UK: Haemophilia: The Impact Of A Single Gene Disorder On World History

Last Updated: 20 April 2016
Article by Deloitte LLP

Most Read Contributor in UK, August 2017

Earlier this week I was discussing our up and coming Healthcare and Life Sciences Essentials course with a new joiner Pavithra Rallapalli, known as Pavi, who recently completed her Post doctoral fellowship at University College London. Her experience was facinating and, not one to miss a chance, I asked Pavi whether she might be interested in writing a Centre blog, and if so what would she want to write about.

She replied almost immediately asking me if I had heard/read about the haemophilia B gene that Queen Victoria carried and how she, through the marriages of her children, passed the disorder to many other royal families. The genetic mutation played a role in the Russian revolutions and the fall of a number of other royal households. While I was aware of the basic facts, and had seen a number of films that alluded to the problem, I admitted that my knowledge was limited and agreed that I thought our readers would enjoy understanding more about this. This week's blog, therefore, presents Pavi's narration of Haemophilia and its role in the downfall of royal families across Europe.

Many of you may well have read or heard about Haemophilia, and the fact that it is often referred to as "the royal disease". But before I discuss the devastation it caused in royal households during the the 19th and 20th Century I thought I should explain a little about the nature and cause of Haemophilia.

Haemophilia is a rare bleeding disorder in which the blood fails to clot normally. Think of your body as controlled by a large network, with lots of small and interconnected branches/departments, headed by a single gene or a group of genes, with some lateral sense of hierarchy to maintain order. One such small, yet significant network is your coagulation cascade – A group of genes that operate together, to form clots, to prevent the loss of blood at any site of injury. Much like a 24/7 stand-by support team. When the body's protective layer is breeched by a cut, a blow, a tear, the team jumps immediately into action to deliver a fix (a blood clot).

The coagulation cascade has 14 core genes and several other extended and supporting genes. With regard to Haemophilia, there are two core genes - Factor 8 (F8) and Factor 9 (F9), both from the X chromosome. Any mutation in these two genes stops the cascading effect and stops the blood from clotting, this condition is called Haemophilia A (in the case of a dysfunctional F8 gene), and Haemophilia B (in the case of a dysfunctional F9 gene). Haemophilia A and B are hereditary haemorrhagic disorders characterised by deficiency or dysfunction of coagulation genes. Haemophilia being an X-chromosome originator, affects mostly men. Women are usually only the carriers of the disease (the gene with the mutation that is) and pass on the mutation reproductively. This is the case with all the X-chromosome genes; women have two X chromosomes (XX) and men have only one (XY). So even if the woman has a mutation in one of her X chromosome genes, she most likely has another normal copy of the same gene from her other X chromosome. Patient statistics suggest that 1 in 5,000 are affected by Haemophilia A while 1 in 50,000 are affected my Haemophilia B. Hopefully, this brief introduction provides enough background to gain a sense of the principle of Haemophilia. But if you would like to know more, please use other sources available online (For example, the World Federation of Hemophilia).

My own interest in Haemophilia and the reason for choosing it as the subject of this blog is that this disorder is a powerful model of how a healthcare problem can have a wide-ranging impact on other areas and on people's lives and events far removed from the disease itself. The improvement in the quality of life of the patients and the science behind this disorder and subsequently its cure, go hand in hand with technological, clinical and biomedical advancements: From increased understanding of the disease, to the discovery & later the production of recombinant proteins (which is widely administered as a drug to manage the bleeding), the use of the internet in bringing together patients and the support community, and advancements in bioinformatics, molecular modelling and gene therapy. Today there is hope and a potential cure for the disorder which was unimaginable 100 years ago. Haemophilia is a rare disorder, and the patient information, research data and any other relevant information, although complex to interpret, is relatively limited in scale due to the small population of people affected. But if you were to project this case study on to other more prevalent diseases like diabetes, cystic fibrosis or even cancer, you can get a sense of why such insights are important and the need to manage and study them strategically.

Getting to the crux of this story, Queen Victoria and her reign in 19th century England (1819 -1901). The then queen carried a Factor 9 gene mutation, having married Albert (Prince of Saxe-Coburg-Gotha) she went on to have 9 children (4 boys and 5 girls) and unwittingly passed on the haemophilia B gene to 3 of their children. Prince Leopold had Haemophilia B and died of a haemorrhage after a fall when he was 30, while Princess Alice and Princess Beatrice were carriers of this mutation. The evidence that the genetic variant passed down by Queen Victoria was a F9 mutation causing haemophilia B was not discovered until 2009, when a group of scientist decided to genotype the remains of the Romanov family.1

Through the marriage of Princess Alice and Princess Beatrice, this mutation was carried on to the German royal family, and subsequently, through the marriage of their own "carrier" daughters to the Russian and Spanish royal families in the 19th and 20th centuries. Alice's son Friedrich died of severe bleeding due to haemophilia after sustaining an injury. Alice's daughter Alix, who married Nicholas II of Russia, passed on the carrier mutant F9 gene to the Russian royal family. Had Alix, accepted the offer of marriage from Prince Albert in 1890, or his brother Prince George, as intended by Queen Victoria, haemophilia would have been re-introduced into the reigning branch of the British royal family. But Alix married Tsar Nikolas II instead and carried the disease into the Russian Romanov imperial family. She had four daughters before giving birth to the long-awaited son, Alexis, heir to the Russian throne. Once the parents realised their only son had haemophilia, they were distressed and tried everything to find a cure distracting them from the growing state of unrest in the country. Finally, they turn to the "spiritualist" Rasputin, who claimed to be able to relieve their son of his pain. Meanwhile, the deterioration in public affairs culminated in the Russian revolution, and the assassination of the Russian royal family.

The Russian royal family's entanglement with Rasputin, and their deaths during the Bolshevik Revolution have been well chronicled. Less well known is the marriage of Princess Beatrice's daughter, Victoria, to Alfonso XIII of Spain. Beatrice passed on her mutation to the Spanish royal family. Haemophilia was subsequently carried through various royal family members for three generations, before disappearing. The above narration covers hundreds of pages of history so hopefully the image below should help illustrate the trajectory of the royal health hazard, otherwise known as haemophilia. 2

EUROPEAN ROYAL FAMILY PEDIGREE LINE OF HAEMOPHILIA. NOTE: WE HAVE INCLUDED ONLY THOSE WITH RECORDED HAEMOPHILIA B MUTATION.

In Queen Victoria's time there was no cure for haemophilia, indeed, like most genetic disorders prior to the 1960s when effective treatment became available, average life expectancy for haemophiliacs was only 11 years. By the 1980's the life span of the average haemophiliac receiving appropriate anti-coagulant treatment, was 50–60 years. Today with newer more targeted gene therapy persons with haemophilia typically have a near normal quality of life with an average lifespan approximately 10 years shorter than an unaffected male. Today, when we talk about drug development, we do not only mean small drug molecules, but therapeutics also include drug, gene or cell therapy. My reason for sharing this story is to illustrate how our understanding and treatment of diseases has developed and more importantly to remind you that behind every treatment or discovery there is a history, and the importance of sometimes thinking beyond, looking deeper and connecting the dots.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

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