Twelve Diseases that Changed Our World. Irwin W. Sherman

her longest-surviving child, William Henry, Duke of Gloucester. Her death left the country without a Protestant heir in the direct line of descent. Succession to the throne then passed from the House of Stuart to the House of Hanover through descent from Elizabeth, daughter of James I (and granddaughter of Mary Queen of Scots), who had married the King of Bohemia. Although Elizabeth showed no signs of porphyria, she must have transmitted the defective gene to her daughter Sophia, who married the Elector of Hanover, Ernst August, the father of King George I of Britain. Both George I and George II were healthy, but the grandson of George II, George III, manifested many symptoms of porphyria.

      In his play “The Madness of George III,” Alan Bennett gives the King a voice:

      “Why do you shiver? I am not cold. I am warm. I am burning. No, I am not burning. It is my body that is burning. And I am locked inside it . . . Well give me my shirt then. What shirt is this? No. It's rough. Feel. It's like calico. Sailcloth. It's a hairshirt . . . These are not my proper stockings. They itch, too. I burn all inward. My limbs are laced with fire. But I will not give into it . . . Oh God, my blood is full of cramps, lobsters crack my bones, there are stones in my belly.” Then the King's two servants remark, “Look. What? It's blue. I'd call it purple. You and me, we piss plain. Kings piss purple . . . It has been blue since His Majesty has been ill.” The King continues: “Peace of mind! I have no peace of mind. I have had no peace of mind since we lost America . . . All ours. Mine. Gone. A paradise lost. The trumpet of sedition has sounded. We have lost America. Soon we shall lose India, the Indies, Ireland even, our feathers plucked one by one, this island reduced to itself alone, a great state moldered into rottenness and decay. And they will lay it at my door . . . I am not going out of my mind; my mind is going out of me . . . I don't know. I don't know. Madness isn't such a torment. Madness is not half blind. Madmen can stand. They skip. They dance. And I talk. I talk. I hear the words so I have to speak them. I have to empty my head of words. Something has happened. Something is not right. Oh . . . God, please restore me to my senses, or let me die directly for Thy Mercy's sake.”

      King George III was stubborn and unpredictable in his behavior. Although he did have an attack of ill health in 1765, at age 26, there is no indication that this was accompanied by a fit of madness, and it is not certain whether this disease was porphyria or some other malady. Thus, the American War of Independence in 1775 was precipitated not so much by the King's porphyria as by his inflexible attitude and because he backed the policies of his Prime Minister, Lord North, in the passage of the unpopular Stamp Tax in 1765. “The king's bad judgment may have prevented an amicable settlement, but his faults were shared by his ministers, the majority of the House of Commons and a large proportion of the British public.”

      Although the loss of the American colonies in the War of Independence between 1775 and 1781 appears not to be attributable to the “royal malady,” the same cannot be said for the hostile relations between the Irish and the English. During this period, Protestant settlers and native Catholics lived amicably in Ireland, but in 1798 the Catholics, who were not allowed to sit in the Dublin Parliament, began to revolt, encouraged by France. The uprising was suppressed, and William Pitt, the Prime Minister, suggested that the Dublin Parliament abolish itself and declare union with Britain, with the understanding that Catholics would be eligible to sit in Parliament. In short, Pitt had committed himself (and Britain) to Catholic emancipation. However, Pitt did not inform George III, who regarded himself as “Defender of the Protestants.” The King objected to Catholic emancipation, and Pitt resigned. Ten days later, George III suffered an acute attack of what was almost certainly porphyria, and when he recovered a month later, he called back Pitt, who gave the King his solemn promise that Catholic emancipation would never again be mentioned during George's lifetime. This shelved the subject for 28 years, and the Pitt pacification plan for Ireland was doomed to failure. In consequence, the Irish Catholic union with Britain resulted in domination by the alien and oppressive Protestants. Two hundred fifty years later, the troubles in Ireland, due in part to King George's “madness,” continue.

      King George is thought by many to have had eight porphyric attacks between 1762, when he was 24, and 1804, when he was 66, although it has been argued that his episodes of ill health prior to 1788 did not include symptoms consistent with porphyria. In 1810 he again suffered an attack and lapsed into madness for 2 years; his son, the Prince of Wales, became Regent under the Regency Act of 1811. Because there were hopes that King George might recover, the Prince Regent did not replace his ministers; however, the King never rebounded sufficiently to resume the throne, and he died blind and deaf at age 81.

      In 1968, Ida Macalpine and Richard Hunter, a mother-and-son team of psychiatrists, carefully reviewed the clinical features shown by George III and theorized that his behavioral aberrations were not due to his being “mad” (or, in the modern sense, a manic-depressive psychotic); instead, they concluded that the King's symptoms were consistent with porphyria, a metabolic disorder that caused gastrointestinal symptoms, dermatitis, and dementia. He was, according to Macalpine and Hunter, a simple victim of his “bad,” not his “mad,” genes. But why the severity and late onset of the attacks of lameness, abdominal and limb pain, racing pulse, insomnia, temporary mental disturbance, and discolored urine? It has been suggested, based on a recent (2005) chemical analysis of a hair obtained from George III, that this was the result of continual exposure to arsenic and/or antimony in the medicine (emetic tartar) commonly prescribed in the 18th century to reduce fever.

      George IV, son of George III, also had symptoms consistent with porphyria. While Prince of Wales, he married his cousin Caroline of Brunswick, who was also very probably porphyric. Their only child, Princess Charlotte, also very probably suffered from porphyria. She died in childbirth at the age of 21, possibly partly as a result of this condition. When George IV died, he was succeeded by his brother William Duke of Clarence, who ruled as William IV. Since William had no legitimate children, his heir was his younger brother Edward Duke of Kent, who was most probably porphyric. Edward predeceased the King, and his daughter, Princess Victoria of Kent, became heir. She succeeded her uncle in 1837. Queen Victoria was not porphyric, but she had another hereditary disease, which is discussed later in this chapter. Subsequent British monarchs have shown no signs of porphyria, although in 1968 two living female descendants of the House of Hanover were reported to be porphyric. Thus, although the present House of Windsor appears to be free of porphyria, the disease has persisted in the House of Hanover into the 21st century.

      The medical treatment of George III included methods popularly employed to handle the insane: straitjackets, coercion, cupping, and bleeding. However, it is now clear that the “mad King” was misdiagnosed. The illness from which George III presumably suffered, porphyria, and its attendant consequences such as melancholia, depression, sweats, and fits of mania led to the establishment of psychiatry (at that time called the “mad business”) as a branch of medicine. The hereditary “madness” due to porphyria has afflicted the British monarchy and the House of Hanover and affected world history for over 500 years!

      Hemophilia

      Blood will tell

      Queen Victoria (born in 1819), who reigned as Queen of the United Kingdom from 1837 to 1901, was in part responsible for bringing the Bolshevik Party into power, contributed to the demise of the House of Romanov, influenced the rise of Generalissimo Franco in Spain, and even arguably played an unwitting role in the ascendancy of the Third Reich in Germany. She did this not through her politics or her armies but through her genes, for she sowed the seeds of a debilitating and potentially fatal disease among the crowned heads of Europe by marrying off her daughters and granddaughters to them, with devastating effects on some of the royal houses concerned.

      The disease that Queen Victoria passed on to her offspring was hemophilia or “bleeders' disease.” Hemophilia (literally “love of blood”) involves a failure of the blood to clot within a normal time. The defect is caused by a missing protein in the plasma, the liquid part of the blood, which is necessary for clot formation. Normal blood may take 5 to 15 min to clot, but in persons with hemophilia (hemophiliacs) the process may take hours or even days. The danger for a person with hemophilia is that even a small wound or bruise may lead to severe and uncontrolled internal bleeding and death.

      Without clot formation, the