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Variegate porphyria

  • Variegate porphyria, also known by several other names, is an autosomal dominant porphyria that can have acute (severe but usually not long-lasting) symptoms along with symptoms that affect the skin. The disorder results from low levels of the enzyme responsible for the seventh step in heme production. Heme is a vital molecule for all of the body's organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.
  • Variegate porphyria (VP) is an inherited disorder that is caused by mutations in the PPOX gene that lead to the build-up of compounds normally involved in the body’s production of heme and is inherited in an autosomal dominant pattern..
    • Heme is an important part of hemoglobin, the protein in blood that carries oxygen throughout our bodies. It is used in all the body’s organs.
      • People with variegate porphyria have abnormal production of heme. They are very sensitive to sun exposure (photosensitive) and develop skin blisters and sores when they are exposed to sunlight.
      • Mutations in PPOX reduce the activity of that enzyme and this allows compounds called porphyrin precursors to build up in the body.
      • These compounds are formed during the normal process of heme production, but reduced activity of protoporphyrinogen oxidase allows them to accumulate to toxic levels.


  • Symptoms usually begin in adulthood.  
  • Some people who have PPOX gene mutations never have symptoms of porphyria.
  • People with variegate porphyria need to avoid sun exposure.
  • Many people with this disorder never experience symptoms.
  • This condition most often causes skin symptoms, neurological symptoms, or both.
    • Some people with variegate porphyria have skin that is overly sensitive to sunlight (photosensitive) and may develop severe blistering, scarring, changes in pigmentation, and increased hair growth. Exposed skin becomes fragile and is easily damaged.
    • People with variegate porphyria can also have neurological symptoms in the form of episodes (acute attacks) of severe stomach pain, nausea and vomiting.
  • When symptoms occur, they can include acute attacks (similar to acute intermittent porphyria), skin damage, or both.
    • Acute attacks usually begin in adulthood and cause abdominal pain, vomiting, diarrhoea and constipation. During an attack, a person may also experience muscle weakness, seizures, and mental changes such as anxiety and hallucinations. These signs and symptoms are triggered by nongenetic factors such as certain drugs, dieting or fasting, certain hormones and stress.
  • Rarely, the signs and symptoms of variegate porphyria can begin in infancy or early childhood. In such cases, the signs and symptoms are usually more severe than those starting later in life. In addition to the health problems described above, children with this disorder may have mental retardation and grow more slowly than other children.


  • There are seven different types of porphyria and in most cases they are inherited. In each type, there is a lack of one of the enzymes which controls one of the steps in heme synthesis.
  • Variegate porphyria has an autosomal dominant pattern of inheritance.
    • Mutations in the PPOX gene cause variegate porphyria.
      • The PPOX gene makes a membrane bound mitochondrial enzyme called protoporphyrinogen oxidase, which is critical to the chemical process that leads to heme production.
      • The activity of this enzyme is reduced by 50 percent in most people with variegate porphyria.
      • In severe cases that begin early in life, the enzyme is almost completely inactive.
      • Non-genetic factors such as certain drugs, stress, and others listed above can increase the demand for heme and the enzymes required to make heme. The combination of this increased demand and reduced activity of protoporphyrinogen oxidase disrupts heme production and allows byproducts of the process to accumulate in the liver, triggering an acute attack.
    • Variegate porphyria is inherited in an autosomal dominant pattern, which means the defective gene is located on an autosome, and inheriting one copy of the defective gene from an affected parent is sufficient to cause the disorder. More severe cases result from inheriting two copies of the defective gene.
    • The entire PPOX gene has about 8kb with 13 exon sequences. It was successfully cloned from a cDNA library in 1995 revealing that, after processing, it is 477 nucleotides long. It has previously been thought that the PPOX gene was located on human chromosome 14, however mapping experiments (FISH) have shown that it is near 1q22.
  • An additional aggravating mutation affecting variegate porphyria can be found at 6p21.3 on the HFE gene.


  • Attacks are treated with medication and hospitalization.
  • Attacks can be prevented by avoiding the factors that cause the symptoms.
  • Hospitalization is often necessary for acute attacks to help manage the pain and other neurological symptoms.
  • Medications for pain, nausea and vomiting, and close observation are generally required.
  • Mild attacks may be managed by giving the person a large amount of glucose or other carbohydrates.
  • More severe attacks are treated with hemin, an injection of the heme protein, to help stop the attack.
    • The response to heme therapy is best if started early in an attack. Heme must be administered by vein (intravenously). Panhematin® is the only commercially available heme therapy for treatment and prevention of acute porphyria attacks in the United States. Heme arginate, which is marketed in some other countries, is another type of heme.
  • Attacks can also be avoided by avoiding the ‘trigger’ for the attack. The trigger can be different for different people.
    • Triggers include certain medications, alcohol, dieting, and hormonal changes in the body. Sometimes, however, the trigger is unknown.
    • Avoiding excess sun exposure can reduce the blisters and skin lesions.
  • Liver transplant has been used in the treatment of this condition.


The long term outlook for people with variegate porphyria varies with the severity of the symptoms. With early diagnosis and treatment, variegate porphyria is rarely life threatening and it doesn’t usually get worse with time.  People with this condition are at increased risk for liver cancer and kidney disease.


  • Some reports suggest that variegate porphyria affects more women than men.
  • The incidence is estimated to occur in 1 in 100,000 individuals in the general population in European populations.
  • The disorder occurs with the greatest frequency in South Africa in individuals of Dutch ancestry due to a founder effect.
    • A founder effect is when a small isolated population of settlers (founders) expands over several generations leading to a high prevalence of a genetic trait. Most individuals with variegate porphyria in South Africa carry the same PPOX mutation and are descendants of a Dutch settler from the late 1600s.
    • In South Africa among Caucasians, the prevalence of variegate porphyria is approximately 1 to 3 in 1,000 individuals.
  • In Finland, the prevalence is approximately 1 in 75.000.
  • When it does occur in other populations (such as Switzerland), it can be with different mutations than in South Africa.
  • It is also found in Argentina, Sweden, and Australia.
  • Rates of all types of porphyria taken together have been estimated to be approximately one in 25,000 in the United States. The worldwide prevalence has been estimated to be between one in 500 and one in 50,000 people.
    • Porphyrias have been detected in all races and in multiple ethnic groups on every continent, including Africans, Asians, Aboriginal Australians, Caucasians, Peruvians, Mexicans, Native Americans, and Sami.


Hippocrates is often cited as the first to recognize porphyria (which was then referred to as blood/liver disease) but the causal role of porphyrin pigments was only established in 1871 by the great German pioneer of biochemistry Felix Hoppe-Seyer. In 1889, Dr. B.J. Stokvis described the clinical syndrome as "porphyria," and from then on more and more forms of the syndrome were discovered.



  1. American porphyria Foundation
  2. European Porphyria Network
  3. British Porphyria Association
  4. Genetic and Rare Diseases (GARD) Information Center

References & Additional Reading