RETROSPECTIVE ANALYSIS GENETIC DISEASES OF FAMOUS HISTORICAL FIGURES

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The compilation of the medical history of a historical person begins with an assessment of the data common to each individual medical consultation. The assumption becomes an index case if the existing family pedigree indicates the presence of a genetic disease.A medical historian should review all available records, often incomplete in their historical nature, for the presence of clinical symptoms that are repeated in other family members.The classification scheme of historical medical diagnoses was changed by Professor Frederick Holmes.A definite historical diagnosis: in the presence of objective data, such as an autopsy.Probable historical diagnosis: when the detailed history of the members of the dynasty is consistent with a known genetic disease.Questionable: When the family history does not agree with the genetic disease. A complete pedigree is important here, since a genetic disease may be absent in one line and present in another.Uncertain: When there is insufficient data to reach a conclusion regarding the familial occurrence of a genetic disorder.Consider mental illness in the British royal family. Several of George III's children had periodic episodes of physical and mental abnormalities similar to those of their father. The royal physician Johan von Zimmermann wrote to the king: "We have learned that several members of the royal family and, in particular, His Royal Highness the Duke of York and Prince Edward are subject to the same paroxysms, and this makes us suspect of hereditary predisposition."Letters from family and close friends can also be very eloquent about the painful conditions of great dynasties. Edward of Kent, the father of Queen Victoria, also suffered from a similar episodic illness. During her long reign, the Queen wrote literally thousands of letters about this to her children and other relatives, and they turned out to be valuable historical primary sources of information. Her daughter Victoria Adelaide, granddaughter Charlotte and great-granddaughter Theodora suffered from attacks of a similar mental and physical disorder, which passed and then repeated. The women agreed that they all suffered from the same disease.Even minor details of family history can provide important clues regarding the exact diagnosis of hereditary diseases. For example, a more common form of hemophilia is type A, caused by a mutation in the coagulation factor VIII gene. A rare form of the disease, type B, occurs as a result of another mutation in the coagulation factor IX gene. The presence of the paternal age effect was observed in families in which a woman inherits a new mutation from her father only in cases of hemophilia B. Edward of Kent was in his fifties when he became Victoria's father. The fact that her son had hemophilia suggested that she was a carrier of a rare form of hemophilia type B. Women carrying the hemophilia gene usually do not have characteristic symptoms, but sometimes may show a tendency to bleed. Tsar Nicholas and Tsarina Alexandra, the granddaughter of Queen Victoria, had four daughters before Alexei was born with a blood clotting disorder. Other family members noted that the girls seemed to bleed more than usual due to minor cuts and scratches. One of them even had severe bleeding during a routine tonsillectomy. Therefore, it was believed that girls are also carriers of hemophilia B. The effects of various treatments should also be considered as part of a retrospective analysis, since genetic conditions can change the normal response to certain medications. George III did not have a very good opinion of his doctors, because their medicines often made him worse rather than better. He was given James powder, a medicine based on arsenic and calomel, made from mercury. Chemical analysis of hair samples demonstrated elevated levels of these heavy metals, which are known to alter the chemical composition of the blood in people with porphyria and cause symptoms of the disease. Tsarina Alexandra also had symptoms of porphyria. She was prescribed veronal, an early barbiturate that caused severe abdominal cramps, and arsenic drugs that caused painful neuralgia. Princess Adelaide was diagnosed with porphyria in the 1940s. Her illness also apparently resumed after she took barbiturates.The advent of DNA technology in the 1990s provided historians with the opportunity to confirm diagnostic tests using genetic markers found in human tissues obtained from people of historical significance or their families. Now it is possible to accurately identify such diseases.The case of Anna Anderson, who claimed to be the Grand Duchess Anastasia and survived from the Romanov family, was resolved using such methods. Her mitochondrial DNA (mtDNA) was extracted from histological tissues and hair roots, and then compared with mtDNA from a blood sample provided by Prince Philip, Duke of Edinburgh, who is the maternal grandnephew of Queen Alexandra. mtDNA did not match. A police investigation revealed that Anna Anderson was indeed a Polish citizen. Her great-nephew provided a blood sample that showed mtDNA matching Anna, but not the royal line, indicating that she was an impostor. One of the first studies to diagnose a historical genetic disorder involved analyzing DNA extracted from dried fragments of the eyes of John Dalton, who suffered from color blindness. DNA has demonstrated a specific type of disorder that struck the famous British chemist.The Romanov family died during the Russian Revolution. Currently, bone fragments from the burial site of individual family members have been identified and DNA has been extracted. Mutated hemophilia B genes were isolated from the remains of Tsarina Alexandra, Alexei's heir and one of his sisters. This investigation confirmed the presence of a rare form of hemophilia B, inherited from the royal line of Queen Victoria.Another way to thoroughly study the families of historical figures who may have had a genetic disease is to work with surviving relatives. Patient and family support groups for the treatment of many of these diseases have been established over the past two decades. Members of families suffering from hereditary diseases are often interested in their historical roots and study their genealogy. Porphyria's group focused their interest on finding potential connections to members of the British royal family who allegedly suffered from this type of hereditary disease; they have accumulated records of more than 23,000 people. In the pilot study, a woman descended from Edward III provided a blood sample in which the R168L mutation in the PPOX gene, characteristic of porphyria, was detected.American medical geneticist Victor MaKkusik noted that doctors who put forward suspicions of hereditary diseases should be astute specialists with broad knowledge in all areas of medicine and be able to focus their attention on the patient as a whole, and not just on his "eyes, skin or kidneys." The same should apply to medical historians interested in determining the probability of a genetic disease in a patient and his family. It is not recommended to focus solely on the mental state of the subject, without also studying physical data and family pedigree. While working, it is important to maintain skepticism, not dogmatism, until all available data has been reviewed.

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Sofya Radikovna Rakhimova

Author for correspondence.
Email: sofarahimova1999@gmail.com
ORCID iD: 0000-0002-6965-0461
SPIN-code: 7139-3558
Russian Federation, 394036, Russia, Voronezh, Studentskaya St, 10

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