The below link is written by the Porphyria ConsortiumExperts Manisha Balwani, MD, MS, FACMG, Robert Desnick, MD, PhD, FACMG; Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network.
Sahil Mittal, MD, MS
Karl E Anderson, MD, FACP
Moise L Levy, MD
Robert T Means, Jr, MD, MACP
Jennifer S Tirnauer, MD
When EPP is due to an ALAS2 mutation it is termed X-linked protoporphyria (XLP), because that gene is found on the X chromosome.
EPP and XLP, combined, are the third most common Porphyria, with an incidence of possibly 2 to 5 per 1,000,000. They are the most common Porphyria in children. EPP is caused by a lack of the X- Linked Protoporphyria (XLP)
enzyme, ferrochelatase due to mutations in the FECH gene.
X-linked Protoporphyria affects males and females. However, males usually develop a severe form of the disorder while females with an ALAS2 mutation may range from having no symptoms (asymptomatic) to developing a severe form of the disorder. The exact incidence or prevalence of X-linked Protoporphyria is unknown. The disorder has only been reported in the medical literature in a handful of families in Europe, South Africa and Japan.
There is an increased risk of gallstones, which contain protoporphyrin. Excess protoporphyrin can also cause liver damage. Less than 5% of EPP patients’ severe liver damage and a condition caused protoporphyric hepatopathy that sometimes requires liver transplantation.
Synonyms of X-Linked Protoporphyria
- X-linked dominant Protoporphyria
- In XLP, mutations of the ALAS2 gene, which is found on the X chromosome, causes an increase in the production of the enzyme ALAS2 in the bone marrow. Several of these “gain of function” mutations have been described in different XLP families. In XLP protoporphyrin production exceeds that needed for heme and hemoglobin formation. Like hemophilia and other X linked genetic diseases, XLP is more common in men. Women have two X chromosomes and are usually not affected because they have a normal as well as a mutated ALAS2 gene. Men have only one X chromosome and will be affected if they inherit an ALAS2 mutation. Women with an ALAS2 mutation will, on average, pass that mutation to half of their daughters (who will usually be unaffected carriers) and to half of their sons (who will be affected).
- In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.
- Signs and Symptoms
- Swelling, burning, itching, and redness of the skin may appear during or after exposure to sunlight, including sunlight that passes through window glass. This can cause mild to severe burning pain on sun-exposed areas of the skin. Usually, these symptoms subside in 12 to 24 hours and heal without significant scarring. Blistering and scarring are characteristic of other types of cutaneous Porphyria but are unusual in EPP. Skin manifestations generally begin early childhood and are more severe in the summer.
- The most common symptom of XLP is hypersensitivity of the skin to sunlight and some types of artificial light (photosensitivity), with pain, itching, and/or burning of the skin occurring after exposure to sunlight and occasionally to fluorescent light. Affected individuals may also exhibit abnormal accumulations of body fluid under affected areas (edema) and/or persistent redness or inflammation of the skin (erythema). In rare cases, affected areas of the skin may develop sac-like lesions (vesicles or bullae), scar, and/or become discolored
- A diagnosis of X-linked protoporphyria may be made through blood tests that can detect markedly increased levels of metal-free and zinc-bound protoporphyrins within red blood cells (erythrocytes). A higher ratio of zinc-bound protoporphyrin to metal-free protoporphyrin can differentiate X-linked protoporphyria from EPP.
- Molecular genetic testing can confirm a diagnosis of X-linked protoporphyria by detecting mutations in the ALAS2 gene (the only gene known to cause this disorder).
- An experienced biochemical laboratory can usually distinguish between patients with EPP and XLP, because the former has much less zinc protoporphyrin in their erythrocytes. This can be explained because in the marrow the enzyme ferrochelatase not only normally makes heme (iron protoporphyrin) from protoporphyrin and iron, but can also make zinc protoporphyrin, especially when excess protoporphyrin is present or iron is deficient. However, this does not replace DNA studies.