Erythropoietic Protoporphyria and X-Linked Protoporphyria: pathophysiology, genetics, clinical manifestations, and management.
Genetics
Heme-biosynthesis
Metabolic
Photodermatosis
Porphyria
Journal
Molecular genetics and metabolism
ISSN: 1096-7206
Titre abrégé: Mol Genet Metab
Pays: United States
ID NLM: 9805456
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
18
10
2018
revised:
23
01
2019
accepted:
23
01
2019
pubmed:
2
2
2019
medline:
1
7
2020
entrez:
2
2
2019
Statut:
ppublish
Résumé
Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare, genetic photodermatoses resulting from defects in enzymes of the heme-biosynthetic pathway. EPP results from the partial deficiency of ferrochelatase, and XLP results from gain-of-function mutations in erythroid specific ALAS2. Both disorders result in the accumulation of erythrocyte protoporphyrin, which is released in the plasma and taken up by the liver and vascular endothelium. The accumulated protoporphyrin is activated by sunlight exposure, generating singlet oxygen radical reactions leading to tissue damage and excruciating pain. About 2-5% of patients develop clinically significant liver dysfunction due to protoporphyrin deposition in bile and/or hepatocytes which can advance to cholestatic liver failure requiring transplantation. Clinically these patients present with acute, severe, non-blistering phototoxicity within minutes of sun-exposure. Anemia is seen in about 47% of patients and about 27% of patients will develop abnormal serum aminotransferases. The diagnosis of EPP and XLP is made by detection of markedly increased erythrocyte protoporphyrin levels with a predominance of metal-free protoporphyrin. Genetic testing by sequencing the FECH or ALAS2 gene confirms the diagnosis. Treatment is limited to sun-protection and there are no currently available FDA-approved therapies for these disorders. Afamelanotide, a synthetic analogue of α-melanocyte stimulating hormone was found to increase pain-free sun exposure and improve quality of life in adults with EPP. It has been approved for use in the European Union since 2014 and is not available in the U.S. In addition to the development of effective therapeutics, future studies are needed to establish the role of iron and the risks related to the development of hepatopathy in these patients.
Identifiants
pubmed: 30704898
pii: S1096-7192(18)30641-3
doi: 10.1016/j.ymgme.2019.01.020
pmc: PMC6656624
mid: NIHMS1520451
pii:
doi:
Substances chimiques
Heme
42VZT0U6YR
5-Aminolevulinate Synthetase
EC 2.3.1.37
ALAS2 protein, human
EC 2.3.1.37
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
298-303Subventions
Organisme : NIDDK NIH HHS
ID : K23 DK095946
Pays : United States
Organisme : NCATS NIH HHS
ID : U2C TR002818
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK083909
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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