What is Variegate Porphyria (VP)?

The haem synthetic pathway
Variegate porphyria is one of seven different types of porphyria. The enzyme protoporphyrinogen oxidase (PPOX) is defective in people with VP, as a result of a mutation in the gene for this enzyme. (Look this up by clicking on the diagram on the right). The consequence is that people with VP may have difficulty converting protoporphyrinogen to protoporphyrin, which may result in an accumulation ofporphyrins, particularly coproporphyrin and protoporphyrin.

Variegate porphyria is found throughout the world, but is particularly common in South Africa. There is an interesting history attached to VP in South Africa. Here it is due to a founder mutation introduced to the Cape of Good Hope in 1688. At this time, there was a small Dutch settlement at the Cape, the southernmost part of the African continent. It had been established 36 years earlier, in 1652, by the Dutch East India Company in order to supply fresh meat, fruit and vegetables to ships sailing around the Cape during the long journey between Europe and the East Indies. By 1688, a number of Dutch settlers had left the Company and were farming on their own account in the expanding settlement. There was a preponderance of men in the settlement, and at the request of the local authorities, the Dutch East India Company agreed to bring a group of Dutch orphan women to the Capemet die oog op huwelik ("with an eye to marriage"), which they did. One of these orphans, a young woman named Adriaantje Adriaanse van Rotterdam, married a local farmer named Gerrit Jansz van Deventer. We are not sure whether it was Gerrit or Adriaantje who carried the mutation which results in VP into South Africa, but together they founded a dynasty which expanded very rapidly and carried VP with it. Currently we estimate that there are approximately 30-40 000 people in South Africa with variegate porphyria! It was however another 300 years before we able to show that all the affected people in this family, all descended from this single settler couple, do indeed carry a single mutation, the R59W mutation, which is responsible for the disease. Our colleagues in Rotterdam have confirmed that the R59W mutation is indeed derived originally from Holland, by showing close similarities between the DNA of Dutch and South African families with VP. Hence VP in South Africa is highly associated with the Afrikaner population, though the link may not always be obvious in present-day South African patients since the disease has spread into English-speaking South African families and into the South African population of mixed racial origins as a result of intermarriage.

The R59W mutation is not the only mutation accounting for VP. Even in South Africa, there are a handful of families carrying other mutations—we have identified nine others—who are not related to the large family described above. In the world as a whole, over 100 different mutations have been identified, all resulting in VP, since they all affect the gene for protoporphyrinogen oxidase. None of these families are however related (if they were, they would share the same mutation).

Inheritance of VP

VP is inherited as an autosomal dominant condition. In simple terms, this means that only one parent need be affected for the children to run the risk of showing the disease. In fact, each child will have a 50% chance of inheriting that disease. Both boys and girls stand an equal chance of inheriting the disease.

Will everyone who inherits the gene show the disease?

Not at all. Our research suggests that 40% of people who inherit the disease show no clinical evidence of it. There are even some people who inherit the mutation who show no biochemical evidence of porphyria on biochemical testing, though this is unusual if the sensitive plasma fluoresence scanning test is used. Nearly all the remainder present with mild skin disease alone. All patients are at risk of the acute attack, but are highly unlikely to develop one provided they take care, and particularly if they observe appropriate drug precautions. Both these clinical problems are described in more detail below.

In summary, it is true to say that only a minority of patients carrying VP are particularly troubled by the disease. Most are entirely healthy people, troubled perhaps by minor skin symptoms, but whose lives are subject to minimal disruption provided they look after themselves.

Symptoms of VP

The acute attack

The acute attack is a specific condition in which an accumulation of ALA and PBG leads to interference with the function of the nervous system. This results in the following symptoms:

  • Abdominal pain which is severe, unrelenting and often felt in the loins and thighs as well as the abdomen.
  • Autonomic instability, leading to vomiting, constipation, hypertension and tachycardia.
  • Possible motor nerve damage, resulting in paralysis.

Characteristically, the urine may be very dark which reflects the large amount of PBG and porphyrins excreted in it during this phase.

Note that this is a very specific complex of symptoms. One cannot ascribe every odd ache, pain or sense of being unwell to one's VP. After all, there are many people who do not have VP who experience pain in the abdomen or some nausea from time to time.

Patients with VP are sometimes told that the disease may be associated with insanity. This is not true. It is known that during a severe acute attack the patient may become anxious, difficult or disturbed. This is only during the period that he is very ill with the acute attack, and he returns to complete normality as the attack passes. There is also no doubt that the vast majority of people with VP are entirely sane and will remain so.

What causes the acute attack?

In many instances, the factor which triggers an acute attack can be identified. These include:

  • Administration of dangerous (porphyrinogenic) medication. This is the commonest factor and is something that must always be guarded against. It is described in more detail below.
  • Possibly, fasting and stressful physical circumstances such as illness or operations.

Read more about acute attacks in The acute attack.

Skin disease

Skin changes in the hand of a patient with VP
The commonest symptom of variegate porphyria is skin disease. This is essentially the same type of symptom seen in porphyria cutanea tarda and hereditary coproporphyria. Skin disease is seen only in sun-exposed areas: typically the backs of the hands, though the forearms, face, back of the neck and even the lower legs and feet are sometimes affected in people who are exposed to a lot of sunlight. Skin disease presents as increased skin fragility, with minor trauma resulting in erosions (sores), blisters and scabs.

Read more in Skin disease in porphyria.

How Do the Symptoms of VP Come About?

The defective enzyme protoporphyrinogen oxidase is unable to convert protoporphyrinogen to protoporphyrin efficiently. Consequently, protoporphyrin and the preceding porphyrins, tend to accumulate. Consequently porphyrin concentrations rise in the plasma and eventually accumulate in the skin as well. Since porphyrins react with sunlight, a typical photosensitivity results in sun-exposed areas. You will find further explanation in Skin disease in porphyria.

When VP is extremely active, there may even be difficulty in converting the simple precursors ALA and PBG to the porphyrins. Consequently levels of ALA and PBG rise, resulting in an acute attack. It is not known whether the ALA and PBG themselves are directly responsible for the acute attack, or whether it is some related mechanism which is responsible.

Drug Safety in VP?

The single most important factor triggering the acute attack is exposure to porphyrinogenic medication. Essentially drugs which increase the body's requirement for haem may bring about an increased production of porphyrins, a rise in ALA and PBG, and the acute attack. It is essential that patients with VP read the informationon drug safety in porphyria available from this site (follow the links on our menu) and ensure that they follow the suggestions closely.

In brief:

  • Wherever possible, avoid all drugs if you have VP
  • If medication is absolutely essential, ensure that you take only those listed as safe in our lists.
  • Never take a medication whose name does not appear in our list. This is no guarantee that it is safe. It merely means that it has not been tested.
  • If your medical condition is so serious that only medication listed as doubtful, dangerous or unlisted must be taken, then you should do so only after the most careful assessment by and under close supervision by your doctor.

How Should the Acute Attack Be Handled?

It is essential that anybody with VP who experiences severe abdominal pain, should immediately cease any medication and report to a doctor. Such people must be tested for the presence of PBG which will confirm or exclude an acute attack. (One should not just assume that the problem is an acute attack. This frequently leads to the difficult situation where other problems are overlooked because they are incorrectly called acute attacks.) Treatment begins with the immediate withdrawal of any potentially porphyrinogenic medication. Simple analgesics such as paracetamol and codeine are given for the pain. If these are inadequate to control the pain, admission to hospital will be necessary. The pain may then be controlled by morphine and pethidine, but it will be necessary to consider other aspects of treatment including the administration of a specific compound called haem arginate.

Read Acute Symptoms for more information.

Who Should Take These Drug Precautions?

All patients known with VP must following these precautions. The safest advice is that all their blood relatives, including brothers, sisters and children should take these precautions too, unless they have been adequately tested by a laboratory skilled in the diagnosis of porphyria and pronounced clear of this disease.

Can One Suffer Repeated Attacks of VP?

This is extremely rare. In our experience, the few patients with VP who were thought to be having repeated attacks turned out to be suffering from some other problem.

Diagnosis Of VP

It is absolutely essential that all people thought to have VP and all their family members should be thoroughly and adequately tested. Full instructions are given in Diagnosing porphyria: Introduction and subsequent pages.