Porphyria

Porphyria is a group of disorders caused by abnormalities in the chemical steps that lead to heme production. Heme is a vital molecule for all of the body's organs. It is found mostly in the blood, bone marrow, and liver. Heme is a component of hemoglobin, the molecule that carries oxygen in the blood.

The major types of porphyria are each caused by mutations in one of the genes required for heme production. Forms of porphyria include ALAD deficiency porphyria, acute intermittent porphyria, congenital erythropoietic porphyria, erythropoietic protoporphyria, hepatoerythropoietic porphyria, hereditary coproporphyria, porphyria cutanea tarda, and variegate porphyria.

In addition to the genetic forms of porphyria, some cases of this disorder are caused by nongenetic factors such as infections or exposure to certain prescription drugs. These cases are described as sporadic or acquired porphyria.

The signs and symptoms of porphyria vary among the types. Some types of porphyria (called cutaneous porphyrias) cause the skin to become overly sensitive to sunlight. Areas of the skin exposed to the sun are fragile and easily damaged. Exposed skin may develop redness, blistering, infections, scarring, changes in pigmentation, and increased hair growth. Cutaneous porphyrias include congenital erythropoietic porphyria, erythropoietic protoporphyria, hepatoerythropoietic porphyria, and porphyria cutanea tarda.

Other types of porphyria (called acute porphyrias) mostly affect the nervous system. Appearing quickly and lasting from days to weeks, acute signs and symptoms include abdominal pain, vomiting, constipation, and diarrhea. During an attack, a person may also experience muscle weakness, seizures, fever, loss of sensation, and mental changes such as anxiety and hallucinations. These symptoms can be life-threatening in rare cases, especially if the muscles that control breathing become paralyzed. Acute porphyrias include acute intermittent porphyria and ALAD deficiency porphyria. Two other forms of porphyria, hereditary coproporphyria and variegate porphyria, have a combination of acute symptoms and symptoms that affect the skin.

Additional medical problems associated with some types of porphyria include a low number of red blood cells (anemia), enlargement of the spleen, abnormal liver function, and an increased risk of developing liver cancer.

Some people with the genetic changes that cause porphyria, particularly the acute forms of porphyria, never experience any features of this condition. Environmental factors can strongly influence the occurrence and severity of signs and symptoms in some types of porphyria. Alcohol, smoking, certain drugs, hormones, exposure to sunlight, other illnesses, stress, and dieting or periods without food (fasting) can all trigger the signs and symptoms of these disorders.

The exact prevalence of this condition is unknown, but probably ranges from 1 in 500 to 50,000 people worldwide. Overall, porphyria cutanea tarda is the most common type of the disease, affecting 1 to 2 in 100,000 people. For some forms of porphyria, the incidence is uncertain because many people with a gene mutation never experience signs or symptoms.

Acute intermittent porphyria is the most common form of acute porphyria in most countries. It occurs most frequently in northern European countries, particularly Sweden, and in the United Kingdom. Another form of the disorder, hereditary coproporphyria, has been reported mostly in Europe and North America.

Variegate porphyria is most common in the Afrikaner (white) population of South Africa; about 3 in 1,000 people in this population are diagnosed each year. This form of the disorder occurs much less frequently in other parts of the world.

Mutations in the ALAD, CPOX, FECH, HMBS, PPOX, UROD, and UROS genes cause porphyria.

Variations of the HFE gene increase the risk of developing porphyria.

The genes related to porphyria provide instructions for making the enzymes needed to produce heme. Mutations in any of these genes reduce enzyme activity, which limits the amount of heme the body can produce. In some forms of porphyria, nongenetic factors (such as certain drugs) also increase the demand for heme and the enzymes required to make heme. The combination of increased demand for this molecule and reduced enzyme activity disrupts heme production. As a result, byproducts of the process (compounds called porphyrins and porphyrin precursors) build up in the body's tissues. When these toxic substances accumulate in the skin and interact with sunlight, they cause the cutaneous forms of porphyria. The acute forms of the disease occur when porphyrins and porphyrin precursors build up and damage the nervous system and other organs.

One type of porphyria, porphyria cutanea tarda, has both genetic and nongenetic causes. About 20 percent of cases are caused by mutations in the UROD gene. The remaining 80 percent of cases do not have UROD mutations and are classified as sporadic or acquired. These cases occur in people with no family history of the disorder. Sporadic or acquired porphyria cutanea tarda may be triggered by many factors, including alcohol consumption, infections (such as hepatitis C), an overload of iron in the body, or certain prescription drugs. Mutations in the HFE gene (which cause an iron overload disorder called hemochromatosis) also increase the risk of developing porphyria cutanea tarda. Additionally, other unidentified genetic factors may be associated with this form of porphyria.

Read more about the ALAD, ALAS2, CPOX, FECH, HFE, HMBS, PPOX, UROD, and UROS genes.

Some types of porphyria are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to reduce enzyme activity and increase the risk of developing signs and symptoms. Autosomal dominant porphyrias include acute intermittent porphyria, most cases of erythropoietic protoporphyria, hereditary coproporphyria, and variegate porphyria. Although porphyria cutanea tarda can have an autosomal dominant inheritance pattern, most cases of this type of porphyria are acquired or sporadic, which means they are not inherited.

Other porphyrias are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition. Porphyrias with an autosomal recessive pattern of inheritance include ALAD deficiency porphyria, congenital erythropoietic porphyria, and rare cases of erythropoietic protoporphyria.

Mutations in the UROD gene are responsible for both porphyria cutanea tarda and hepatoerythropoietic porphyria. Individuals who have one altered copy of the UROD gene in each cell have porphyria cutanea tarda. People with two altered copies of the UROD gene in each cell, one inherited from each parent, have hepatoerythropoietic porphyria.