What is Variegate Porphyria (VP)?
The haem synthetic pathwayVariegate 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 Cape met 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. 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 fluorescence 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.