A recent large analysis indicates that the prevalence of erythropoietic protoporphyria (EPP) is nearly 2.3 times higher than previously estimated in the U.K.
The analysis of the UK Biobank data set, which includes more than 500,000 people, also identified an association between the FECH gene — whose mutations cause EPP — and both smaller red blood cells and lower levels of hemoglobin (the oxygen-carrying protein found in red blood cells).
The analysis, “Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria,” was published in the journal Genetics in Medicine.
The FECH gene provides instructions for making an enzyme called ferrochelatase, which converts the light-sensitive molecule protoporphyrin IX (PPIX) to heme, a component of hemoglobin. The resulting accumulation of PPIX in the blood, skin, bone marrow, and liver leads to symptoms including extreme sensitivity to the sunlight.
Most EPP patients carry rare FECH mutations that are in trans (on a different chromosome) of the common variant, called c.315-48T>C, which dramatically reduces ferrochelatase’s activity. The prevalence of EPP, based on diagnoses in Europe, has been estimated at 0.00092%. However, the reliability of this estimate is uncertain due to difficulties and delays in EPP diagnosis.
Investigators at Harvard University and their collaborators sought to estimate EPP prevalence using clinical and genetic data sets, including the UK Biobank, and the Porphyrias Consortium, Partners Biobank and Women’s Genome Health Study in the U.S.
Through assessment of the number of individuals with FECH variants that cause disease when in trans of c.315-48T>C and the frequency of this mutation, the researchers estimated that EPP prevalence in individuals of European ancestry in the U.K. is 0.0052%.
Then, when comparing frequencies across the different data sets to account for a calculation of unidentified mutations, they found that the estimated prevalence increased to 0.0059%, which is 2.3 times the current prevalence estimation in the U.K.
In the U.K, the prevalence of c.315-48T>C varied across ethnicities, with individuals of Asian descent have the highest prevalence. In this population, 42.1% are heterozygotes, meaning that they inherited one mutated gene copy from one parent, and 8.8% are homozygotes, as they inherited an altered copy from both parents.
“This study provides evidence that EPP is under-diagnosed, which should encourage efforts to decrease the many barriers that EPP patients face in their attempt to find a diagnosis,” the researchers wrote.
In people with one or two mutated copies, as well as in patients with one c.315-48T>C mutation and a rare FECH variant, the more common mutation was associated with smaller red blood cells, measured by red blood cell mean corpuscular volume (MCV). Hemoglobin levels also were reduced in people with the c.315-48T>C mutation in both gene copies, who had a 1.4 times higher likelihood of hemoglobin deficiency. Together, these findings demonstrate a previously unidentified relationship between c.315-48T>C and red blood cell count and hemoglobin levels.
Among the study limitations were the inability to diagnose EPP or test for iron deficiency, the possibility for error in correction predictions, and the overrepresentation of healthy individuals in the data set. Further research is necessary to assess the prevalence of EPP and to determine how c.315-48T>C correlates with MCV and hemoglobin deficiency.
“A new treatment for EPP called afamelanotide [Scensesse] was approved in Europe a few years ago and recently approved by the US FDA [U.S. Food and Drug Administration]; consequently, efforts to identify patients is increasingly important to bring this and future new therapies to individuals who could benefit from them,” the research team wrote.
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