Diseases Studied: The Porphyrias

Inherited genetic disorders happen when changes, or mutations, occur in genes. Genes are like instruction manuals inside your body that tell your cells how to work. A mutation in a gene is like a typo in these instructions—sometimes it has no effect, but other times it can cause problems that make it harder for the body to work properly. Mutations can happen randomly during a person’s lifetime when cells make copies of genes. If the mutation occurs in a sperm or egg cell, they can be passed down from parent to child and continue through generations. This is how inherited genetic disorders are passed down in families.

Porphyrias are a group of mostly inherited disorders caused by mutations in genes that help the body make heme – a molecule needed for carrying oxygen in the blood and for other vital functions. In porphyrias, the mutations cause heme building blocks to build up in the body instead of being used properly. These chemicals, called porphyrin precursors and porphyrins, give the disorders their names. The buildup of these chemicals can lead to a range of symptoms, including pain, skin problems, and nervous system issues. The specific symptoms a person experiences depend on where the defect occurs in the heme production process and which cells are most affected. Each type of porphyria is caused by a defect in a specific enzyme in the heme production pathway, leading to the buildup of different heme precursors. This is why the different types of porphyrias have different symptoms.

The porphyrias can be grouped into two main categories based on their primary symptoms:

1. Acute Porphyrias - aka acute hepatic porphyrias

Acute porphyrias cause episodes of severe abdominal pain, known as attacks, which can last for several days. Other symptoms may also occur during these attacks. Triggers for attacks include certain medications, fasting, hormonal changes, infections, or stress. Some people with acute porphyrias may also develop long-term health issues, such as chronic pain and kidney disease. The types of acute porphyrias are acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and ALA-dehydratase deficiency porphyria. Most acute porphyrias do not affect the skin, but hereditary coproporphyria and variegate porphyria can sometimes cause blistering of the skin after sun exposure.

2. Cutaneous Porphyrias

Cutaneous porphyrias primarily affect the skin after sun-exposure. People with these disorders experience photosensitivity, meaning their skin reacts to sunlight on exposed areas like the hands and face. There are two main patterns of skin symptoms that different types of cutaneous porphyrias are characterized by: 

• Blistering and fragile skin. This is seen in porphyria cutaneous tarda, hepatoerythropoietic porphyria, and congenital erythropoietic porphyria. These skin symptoms look the same as the skin symptoms in two of the acute porphyrias, hereditary coproporphyria and variegate porphyria.
• Pain, burning, tingling, and swelling. This is seen in erythropoietic protoporphyria and X-linked protoporphyria.

Each type of porphyria is caused by a mutation in the gene coding for a specific enzyme in the heme production pathway. Porphyria cutaneous tarda (PCT) is different from other types of porphyria. Most people with PCT do not have a gene mutation. Instead, they develop the condition due to other factors, meaning it is mostly acquired rather than inherited.

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.

There are four acute porphyrias; acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and δ-aminolevulinic acid dehydratase deficiency porphyria (ADP). Most people who have a gene mutation that can cause acute intermittent porphyria, variegate porphyria, or hereditary coproporphyria never have symptoms. About 80-90% of these individuals remain healthy. Others may have a few attacks of abdominal pain or other symptoms in their lifetime. A small number suffer from recurrent attacks.