What is Variegate Porphyria (VP)?
VP is an autosomal dominant disorder caused by mutations in the PPOX gene. These mutations reduce the function of an enzyme called protoporphyrinogen oxidase, which is needed for heme production. Without enough of this enzyme, the body can’t properly convert the chemical protoporphyrinogen into protoporphyrin, an essential step in making heme. Certain triggers, such as some medications, fasting, hormonal changes, infections, or stress increase the activity of ALA synthase-1, the first enzyme in the heme production pathway in the liver. This puts extra demand on the deficient PPOX enzyme. As a result, ALA, PBG, and porphyrin build up, leading to nerve damage and other manifestations of an acute attack and sometimes fragility and blistering lesions on sun-exposed skin.
Worldwide, variegate porphyria is rarer than acute intermittent porphyria but more common than HCP. It is more common in South African individuals of Dutch ancestry, of whom ~ 1 in 300 individuals have inherited a PPOX mutation that was brought to South Africa by early Dutch settlers and then passed down through many generations. The specific mutation is referred to as the R59E mutation.
The symptoms of an acute attack in VP are similar to those in acute intermittent porphyria (AIP). However, attacks in VP are often milder than those in AIP. One key difference is that VP can cause skin problems, while AIP does not. People with VP may develop blisters and fragile skin in areas exposed to the sun, such as the face and the back of the hands. This happens because porphyrins, in addition to PBG and ALA, build up in VP. These porphyrins are sensitive to sunlight and can lead to skin damage. Blistering skin lesions are more common in VP than in hereditary coproporphyria (HCP), another type of acute porphyrin that can affect the skin.
Most people with a PPOX mutation never experience a VP attack, suggesting that other unknown factors contribute to disease development. Symptoms develop most commonly in menstruating people with disease onset after puberty.
Patients with VP, like AIP patients, face an increased risk of chronic kidney disease and liver cancer.
How is Variegate Porphyria diagnosed?
Acute porphyrias, including VP, are diagnosed using biochemical testing, starting with a urine test. The sample should ideally be taken during symptoms, as porphyrin and precursors may return to normal between attacks, especially in those who have only a few attacks in their lifetime. A spot urine sample is used – a 24-hour urine sample is not needed. The urine is tested for levels of porphyrin precursors and porphyrins. The levels of urinary ALA and PBG during an attack are expected to be markedly elevated (>5 X normal). Minor isolated increases in a chemical called coproporphyrin are not diagnostic of an acute porphyria. The pattern of elevations in ALA, PBG, and porphyrins in the urine provide important clues to help determine the specific type of acute porphyria. Additional blood and stool tests may also be needed to help determine the specific type of acute porphyria. Blood and stool testing are especially useful for diagnosing VP.
Genetic testing can confirm the specific type of porphyria, but it does not replace biochemical testing, which is needed to diagnose the disorder. Genetic testing is not recommended to establish the diagnosis because results can sometimes be unclear or miss cases where biochemical signs of acute porphyria are present. Additionally, carrying a genetic mutation does not always mean that a person will develop symptoms.
Family members of individuals diagnosed with acute porphyria may benefit from consulting with a specialist to explore whether further evaluation for an acute porphyria is appropriate. This decision should be guided by a shared discussion that considers their personal health goals, medical history, and overall care preferences. A specialist can help provide individualized information to support informed decision-making based on their unique needs.
What are treatments for Variegate Porphyria?
The treatments and preventive measures are the same as in AIP.
People with blistering from sun exposure should also take steps to protect their skin from sunlight.
How is Variegate Porphyria Inherited?
VP is an autosomal dominant condition. Autosomal means that the defect is not on the chromosomes that determine sex, and dominant means that you only need to inherit one mutated gene to manifest the disease. The gene that causes VP is called PPOX.
Most VP patients have one mutated copy and one normal copy. It is random which of these two copies are inherited, so this means that each child of an VP patient will have a 50% chance of inheriting the mutated copy and 50% chance of inheriting the working copy.