- Diagnosis of erythropoietic protoporphyria (EPP), a rare inherited disease characterized by lifelong severe, painful cutaneous photosensitivity, is often delayed more than a decade or missed altogether
- In this analysis of the UK Biobank, the estimated genetic prevalence of EPP among individuals of European ancestry was 0.0052%
- That estimate increased to 0.0059% after correction for pathogenic variants not reported in the UK Biobank exomic sequences and variants that could not be identified as pathogenic
- The 0.0059% prevalence figure is 2.3 times higher than a previous estimate for the UK that was based on the rate of diagnosis of EPP
Erythropoietic protoporphyria (EPP) is a rare inherited disease characterized by lifelong severe, painful cutaneous photosensitivity. Patients may also experience iron deficiency anemia, gallstones and rapidly progressive cholestatic liver failure, which without liver transplant is often fatal.
In a previous study published in the Journal of Inherited Metabolic Disease, the prevalence of EPP in Europe was estimated at 0.00092%. That figure was suspected to be low, however, because the diagnosis of EPP is often delayed more than a decade or missed altogether. A treatment for EPP, afamelanotide, has been approved for several years in Europe and was recently approved in the U.S., and it's important to get it to people who could benefit.
Physician-Investigators David C. Christiani, MD, MPH, and Amy K. Dickey, MD, MSc, of the Division of Pulmonary and Critical Care Medicine at Massachusetts General Hospital, and colleagues recently became the first to estimate EPP prevalence using a large genetic data set. In Genetics in Medicine, they report that EPP is twice as common in Europe as previously reported.
The team analyzed the UK Biobank, which contains clinical and genetic data on 500,953 individuals ages 40 to 69. They assessed genotypes for all participants using a single-nucleotide polymorphism array, then performed exome sequencing on 49,960 of the participants, of whom 38,841 were unrelated individuals of European ancestry.
Frequency of Pathogenic Variants
EPP is caused by pathogenic variants in ferrochelatase (FECH), the last enzyme in the heme biosynthetic pathway that causes accumulation of protoporphyrin IX, a light-sensitive molecule, in erythrocytes. About 96% of people with EPP carry rare FECH mutations that are in trans of (on a different chromosome from) a common FECH variant, c.315-48T>C.
54 of the 49,960 individuals had FECH variants pathogenic for EPP when in trans of the c.315-48T>C variant. Among the individuals of European ancestry, the estimated genetic prevalence of EPP was 0.0052%.
This estimate increased to 0.0059% when the researchers corrected for pathogenic variants not reported in the UK Biobank exomic sequences and for variants that could not be identified as pathogenic due to insufficient clinical data. The 0.0059% figure is 2.3 (95% CI, 1.7–3.0) times higher than the previous estimate for Europe.
Doing Better by Patients with EPP
This study suggests EPP is underdiagnosed. Efforts are needed to decrease the barriers EPP patients face in their attempt to find an explanation for their symptoms, such as:
- Few physicians know about EPP
- Some patients have minimal or no visible skin changes, despite severe pain, and even specialists may not consider EPP in the differential diagnosis
- Some major commercial labs, such as Quest and LabCorp, provide a "free erythrocyte protoporphyrin" test, but it measures zinc protoporphyrin, which is often normal in EPP
Possible solutions include routine genomic sequencing, adding clinical decision support tools to the electronic medical record and ensuring that laboratory testing includes measurement of erythrocyte total and metal-free protoporphyrin.
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