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Not just for boys: X-linked erythropoietic protoporphyria

DII small banner By Warren R. Heymann, MD
Sept. 7, 2017

I was anxiously awaiting the results of erythrocyte protoporphyrin levels obtained from a 4 year-old boy who avoids sunlight because his “skin hurts” when not in the shade. Until I read the article by Balwani, et al (1), I was unaware of the existence of X-linked erythropoietic protoporhyria (XLEPP), also referred to as X-linked dominant protoporphyria). How does XLEPP differ from classical EPP?

Classical EPP arises from the loss-of-function mutations of the ferrochelatase (FECH) gene in approximately 90% of all cases. First described in 2008, XLEPP is due to an increased enzymatic activity of erythroid-specific 5-aminolevulinate synthase 2 (ALAS2), the first enzyme in erythroid heme biosynthesis. Recently, two additional ALAS2 mutations were described. These mutations result in stop or frameshift lesions that prematurely truncate or abnormally elongate the wild-type enzyme, leading to increased ALAS2 activity. Because most of ALA produced is metabolized to porphyrin and that the insertion of Fe2+ into protoporphyrin IX by ferrochelatase (FECH) is a rate-limiting step for erythroid heme synthesis, the continuously increased ALA formation leads to the erythroid accumulation of free and zinc-chelated protoporphyrin IX. XLEPP has been described as an X-linked dominant trait with essentially 100% penetrance; the clinical presentation in females is variable, based on the Lyon hypothesis of random X-inactivation. (2)
EPP has been reported worldwide, with prevalence between 1:75,000 and 1:200,000. Both forms usually present in early infancy upon the first sun exposures, characterized by cutaneous manifestations of acute painful photosensitivity with erythema and edema, sometimes with petechiae, together with stinging and burning sensations upon exposure to sunlight, without blisters. These episodes have a variable severity depending on the exposure duration and may result in chronic permanent lesions on exposed skin. The differential diagnosis includes phototoxic drug reactions, hydroa vacciniforme, solar urticaria, contact dermatitis, angioedema and, in some cases, other types of porphyria. Because protoporphyrin is a lipophilic molecule excreted by the liver, EPP patients are at risk of cholelithiasis with obstructive episodes, and rapid acute liver failure could ensue. According to Lecha et al, the diagnosis is established by finding increased levels of protoporphyrin in plasma and red blood cells, and detection of a plasma fluorescence peak at 634 nm. Investigations for hepatic involvement, ferrochelatase activity level, genetic analysis (FECH mutations and ALAS2 mutations) and family studies are advisable. (3)
The diagnosis of EPP requires a marked increase in total erythrocyte protoporphyrin and a predominance (85%–100%) of metal-free protoporphyrin. XLEPP causes a similar increase in total erythrocyte protoporphyrin but with a somewhat lower fraction of metal-free protoporphyrin (50%–85% of the total). (4). In their study of 226 patients, Balwani et al found that higher erythrocyte protoporphyrin levels correlated with an earlier age of symptom onset, decreased sun tolerance, and increased risk of liver dysfunction. Patients with erythropoietic protoporphyria and FECH missense mutations had lower erythrocyte protoporphyrin levels and a less severe phenotype, and male patients with X-linked protoporphyria had significantly higher erythrocyte protoporphyrin levels than did patients with erythropoietic protoporphyria. (1)
When presenting as an adult, one must consider the possibility of an “acquired” ferrochelatase (FECH) deficiency due to somatic mutations secondary to a myelodysplastic syndrome, as we have previously discussed in DI&I (April 19th, 2016)

Management includes avoidance of exposure to light, including sunscreens, reduction of protoporphyrin levels and prevention of progression of possible liver disease to liver failure. Unfortunately, beta-carotene is not very effective, although cimetidine may have some value (DI&I November 16th, 2016). As the major risk in EPP patients is liver disease, regular follow-up for hepatic involvement is essential. Afamelanotide (Scenesse®) is a first-in-class synthetic analog of alpha-melanocyte stimulating hormone. Afamelanotide mimics the naturally occurring hormone to increase skin pigmentation by increasing melanin production in melanocytes, resulting in increased sunlight tolerance in those with EPP/XLPP. Afamelanotide is currently approved for use in the European Union and Switzerland, and it is under review in the United States by the Food and Drug Administration for use in patients with EPP/XLPP. (5) Sequential hepatic and bone marrow transplantation should be considered as a suitable treatment for the most severe cases of EPP with hepatic involvement. EPP is a lifelong disorder whose prognosis depends on the evolution of the hepatic disease. Photosensitivity, however, may have a significant impact on the quality of life of EPP patients. (3)

My patient’s protoporphyrin levels came back in the normal range — I will need to consider other photosensitive disorders. Personally, I have never made the diagnosis of EPP, let alone XLEPP. Regardless, it remains a life-altering diagnosis that I will continue to search for in the right context.

1. Balwani M, et al. Clinical, biochemical, and genetic characterization of North American patients with erythropoietic protoporphyria and X-linked protoporphyria. JAMA Dermatol 2017; 789-96.
2. Brancaleoni V, et al. X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporhyria. Clin Genet 2016; 89: 20-6.
3. Lecha M, et al. Erythropoietic protoporphyria. Orphanet J Rare Dis 2009; 4: 19.
4. Gou EW, et al. Pitfalls in erythrocyte protoporphyrin measurement for diagnosis and monitoring of protoporphyrias. Clin Chem 2015; 61: 1453-6.
5. Lane AM, et al. Advances in the management of erythropoietic protoporphyria – role of afamelanotide. Appl Clin Genet 2016; 9: 179-89.

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