Wednesday, April 11, 2018

What is Erythropoietic Protoporphyria and X-Linked Protoporphyria

Erythropoietic Protoporphyria and X-Linked Protoporphyria

NORD gratefully acknowledges Manisha Balwani, MD, MS, Associate Professor, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, for assistance in the preparation of this report.

Synonyms of Erythropoietic Protoporphyria and X-Linked Protoporphyria

  • EPP
  • erythrohepatic protoporphyria
  • protoporphyria

General Discussion

Summary
Erythropoietic protoporphyria (EPP) is a rare inherited metabolic disorder caused by a deficiency of the enzyme ferrochelatase (FECH), which results from changes (mutations) in the FECH gene. Due to abnormally low levels of this enzyme, excessive amounts of protoporphyrin accumulate in the bone marrow, blood plasma, and red blood cells. Some patients with symptoms of EPP have a genetic change in a different gene called ALAS2. When a patient has a genetic change in this gene, the condition is referred to as X-linked protoporphyria (XLP).
The major symptoms of these disorders is severe pain on exposure to sunlight and some types of artificial light, such as fluorescent lights (phototoxicity). On sun exposure, patients may first experience tingling, itching, burning of the skin. After continued exposure to light, the skin may become red and swollen. The hands, arms, and face are the most commonly affected areas. Some people with EPP/XLP may also have complications related to liver and gallbladder function.
Introduction
Erythropoietic protoporphyria is one of a group of disorders known as the porphyrias. The porphyrias are all characterized by abnormally high levels of particular chemicals (porphyrins) in the body due to deficiencies of certain enzymes essential to the synthesis of hemoglobin. There are at least eight types of porphyria. The symptoms associated with the various types of porphyria differ, depending upon the specific enzyme that is deficient. It is important to note that people who have one type of porphyria do not develop any of the other types.

Signs & Symptoms

The most common symptom of erythropoietic protoporphyria and X-linked protoporphyria is severe pain on sun exposure. Some patients may also be sensitive to some types of artificial light. When the skin is exposed to sun, patients first develop tingling, itching, and/or burning of the skin. These symptoms serve as warning signs as longer exposure can result in severe pain. Affected individuals may also have an abnormal accumulation 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 (blisters) and scar if exposure to sunlight is prolonged. However, scarring and/or discoloring of the skin is uncommon and rarely severe. These affected areas of skin may become abnormally thick. The severity and degree of symptoms is different from case to case. Some patients may only be able to tolerate a few minutes of sun exposure while others may be able to tolerate longer sun exposure without symptoms. The amount of sun tolerated may also be different based on weather conditions. Symptoms are often seen during infancy; however, in some cases, it may not occur until adolescence or rarely in adulthood.
In some affected individuals, the flow of bile through the gallbladder and bile ducts (biliary system) may be interrupted (cholestasis) causing gallstones (cholelithiasis) to form. In turn, such stones can cause obstruction and/or inflammation of the gallbladder (cholecystitis). 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.
Symptoms usually start in childhood but diagnosis is often delayed since blistering is not common and, because the porphyrins are insoluble, they cannot be detected on urinanalysis. The diagnosis is made upon finding increased levels of the protoporphyrin in the plasma or red blood cells in both EPP and XLP. Genetic testing is useful to confirm the diagnosis.
Patients with EPP and XLP may also have mild anemia (low blood counts). In many cases, this may be due to low iron stores. They may also have high levels of liver enzymes on blood tests.

Causes

EPP is a rare genetic disorder caused by genetic changes in the FECH gene. The FECHgene is responsible for providing instructions for the body to create an enzyme called ferrochelatase. This enzyme is involved in a long process to make heme, a chemical that functions to transport oxygen around the body. Without enough of the enzyme, ferrochelatase, the body is not able to finish converting a heme precursor called protoporphyrin into heme, causing buildup of protoporphyrins in certain tissues in the body (i.e., the plasma, red blood cells, and the liver). These protoporphyrins also build up in the superficial blood vessels under the skin. These protoporphyrins are highly sensitive to sunlight. When they absorb sunlight, it results in a reaction which causes severe pain and inflammation resulting in symptoms of EPP.
EPP is inherited, or passed down through the generations, in an autosomal recessive manner. Everyone has two copies of the FECH gene, one inherited from the mother and one from the father. Most individuals with EPP have a different gene change on each copy of the FECH genes. On one copy, the change, called a mutation, has stopped this copy of the gene from working properly. On the other copy, there is a small change called a “low-expression allele” or a polymorphism. This alteration still affects the way the FECH gene works; it produces less ferrochelatase enzyme than normal. This small change is common in the general population, with up to 10% of Caucasians with one copy of this change. This alteration will not cause EPP by itself, and people who have the alteration on each copy of the FECH gene will NOT develop EPP. But when someone inherits the small alteration from one parent and a mutation from the other, they will develop EPP, because there will not be enough enzyme made. Most patients with EPP have the low-expression alteration on one copy of the FECH gene and a mutation on the other copy. The risk for patients with EPP to have a child who also has the condition depends on the genetic changes in their partner.
Some patients with symptoms of EPP have a genetic change in a different gene called ALAS2, a gene located on the X chromosome. When a patient has a genetic change in this gene, the condition is referred to as X-linked protoporphyria (XLP). XLP is passed down through families in an X-linked manner. Males have one X chromosome and one Y chromosome, while females have two X chromosomes.This means that males have only one copy of the ALAS2 gene and females have two copies of the ALAS2 gene. When a male has a mutation is his single copy of ALAS2, he is expected to have symptoms of XLP. In a woman with a mutation in one of her ALAS2 genes, the second functioning copy of the gene can help compensate and may lead to less severe symptoms or no symptoms at all. It is not possible to predict or control the severity of disease in females. Men with XLP pass on their X chromosome to their daughters and their Y chromosome to their sons. Therefore, a man with XLP with pass on his genetic change to all his daughters, and none of his sons. For a female with XLP, she will pass on the X chromosome with the genetic change 50% of the time. Thus, in each pregnancy, there is a 50% chance of having a child with a mutation in ALAS2.
Genetic counseling is recommended for affected individuals and their families.

Affected Populations

EPP is a very rare inherited disorder that affects males and females in equal numbers. It is estimated that the disorder occurs in about 1 in about 75,000 to 1 in 200,000 individuals in Europe. The number of patients affected by these disorders in the US is unknown. XLP accounts for about 10% of cases in the United States. It is more likely to present in males. Females with XLP may or may not have symptoms.
The onset of symptoms affecting the skin usually occurs in infancy, with an average of diagnosis at age 4; however, in some cases, onset may not occur until adolescence or rarely even adulthood.

Diagnosis

The diagnosis of EPP and XLP may be made by a thorough clinical evaluation, and specialized laboratory tests. EPP and XLP are usually diagnosed during infancy or early childhood, due to characteristic symptoms, and by testing the red blood cells (erythrocytes) for increased levels of protoporphyrin. Genetic testing is useful to confirm the diagnosis and identify if it is EPP or XLP. This information is useful for genetic counseling and testing family members as both are inherited in a different manner.

Standard Therapies

Treatment
Avoidance of sunlight will be of benefit to individuals with EPP. The use of sun protective clothing such as long sleeves, hats, and sunglasses will also benefit patients. Tanning creams which increase skin pigmentation or sunscreens which contain physical reflecting agents may be beneficial to some patients. Individuals with EPP and XLP may also benefit from window tinting or using films to cover the windows in their car or house. Before tinting or shading car windows, affected individuals should check with their local Registry of Motor Vehicles to ensure that such measures do not violate any local codes.
In EPP, a high potency form of oral beta-carotene (Lumitene, Tishcon) has been used to improve an affected individual’s tolerance of sunlight. While some patients report improvement, recent studies show that there is no data to support the benefit of this treatment.
A drug called Scenesse (afamelanotide) has been approved for the treatment of EPP in Europe. This drug is an injectable implant and works by increasing skin pigmentation which provides protection and improves sun tolerance. This drug is not available in the United States and it has not been tested in children.
When iron deficiency is present, iron supplements may be given. A drug called cholestyramine or activated charcoal maybe prescribed to interrupt the circulation of protoporphyrin through the liver and intestines in patients with liver disease.
In addition, individuals with high levels of protoporphyrin in the plasma and red blood cells should be observed closely by a physician for possible liver malfunction that could eventually lead to liver failure.
Liver transplantation has been performed as a life-saving measure in patients with EPP and XLP related liver failure. Bone marrow transplant can also be performed after liver transplant to prevent further damage to the liver.
EPP and XLP patients should take vitamin D supplements as they are likely to have low vitamin D levels since they avoid sunlight. They should also receive vaccination against hepatitis A and B to prevent other causes of liver damage.
Patients should be seen at least yearly to monitor protoporphyrin levels, anemia, liver enzymes, iron and vitamin D levels.
Other treatment is symptomatic and supportive.

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