Alexei and Haemophilia

[Elspeth]

Where is your informations about scientists from (TV, magazine, Internet or what) ?

Anna was Franziska has been in communication with some of the scientists involved in the studies of the Romanov remains, as have I.

 

[J Kendrick]

What's medically unsound about them?

Again, you will find my very detailed answer in the American Journal of Hematology, Volume 77, Number 1, September 2004, Pages 92-102.

It is a matter of public record, now kept in the US National Library of Medicine in Bethesda, Maryland.

... And, by the way... about Leopold... since you insist...

The odds are always 50/50 that a female carrier will give birth to a son with hemophilia, and yet -- if the claim that Victoria was a carrier is actually to be believed -- Her Majesty, somehow, magically manages to defy the known mathematical odds and has three sons in a row with no sign of hemophilia at all until the claimed first evidence finally appears in her fourth of four sons, her eighth of nine children.... and that's just the first major flaw in the story.

Leopold is known to have had epileptic-like fits during his most serious haemorrhaging episodes, but those fits have always been written off as being separate and unrelated to his disease because they are not a known symptom of haemophilia. Those very same epileptic-like fits that Leopold had experienced are, however, a symptom that is known to occur in the haemorrhaging episodes of aplastic crisis in haemolytic anaemia... which certainly is a blood disorder... but most certainly is not haemophilia.

JK

 

[Elspeth]

Again, you will find my very detailed answer in the American Journal of Hematology, Volume 77, Number 1, September 2004, Pages 92-102.

It is a matter of public record, now kept in the US National Library of Medicine in Bethesda, Maryland.

Doesn't preclude your giving a summary here.

... And, by the way... about Leopold... since you insist...

The odds are always 50/50 that a female carrier will give birth to a son with hemophilia, and yet -- if the claim that Victoria was a carrier is actually to be believed -- Her Majesty, somehow, magically manages to defy the known mathematical odds and has three sons in a row with no sign of hemophilia at all until the claimed first evidence finally appears in her fourth of four sons, her eighth of nine children.... and that's just the first major flaw in the story.

When the odds of something happening are 50:50, it isn't "defying" the odds for it to appear in one out of four. Maybe it'd be defying the odds for it to happen in one out of forty, but one out of four isn't out of the ordinary.

There's also the matter of haemophilia in male descendants of two of Victoria's daughters, another case where the pattern is consistent with haemophilia.

Leopold is known to have had epileptic-like fits during his most serious haemorrhaging episodes, but those fits have always been written off as being separate and unrelated to his disease because they are not a known symptom of haemophilia. Those very same epileptic-like fits that Leopold had experienced are, however, a symptom that is known to occur in the haemorrhaging episodes of aplastic crisis in haemolytic anaemia... which certainly is a blood disorder... but most certainly is not haemophilia.

And the appearance of haemophilia in female-line grandsons of his is another coincidence, is it?

Speaking of defying the odds, you have a situation where a woman has two daughters with male (but not female) descendants who have symptoms consistent with haemophilia, and a son with the disease, which also shows up in his female-line male descendants. This hereditary pattern is fully consistent with haemophilia. If we're going to discount haemophilia in this family as actually being something different and discount it in that family as being something different again and likewise for a third family, and also if we're going to claim that Victoria couldn't have been a carrier even though there's a mechanism by which she could have been, I think we're getting into defying the odds in a much bigger way than the case where one rather than two sons shows signs of the disease.

 

[J Kendrick]

Doesn't preclude your giving a summary here.

... and deprive you the pleasure of looking it up for yourself in the American Journal of Hematology at your nearest convenient medical library... so that you can pick it apart, line by line and footnote by footnote?

Now, what fun would that be?

Some of its loudest opponents have already pulled it apart in detail on numerous previous occasions on other Royalty boards.. and it continues to stand the test of time. What purpose would it now serve to jump through all of those very same hoops again here, which will change nothing?

It has already passed the test that really matters... a full and proper medical peer-review and publication in a recognised medical journal that specializes in hematology. In spite of any of the possible challenges that may be made here -- and have already been made elsewhere -- it will continue to remain a medically sound alternative hypothesis that counters the consensus opinion.

The only thing that can change this situation is the proper laboratory testing that will reveal once and for all whether or not Empress Alexandra was really a carrier... and whether or not her son actually had the defective gene. Until that day finally comes, the question of which one of these two opposing hypotheses may be the correct one will continue to remain unresolved.

 

[Elspeth]

... and deprive you the pleasure of looking it up for yourself in the American Journal of Hematology at your nearest convenient medical library... so that you can pick it apart, line by line and footnote by footnote?

Now, what fun would that be?

Some of its loudest opponents have already pulled it apart in detail on numerous previous occasions on other Royalty boards.. and it continues to stand the test of time. What purpose would it now serve to jump through all of those very same hoops again here, which will change nothing?

It would serve the purpose of having an actual conversation here rather than just referring to other conversations.

It has already passed the test that really matters... a full and proper medical peer-review and publication in a recognised medical journal that specializes in hematology. In spite of any of the possible challenges that may be made here -- and have already been made elsewhere -- it will continue to remain a medically sound alternative hypothesis that counters the consensus opinion.

The consensus opinion has also been given space in established medical journals, including ones that specialise in haematology. Without actual scientific proof, your challenge, which doesn't seem to have been supported by anyone else, doesn't override the consensus by any means. Given some of the mistakes you've made in this conversation already, I'm not convinced that this alternative of yours holds a lot of weight, especially considering that you apparently have an ulterior motive and are therefore not looking at the issue from the point of view of a disinterested observer.

The only thing that can change this situation is the proper laboratory testing that will reveal once and for all whether or not Empress Alexandra was really a carrier... and whether or not her son actually had the defective gene. Until that day finally comes, the question of which one of these two opposing hypotheses may be the correct one will continue to remain unresolved.

Maybe. But the haemophilia in the Spanish, Hessian, and Albany families would tend to suggest that the haemophilia hypothesis for the Russian family is the correct one.

 

[ferrymansdaughter]

a symptom that is known to occur in the haemorrhaging episodes of aplastic crisis in haemolytic anaemia... which certainly is a blood disorder... but most certainly is not haemophilia.

JK

I have no idea if Alexei had haemophilia or not but I do find this interesting because my father had haemolytic anaemia. Every account I have read of Alexei's episodes (especially the one at Spala) sounds just like the illness Dad had, although unlike Leopold he certainly didn't have fits. Haemolytic anaemia can be either genetic or acquired.

​

 

[J Kendrick]

I have no idea if Alexei had haemophilia or not but I do find this interesting because my father had haemolytic anaemia. Every account I have read of Alexei's episodes (especially the one at Spala) sounds just like the illness Dad had, although unlike Leopold he certainly didn't have fits. Haemolytic anaemia can be either genetic or acquired.

Then you will be far more familiar than most on these boards with the part that thrombocytopenia can play in cases of haemolytic anaemia... and with some of its more visible effects.

The epileptic-like fits that are known to appear in Prince Leopold's medical history are also known to happen in the blood disease of Porphyria, which reminds us not of Alexei and haemophilia... but of Leopold's great-grandfather George III and his niece Princess Charlotte (Wilhelm II's sister).

For Porphyria to have been present in both George III and Princess Charlotte, then that disease too can only have passed from one to the other through Queen Victoria. The mathematical odds of not just one... but two rare blood diseases existing so closely together in a single family line and passing down that same single line through a single female carrier are absolutely astronomical. While it might well be have been either one of those blood diseases or the other that Victoria had passed down the line, it most certainly cannot have been both.

 

[Elspeth]

For Porphyria to have been present in both George III and Princess Charlotte, then that disease too can only have passed from one to the other through Queen Victoria. The mathematical odds of not just one... but two rare blood diseases existing so closely together in a single family line and passing down that same single line through a single female carrier are absolutely astronomical.

Easy to say, of course. Feel free to back up this assertion.

While it might well be have been either one of those blood diseases or the other that Victoria had passed down the line, it most certainly cannot have been both.

Your scientific evidence being?

 

[J Kendrick]

Easy to say, of course. Feel free to back up this assertion.

> While it might well be have been either one of those
> blood diseases or the other that Victoria had passed
> down the line, it most certainly cannot have been both.

Your scientific evidence being?

Do the math.

Odds of being a carrier of hemophilia: 1 in 5000
Odds of being an asymptomatic carrier of porphyria: 1 in 1500
Odds of being an asymptomatic carrier of both hemophilia and porphyria: 5000 x 1500 = 1 in 7.5 million

 

[NotAPretender]

Taking this thread in a slightly different direction:

I was re-reading for about the thousandth time, the tome "Nicholas and Alexandra." In it, the author states that no pain relief in the way of available medicines was provided to the Heir during his episodes. Indeed, his cries of pain were so loud at Spala that household staff stuffed their ears with cotton or wool to carry on their tasks.

The reason given was the concern of potential addiction to painkillers.

However, I'm certain that Nicholas and Alexandra were aware that their son would likely have a shortened life span as a result of his illness regardless of pain relievers provided. Indeed, pain medication could have shortened the episodes, as blood pressure increases notably with severe pain, and such elevated blood pressure could have dislodged a newly-forming blood clot that would have ended the episodes.

Why was the Imperial family so fearful of addiction in someone so young? I do not recall any members of the Imperial family having significant addictions, although I do remember that Alex's aunt, Princess Christian (Princess Helena, Lenchen) was overly fond of opiates and laudanum.

It could have eased this child's life immensely.

Does anyone have any thoughts or input into this?

 

[Russophile]

That's interesting cuz I had read (will have to look up) that N & A were doped up a lot of the time.

 

[Grace Angel]

I've read that too, but you have to remember those were the days of cocaine in Coke.. people didn't realize the long term of effects of using certain things, in all cases. Some things were known about drugs, but not all. No, there were no addictions among the members of the Imperial Family, although it's true that commonly used medicines back then were things we wouldn't use today, at least not for the same reasons.

 

[J Kendrick]

Time to shake up this tree again.

The results of the latest research in Molecular Genetics at the University of Pennsylvania now say a great deal about how spontaneous mutations will cause an X-linked disease... with the mutation not happening first in the mother... but in the child:

Jumping Genes Discovery Challenges Current Assumptions

Science Daily (June 11, 2009) — Jumping genes do most of their jumping, *not* during the development of sperm and egg cells, but during the development of the embryo itself. The research, published this month in Genes and Development, "challenges standard assumptions on the timing of when mobile DNA, so-called jumping genes, insert into the human genome," says senior author Haig H. Kazazian Jr., MD, Seymour Gray Professor of Molecular Medicine in Genetics at the University of Pennsylvania School of Medicine.

Jumping genes – also called transposons – are sequences of DNA that can move or jump to different areas of the genome within the same cell. Jumping gene insertions do cause disease; however, it's not known how frequently diseases due to insertions can be inherited in the next generation. They are a rare cause of several genetic diseases, such as hemophilia and Duchenne muscular dystrophy. In addition, transposon insertion into the genome could play a role in the development of cancer.

The current work alters thinking in the field of jumping genes, challenging standard assumptions that mobile DNA inserts only in eggs and sperm during their respective early development. In this study, the researchers found that insertions took place during embryogenesis after fertilization, at a time when nearly all of the changes cannot be inherited. The researchers now purport, based on the study's findings, that many of those insertions occur in the early embryo, perhaps in the 4- or 8-cell stage.

The study looked at retrotransposons, one class of jumping genes, with the L1 family the most abundant type of retrotransposon in the human genome. Retrotransposons move by having their DNA sequence transcribed or copied to RNA, and then instead of the genetic code being translated directly into a protein sequence, the RNA is copied back to DNA by the retrotransposon's own enzyme called reverse transcriptase. This new DNA is then inserted back into the genome. The process of copying is similar to that of retroviruses, such as HIV, leading scientists to speculate that retroviruses were derived from retrotransposons.

The L1 family of retrotransposons comprises about 17 percent of the human genome. Eventually, continuous jumping by retrotransposons expands the size of the human genome and may cause shuffling of genome content. For example, when retrotransposons jump, they may take portions of nearby gene sequences with them, inserting these where they land, and thereby allowing for the creation of new genes. Even otherwise unremarkable insertions of L1 may cause significant effects on nearby genes, such as lowering their expression.

Insertions can come from an L1 retrotransposon that is in the genome of the embryo or it can arise from an L1 that was in a parent and is not in the embryo. In the latter case, the L1 RNA from that parent is carried over through fertilization and inserts in the embryo. Insertions in the latter case are much less frequent than when the L1 itself is present in the genome of the embryo.

Despite L1 abundance in the genomes of mammals, relatively little is understood about L1 retrotransposition outside of the test tube. Using transgenic mice and rats containing human or mouse L1 elements, the team demonstrated abundant L1 RNA in both egg and sperm cells and embryos. However, the integration events usually occur during the development of the embryo rather than in egg or sperm cells and are not heritable.

-30-

This latest research now clearly demonstrates that the spontaneous mutations that can cause X-linked diseases such as hemophilia have now been shown to start with the first in a line to have the disease.... and not with the mother of the first male in the line who is said to have suffered the disease.

...and so... I will say it yet again... Victoria was not a carrier.

JK

 

[COUNTESS]

Perhaps, yes, perhaps no. It is still a study. They all got it from somewhere. Is it a blame game? It affected numerous children, grandchildren and great-grandchildren of Victoria. I don't think they picked it up from a toilet seat.

 

[J Kendrick]

Perhaps, yes, perhaps no. It is still a study. They all got it from somewhere.

...or they did not get it at all ... and the blood disorder has been seriously misdiagnosed right from the beginning.

True, the hemophilia story does remain to this day the most popular interpretation of the evidence... but it still has not been proved.

This latest science explaining the mutations that can cause such X-linked diseases does not now support it, and to this very day -- even in spite of the claimed DNA identification of those few bone fragments that were uncovered in July of 2007 -- there is still no genetic laboratory proof. All we have now are the most recent excuses from those same DNA researchers who have done the identification work as to why they cannot now find that same very necessary genetic proof.

JK

 

[Anna was Franziska]

even in spite of the claimed DNA identification of those few bone fragments that were uncovered in July of 2007 -- there is still no genetic laboratory proof. All we have now are the most recent excuses from those same DNA researchers who have done the identification work as to why they cannot now find that same very necessary genetic proof.

JK

There weren't any 'excuses' only a real explanation- they did not have enough usable sample to do both the DNA test and the test for hemophilia and had to choose one over the other. Since proving identity was the more important issue, that is what they chose. Besides, no one but you doubts he had hemophilia. (and from your post it appears you still doubt the authenticity of the 2007 remains )

 

[Lumutqueen]

In my opinion i don't doubt that any member of any house who claimed to have haemophilia did have it. Even if Victoria was not a carrier, the royals of all people wouldn't lie about something like that. And i don't believe the russians would either. I also think that the remains found in 2007 were the family of the Tsar.

 

[J Kendrick]

There weren't any 'excuses' only a real explanation- they did not have enough usable sample to do both the DNA test and the test for hemophilia and had to choose one over the other.

That is just an excuse... and it is nothing more than that. They have six chances to find that suspected faulty gene on the X-Chromosome... not just the one chance in Alexei... but also in his mother and in all four of his sisters.

If they fail to find it in any of those six... and especially if they fail to find it in his mother... then he did not have it.

... and Victoria was not a carrier.

Thus far, they have failed to find it.

JK

 

[Anna was Franziska]

In my opinion i don't doubt that any member of any house who claimed to have haemophilia did have it. Even if Victoria was not a carrier, the royals of all people wouldn't lie about something like that. And i don't believe the russians would either. I also think that the remains found in 2007 were the family of the Tsar.

I agree. There is no reason for anyone to lie. The conspiracy theories really have no point or basis.

As for not testing the sisters and mother for the gene, well, JK, somebody has to pay for all that work, maybe you can cough up the money since you seem to be the only one who has a problem with it.

 

[Anna was Franziska]

I still doubt it's ever going to happen because no one in the scientific community challenges it. There is no reason to believe there is any strange coverup, other than those who cannot accept that the whole family died because they like claimant stories.
.

 

[J Kendrick]

I agree. There is no reason for anyone to lie. The conspiracy theories really have no point or basis.

As for not testing the sisters and mother for the gene, well, JK, somebody has to pay for all that work, maybe you can cough up the money since you seem to be the only one who has a problem with it.

This issue has absolutely nothing at all to do with any of your so-called "conspiracy theories".

This issue has absolutely everything to do with the still questionable identity of the blood disease that has been popularly claimed to have brought down a dynasty... which has never been proved by any form of scientific laboratory testing.

Now that the missing remains have been claimed to be found and identified, there can no longer be any excuses for not being able to prove the claims of history with every possible scientific test that is now available.

The question of cost cannot be an excuse either, given the large amounts of money, time, and labour that have already been exerted over the better part of the last two decades to find and identify those same missing remains.

The list of the products that are required for that very same laboratory testing for possible mutations in the Factor VIII gene and the costs of each of those products are well-known, as are the most efficient and cost-effective methods of screening for those mutations

As examples:
http://www.genelink.com/Literature/ps/PS40-2036-XX%20Ver1.1.pdf
... and...
Detection of Factor VIII Gene Mutations by High-Resolution Melting Analysis -- Laurie et al. 53 (12): 2211 -- Clinical Chemistry

Until those still very necessary tests have finally been done to prove the existence of the blood disease that is claimed to have brought down the Russian monarchy... both the research... and the truth... will remain incomplete.

It is well past time that all of those experts who have been involved in this matter since the first of the bones were unearthed nearly 20 long years ago now step up to the plate and finish the job properly... by finally proving -- once and for all and with proper genetic laboratory testing -- whether or not the DNA evidence of that long-claimed blood disease had actually existed in the last of the Romanovs.

JK

 

[ottobre]

Genotype Analysis Identifies the Cause of the "Royal Disease" -- Rogaev et al., 10.1126/science.1180660 -- Science

Published Online October 8, 2009
Science DOI: 10.1126/science.1180660
Science Express Index

Brevia

Genotype Analysis Identifies the Cause of the "Royal Disease"

Evgeny I. Rogaev 1

*, Anastasia P. Grigorenko 2

, Gulnaz Faskhutdinova 3, Ellen L. W. Kittler 3, Yuri K. Moliaka 3
1 University of Massachusetts Medical School, 303 Belmont Street, Worcester, MA 01604, USA.; Vavilov Institute of General Genetics RAS, Gubkina Street, 3, Moscow, 119991, RF.; Research Center of Mental Health RAMS, Moscow, 113152, RF.; Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, 119992, Moscow, RF.
2 University of Massachusetts Medical School, 303 Belmont Street, Worcester, MA 01604, USA.; Vavilov Institute of General Genetics RAS, Gubkina Street, 3, Moscow, 119991, RF.; Research Center of Mental Health RAMS, Moscow, 113152, RF.
3 University of Massachusetts Medical School, 303 Belmont Street, Worcester, MA 01604, USA.

* To whom correspondence should be addressed.
Evgeny I. Rogaev , E-mail: Evgeny.Rogaev@umassmed.edu

These authors contributed equally to this work.


The "royal disease," a blood disorder transmitted from Queen Victoria to European royal families, is a striking example of X-linked recessive inheritance. Although the disease is widely recognized to be a form of the blood-clotting disorder hemophilia, its molecular basis has never been identified, and the royal disease is now extinct. We identified the likely disease-causing mutation by applying genomic methodologies (multiplex target amplification and massively parallel sequencing) to historical specimens from the Romanov branch of the royal family. The mutation occurs in F9, a gene on the X chromosome that encodes blood coagulation Factor IX, and is predicted to alter RNA splicing and lead to production of a truncated form of Factor IX. Thus, the royal disease is the severe form of hemophilia, also known as hemophilia B or Christmas disease.

 

[Russophile]

I wanted to see why they called it "Christmas Disease" so I looked that up. It seems that Christmas disease is a FORM of hemophaelia but not the same, according to this article here.
Christmas Disease

 

[J Kendrick]

I wanted to see why they called it "Christmas Disease" so I looked that up. It seems that Christmas disease is a FORM of hemophaelia but not the same, according to this article here.
Christmas Disease

I'm not buying it... and here's why:

This latest study also now tells us...

They did *not* find any mutations in either the Factor VIII or Factor IX Gene.

From Genome Web Daily News:
Study Finds Hemophilia B-Causing Mutation in Russian Royal Remains | GenomeWeb Daily News | Sequencing | GenomeWeb
"The researchers did *not* find missense mutations, insertions, or deletions in any of the F8 or F9 gene sequences they tested. On the other hand, they did identify a substitution upstream of one of the F9 exons."

This sounds like they're just grabbing at straws to me.

and then... it goes on to say...

"Two members of the Romanov family carried this F9 mutation: Alexei was hemizygous for the mutation and one of his sisters, likely Anastasia, was a heterozygous carrier."

So, this means.. They *did* do tests on the earlier Ekaterinburg remains because they found part of their evidence in bones that were "probably Anastasia"... because we already know that they insist that the bone fragments from 2007 were probably Maria..

But here's the biggest flaw... This also means that there is *no evidence* in this study of any such mutations in the bones of
Alexandra... and it *must* be in Alexandra for their conclusions to be true.

There is also a major problem with claiming that it's Hemophilia B in Factor IX.. or Christmas disease... because Hemophilia B is seven times more rare than Hemophilia A and generally does not show up until adulthood.

Just to give you an example of how rare Hemophilia B really is, there are only 3300 cases in all of the US... out of 300 million people.

JK

 

[ottobre]

To avoid misunderstanding, please read the full text and supplementary information of the papers (Rogaev et al., 2009, PNAS and Science), the mutation in F9 gene was found in Alexandra first.

 

[J Kendrick]

To avoid misunderstanding, please read the full text and supplementary information of the papers (Rogaev et al., 2009, PNAS and Science), the mutation in F9 gene was found in Alexandra first.

Okay, then... What about this:

"Two members of the Romanov family carried this F9 mutation: Alexei was hemizygous for the mutation and one of his sisters, likely Anastasia, was a heterozygous carrier."

One of his sisters was a "heterozygous carrier"?

"Heterozygous" means that the sister had carried two copies of the mutation.. one from each parent...

But... Nicholas could not have been a carrier.

So, how do they explain that one?

JK

 

[kell]

because wasnt it from alix they inheriteed the mutated gene like every book says whom inheatited it from queen victoria

 

[Russophile]

because wasnt it from alix they inheriteed the mutated gene like every book says whom inheatited it from queen victoria

Kell, John is saying that the scientists say that "Anastasia" inherited from BOTH parents. Do you remember reading anything about Dagmar and Alex III being carriers? I don't.

 

[kell]

they had russ a differing muttation it was a melding of 2 genes if i recall and russ plz i have just wasnt sure which mutatetion he meant since both nicolhas his brothers had a type and so did his wife a differing type of gene mutation remember the test of 1991 bones they done a test which showed a differing gene type to mordern day dagmars reletives then to her own descandants thats all since it they both had a genetic mutations question is alix given her childern hemophillia nothing else i meant by it russ and russ the dagmar did pass a mutation to her childern which is diferrant then from the hemophillia gene mutation

 

[Russophile]

Kell can you give us some books or articles on this? Thanks!