In ferrochelatase-deficient protoporphyria patients, ALAS2 expression is enhanced and erythrocytic protoporphyrin concentration correlates with iron availability

Barman‐Aksözen, Jasmin; Minder, Elisabeth I.; Schubiger, Carina; Biolcati, G.; Schneider‐Yin, Xiaoye

doi:10.1016/j.bcmd.2014.07.017

Cited by 39 publications

(51 citation statements)

References 31 publications

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“…We found increases in both ALAS2 and the aberrant FECH splice product in patients compared with controls, and no differences in GDF15, HMBS,andALAS1 between the two groups (data not shown). The increase in both ALAS2 mRNA and protein were reported in our previous work (Barman-Aksozen et al 2015).…”

Section: Comparison Between Epp Patients and Healthy Volunteerssupporting

confidence: 81%

“…We found that iron deficiency decreases ferrochelatase activity by up-regulation of the alternative splicing site in intron 3 of the FECH gene-a mechanism called regulation of unproductive splicing and translation (RUST) (Barman-Aksozen et al 2013). We also described that PPIX concentration was positively correlated with hemoglobin level in individual patients but not among them (Barman-Aksozen et al 2015). We concluded that iron deficiency limits both PPIX overproduction and hemoglobin concentrations in EPP, which are in disagreement with the assumptions of Holme et al (2007) and Delaby et al (2009).…”

Section: Discussionmentioning

confidence: 57%

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Disturbed iron metabolism in erythropoietic protoporphyria and association of GDF15 and gender with disease severity

Barman-Aksoezen

Girelli

Aurizi

et al. 2017

J of Inher Metab Disea

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Patients with erythropoietic protoporphyria (EPP) have reduced activity of the enzyme ferrochelatase that catalyzes the insertion of iron into protoporphyrin IX (PPIX) to form heme. As the result of ferrochelatase deficiency, PPIX accumulates and causes severe photosensitivity. Among different patients, the concentration of PPIX varies considerably. In addition to photosensitivity, patients frequently exhibit low serum iron and a microcytic hypochromic anemia. The aims of this study were to (1) search for factors related to PPIX concentration in EPP, and (2) characterize anemia in EPP, i.e., whether it is the result of an absolute iron deficiency or the anemia of chronic disease (ACD). Blood samples from 67 EPP patients (51 Italian and 16 Swiss) and 21 healthy volunteers were analyzed. EPP patients had lower ferritin (p = 0.021) and hepcidin (p = 0.031) concentrations and higher zinc-protoporphyrin (p < 0.0001) and soluble-transferrin-receptor (p = 0.0007) concentrations compared with controls. This indicated that anemia in EPP resulted from an absolute iron deficiency. Among EPP patients, PPIX concentrations correlated with both growth differentiation factor (GDF) 15 (p = 0.012) and male gender (p = 0.015). Among a subgroup of patients who were iron replete, hemoglobin levels were normal, which suggested that iron but not ferrochelatase is the limiting factor in heme synthesis of individuals with EPP.

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Section: Comparison Between Epp Patients and Healthy Volunteerssupporting

confidence: 81%

Section: Discussionmentioning

confidence: 57%

Disturbed iron metabolism in erythropoietic protoporphyria and association of GDF15 and gender with disease severity

Barman-Aksoezen

Girelli

Aurizi

et al. 2017

J of Inher Metab Disea

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“…In another recent report, three subjects with classical EPP and iron deficiency were found to have somewhat lower levels of PP in RBCs when they were more iron deficient and to exhibit increased levels of ALA synthase‐2 mRNA and protein in their younger erythrocytes . Increased activity of ALA synthase‐2, despite iron deficiency was found even though translation of the mRNA of the synthase is down‐regulated by iron regulatory proteins 1 and 2, which bind to iron‐responsive elements in the 5′‐region of the message and block its translation.…”

Section: Discussionmentioning

confidence: 90%

Homeostasis of iron and hepcidin in erythropoietic protoporphyria

Bossi

Lee

Schmeltzer

et al. 2015

Eur J Clin Investigation

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“…One might anticipate that such deficiency would exacerbate clinical disease due to increased accumulation of PP, which is not converted to heme by FECH, owing to a lack of the necessary iron substrate. Indeed, several case reports have been published showing improvement in symptoms and decreases in PP levels in patients treated with iron supplements 26–28. However, there is controversy in the field regarding the efficacy of iron therapies.…”

Section: Overview Of Management Optionsmentioning

confidence: 99%

“…However, there is controversy in the field regarding the efficacy of iron therapies. Limited evidence shows that some EPP patients had lower red blood cell (RBC) PP levels when they were iron deficient,28,29 while others noted improvements with iron-replacement therapy 13,26,27,30,31. It was recently shown that subjects with EPP or XLPP are able to absorb iron well from the gastrointestinal tract and lack inappropriately high levels of hepcidin 32.…”

Section: Overview Of Management Optionsmentioning

confidence: 99%

Advances in the management of erythropoietic protoporphyria – role of afamelanotide

Lane¹,

McKay²,

Bonkovsky³

2016

TACG

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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.

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In ferrochelatase-deficient protoporphyria patients, ALAS2 expression is enhanced and erythrocytic protoporphyrin concentration correlates with iron availability

Cited by 39 publications

References 31 publications

Disturbed iron metabolism in erythropoietic protoporphyria and association of GDF15 and gender with disease severity

Disturbed iron metabolism in erythropoietic protoporphyria and association of GDF15 and gender with disease severity

Homeostasis of iron and hepcidin in erythropoietic protoporphyria

Advances in the management of erythropoietic protoporphyria – role of afamelanotide

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In ferrochelatase-deficient protoporphyria patients, ALAS2 expression is enhanced and erythrocytic protoporphyrin concentration correlates with iron availability

Cited by 39 publications

References 31 publications

Disturbed iron metabolism in erythropoietic protoporphyria and association of GDF15 and gender with disease severity

Disturbed iron metabolism in erythropoietic protoporphyria and association of GDF15 and gender with disease severity

Homeostasis of iron and hepcidin in erythropoietic protoporphyria

Advances in the management of erythropoietic protoporphyria &ndash; role of afamelanotide

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Advances in the management of erythropoietic protoporphyria – role of afamelanotide