X-linked Dominant Protoporphyria
What else is it called?
- X-linked dominant protoporphyria
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What causes it?
X-linked protoporphyria is caused by mutations (changes) of the ALAS2 gene located on the X chromosome. This gene encodes (converts) a protein called erythroid specific 5-aminolevulinate synthase 2. Mutations of the ALAS2 gene cause an overproduction of this enzyme which lead to elevated levels of a chemical called protoporphyrin. This results in an abnormal build–up of protoporphyrin in the blood, liver and skin. This build-up of protoporphyrin causes the symptoms associated with this condition such as toxic damage to the liver and the formation of gallstones.
How common is it?
This condition affects both males and females, however, males usually develop a more severe form of the disorder whereas females can range from having no symptoms at all (asymptomatic) to developing a severe form of the condition.
The exact prevalence of XLP is unknown. The condition has only been reported in a handful of families. These families were in Europe, South Africa and Japan.
What are the signs and symptoms?
Signs and symptoms of this condition may include:
- Hypersensitivity of the skin to sunlight
- Liver disease
- Mild anaemia (low levels of circulating red blood cells)
- Iron deficiency
The first sign and main characteristic of XLP is hypersensitivity of the skin to sunlight. Individuals with this condition develop pain, itching and burning of the skin after being exposed to sunlight. These symptoms may be accompanied with, erythema (swelling and redness) of the affected areas. Symptoms may appear as soon as a few minutes after being exposed to the sun. Most symptoms usually subside within 24-48 hours however, pain and a red or purple discoloration of the skin can be present for several days after being exposed to sunlight. Pain associated with this condition is severe. The pain can be excruciating and often does not respond to pain medication, even narcotics. Repeated episodes of exposure to sunlight can lead to thickening and hardening of the skin, development of a rough or leathery texture, small facial pock-like pits and grooving around the lips. Large blisters and severe scarring are common in other forms of cutaneous porphyria such as EPP (erythropoietic protoporphyria) but usually does not occur in individuals with XLP.
Some patients with XLP develop liver disease, ranging from mild liver abnormalities to liver failure. Individuals may have back pain and severe abdominal pain in the upper right area of the abdomen. In some cases, the flow of bile through the gallbladder and bile ducts can be interrupted (cholestasis) which can lead to gallstones. This may lead to cholecystitis (obstruction and inflammation of the gallbladder), cirrhosis (scarring of the liver) and in some individuals may develop into end stage liver failure.
Other symptoms that have been present in individuals with XLP include, mild anaemia (low levels of circulating red blood cells) and iron deficiency.
How is it diagnosed?
A diagnosis of XLP is made based on a number of things including, identifying characteristic symptoms (such as non-blistering photosensitivity), detailed patient history, clinical evaluation and a range of specialized tests.
Blood tests can show increased levels of metal-free and zinc-bound protoporphyrin in the red blood cells. A higher ratio of zinc-bound protoporphyrin to metal-free protoporphyrin can distinguish between X-linked protoporphyria and EPP (Erythropoietic protoporphyria).
The diagnosis can be confirmed through molecular genetic testing, showing mutations in the ALAS2 gene.
Can it be treated?
Treatment for this condition is directed at specific symptoms present in the individual. Due to this condition being so rare, a lot of the treatment information is based on EPP (Erythropoietic protoporphyria) as it is clinically similar to XLP.
Individuals with XLP will benefit from avoiding sunlight. This can be done through wearing special clothing made with double layers of fabric or light-exclusive fabrics, special sunscreen with light-reflective ingredients, window tinting and the use of light-filtering vinyl or films to cover the windows of their cars and homes. Some individuals may require vitamin D supplements as avoiding sunlight can cause vitamin D deficiency.
Drugs such as Lumitene or Cysteine may be prescribed in order to improve a patient’s tolerance to sunlight. Other drugs that may be used in some XLP patients are cholestyramine and activated charcoal which absorb porphyrin and may improve liver disease.
Individuals with XLP should avoid any substances associated with cholestasis including, alcohol and certain drugs such as oestrogen. Immunizations for hepatitis A and B are also recommended for all patients with XLP.
Do my family need to be tested?
XLH is an inherited condition. Humans have chromosomes made up of DNA. Genes are pieces of DNA that carry the genetic information. Each chromosome may have several thousand genes. We inherit chromosomes from the egg of the mother and sperm of the father. The genes on those chromosomes carry the instructions that determine a person’s characteristics, which are a combination of the parents.
The pattern of inheritance in this condition is an X-linked dominant pattern. This is because the ALAS2 gene is located on the X chromosome (one of the two sex chromosomes). In females (who have two X chromosomes) a mutation in one of the two copies of the gene in each cell is enough to cause the disorder. In males (who have only on X chromosome), a mutation in the only copy of the gene in each cell causes the disorder. Therefore, a female with XLH has a 50% chance of passing XLH to each of her children. A male with XLH will pass the condition to all his daughters but to none of his sons.
Genetic counselling can be requested to get a full explanation.