For patients with rare diseases, finding the right diagnosis can be a significant challenge. When that disease has no visible symptoms, the challenge becomes even greater.

Sadly, this is often the experience for patients with erythropoietic protoporphyria (EPP), a rare inherited disorder in which exposure to sunlight and some types of artificial light causes severe pain.

While some EPP patients experience outward signs of the disease such swelling or burst blood vessels, many have no visible symptoms despite being in severe pain.

The lack of visible symptoms—along with a general lack of awareness about EPP in the medical community—often leads to skepticism among doctors, who frequently believe patients are making up or exaggerating their symptoms.

EPP patients have stories of being sent to psychiatrists or forced into the sun, compounding the distress of an already difficult disease.

Amy Dickey, MD, a Massachusetts General Hospital physician and EPP patient, is all too familiar with this struggle.

Dickey’s family first sought medical help for the pain soon after she developed symptoms at age three, but her parents were told she was making it up.

She did not receive the correct diagnosis until she was 12, when she had a particularly bad reaction that included severe swelling and burst blood vessels.

As with many newly diagnosed patients, she felt a sense of relief. “Growing up not knowing what was happening felt isolating and confusing,” she says. “Having a diagnosis was empowering.”

Despite the nine-year wait for answers, Dickey considers herself lucky. “A lot of people are diagnosed with EPP much later, in their forties or fifties, despite having severe disease.” EPP wasn’t even discovered until 1961.

Dickey’s experience—and that of other EPP patients—leads her to believe there are more individuals with EPP out there who have yet to be diagnosed.

A recent research study she co-led with Mass General’s David Christiani, MD, found compelling evidence to support that belief. The results of that study were recently published in Genetics in Medicine.

About EPP

EPP is caused by a harmful genetic variant in the FECH gene. This variant impairs the production of the enzyme ferrochelatase, which is important to the production of heme—an iron-containing molecule in the blood that helps carry oxygen throughout the body.

Most individuals have two fully expressing FECH genes, but about 10% of people have one low expression gene. EPP occurs when an individual inherits both a non-functioning gene and the common low expression gene.

This genetic combination causes red blood cells to have a buildup of a substance called metal-free protoporphyrin, which is heme that lacks the iron necessary to function correctly.

Protoporphyrin is very similar to chlorophyll, the light-catching particles in plants. It also catches light, and this causes severe pain reactions in patients with EPP that can last up to a week.

“It’s basically the worst pain you can think of,” says Dickey. “It starts off as an itching and tingling sensation, and then it gets worse. It feels like you’re on fire, but there’s no way to put it out.”

Sunscreen does not offer protection because EPP patients are affected by visible light, not the UV light that sunscreen is formulated to block.

“Because they are so painful, I avoid reactions at all costs,” she says. “I use sun-protective clothing when needed and avoid being in the sun for too long.”

While Dickey can be in the sun for up to an hour, most patients can only tolerate a few minutes or less. Some patients even develop symptoms when exposed to bright indoor lights. EPP patients are also at risk for anemia, and about 2% of patients need a liver transplant because of liver failure.

Evidence of Under-Diagnosis

In a study of genetic data from 50K participants in the UK Biobank, Dickey and team found that the number of individuals with the genetic pairing that causes EPP was seven times higher than the number of individuals who had been diagnosed.

In EPP, researchers have previously shown that anyone with the right combination of genetic variants will have the disease.

The prevalence of EPP in the data set turned out to be 1 in 17,000 people, which is 2.3 times higher than the previously reported prevalence of EPP in the UK and almost 6 times higher than what had previously been reported across all of Europe.

To ensure that the data within the UK Biobank was not an outlier, the team compared their results to genomic information in three additional data sets (the Partners Biobank, gnomAD, and the Women’s Genome Health Study), and found no statistically significant differences.

“This study provides evidence that EPP is under-diagnosed, which should encourage efforts to decrease the many barriers EPP patients face in their attempts to find a diagnosis,” the team writes.

“A new treatment (afamelanotide) was recently approved by the FDA; consequently, efforts to identify patients is increasingly important to bring this and future new therapies to individuals who could benefit from them.”

Biochemical data from the UK Biobank also shows that the 10% of people with the FECH low expression gene also have higher rates of anemia and a decrease in the size of their red blood cells, suggesting that the gene responsible for EPP also has a role in anemia and iron deficiency. These findings open another avenue of research.

Raising Awareness

Moving forward, Dickey hopes to raise awareness of EPP so that more doctors will more readily consider it when patients present with symptoms and test them for it (see fact sheet below).

She is also collaborating with Rebecca Karp, MD to start a porphyria clinic at Mass General so that patients with EPP and similar disorders can have a comprehensive place to get diagnosed and receive care.

“My heart goes out to those people who have EPP and still don’t why they are experiencing these symptoms that no one else has,” she says.

Dickey wants to help patients with other rare diseases find a diagnosis too. She hopes that her story and her research will motivate doctors to take strange symptoms seriously, even when they are invisible.

“I think it points to a bigger problem in medicine in general that many doctors are quick to blow off symptoms they don’t understand,” she says. “They may be bizarre, but it doesn’t mean that patients are making them up.”

EPP Fact Sheet for Clinicians and Patients

Click on the image to download a printable PDF version of this fact sheet.

About the Mass General Research Institute
Research at Massachusetts General Hospital is interwoven through more than 30 different departments, centers and institutes. Our research includes fundamental, lab-based science; clinical trials to test new drugs, devices and diagnostic tools; and community and population-based research to improve health outcomes across populations and eliminate disparities in care.
Support our Research