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Erythropoietic Protoporphyria and X-Linked Protoporphyria

What is Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP)?

EPP is a rare genetic disorder caused by the decreased activity of an enzyme called ferrochelatase, which results from mutations in the FECH gene. Decreased levels of this enzyme result in the excessive accumulation of protoporphyrin in the bone marrow, plasma and red blood cells. About 10% of patients with symptoms of EPP have a mutation in a different gene called ALAS2, and the disorder is called X-linked Protoporhyria.

EPP and XLP, typically present in childhood and combined, are the third most common porphyria, with an estimated incidence of about 2 to 5 in 1,000,000.

Both EPP and XLP result in excess production of protoporphyrin in the bone marrow, which is taken up in the blood stream and transported to the liver and blood vessels. These protoporphyrins also build up in the superficial blood vessels under the skin. Protoporphyrins are highly sensitive to sunlight and on absorption of sunlight, they release certain chemicals which cause severe pain and inflammation resulting in symptoms of EPP/XLP.

As protoporphyrin deposits in the liver, some patients with EPP/XLP may also have complications related to liver and gallbladder function. Rarely, affected individuals may also develop liver damage that, in very severe cases, may lead to liver failure requiring transplantation. As liver transplantation does not cure EPP or XLP, a bone marrow transplant following liver transplant may be necessary in some cases.

The most common symptom in EPP/XLP is severe pain on exposure to sunlight. Patients first experience tingling, itching or burning which severe as warning signs to avoid sun exposure. With ongoing exposure, patients develop severe pain which may be followed by swelling or redness. The most common areas affected include are the back of the hands and face. Blistering or scarring is rare in EPP/XLP patients and the diagnosis is often delayed as there are often no visible signs in between phototoxic episodes.

The amount of sunlight tolerance varies between patients with some able to tolerate only a few minutes and others who can stay out in the sun for much longer. Sun tolerance also depends on weather conditions.

How is Erythropoietic Protoporphyria or X-Linked Protoporphyria diagnosed?

There are two types of testing; biochemical, meaning looking for “biomarkers” in the blood or urine, and genetic, meaning looking at the gene we know causes the disease directly from a blood sample.

Biochemical: To diagnose EPP/XLP the tests that need to be done are to measure the levels of protoporphyrin in the blood. These levels are generally very high in people with EPP/XLP.

Genetic: A blood sample is used to look at a person’s genes and by doing this it is possible to see if their genes have changes that can cause disease, called mutations. The gene that causes EPP is called FECH, and the gene that causes XLP is called ALAS2. Genetic testing is recommended for all patients even if they have a biochemical diagnosis.

Also see FAQ: What diagnostic tests are available?

What are treatments for Erythropoietic Protoporphyria and X-Linked Protoporphyria?

The primary mode of management for EPP/XLP is avoidance of sunlight or use of protective clothing and gear. Treatment with pharmaceutical grade β-carotene (Lumitene, Tishcon) and cysteine have been used in the past but studies suggest that there is no evidence that these are effective.

Anti-itch treatments like cortisone or antihistamines do not help the symptoms of EPP/XLP Iron and Vitamin D levels can be low in patients with EPP and XLP so these should be checked and supplemented accordingly. To protect the liver from further injury, Hepatitis A and B vaccinations are recommended, as is the avoidance of large amounts of alcohol and medications which may be harmful to the liver.

Liver failure can appear suddenly and progress quickly in some patients. It is generally treated with a combination of plasmapheresis (liquid from the blood, called plasma, is separated from the other components of the blood), blood transfusions, infusions of Panhematin (the treatment usually given for the acute porphryias), the medications like cholestyramine, vitamin E, and ursodeoxycholic acid. The level of protoporphyrin in the blood should be followed closely during treatment. Liver transplantation is sometimes necessary. It is not yet possible to predict which patients will develop liver failure.

Recently, Scenesse (Afamelonotide) was approved by the FDA for the treatment of EPP and XLP. Scenesse works by increasing pigmentation (darkening) of the skin and also has anti-oxidant properties. This drug is in the form of an implant which is inserted in the fat just below the skin and given every two months. The implant dissolves by itself and does not need to be removed. Studies have shown that patients on Scenesse were able to tolerate more sunlight without pain and that it was safe to use long term.

Another potential treatment (MT-7117) is currently being tested for EPP/XLP. This drug is in the form of a pill taken by mouth. It also increases skin pigmentation and studies to test its effectiveness are ongoing.

How is Erythropoietic Protoporphyria inherited?

EPP is an autosomal recessive condition. Autosomal means that the defect is not on the chromosomes that determine sex, and recessive which means that patients who have EPP have inherited two mutated copies of the FECH gene, one from each parent. All children of an EPP patient will inherit one of the mutated copies of the FECH gene.

How is X-Linked Protoporphyria inherited?

XLP is an X-linked inherited genetic disorder. This means that the defect is on the X chromosome. Females have two copies of the X chromosome, while males have only one copy. The gene that causes XLP is called ALAS2. Because females have two copies of the X chromosome, they have one mutated copy of ALAS2 and one working copy. A random process in the body causes one X chromosome to be turned off. For this reason, females can present with a varying degree of symptoms ranging from no symptoms to severe XLP symptoms. There is no way to predict this ahead of time. Therefore it is important for family members of XLP patients to be tested for this mutation so that they can receive appropriate counseling.

Genes are inherited randomly, so each parent has an equal chance of passing on either one of their sex chromosomes. If the father has XLP, each of his children has a 50% chance of inheriting his X chromosome (which has the mutated gene) and a 50% chance of inheriting his Y chromosome (which does not have the gene). If they have inherited the X chromosome, they will be female and have one mutated copy of ALAS2. If they have inherited the Y chromosome, they will be male and not have XLP.

If a father has XLP, all of his daughters will have XLP but none of his sons will be affected.