Haemophilia in European royalty

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Queen Victoria's descendants with haemophilia and known female carriers
Inheritance by female carriers

Haemophilia figured prominently in the history of European royalty in the 19th and 20th centuries. Queen Victoria of the United Kingdom, through two of her five daughters - Princess Alice and Princess Beatrice - passed the mutation to various royal houses across the continent, including the royal families of Spain, Germany, and Russia. Victoria's youngest son, Prince Leopold, Duke of Albany, also suffered from the disease, though none of her three elder sons did. Tests on the remains of the Romanov imperial family show that the specific form of haemophilia passed down by Queen Victoria was probably the relatively rare haemophilia B.[1] The presence of haemophilia B within the European royal families was well-known, with the condition once popularly known as "the royal disease".

The sex-linked X chromosome bleeding disorder manifests almost exclusively in males, even though the genetic mutation causing the disorder is located on the X chromosome and can be inherited from the mother by male children or from either mother or father by female children. This is because the trait is recessive, meaning that only one correctly-functioning copy of the blood clotting factor gene is necessary for normal clotting. Females have two X chromosomes, and hence redundant copies of the blood clotting factor gene located on them. A female who inherits a mutated copy on one X chromosome has also inherited a second X chromosome from the other parent that is likely to carry a non-mutated copy of the gene, capable of directing appropriate clotting. Such a female, with normal clotting but possessing a single mutated copy of the gene, is called a carrier. Males possess only a single X chromosome, inherited from their mother, having received a Y chromosome from their father instead of a second X. If their sole X chromosome contains the haemophilia mutation they possess no second copy to provide for normal function, as in carrier females. Each child of a carrier will have a 50% chance of inheriting their mother's mutation, of being a haemophiliac (sons) or carrier (daughters). The daughter of a male haemophiliac will always inherit his mutation, while a son cannot ever inherit it. A female will be affected with haemophilia only in the rare circumstance that she inherits mutated X chromosomes from both a haemophiliac father and a carrier or a haemophiliac mother. No case of such double inheritance is known among Queen Victoria's descendants.

Although an individual's haemophilia can usually be traced in the ancestry, in about 30% of cases there is no family history of the disorder, and the condition is speculated to be the result of spontaneous mutation in an ancestor.[2] Victoria's appears to have been a spontaneous or de novo mutation, most likely inherited from one of her parents, and she is usually considered the source of the disease in modern cases of haemophilia among her descendants. Queen Victoria's father, Prince Edward, Duke of Kent, was not a haemophiliac, but the mutation may have arisen as a germline mutation within him. The rate of spontaneous mutation is known to increase with paternal age (and is higher in fathers than in mothers at all ages); Victoria's father was 51 at her birth. The probability of her mother having had a lover with haemophilia is minuscule given the low life expectancy of 19th-century haemophiliacs. Her mother, Victoria, Duchess of Kent, was not known to have a family history of the disease, although it is possible that she was a carrier, but among her children only Victoria received the mutated copy.

Queen Victoria's eldest daughter, Victoria, Princess Royal, apparently escaped the haemophilia gene, as it did not appear in any of her matrilineal descendants. Victoria's fifth child, Princess Helena, may or may not have been a carrier; two healthy sons survived to adulthood, but two other sons died in infancy, and her two daughters did not have issue. Victoria's sixth child, Princess Louise, died without issue. Queen Victoria's sons Edward VII, Alfred, Duke of Saxe-Coburg and Gotha, and Prince Arthur, Duke of Connaught and Strathearn were not haemophiliacs; however, her daughters Alice and Beatrice were confirmed carriers of the gene, and Victoria's son Leopold had haemophilia, making his daughter Princess Alice, Countess of Athlone a carrier as well.

Queen Victoria family tree[edit]

Children[edit]

Queen Victoria
Xx
Albert
XY
Victoria
X?
Edward VII
XY
Alice
Xx
Louis IV
XY
Alfred
XY
Helena
X?
Louise
X?
Arthur
XY
Leopold
xY
Helen
XX
Beatrice
Xx
Henry
XY
Victoria
X?
Elisabeth
X?
Irene
Xx
Henry
XY
Ernest Louis
XY
Frederick
xY
Alix
Xx
Nicholas II
XY
Alice
Xx
Alexander
XY
Waldemar
xY
Sigismund
XY
Henry
xY
Olga
XX?
Tatiana
XX?
Maria
Xx?
Anastasia
XX?
Alexei
xY
May
X?
Rupert
xY
Maurice
?Y
Alexander
XY
Victoria Eugenie
Xx
Alfonso XIII
XY
Leopold
xY
Maurice
xY
Alfonso
xY
Jaime
XY
Beatriz
X?
Maria Cristina
X?
Juan
XY
Gonzalo
xY

Legend: X – unaffected X chromosome; x – affected X chromosome; Y – Y chromosome; ? - unknown carrier status
Source: Aronova-Tiuntseva, Yelena; Herreid, Clyde Freeman (20 September 2003). "Hemophilia: 'The Royal Disease'" (PDF). SciLinks. National Science Teachers Association. p. 7. Archived from the original (PDF) on 10 January 2018.

Princess Alice[edit]

Alice (1843–1878), Victoria's third child, and wife of the future Grand Duke Louis IV of Hesse and by Rhine (1837–1892), passed it on to at least three of her children: Irene, Friedrich, and Alix.

Prince Leopold[edit]

Leopold (1853–1884), Victoria's eighth child, was the first member of the family to manifest haemophilia; he died at age 30 from bleeding after a minor fall,[5] only two years after marrying Princess Helena of Waldeck and Pyrmont. (1861–1922)

He passed the gene on to his only daughter, as all of the daughters of a haemophiliac father would inherit the gene:

Alice's younger son Prince Maurice of Teck died in infancy, so it is not known if he was a carrier of the gene. Her daughter Lady May Abel Smith (1906–1994), Leopold's granddaughter, has living descendants none of whom has been known to have or to transmit haemophilia.

Leopold's posthumous son, Charles Edward (1884–1954), was unaffected, as a father cannot pass the gene to a son.

Princess Beatrice[edit]

Beatrice (1857–1944), Victoria's ninth and last child, and wife of Prince Henry of Battenberg (1858–1896) passed it on to at least two, if not three, of her four children:

Today[edit]

Albero-discendenza-vittoria.jpg

No living member of the present or past reigning dynasties of Europe is known to have symptoms of haemophilia or is believed to carry the gene for it. The last descendant of Victoria known to have the disease was Infante Gonzalo, born in 1914, although hundreds of descendants of Queen Victoria's (including males descended only through females) have been born since 1914. However, because the haemophilia gene usually remains hidden in females who only inherit the gene from one parent, and female descendants of Victoria have left many descendants in royal and noble families, there remains a small chance that the disease could appear again, especially among the female-line Spanish descendants of Princess Beatrice.

Chronological order[edit]

Queen Victoria died in 1901 and outlived her youngest son and a grandson, both of whom had the disease. The gene can be passed down the female line without a haemophiliac son being born, but as the family line continues and no haemophiliac sons are born, it becomes less likely that a certain ancestor had the gene and passed it on through the female line.

Men who had haemophilia in order of death
# Name Death Relation to Queen Victoria
1 Prince Friedrich of Hesse and by Rhine 29-May-1873 grandson
2 Prince Leopold, Duke of Albany 28-Mar-1884 son
3 Prince Henry of Prussia 26-Feb-1904 great-grandson
4 Tsarevich Alexei of Russia 17-Jul-1918 great-grandson
5 Lord Leopold Mountbatten 23-Apr-1922 grandson
6 Rupert Cambridge, Viscount Trematon 15-Apr-1928 great-grandson
7 Infante Gonzalo of Spain 13-Aug-1934 great-grandson
8 Alfonso, Prince of Asturias 6-Sep-1938 great-grandson
9 Prince Waldemar of Prussia 2-May-1945 great-grandson

Type of haemophilia discovered[edit]

Because the last known descendant of Queen Victoria with haemophilia died in the 1940s, the exact type of haemophilia found in this family remained unknown until 2009. Using genetic analysis of the remains of the assassinated Romanov dynasty, and specifically Tsesarevich Alexei, Rogaev et al. were able to determine that the "Royal Disease" is actually haemophilia B. Specifically, they found a single-nucleotide change in the gene for clotting Factor IX that causes incorrect RNA splicing and produces a truncated, nonfunctional protein.[6]

Notes[edit]

  1. ^ a b "Case Closed: Famous Royals Suffered from Hemophilia". Archived April 12, 2010, at the Wayback Machine Michael Price, ScienceNOW, October 9, 2009.
  2. ^ "Hemophilia B". Retrieved 2007-11-21.
  3. ^ Ian Vorres, The Last Grand Duchess, 1965 p. 115.
  4. ^ Massey, Nicholas and Alexandra, 1967
  5. ^ Aronova-Tiuntseva, Yelena; Clyde Freeman Herreid (2003). "Hemophilia: "The Royal Disease"" (PDF). Science Cases: 1–7. Archived from the original (PDF) on 28 September 2013. Retrieved 23 March 2013.
  6. ^ Rogaev EI, Grigorenko AP, Faskhutdinova G, Kittler EL, Moliaka YK (November 2009). "Genotype analysis identifies the cause of the "royal disease"". Science. 326 (5954): 817. Bibcode:2009Sci...326..817R. doi:10.1126/science.1180660. PMID 19815722.

References and external links[edit]