OBJECTIVES:Erythropoietic protoporphyria (EPP) is a genetic disorder in which deficient ferrochelatase (FECH) activity causes the excessive production and excretion of protoporphyrin. This in turn ...causes the major clinical manifestation of EPP, photosensitivity and, in some patients, hepatobiliary disease that may be severe. The objective of this study was to define genotypic determinants of phenotype in EPP.
METHODS:FECH activity was measured in 30 tissue samples from 26 patients with symptomatic EPP to determine the degree of deficient activity. FECH DNA analysis was also done in 26 families with EPP to identify mutations and examine for the presence of a polymorphism (IVS3-48c) that causes low gene expression.
RESULTS:The level of residual FECH activity that was measured in tissue samples of patients with symptomatic EPP was ≤30% of the mean normal level in all patients except one. Lowest levels (4-20% normal) were in patients with advanced EPP liver disease. Heterozygous FECH mutations were found in 45 individuals from 26 families with EPP. In 94% of the 32 symptomatic individuals, 15 of whom had liver disease, the polymorphism was present in the nonmutant allele. In 13 asymptomatic patients, the polymorphism was absent.
CONCLUSIONS:Patients with symptomatic EPP (photosensitivity with/without hepatobiliary disease) usually have a mutation in 1 FECH allele that alters enzyme structure/function, together with a polymorphism in the nonmutant allele that causes low gene expression. This leads to a significant reduction in FECH activity that causes symptomatic disease to develop because of the excess protoporphyrin produced.
Afamelanotide for Erythropoietic Protoporphyria Langendonk, Janneke G; Balwani, Manisha; Anderson, Karl E ...
The New England journal of medicine,
07/2015, Letnik:
373, Številka:
1
Journal Article
Recenzirano
In patients with erythropoietic protoporphyria, sensitivity to the sun leads to pain and compromised quality of life. In two clinical trials, one in Europe and one in the United States, a peptide ...analogue of an α-melanocyte–stimulating hormone alleviated symptoms.
Erythropoietic protoporphyria is a rare, autosomal recessive inborn error of metabolism that typically manifests in early childhood as severe painful photosensitivity. The photosensitivity results from accumulated protoporphyrin in erythroid cells and tissues because of the decreased activity of ferrochelatase, the heme biosynthetic enzyme that inserts iron into protoporphyrin to form heme.
1
–
4
An X-linked form of erythropoietic protoporphyria
5
,
6
that accounts for 2 to 10% of cases results from a gain of function of erythroid-specific aminolevulinic acid synthase 2.
Pathophysiologically, protoporphyrin is released from erythroid cells into the circulation, gains access to the vascular endothelium and liver, and is excreted . . .
Acute myelogenous leukemia occurred in a 47-year-old woman whose 25-year history of cutaneous photosensitivity had been undiagnosed until abnormally high erythrocyte, plasma, and fecal protoporphyrin ...levels were discovered during evaluation for her hematologic disorder. She was found to be heteroallelic for ferrochelatase gene mutations, bearing a novel missense mutation caused by a C185→G (Pro62→Arg) transversion in exon 2 of one allele, and a previously described g→a transition at the +5 position of the exon 1 donor site of the other allele, confirming a diagnosis of erythropoietic protoporphyria. Successful bone marrow transplantation from her brother, who is a mildly affected bearer of the second mutation, resulted in remission of the leukemia and in conversion of the protoporphyria phenotype of the recipient to one resembling that of the donor. (J Am Acad Dermatol 2002;46:861-6.)
IMPORTANCE: Autosomal recessive erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses presenting with variable degrees of painful phototoxicity that markedly ...affects quality of life. The clinical variability, determinants of severity, and genotype/phenotype correlations of these diseases are not well characterized. OBJECTIVE: To describe the baseline clinical characteristics, genotypes, and determinants of disease severity in a large patient cohort with EPP or XLP. DESIGN, SETTING, AND PARTICIPANTS: A prospective observational study was conducted among patients with confirmed diagnoses of EPP or XLP from November 1, 2010, to December 6, 2015, at 6 academic medical centers of the Porphyrias Consortium of the National Institutes of Health Rare Diseases Clinical Research Network. Detailed medical histories, including history of phototoxicity and treatment, were collected on standardized case report forms. Patients underwent baseline laboratory testing, total erythrocyte protoporphyrin (ePPIX) testing, and molecular genetic testing. Data were entered into a centralized database. MAIN OUTCOMES AND MEASURES: Results of biochemical and genetic tests were explored for association with clinical phenotype in patients with EPP or XLP. RESULTS: Of the 226 patients in the study (113 female and 113 male patients; mean SD age, 36.7 17.0 years), 186 (82.3%) had EPP with a FECH (OMIM 612386) mutation and the common low-expression FECH allele IVS3–48T>C, and only 1 patient had 2 FECH mutations. Twenty-two patients had XLP (9.7%; 10 male and 12 female patients), and 9 patients (4.0%) had elevated ePPIX levels and symptoms consistent with protoporphyria but no detectable mutation in the FECH or ALAS2 (OMIM 301300) gene. Samples of DNA could not be obtained from 8 patients. Patients’ mean (SD) age at symptom onset was 4.4 (4.4) years. Anemia (107 47.3%), history of liver dysfunction (62 27.4%), and gallstones (53 23.5%) were commonly reported. Higher ePPIX levels were associated with earlier age of symptom onset (median ePPIX levels for those who developed symptoms before vs after 1 year of age, 1744 vs 1567 µg/dL; P = .02), less sun tolerance (median ePPIX levels for those reporting symptoms before vs after 10 minutes of sun exposure, 2233 vs 1524 µg/dL; P ≤ .001), and increased risk of liver dysfunction (median ePPIX levels for those with liver dysfunction vs normal liver function, 2016 vs 1510 µg/dL; P = .003). Patients with EPP and FECH missense mutations had significantly lower ePPIX levels than those with other mutations (1462 vs 1702 µg/dL; P = .01). Male patients with XLP had significantly higher ePPIX levels, on average, than did patients with EPP (3574 vs 1669 µg/dL; P < .001). Marked clinical variability was seen in female patients with XLP owing to random X-chromosomal inactivation. CONCLUSIONS AND RELEVANCE: These data suggest that higher ePPIX levels are a major determinant of disease severity and risk of liver dysfunction in patients with EPP or XLP. These findings provide a framework for clinical monitoring and management of these disorders.
Erythropoietic protoporphyria (EPP) is characterized by excess accumulation of protoporphyrin, which is due to deficient activity of the enzyme ferrochelatase (FECH). This results in photosensitivity ...and in some patients liver disease which may necessitate liver transplantation. The aim of this study was to delineate the abnormalities in the
FECH gene which cause phenotypic expression in EPP. We identified 43 individuals from 25 North American families with EPP who were heterozygous for various
FECH mutations, but the mutations did not adequately explain the variable phenotype. We also examined the presence of an intron polymorphism (IVS3-48c) in the
FECH gene which was shown to cause the formation of aberrantly spliced FECH mRNA
1.
FECH DNA analysis demonstrated that 94% of 31 symptomatic individuals with
FECH mutations were heterozygous for IVS3-48c, whereas 12 asymptomatic individuals with
FECH mutations were homozygous for IVS3-48t. Haplotype analysis in four families showed that symptomatic members had the IVS3-48c polymorphism in the non-mutant
FECH allele. Sequencing of the proximal
FECH gene promoter showed no additional changes which might affect gene expression. The levels of normal FECH mRNA, measured by relative quantitative RT-PCR, and FECH enzyme activity were correspondingly lower in the cultured lymphoblasts of family members with the IVS3-48c polymorphism. These results indicate that symptomatic disease in most North American patients with EPP is explained by the inheritance of a mutation in one
FECH allele which causes a structural alteration in the protein, together with a low expressing non-mutant
FECH allele which is caused by the IVS3-48c polymorphism.
Erythropoietic protoporphyria (EPP) is a rare inherited disorder of the heme biosynthetic pathway in which toxic levels of protoporphyrins often precipitate in the liver, leading to cirrhosis, liver ...failure, and the need for liver transplantation (OLT). Because the underlying enzyme defect in EPP is bone marrow derived, the risk for recurrent EPP allograft dysfunction is high. Although plasmapheresis may ameliorate acute allograft disease, strategies to maintain disease remission are needed. A 59-year-old man who underwent OLT for hepatic EPP experienced increased bilirubin and aminotransferases on postoperative day 700. Allograft biopsy demonstrated recurrent EPP. He was managed initially with plasmapheresis, hypertransfusion, and infusions of i.v. hematin. After normalization of liver tests, the hematin infusions have been given intermittently, are well tolerated, and associated with normal allograft function for nearly 2 years. This is the first case of the use of hematin given post-OLT to help achieve and maintain remission of allograft EPP disease.
PDF
