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Attacks of King George III's madness linked to key metabolism molecule

BOSTON--Dana-Farber Cancer Institute researchers say they have uncovered a molecular explanation for the episodic attacks of irrational and demented behavior in porphyria, the disease believed to have afflicted "Mad" King George III, the British ruler blamed for the loss of the American colonies in the Revolutionary War.

The mental and physical symptoms of porphyria, a rare genetic blood disease which a number of modern researchers believe plagued King George intermittently throughout his tumultuous reign, can be brought on by fasting and exposure to certain drugs, and is successfully treated by feedings of sugar and high-carbohydrate food. A biological explanation for these nutritional effects has been lacking.

The Dana-Farber scientists say in a report featured on the cover of the August 26 issue of Cell that the nutritional component of porphyria involves a key master metabolic molecule, PGC-1 alpha, in cells of the liver. The gene that makes PGC-1 alpha was isolated in 1998 in the laboratory of Bruce Spiegelman, PhD, who is senior author of the new report. Postdoctoral fellow Christopher Handschin, PhD, is lead author.

"We've explained how porphyria symptoms can occur in episodic attacks triggered by fasting, and why they can be treated by feeding carbohydrates and glucose," says Spiegelman.

King George III suffered from five prolonged, severe episodes of madness during his rule from 1760 to 1820, a period in which he both expanded the British Empire and so stubbornly refused to negotiate with the rebellious American Colonists that they felt only a revolution against England could resolve their grievances. The symptoms recorded at the time sound to modern diagnosticians as typical of porphyria, though the King's attacks were unusual in their severity and that they didn't appear until he was 50.

Several types of porphyria exist, all of them stemming from inherited mutations that disrupt the body's manufacture of heme. A
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Contact: Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute
25-Aug-2005


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