Diseases Studied

The porphyrias are inherited genetic conditions, which means that people with a porphyria have changes to certain genes that affect their body’s ability to regulate itself. When genes are copied, either to make new cells or to make a child, sometimes the body makes an imperfect copy. There can be little changes in the genes, called mutations, which can occur randomly. Sometimes these changes do not make any difference in how well the gene works, but other times they can keep the gene from working properly (referred to as mutations) and are disease causing.

In the porphyrias, these mutations are in the genes involved in a certain chemical pathway, called the heme biosynthetic pathway. Heme is a compound that the body needs to make hemoglobin and there are several steps to make this compound in the body. Each type of porphyria is caused by a defect in a specific enzyme in the heme biosynthetic pathway. Without these enzymes working properly, the body is not able to finish making heme and it causes a buildup of other compounds, called porphyrins. It is the buildup of different types of porphyrins that causes the different types of porphyria.

Most commonly the porphyrias are divided into the “acute“ and “cutaneous” porphyrias, depending on the primary symptoms. The acute porphyrias [acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and ALA-dehydratase deficiency porphyria (ALD)] present with sudden attacks of severe stomach pain that last for several days; VP and HCP may also have skin symptoms of blistering after sun exposure. The cutaneous porphyrias present with blistering and scarring of the skin, pain, and/or redness and swelling in sun-exposed areas.

The Acute Porphyrias

There are four types of acute porphyrias; acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and δ-aminolevulinic acid dehydratase porphyria (ADP), and they have similar symptoms. These are genetic disorders that are very rare and may be difficult to diagnose for this reason. It is estimated that about 1 in 10,000 Europeans or people of European ancestry have a mutation in one of the genes that cause AIP, VP or HCP. These mutations have been found in all races and many other ethnicities in addition to Europeans.

Approximately 80-90% of individuals who carry a gene mutation for acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria, remain asymptomatic, and others may have only one or a few acute attacks throughout life. The most frequent symptom is severe abdominal pain and is often accompanied by nausea, vomiting, and constipation. Other symptoms may include heart palpitations, seizures, and hallucinations. People with VP and HCP may also have skin symptoms of blistering after sun exposure.

The Cutaneous Porphyrias

All but one of the cutaneous porphyrias cause skin blistering and fragility on sun-exposed areas of the body, most commonly the backs of the hands, forearms, face, ears and neck. The cutaneous porphyrias are porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP), congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP), and X-linked protoporphyria (XLP).

CEP and HEP occur in childhood with severe blistering skin lesions. PCT occurs in adulthood generally and less severe blistering skin lesions after sun exposure. Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) have the same symptoms of painful, but nonblistering, reactions to sunlight. There can also be swelling and redness of the sun exposed areas of the skin with EPP and XLP.

Each type of porphyria is caused by a mutation, or change, in the gene coding for a specific enzyme in the heme pathway. PCT is unique as it is the only porphyria where most patients do not have mutations in a gene, but instead have acquired, or sporadic, PCT.

Types of porphyria, their patterns of inheritance, and the enzyme that is deficient in each.

The inherited porphyrias are either autosomal dominant (inherited from one parent), autosomal recessive (inherited from both parents), or X-linked (the gene is located on the X-chromosome). "Autosomal" genes always occur in pairs, with one coming from each parent. Individuals with an autosomal dominant form of porphyria have one mutated gene paired with a normal gene, and there is a 50% chance with each pregnancy that the mutated gene will be passed to a child.

Individuals with an autosomal recessive type of porphyria have mutations on both copies of a specific gene, one passed to them from each of their parents. Each of their children will inherit one mutated gene for that porphyria, and the child will be a “carrier” but will not have symptoms.

In X-linked disorders, the gene is located on one of the sex chromosomes, called the X-chromosome. Females have two X-chromosomes, and males have one X-chromosome and one Y-chromosome. Both males and females will likely have symptoms from a mutated gene on the X-chromosome, but females, with a normal gene on the other X-chromosome, usually are less severely affected than males. The risk for children depends on the gender of the affected parent. A female with an X-linked gene mutation will have a 50% risk of passing that mutation to any of her children with each pregnancy. However, a male will pass the mutation to all of his daughters but none of his sons.

There are many laboratory tests available for the porphyrias, and the right tests to order depend on the type of porphyria the doctor suspects. When abdominal and neurological symptoms suggest an acute porphyria, the best screening tests are urinary aminolevulinic acid (ALA) and porphobilinogen (PBG). When there are cutaneous symptoms that suggest porphyria, the best screening test is a plasma porphyrin assay. If one of these screening tests is abnormal, more extensive testing, including urinary, fecal, and red blood cell porphyrins, are often indicated.

DNA testing to identify the specific mutation in an individual’s porphyria-causing gene is also recommended. Before requesting DNA testing, it is helpful that patients have biochemical testing. However, many patients have not had an acute attack or are not symptomatic at present, so biochemical testing may be inconclusive.

In contrast, DNA testing is the most accurate and reliable method for determining if a person has a specific porphyria and is considered the "gold standard" for the diagnosis of genetic disorders. If a mutation (or change) in the DNA sequence is found in a specific Porphyria-causing gene, the diagnosis of that Porphyria is confirmed. DNA analysis will detect more than 97% of disease-causing mutations. DNA testing can be performed whether the patient is symptomatic or not. Once a mutation has been identified, DNA analysis can then be performed on other family members to determine if they have inherited that Porphyria, thus allowing identification of individuals who can be counseled about appropriate management in order to avoid or minimize disease complications.