The rare incurable disorder that made King George III suffer bouts of insanity may soon be treatable. The disease, which is known as porphyria, afflicted a long line of monarchs in Europe.
Porphyria develops when the body produces excess amounts of molecules called porphyrins. Porphyrins are the building blocks for haem, the iron-rich component of haemoglobin. If the body fails to synthesise haem properly, porphyrins build up and can reach toxic levels.
Patients with this disorder can suffer from a wide range of symptoms including port-coloured faeces, stomach pains, muscle weakness and hypersensitivity to light. The chemicals can also interfere with the nervous system, causing mental illness.
John Rshl, a historian at Sussex University, says convincing evidence has recently come to light that Mary Queen of Scots suffered from a hereditary form of the disease, called variegate porphyria. This was passed down to George III, England's "mad" king.
The disorder continued through his son George IV and Queen Victoria to the last confirmed sufferer, Elizabeth II's first cousin Prince William of Gloucester, who died in a plane crash in 1972. Germany's last kaiser, Wilhelm II, and the last Russian empress, Tsarina Alexandra-who were related to the British royal family-may also have had the disease.
Variegate porphyria is caused by a genetic mutation that affects the efficiency of an enzyme called protoporphyrinogen oxidase found in the mitochondria of cells. When this enzyme fails to work properly, excess protoporphyrinogen spills out into the surrounding cell. Scientists aren't clear what happens next, but they think that oxygen oxidises the protoporphyrinogen molecules, forming large amounts of the porphyrin "protoporphyrin" in an uncontrolled reaction.
Now a team of researchers led by Nick Jacobs at Dartmouth Medical School in New Hampshire and Franck Dayan at the US Department of Agriculture's Natural Products Utilization Research Unit in Mississippi have discovered naturally occurring enzymes can detoxify these porphyrins. They can only do this with help from two substances in the body-glutathione, an antioxidant peptide, and the amino acid cysteine.
The team showed that an enzyme from cows called lactoperoxidase could use glutathione or cysteine to convert protoporphyrin into a more water-soluble porphyrin in a test tube. "This would, in theory, greatly improve the ability of the body to eliminate protoporphyrin, either in the urine or in the faeces," says Dayan. The results will be reported in a future issue of Biochemical and Biophysical Research Communications.
Enzymes that could do the same job exist in humans, the researchers believe, raising the possibility that patients could take glutathione or cysteine supplements to fight porphyria. "The stage is set for other researchers to feed people glutathione," says Dayan.
If a treatment for the disease had been available centuries ago, it may well have changed the course of history. "Because of his illness, George III did not do things he might have. He intended to rule Parliament and establish a strong monarchy," says Rshl. "Instead, the power of Parliament took rapid strides during his reign."
Author: Matt Walker
New Scientist - issue 22 May 1999
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