated with the tricarboxylic acid (TCA) cycle. Overall, our study shows that the mitochondrial heme metabolon in erythroid and non-erythroid cells has similarities and differences, and suggests new roles for the mitochondrial heme metabolon and heme in regulating metabolic flux and key cellular processes. Full article

(This article belongs to the Special Issue Heme Metabolism and Porphyria)

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13 pages, 4786 KiB

Open AccessArticle

Protoporphyrin IX Binds to Iron(II)-Loaded and to Zinc-Loaded Human Frataxin

by Ganeko Bernardo-Seisdedos, Andreas Schedlbauer, Tania Pereira-Ortuzar, José M. Mato and Oscar Millet

Life 2023, 13(1), 222; https://doi.org/10.3390/life13010222 - 12 Jan 2023

Cited by 2 | Viewed by 2127

Abstract

(1) Background: Human frataxin is an iron binding protein that participates in the biogenesis of iron sulfur clusters and enhances ferrochelatase activity. While frataxin association to other proteins has been extensively characterized up to the structural level, much less is known about the putative capacity of frataxin to interact with functionally related metabolites. In turn, current knowledge about frataxin’s capacity to coordinate metal ions is limited to iron (II and III); (2) Methods: here, we used NMR spectroscopy, Molecular Dynamics, and Docking approaches to demonstrate new roles of frataxin; (3) Results: We demonstrate that frataxin also binds Zn²⁺ in a structurally similar way to Fe²⁺, but with lower affinity. In turn, both Fe²⁺-loaded and Zn²⁺-loaded frataxins specifically associate to protoporphyrin IX with micromolar affinity, while apo-frataxin does not bind to the porphyrin. Protoporphyrin IX association to metal-loaded frataxin shares the binding epitope with ferrochelatase; and (4) Conclusions: these findings expand the plethora of relevant molecular targets for frataxin and may help to elucidate the yet unknown different roles that this protein exerts in iron regulation and metabolism. Full article

(This article belongs to the Special Issue Heme Metabolism and Porphyria)

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8 pages, 1068 KiB

Open AccessArticle

Mortality in Pedigrees with Acute Intermittent Porphyria

by Rochus Neeleman, Kyra Musters, Margreet Wagenmakers, Sophie Mijnhout, Edith Friesema, Eric Sijbrands and Janneke Langendonk

Life 2022, 12(12), 2059; https://doi.org/10.3390/life12122059 - 8 Dec 2022

Cited by 1 | Viewed by 1539

Abstract

High mortality rates have been reported in historical cohorts of acute intermittent porphyria (AIP) patients. The mortality associated with (hydroxymethylbilane synthase) HMBS variant heterozygosity is unknown. This study estimates all-cause mortality in pedigrees with HMBS gene variants that cause AIP. We collected data on the lifespan of individuals in Dutch AIP pedigrees and performed analyses using the family tree mortality ratio method. This gave us standardized mortality ratios for these pedigrees compared to the Dutch general population as a primary outcome. Between 1810 and 2017, the overall mortality in these pedigrees was identical to that of the general Dutch population: (SMR 1.01, p = 0.441). However, compared with the general population the SMR was significantly higher in women aged 45–64 years (SMR 1.99, p = 0.00003), which was based on excess mortality between 1915 and 1964 (SMR 1.94, p < 0.00002). In men aged 70–74 years, the SMR was 1.55 (p = 0.0021), based on excess mortality that occurred between 1925 and 1964 (SMR 1.92, p = 0000000003). Overall, mortality from HMBS variant heterozygosity was not increased compared with the general population. Severe excess mortality occurred in young women and old men between 1915 and 1964. Heterozygotes reached a normal lifespan during the past half-century, in parallel with disease awareness and the prevention of new attacks through family counselling. Full article

(This article belongs to the Special Issue Heme Metabolism and Porphyria)

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18 pages, 722 KiB

Open AccessArticle

Dental and Periodontal Health in Acute Intermittent Porphyria

by Elin Storjord, Stella Airila-Månsson, Katarzyna Karlsen, Martin Madsen, Jim André Dahl, Anne Landsem, Hilde Fure, Judith Krey Ludviksen, Johannes Østrem Fjøse, Amy K. Dickey, Bård Ove Karlsen, Erik Waage Nielsen, Tom Eirik Mollnes and Ole-Lars Brekke

Life 2022, 12(8), 1270; https://doi.org/10.3390/life12081270 - 19 Aug 2022

Cited by 5 | Viewed by 4131

Abstract

In the inherited metabolic disorder acute intermittent porphyria (AIP), high sugar intake prevents porphyric attacks due to the glucose effect and the following high insulin levels that may lower AIP disease activity. Insulin resistance is a known risk factor for periodontitis and sugar changes diabetogenic hormones and affects dental health. We hypothesized differences in homeostasis model assessment (HOMA) scores for insulin resistance in AIP cases vs. controls and in those with periodontitis. Our aim was to systematically study dental health in AIP as poor dental health was previously only described in case reports. Further, we aimed to examine if poor dental health and kidney failure might worsen AIP as chronic inflammation and kidney failure might increase disease activity. In 47 AIP cases and 47 matched controls, X-rays and physical examination of clinical attachment loss (CAL), probing pocket depth (PPD), and decayed missing filled teeth (DMFT) were performed. Dietary intake was evaluated through a diet logbook. Plasma cytokines and diabetogenic hormones were measured using multiplex technology and urine porphobilinogen and kidney and liver function by routine methods. An excel spreadsheet from the University of Oxford was used to estimate HOMA scores; beta cell function, HOMA%B (%B), insulin sensitivity, HOMA%S (%S), and insulin resistance HOMA-IR (IR), based on glucose and plasma (P) C-peptide. The Wilcoxon matched-pairs signed rank test, the Mann–Whitney U-test, and Spearman’s non-parametric correlation were used. Insulin (p = 0.007) and C-peptide (p = 0.006) were higher in the AIP cases with periodontitis versus those without. In AIP patients, the liver fibrosis index 4 correlated with DMFT (p < 0.001) and CAL ≥4 mm (p = 0.006); the estimated glomerular filtration rate correlated with DMFT (p < 0.001) and CAL ≥4 mm (p = 0.02). CAL ≥4 mm was correlated with chemokine ligand 11 and interleukin (IL)-13 (p = 0.04 for both), and PPD >5 mm was correlated with plasminogen activator inhibitor-1 (p = 0.003) and complement component 3 (p = 0.02). In conclusion, dental health in AIP cases was correlated with insulin resistance, inflammatory markers, and biomarkers of kidney and liver function, demonstrating that organ damage in the kidney and liver are associated with poorer dental health. Full article

(This article belongs to the Special Issue Heme Metabolism and Porphyria)

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Review

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15 pages, 1381 KiB

Open AccessReview

Recent Insights into the Pathogenesis of Acute Porphyria Attacks and Increasing Hepatic PBGD as an Etiological Treatment

by Daniel Jericó, Karol M. Córdoba, Ana Sampedro, Lei Jiang, Gilles Joucla, Charlotte Cabanne, José Luis Lanciego, Paolo G. V. Martini, Pedro Berraondo, Matías A. Ávila and Antonio Fontanellas

Life 2022, 12(11), 1858; https://doi.org/10.3390/life12111858 - 11 Nov 2022

Cited by 11 | Viewed by 3014

Abstract

Rare diseases, especially monogenic diseases, which usually affect a single target protein, have attracted growing interest in drug research by encouraging pharmaceutical companies to design and develop therapeutic products to be tested in the clinical arena. Acute intermittent porphyria (AIP) is one of these rare diseases. AIP is characterized by haploinsufficiency in the third enzyme of the heme biosynthesis pathway. Identification of the liver as the target organ and a detailed molecular characterization have enabled the development and approval of several therapies to manage this disease, such as glucose infusions, heme replenishment, and, more recently, an siRNA strategy that aims to down-regulate the key limiting enzyme of heme synthesis. Given the involvement of hepatic hemoproteins in essential metabolic functions, important questions regarding energy supply, antioxidant and detoxifying responses, and glucose homeostasis remain to be elucidated. This review reports recent insights into the pathogenesis of acute attacks and provides an update on emerging treatments aimed at increasing the activity of the deficient enzyme in the liver and restoring the physiological regulation of the pathway. While further studies are needed to optimize gene therapy vectors or large-scale production of liver-targeted PBGD proteins, effective protection of PBGD mRNA against the acute attacks has already been successfully confirmed in mice and large animals, and mRNA transfer technology is being tested in several clinical trials for metabolic diseases. Full article

(This article belongs to the Special Issue Heme Metabolism and Porphyria)

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Other

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9 pages, 2223 KiB

Open AccessBrief Report

Afamelanotide for Treatment of the Protoporphyrias: Impact on Quality of Life and Laboratory Parameters in a US Cohort

by Rebecca K. Leaf, Hetanshi Naik, Paul Y. Jiang, Sarina B. Elmariah, Pamela Hodges, Jennifer Mead, John Trinidad, Behnam Saberi, Benny Tran, Sarah Valiante, Francesca Mernick, David E. Leaf, Karl E. Anderson and Amy K. Dickey

Life 2024, 14(6), 689; https://doi.org/10.3390/life14060689 - 28 May 2024

Viewed by 1091

Abstract

Background: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare disorders of heme biosynthesis characterized by severe cutaneous phototoxicity. Afamelanotide, an α-melanocyte-stimulating hormone analogue, is the only approved treatment for protoporphyria and leads to increased light tolerance and improved quality of life (QoL). However, published experience with afamelanotide in the US is limited. Methods: Here, we report on all adults who received at least one dose of afamelanotide at the Massachusetts General Hospital Porphyria Center from 2021 to 2022. Changes in the time to phototoxic symptom onset, QoL, and laboratory parameters were assessed before and during treatment with afamelanotide. Results: A total of 29 patients with protoporphyria were included, 26 of whom (72.2%) received ≥2 afamelanotide implants. Among the patients who received ≥2 implants, the median time to symptom onset following sunlight exposure was 12.5 min (IQR, 5–20) prior to the initiation of afamelanotide and 120 min (IQR, 60–240) after treatment (p < 0.001). Improvements in QoL during afamelanotide treatment were measured using two QoL tools, with good correlation observed between these two instruments. Finally, we found no improvements in the median levels of metal-free erythrocyte protoporphyrin, plasma protoporphyrin, or liver biochemistries during versus prior to the initiation of afamelanotide treatment. Conclusions: This study highlights a dramatic clinical benefit of afamelanotide in relation to light tolerance and QoL in protoporphyria, albeit without improvement in protoporphyrin levels or measures of liver function. Full article

(This article belongs to the Special Issue Heme Metabolism and Porphyria)

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