Discussion:
Porphyria through the centuries
(too old to reply)
Leo van de Pas
2003-10-05 21:38:19 UTC
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King James VI-I of England and Scotland, reputedly, suffered from porphyria in a lesser degree, and is supposed to have inherited his this disease from King Charles VI of France.
Sufferers have been traced (?) till the present, King George III being probably the greatest victim of this condition.

My interest is the origin. I always thought that Jeanne de Bourbon (mother of Charles VI) was as far back as the disease could be traced, but then I read what David Williamson had to say in his book on the Kings of Europe :

"Charles's son and successor, Charles VI, has gone down in history as Charles the Mad, and we now know that his madness was a symptom of porphyria, the 'royal malady' which can perhaps be traced back as far as Alfred the Great of England and afflicted many of Charles's descendants, the most notable being King George III of Great Britain. Charles VI's father's condition may well have been attributed to the same cause and as his mother, too, had exhibited signs of instability, poor Charles VI probably inherited the disease in good measure.

I never knew about Charles V, I always thought the disease was attributed only to Jeanne de Bourbon. Does anyone know via whom this disease is supposedly to be traced to Alfred the Great?

Many thanks.
Leo van de Pas
Canberra, Australia
Paul Moynagh
2003-10-06 01:31:28 UTC
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In message <02aa01c38b86$f30d00a0$***@old>
***@bigpond.com (Leo van de Pas) wrote:

< Does anyone know via whom this disease is supposedly to be traced to
Alfred the Great?

No, but I guess tracing it back that far is rather fanciful. The
'accepted' story I thought was that it could only be traced back to
Henry V's wife, Katherine of France, and then via Henry VI --> Henry VII
--> Margaret Tudor --> James IV of Scotland and so via the Stewarts to
Farmer George.

A quick look at the bibliography of porphyria and the Royal Family listed
by the Wellcome History of Medicine library in London comes up with
'George III: a personal history' by Chris Hibbert (pub by Basic Books,
New York, 1998) as the most recent to address the topic, which would
hopefully reference all sources up to then. That library is usually pretty
good at listing anything relevant, even if they do not hold it, and my
guess is that this is the 'latest'. If you cannot get hold of a copy,
I'll try and remember to have a look at it myself when I am next in that
library and let you know what he says.

Best wishes,
--
Paul Moynagh
***@argonet.co.uk
Paul Moynagh
2003-10-12 03:03:08 UTC
Permalink
Post by Paul Moynagh
< Does anyone know via whom this disease is supposedly to be traced to
Alfred the Great?
No, but I guess tracing it back that far is rather fanciful. The
'accepted' story I thought was that it could only be traced back to
Henry V's wife, Katherine of France, and then via Henry VI --> Henry VII
--> Margaret Tudor --> James IV of Scotland and so via the Stewarts to
Farmer George.
A quick look at the bibliography of porphyria and the Royal Family listed
by the Wellcome History of Medicine library in London comes up with
'George III: a personal history' by Chris Hibbert (pub by Basic Books,
New York, 1998) as the most recent to address the topic, which would
hopefully reference all sources up to then. That library is usually pretty
good at listing anything relevant, even if they do not hold it, and my
guess is that this is the 'latest'. If you cannot get hold of a copy,
I'll try and remember to have a look at it myself when I am next in that
library and let you know what he says.
Follow-up after my library visit, as promised: Refs '[n]' at the end.

1. Hibbert [1] is not the good source I predicted - he just
repeats Macalpine and Hunter's [2-5] arguments and hypotheses
(the two doctor (medic) / historians who first suggested that
George III had porphyra). Lots about it since then, some
'anti', but most 'pro'. The main 'anti' was early on - Geoffrey
Dean, a South African haematologist [6], the then world's top
expert in 'variegate' porphyria - the type of the disease
supposed for GIII; the other, rather more common sort, is
'acute intermittent porphyria', though there are lots of
similarities. Dean argued that it being inherited as a dominant
gene there should be many more cases in the European Royal
family, and also that the symptoms were not right for it. But
few have backed him since then, and most historians and doctors
seem now to agree with Macalpine and Hunter.

The best referenced and most detailed recent text seems to be
Röhl, Warren, and Hunt - a historian and 2 geneticists [7].
They are highly sceptical of porphyria in any royal ancester
before Mary Queen of Scots, whom, with her son James VI/I, they
reckon fairly certainly had porphyria. The case for and against
the two strongest medieval candidate ancestors, Charles V of
France and Henry VI of England, are described in some detail.
They conclude that having none of the physical, as opposed to
mental, symptoms of porphyria, there is simply not enough
evidence to say they had it, and what little there is points
more to a solely psychiatric disorder, probably schizophrenia,
than to the mixed mental and physical picture of porphyria.
They are even more sceptical about any others, such as Margaret
Tudor, who has been 'blamed' as the gateway for transferring
any gene to the Stewarts. James VI's cousin Arabella Stuart,
Darnley's sister, is also often said to have had porphyria, but
the evidence is not that convincing.

Thus we are left with good presumptive evidence of a gene for
variegate porphyria, possibly starting as a new mutation with
MQoS, else passed to her by 'god knows who', and transmitted
through the Stuarts to George III. It must be recalled that
then 'porphyria' was not recognised as a disease entity - an
inborn error of metabolism of the blood. Its chemistry only
began to be elucidated in the 19th century and it was not
really until around the 1930s that enough was understood to
start diagnosing it confidently. While it was recognised as
being a hereditary disease, the precise gene causing it has
only very recently been discovered. But being rare, even now
the diagnosis is often missed or delayed. Unless one can
obtain specimens of past bodies - difficult when they are
royals - to do DNA testing (and interpreting this is not at
all straightforward), there can be no certain way of
retrospectively diagnosing past sufferers except by
contemporary description of their symptoms. One 'give away' is
the colour of the urine - variously described as red or purple;
this has been described in some - eg James VI/I and George III,
but by no means all, which does not mean they did not have
coloured urine. Not all have mental symptoms. Some can be mild
and live long; others have it severely and die young, often
apparently suddenly. It has been suggested that some
medieval royals who died suddenly and inexplicably, of
which circumstance some historians impute dirty play such as
poisoning, might instead have had porphyria. But this is pure
sepeculation, the evidence being very thin or non-existent.

Those imputed to most probably have suffered from porphyria
are not 'medieval', - I hope the ng will forgive listing
them here - are:

Mary Queen of Scots;
James VI/I ;
Henry, Prince of Wales (Charles I's brother)
Henrietta Anne, Duchess of Orleans (Ch I's daughter)
Queen Anne (and hence why she had so many miscarriages)

then a bit of a jump of 3 porphyria free generations to:

Friedrich Wilhelm I of Prussia
Carloline Matilda, Queen of Denmark
Frederick II 'the Great'
George III
Willhelm I of Hesse-Kessel

Caroline of Brunswick who married cousin George IV were both
affected, as were 3 of his brothers, Frederick, Duke of York;
Edward, Duke of Kent, and Augustus Duke of Sussex; and their
daughter Caroline (who married Leopold of Saxe-Coberg, later
King of Belgium).

It is felt possible that Queen Victoria may have suffered a
mild version of porphyria. We then have another 3 disease free
generations (which may be because these intervening royals
managed to keep their medical ailments private?) until we get
to modern almost living memory. Princess Adelaide(1870-1948) of
Lippe-Biesterfeld, a ggg grandaughter of William I of
Hesse-Kessel, and her daughter, Princess Feodora of
Saxe-Meiningen (1892-1972) were both affected, as was Kaiser
Bill's sister Charlotte of Prussia (1860-1919).

News to me, and much nearer home to the current British Royal
family, is Prince William of Gloucester who died in an air
crash in 1972, for whom convincing evidence of the disease is
made. That the Queen's sister Princess Margaret had it has been
suggested, but seems doubtful.

DNA testing has been undertaken on Charles I's blood stained
execution shroud and the exhumed remains of Princess Adelaide -
both negative (but there is some doubt that the Princess's
remains were actually hers). However DNA tests on Princess
Charlotte of Prussia's exhumed remains were positive for the
PPOX gene - what one expects with porphyria, so the only one to
be conscusively 'proved' to have had it.

I hope I noted all the above correctly - it was a long book and
I only skimmed it quickly. The relevant references (the last
one further referencing pretty much all the literature on the
topic for those who wish to read further - its a fascinating
read) are:

[1] Chris Hibbert (ref given in my previous post)

[2] Ida Macalpine and Richard Hunter, 'The insanity of King
George III; a classic case of porphyria'. British Medical
Journal (BMJ) 1966, i: on 8 Jan 68 - (sorry, I did not note
the page number)

[3] Ida Macalpine and Richard Hunter, 'Porphyria in the Royal
Houses of Stuart, Hanover and Prussia: a follow-up study of
George III's illness'. BMJ 1968, i: on 6 Jan 68 (ditto re page
No)

[4] These BMJ articles were reprinted with commentaries by
others in a booklet 'Porphyria: A Royal Malady', London,
British Medical Association, 1968.

[5] and for public consumption, in Macalpine and Hunter's book:
'George III and the Mad-Business', London, Allen Lane Penguin
Press, 1968.

[6] - Geoffrey Dean, 'The Porphyrias', London, Pitman & Sons,
1971 (2nd Edition of what is basically an ordinary medical
textbook, but ending with a vituperative anti Macalpine/Hunter
polemic).

[7] John CG Röhl, Martin Warren, & David Hunt
"Purple Secret. Genes,'Madness' and the Royal Houses of
Europe", London, New York, Toronto, Sydney & Aukland, Bantam
Press, 1998

If there is anything later of substance, then the usually
excellent Wellcome library catalogue has overlooked it and I am
unaware of it.
--
Paul Moynagh
***@argonet.co.uk
d***@verizon.net
2003-10-13 01:26:33 UTC
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in article ***@pmoynagh.argonet.co.uk, Paul Moynagh at
***@argonet.co.uk wrote on 10/11/2003 11:03 PM:

Just one comment with regard to Paul's excellent summary about porphyria.

Röhl et alia's DNA testing on Princess Charlotte of Prussia's exhumed
remains showed only one altered nucleotide in the PPOX gene (it was a single
T-to-C mutation, in a non-protein-coding area).

What wasn't shown was that this was a mutation that could cause porphyria,
so Charlotte's diagnosis can't be said to be proven by DNA testing.

Two pages on the "Online Mendelian Inheritance in Man" site might be of
interest:

[1] <http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?176200> describes
porphyria variegata, its molecular genetics, and has links to pertinent
references.
[2] <http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600923> describes
the protoporphyrinogen oxidase gene and lists those allelic variants that
have been demonstrated to cause disease.

- Dennis J. Cunniff
l***@gmail.com
2015-11-25 07:18:42 UTC
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http://www.sussex.ac.uk/internal/bulletin/archive/25jun99/article1.html

The above is a good informative quick read.
I also suggest The American Porphyria Foundation and The British Porphyria Foundation in order to become more aquainted and educated in this highly complex and misunderstood disease.

The Queen's cousin William of Gloucester was confirmed to have Variegate Porphyria and yes Charlotte was exhumed and confirmed to have inherited the faulty autosomal dominant gene for Porphyria as well.

People who have inherited the faulty gene of a Porphyria (There are seven groups of these variants Porphyria is a general term) usually have indicative markers of 95% prevalence of excruciating abdo pain, with intractable vomiting, neurological disturbances, neuropathic pain, hallucinations and the infamous tea coloured or port wine coloured urine during attacks. People who have inherited the gene always have the gene but, these people can be asymptomatic until a contraindicating factor precipitates an attack. Descendant children of a parent with a Porphyria have a 50/50 chance of inheriting the faulty gene and same ratio of passing on the gene to further generations.

In theory, with such a high ratio of inheritance this could be consistent and plausible with the high prevalent suspicions of Porphyria rampant in the royal families.
taf
2015-11-25 09:02:00 UTC
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Post by l***@gmail.com
The Queen's cousin William of Gloucester was confirmed to have Variegate
Porphyria
'Confirmed' is a bit strong. This is all retrospective diagnosis, with no surviving samples to be tested.
Post by l***@gmail.com
and yes Charlotte was exhumed and confirmed to have inherited the faulty
autosomal dominant gene for Porphyria as well.
I would feel better if the genetic analysis had been peer-reviewed, rather than appearing in a privately-published book. Perhaps the nature of the finding precluded this. The analysis showed that in the purported Charlotte sample there was a nucleotide substitution in an area that (contrary to what Rohl suggests) would not necessarily be expected to affect protein expression at all - it is in a dead zone, between critical sequences and not within them. What is then said about the typical electrophoretic appearance of PCR products from mutated genes is patently false. I will be charitable and attribute this to a failed attempt at over-simplification for the common reader rather than conclude he didn't understand what he was talking about, but it does raise a big red flag and is all the more reason for concern.

As recently as four years ago (over a decade after Rohl published his book) the retrospective diagnosis of porphyria as the case of the Royal Malady was questioned by a review in the Journal of Clinical Pathology.

I would not consider this to be a closed case.

taf
l***@gmail.com
2015-11-25 20:53:48 UTC
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Of course this is not a closed case.
What I am reiterating is just that. There is a strong case for Porphyria. To deny that could be considered reckless and the absolute belief that all of the Royals speculated to have Porphyria without evidentiary proof suffered from this disease looses objectivity.

William was indeed confirmed clinically by three different independent physicians to have Variegate Porphyria, in accordance with the cutaneous manifestations upon exposure to sunlight and the typical clinical signs that an Acute Porphyria exhibit.

With all the advances in research technology with Mutation analysis by gene sequencing we may in the near future have definitive proof. We may not.

The research conducted was indeed peer reviewed and made transparent with strict provisions. This reasearch was made subject in a documentary called "Haemophilia and Porphyria Royal diseases from Tainted Blood" One of the many reasons the research was funded was the unanimous high suspicion of Porphyria in the Royal bloodlines.

With research undertaken in this grand manner, it brings some much needed attention to this relatively rare disease.
GEN-MEDIEVAL Administrator via
2015-11-26 02:59:34 UTC
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On Wed, Nov 25, 2015 at 12:53 PM, lindsaygdjwatson via <
Post by l***@gmail.com
Of course this is not a closed case.
What I am reiterating is just that. There is a strong case for
Porphyria. To deny that could be considered reckless and the absolute
belief that all of the Royals speculated to have Porphyria without
evidentiary proof suffered from this disease looses objectivity.
The problem is that all of these retrospective diagnoses are interrelated.
Once the original argument was made that the documented symptomology of
George III could be explained by porphyria, then since porphyria is
hereditary the search was on for other royal relatives with symptoms that
might also indicate porphyria. These other cases would fall well short of
being diagnostic were it not for the underlying conclusion that there was
porphyria in the family. This means that rather than being independent,
such that a 'they couldn't be wrong in every case' argument might be
appropriate, they are instead all interrelated. Were the royal malady not
porphyria, there are other disorders that could explain the diverse
symptoms seen in the other individual royals.
Post by l***@gmail.com
William was indeed confirmed clinically by three different independent
physicians to have Variegate Porphyria, in accordance with the cutaneous
manifestations upon exposure to sunlight and the typical clinical signs
that an Acute Porphyria exhibit.
Symptoms were identified at the time, but at least from Rohl's description
it is far from clear that a diagnosis of variegate porphyria was made at
the time.
Post by l***@gmail.com
With all the advances in research technology with Mutation analysis by
gene sequencing we may in the near future have definitive proof. We may
not.
It is not about technology. The claim is that the Charlotte sequence
variant is disease-causing is simple to test, and has been since the
1990s. As a historian trying to figure out DNA stuff, Rohl probably just
didn't know how to address the question, and this is why his findings were
never published in a scientific setting - you can't just show a base
difference in the DNA, you have to show that it matters. (Which, in
contrast, was done for the formally published DNA analysis of the royal
hemophilia, but they got lucky and found a mutation that had already been
characterized.)


The research conducted was indeed peer reviewed and made transparent with
Post by l***@gmail.com
strict provisions. This research was made subject in a documentary called
"Haemophilia and Porphyria Royal diseases from Tainted Blood" One of the
many reasons the research was funded was the unanimous high suspicion of
Porphyria in the Royal bloodlines.
The results were not published in a peer-reviewed venue,
made-for-television documentary notwithstanding. Further, the text for the
book was clearly not read by someone with expertise in DNA analysis.


With research undertaken in this grand manner, it brings some much needed
Post by l***@gmail.com
attention to this relatively rare disease.
Certainly the interest engendered by Royal Malady hypothesis has helped in
the progress of our understanding of the disease, whether the hypothesis is
correct or not. If you look at some of the early critiques of MacAlpine and
Hunter's original hypothesis in the medical literature, at least one
porphyria expert denied that porphyria could even be inherited.

taf
Ian Goddard
2015-11-25 23:00:00 UTC
Permalink
Post by l***@gmail.com
Descendant children of a parent with a Porphyria have a 50/50 chance of inheriting the faulty gene and same ratio of passing on the gene to further generations.
This needs clarification. Each descendant child will have a 50%
probability of inheriting the gene. *Of those that do inherit it* each
descendant child will have a 50% chance of inheriting it and so on.
Barring a new mutation or marriage with another carrier *none* of the
children of those who didn't inherit the gene will inherit it. So the
probability of a grandchild inheriting is 25%, of a great grandchild
12.5% and so on.

These probabilities can be distorted by cousin marriages amongst the
descendants, of course but otherwise this simple principle does call
into doubt your use of the word "rampant".
--
Hotmail is my spam bin. Real address is ianng
at austonley org uk
l***@gmail.com
2015-11-26 01:07:06 UTC
Permalink
Each person who has inherited the faulty gene of a Porphyria does not always exhibit symptoms of Porphyria (asymptomatic). However, if a person has a contraindicating precipitating factor this can cause an attack at any point in their life (latent Porphyria) which accounts for ninety percent of attacks. The person who has inherited the gene stands to pass on to any children they may have at any point a one in two chance of inheriting the gene whether it is active or not. People do not always inherit the gene, those who do may be carriers and never be aware of it. It is vital to anyone who has Porphyria in their family to be tested and that is why there is such urgency by geneticists and doctors to test and screen for Porphyria.

A good suggestion may be the APF or BPA for you to clarify the numbers. With a high prevalancy of a ratio as a one in two chance of inheriting the gene the odds are exponential especially in larger families. That speaks for itself.
Ian Goddard
2015-11-26 12:39:50 UTC
Permalink
Post by l***@gmail.com
With a high prevalancy of a ratio as a one in two chance of inheriting the gene the odds are exponential especially in larger families. That speaks for itself.
A 50% probability is neither high nor low unless you have some
expectation to which you're comparing it. In this case it's the same
old Mendelian inheritance that I learned about over half a century ago
and hence just what's expected.

Let's consider the consequences a little further. For this we'll assume
that all marriages are to partners unrelated to the original carrier,
that fresh mutations (including reverse mutations) do not occur and that
the gene does not affect the probability of a carrier's survival or
having children.

As stated the proportion of children (the F1 generation) of the original
carrier would be expected to be 50%, which we can express as a
probability of 0.5 (let's drop the cumbersome "one in two").

All the grandchildren (F2 generation) of non-carriers are themselves
non-carriers. 50% of the children of the carriers would be expected to
be carriers but as carriers are only 50% of the F1 generation the F2
carriers are 50% of 50% of their generation. 50% of 50% is 25%, or a
.25 probability.

By the same arguments the probability of any individual being a carrier
halves in the next generation and halves again in the next and so on.

Where does family size come into it?

Let's assume a family size of 2. So the F1 generation consists of 2
children, the F2 consists of 4 children, the F3 of 8 children & so on.
What are the expected number of carriers in each generation? In the F1
it's 2 times the probability which is 0.5, 2 x 0.5 = 1. In the F2 it's
4 x 0.25 = 1, in the F3, it's 8 x 0.125 = 1 and so on. So in this case
the total expected number of individuals in each generation remains 1
although the number of descendants doubles in each generation.

Let's now look at a family size of 4. In the F1 generation we have 4 x
0.5 = 2 expected carriers, in the F2 we have 16 x 0.25 = 4 and in F3 we
have 64 x 0.125 = 8. So in this case the expected number of carriers
doubles but this is a smaller rate of increase than that of the number
of descendants which quadruples.

So although the expected number of carriers increases with family size
its rate of increase is only half that of the number of descendants.
Also note that as all the children of non-carriers are themselves
non-carriers the number of non-carrier branches increases with each
generation. The gene is not reappearing at random amongst all the
descendants of the original carrier.

We also have to consider sample size. What we're looking at is events
which are themselves random but have known probabilities. The
probability tells you what to expect, the actual outcome only
approximates this and the approximation gets closer to the expected as
sample size increases. This is perfectly normal statistics.

On the other hand, with a family size of two although one carrier and
one non-carrier is the expected outcome for the family of a carrier
neither of the other outcomes, two carriers and two non-carriers is
particularly unexpected. There is, then, the possibility of all the
children of a small family of a carrier being non-carriers. The
remainder of the generations of this branch would then be non-carriers.
Over the long term the gene could be lost entirely if family sizes are
small.

Note my assumptions above. Cousin marriages will raise the probability
in subsequent generations as it introduces the probability of both
parents being carriers. Loss of fertility of carriers will reduce the
probability in subsequent generations. Further mutations will decrease
or increase the probability depending on whether they are reverse
mutations or not.

Also bear in mind taf's strictures on the reliability of retrospective
diagnoses, of one diagnosis being influenced by another, by the
reliability of identification of Charlotte's body and his expert
commentary on the DNA analysis.
--
Hotmail is my spam bin. Real address is ianng
at austonley org uk
Todd A. Farmerie
2003-10-13 03:48:59 UTC
Permalink
Post by Paul Moynagh
I hope I noted all the above correctly - it was a long book and
I only skimmed it quickly. The relevant references (the last
one further referencing pretty much all the literature on the
topic for those who wish to read further - its a fascinating
[1] Chris Hibbert (ref given in my previous post)
[2] Ida Macalpine and Richard Hunter, 'The insanity of King
George III; a classic case of porphyria'. British Medical
Journal (BMJ) 1966, i: on 8 Jan 68 - (sorry, I did not note
the page number)
[3] Ida Macalpine and Richard Hunter, 'Porphyria in the Royal
Houses of Stuart, Hanover and Prussia: a follow-up study of
George III's illness'. BMJ 1968, i: on 6 Jan 68 (ditto re page
No)
[4] These BMJ articles were reprinted with commentaries by
others in a booklet 'Porphyria: A Royal Malady', London,
British Medical Association, 1968.
'George III and the Mad-Business', London, Allen Lane Penguin
Press, 1968.
[6] - Geoffrey Dean, 'The Porphyrias', London, Pitman & Sons,
1971 (2nd Edition of what is basically an ordinary medical
textbook, but ending with a vituperative anti Macalpine/Hunter
polemic).
[7] John CG Röhl, Martin Warren, & David Hunt
"Purple Secret. Genes,'Madness' and the Royal Houses of
Europe", London, New York, Toronto, Sydney & Aukland, Bantam
Press, 1998
If there is anything later of substance, then the usually
excellent Wellcome library catalogue has overlooked it and I am
unaware of it.
The following additional relatively recent references come up with PubMed:

Warren MJ, Jay M, Hunt DM, Elder GH, Rohl JC, "The maddening business of
King George III and porphyria.", Trends in Biochemical Sciences. 1996
Jun;21(6):229-34.

Brownstein S, "George III: a revised view of the royal malady", Journal
of Historical Neuroscience. 1997 Apr;6(1):38-49

Hurst L, "Royal porphyria", Southampton Medical Journal. 1988
Autumn;5(2):53-9.

Pierach CA, Jennewein E., [Friedrich Wilhelm I and porphyria - Article
in German], Sudhoffs Archiv; Zeitschrift fur Wissenschaftsgeschichte.
1999;83(1):50-66.

Miller JM, "Vignette of medical history: porphyria in royalty", Maryland
Medical Journal. 1993 Oct;42(10):1015-7

Several appear to be simple recasting for a local audience. The Pierach
article, based on its English abstract, appears to be a clinical
analysis of Frederick with an eye towards whether or not the hypothesis
is correct, concluding that it probably is.

There are several letters in the BMJ discussing the theory right after
it was put forward, at least two by Dean arguing against. I also recall
a Scientific American article by Macalpine and Hunter that did a good
job of describing it for a lay audience, ca. 1972. Finally, there was a
brief article in a medical history journal where I first read of the
attempt to extend it back past Henry VI to the Capets - unfortunately,
someone borrowed my copy and didn't return it, so I can't give a citation.

taf
Paul Moynagh
2003-10-14 03:58:02 UTC
Permalink
< numerous references >

Thanks Todd. I think most of these are also described and referenced in
Röhl, Warren & Hunt's 'Purple Secret' which I would guess is the best
single source for anyone interested who does not want the fag of
trawling through an extensive literature. Whatever they all say, it is
basically just speculation with larger or smaller degrees of
(un)certainty / scepticism, and unless one can examine and test a living
patient a sure diagnosis is not possible. Even testing exhumed DNA, as
Dennis comments, is by no means that reliable.

But speculation is fun, and for George III, and probably some others of
his family, porphyria is as good an explanation of his illness as one is
ever likely to get. Attempting a genetic trace back to medieval royalty
and France is I fear just a bit too fanciful for the known facts.
--
Paul Moynagh
***@argonet.co.uk
Todd A. Farmerie
2003-10-06 01:27:19 UTC
Permalink
Post by Leo van de Pas
King James VI-I of England and Scotland, reputedly, suffered from
porphyria in a lesser degree, and is supposed to have inherited his
this disease from King Charles VI of France.
Sufferers have been traced (?) till the present,
There are known descendants of George III, and more of his father the
Prince of Wales, who have clinical porphyria.
Post by Leo van de Pas
King George III
being probably the greatest victim of this condition.
It was originally theorized that Frederick the Great was also had the
condition.

Just to play the pedant, George III is not known to have suffered from
porphyria - he is known to have suffered from some of the symptoms seen
in porphyria, and his direct descendants suffer from this genetic
disorder. Thus, a strong argument can be made. Actually, a stronger
argument can be made for James VI/I, as one of the most diagnostic
symptoms of the disease is the red urine, something which was noted for
James since he lived in the age of the "piss doctors" when the amount,
color, and taste of urine was thought to be quite useful in diagnosing
disease. In the time of George III, such an approach was dismissed as
witch-doctoring, it being clearly understood that the feces was much
more illuminating, and so nobody noted whether his urine was discolored
or not. James also indicated that he had gotten it from his mother,
establishing a genetic link, further suggesting porphyria.
Post by Leo van de Pas
My interest is the origin. I always thought that Jeanne de Bourbon
(mother of Charles VI) was as far back as the disease could be traced,
It depends on what you consider to be 'traced'. As I suggest above, a
strong case can be made that James I suffered from it, yet there is the
nagging question of where it went in the generations in between he and
George. One should keep in mind, though, that porphyria was originally
thought to be caused, not by genes, but by certain medications (in fact,
when the George III-porphyria link was first suggested, it was dismissed
out of hand because everybody knew that porphyria was caused by an
adverse reaction to modern pharmaceuticals, and thus George could not
possibly have suffered from it). It was only when it was observed that
the sufferers were more likely to be related that the genetics were
uncovered. What this means is that one inherits the susceptibility for
the disease, but it may never be unmasked due to differences in diet and
environment.

Having said that, we return to James. He himself said he got it from
his mother. Unfortunately, we now pass to a time before we have any
truly useful medical records, and we are left making guesses based on
one symptom or another. Arabella Stuart certainly appeared to have had
some kind of dementia at times, so it was hypothesized that both she and
Mary got it from their common Tudor ancestor. Next, it had been noted
that Henry VIII's older brother was said to have been light-sensitive,
another symptom of porphyria, seemingly confirming that the Tudors had
it. Next, we note that Henry VI seemed to be quite competent at some
times, and non-functional at others, perhaps reflecting bouts of
porphyria similar to George III. The Tudors and Henry VI were most
closely related through Catherine of France, and her brother was Charles
the Mad, so there we have madness again. Finally, apparently Joanne de
Bourbon had a brother who showed signs of madness, and hence she was the
hypothesized source. That, at any rate, is how the story runs.

The problem is that the last few generations of this pedigree are based
on the symptom of madness, but madness is not a disease with just a
single cause. We just don't have enough information to draw these
conclusions.
Post by Leo van de Pas
but then I read what David Williamson had to say in his book on the
"Charles's son and successor, Charles VI, has gone down in history
as Charles the Mad, and we now know that his madness was a symptom
of porphyria, the 'royal malady'
Except we don't know this. It is simply a hypothesis, with no evidence
other than the madness itself (which creates a bit of a circular
argument) and the fact that a descendant of his sister, six generations
down, had a quite probable case of it.
Post by Leo van de Pas
which can perhaps be traced back
as far as Alfred the Great of England and afflicted many of Charles's
descendants, the most notable being King George III of Great Britain.
Charles VI's father's condition may well have been attributed to the
same cause and as his mother, too, had exhibited signs of instability,
poor Charles VI probably inherited the disease in good measure.
I never knew about Charles V,
Hard to say without knowing what the "father's condition" was that
reference is being made to here.
Post by Leo van de Pas
I always thought the disease was
attributed only to Jeanne de Bourbon. Does anyone know via whom this
disease is supposedly to be traced to Alfred the Great?
This connection must be even more tenuous. I am assuming that someone
noted that some description of Alfred would be consistent with
porphyria, and that the Valois descended from him. Certainly, one is
hard pressed to find any documentation for Alfred's descendants for
generations that would point to any symptom of porphyria. Frankly, this
is stretching things a bit too far. With each generation before Mary of
Scotland it becomes less and less likely that the reconstruction is
correct.

Remember, it need not have come from anyone earlier. Wild hypotheses of
crypto-infidelities aside, it appears that the hemophilia among
Victoria's descendants arose because her father was in his 50s at the
time of her conception, at which age the rate of genetic mutation is
heightened. Most genetic diseases in humans can't be traced further
than a few generations, probably because they arise de novo, severely
reduce the reproductive potential of the carriers, and burn themselves
out. It is only rare ones that, due to some selective advantage (or to
unique sociological conditions) appear to be of great antiquity.

taf
D. Spencer Hines
2003-10-06 02:28:01 UTC
Permalink
"Todd A. Farmerie" <***@po.cwru.edu> wrote in message news:***@po.cwru.edu...

[...]

| The Tudors and Henry VI were most closely related through Catherine of
| France, and her brother was Charles the Mad, so there we have madness
| again.

[...]

Todd A. Farmerie
-----------------------------------------------

No, Charles VI was her FATHER.

Deus Vult.

D. Spencer Hines

Lux et Veritas et Libertas

Vires et Honor
Christina
2003-10-06 03:16:30 UTC
Permalink
Post by Todd A. Farmerie
as one of the most diagnostic
symptoms of the disease is the red urine, something which was noted for
James since he lived in the age of the "piss doctors" when the amount,
color, and taste of urine was thought to be quite useful in diagnosing
disease.
Blood in the urine is a symptom of many diseases, including Plasmodium
falciparum (blackwater fever/malaria), certain kidney diseases, urinary
infections, etc. We'll never know for sure if James, George, and anyone
else long dead had porphyria. I suppose a DNA analysis is possible.

I wish I had my biochem book to do a further analysis of this question.
(It's packed.)

Christina
L***@yahoo.com
2004-12-14 15:31:39 UTC
Permalink
I have Porphyria. My genealogy goes back to Frederick The Great thru
his son Prince Rupert of the Rhine(Bavaria) on my father's side and
back thru the royal Spencers and Du Trieux on my mother's side.
It is suspected I have the rarer form of Harderoporphyria that takes
two recessive genes, one from each parent. However, it cannot be proven
unless I can get to France for DNA testing as it is not being done
anywhere else at the moment and biological material cannot be sent from
the US to France right now without complications that would compromise
the sample.
Ravyn, Lady Heresy
m***@gmail.com
2018-11-12 07:28:36 UTC
Permalink
Post by Leo van de Pas
King James VI-I of England and Scotland, reputedly, suffered from porphyria in a lesser degree, and is supposed to have inherited his this disease from King Charles VI of France.
Sufferers have been traced (?) till the present, King George III being probably the greatest victim of this condition.
"Charles's son and successor, Charles VI, has gone down in history as Charles the Mad, and we now know that his madness was a symptom of porphyria, the 'royal malady' which can perhaps be traced back as far as Alfred the Great of England and afflicted many of Charles's descendants, the most notable being King George III of Great Britain. Charles VI's father's condition may well have been attributed to the same cause and as his mother, too, had exhibited signs of instability, poor Charles VI probably inherited the disease in good measure.
I never knew about Charles V, I always thought the disease was attributed only to Jeanne de Bourbon. Does anyone know via whom this disease is supposedly to be traced to Alfred the Great?
Many thanks.
Leo van de Pas
Canberra, Australia
Just wanted to mention that there is DNA evidence of the Royal Line having Porphyria, I believe the work is fairly recent. I watched a clip of the science involved in testing the remains from the deceased.
I have been reading everything I can find! I just tested and my results indicated Elevated Porphyrins and now I am waiting on Genetic testing. I can trace my line back to King James V, and King james IV, On at least two separate branches, King Christian, King CHARLES VI, and The Ottoman EmPire, King Henry the VII, It is very challenging to trace back these lines this far and keep tract. I am trying to make a chart. I am curious which of my branches that lead to the Royal lines may have the possible gene. I have Royalty on at about six branches so far. It's confusing when I get back that far on the Royal lines, Its seems like thy were all related!
Interesting!
Good luck on your research!
Angie Moses
***@gmail.com
taf
2018-11-12 15:17:46 UTC
Permalink
Post by m***@gmail.com
Just wanted to mention that there is DNA evidence of the Royal Line
having Porphyria, I believe the work is fairly recent.
A descendant of George II was confirmed to have a porphyria mutation. They were not specifically identified at the time for privacy reasons, and it was simply assumed that their harboring of the gene was due to this particular line of descent. Notably, the form of porphyria that was diagnosed did not match the form caused by the mutation in question, which could mean the form was misdiagnosed (giving an indication of how hard a proper porphyria diagnosis is even in a living person) or that there are separate independent strains of porphyria bouncing around in the royal classes. More recently, there was a vague statement that it was found in a descendant of George III, but so few details were given that it really is hard to know what to make of it.

In order to truly confirm it, it would be necessary to exhume George III and the other royals of his family, and there is little chance this would be approved solely for the purposes of addressing a historical curiosity. Even that George III's madness was porphyria-related is not universally accepted. Within the past decade, a commentary was published in a scientific journal that argued the whole thing was building a house of cards out of ambiguous symptomology, and that the descendant of George II carrying the gene might just as well have inherited it from someone else or had a spontaneous mutation.
Post by m***@gmail.com
I am curious which of my branches that lead to the Royal lines may have
the possible gene.
The initial claim, now 50 years old, did a retrospective diagnosis focused on two monarchs, first George III and then James I/VI. In the case of James, he himself wrote that he owed the symptoms to his mother, Mary, Queen of Scots. No hint of porphyria was found in intervening generations between James and George. With the conclusion that George was suffering from a genetically-based malady, the proposers looked for a range of symptoms that might be accounted for by the disease and suggested that George's granddaughter, Charlotte, and cousin Frederick the Great might have showed symptoms, but in both cases the symptoms pointed to would not have led to a porphyria diagnosis were genetic porphyria not already thought to be in the family. (It should be remembered that at the time this all was proposed, porphyria wasn't even recognized as having a genetic influence - it was thought to be exclusively caused by an adverse reaction to certain prescription drugs and evidence that there could be a genetic cause was first appearing, and still being strenuously resisted by some.)

This sort of started a feeding frenzy of retrospective diagnosis, where people looked at every symptom found in any member of any royal family and if it could possibly be interpreted as one off the symptoms of porphyria, it was concluded to be so. As just one example, the insanity of Henry VI of England was pointed to, and that of one of his mother's aunts. Note the difference in approach: with George and to a lesser extent James, they took the symptoms and asked 'what disease does this look like?', but in the other cases they said 'if there is porphyria, who else had a symptom that could be porphyria-related?', which sort of biases the study because most of the symptoms of porphyria can just as well have other causes.

So, the strongest evidence is that it was in the late Stuarts, and in the mid-Hanoverians, and the latter is seemingly confirmed by the gene being found in a descendant. All else remains retrospective guesswork.

taf
taf
2018-11-12 15:38:06 UTC
Permalink
Post by taf
Post by m***@gmail.com
Just wanted to mention that there is DNA evidence of the Royal Line
having Porphyria, I believe the work is fairly recent.
A descendant of George II was confirmed to have a porphyria mutation.
They were not specifically identified at the time for privacy reasons,
and it was simply assumed that their harboring of the gene was due to
this particular line of descent.
I had forgotten about the more recent PCR analysis of Charlotte, which may be the 'proof' you had in mind. Let me be clear on that. It was a failed experiment, completely misinterpreted by the historian-author. The claimed result showed a double-band on the electrophoretic gel. Contrary to what the author claimed, this is not something commonly seen when there is a mutation. It is only seen when the experiment did not work properly, or when there is some confounding factor unrelated to what is being evaluated, and the experiment needed to be redesigned from scratch to avoid that problem. Any conclusion reached from such a result is invalid.

taf
Olivier
2018-11-12 18:35:45 UTC
Permalink
More about royal porphyria :

http://www.englishmonarchs.co.uk/hanover_15.html

http://images.biomedsearch.com/7047941/medhist00087-0064.pdf

https://books.google.fr/books?id=LU8lc56XyVMC&pg=PA141&lpg=PA141&dq=porphyria+charles+VI&source=bl&ots=MnBvzI-c1U&sig=mKeHOrYo6lZDE_bnX8qd6Kh3YnA&hl=fr&sa=X&ved=2ahUKEwjh6-vrvs_eAhUuxYUKHfspC7MQ6AEwCXoECAMQAQ#v=onepage&q=porphyria%20charles%20VI&f=false
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