The Martells - gout and hyperuricemia

[Greymoon]

Genetic disorder? Doran and Elia Martell.

Basic summary here:

the hypothesis is that Elia and Doran suffer(ed) from a genetic disorder that translated as hyperuricemia (abnormally high level of uric acid in the blood); this increased the likeliness for Doran to develop gout and was the cause of Elia's frail health and possible complications during pregnancy and childbirth.

...

Also, if this has been discussed before, please tell me so.

I’ve just read on the asoiaf wiki, that Doran Martell has gout. The book symptoms seem to fit, but is this canon, or is it simple deduction? (I don’t remember reading it precisely) In any case, the occurrence of gout is (according to Wikipedia, this time) partly genetic.

Elia was reportedly frail of health. We also know that Doran’s mother had several miscarriages, that Doran had brothers that died in childhood (early childhood?)...this is not so exceptional considering high mortality rates in Westeros (or at least medieval times). But I was wondering if perhaps there was also, another factor involved here...a genetic disorder (more on hyperuricemia and pregnancy later).

“The occurrence of gout is partly genetic, contributing to about 60% of variability in uric acid level. Three genes called SLC2A9, SLC22A12 and ABCG2 have been found commonly to be associated with gout, and variations in them can approximately double the risk. Loss-of-function mutations in SLC2A9 and SLC22A12 cause hereditary hypouricaemia by reducing urate absorption and unopposed urate secretion. A few rare genetic disorders, including familial juvenile hyperuricemic nephropathy, medullary cystic kidney disease, phosphoribosylpyrophosphate synthetase superactivity, and hypoxanthine-guanine phosphoribosyltransferase deficiency as seen in Lesch-Nyhan syndrome, are complicated by gout.”

http://en.wikipedia.org/wiki/Gout

I looked up the two bolded disorders. Now, I’m not a medical student – in case there’s a gross mistake, do please mention it ;). Hereditary hypouricaemia is benign, and not a medical condition in itself...the search got confusing after that, so I stuck to familial juvenile hyperuricemic nephropathy...

“Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder heralded by hyperuricemia during childhood; it is characterized by chronic interstitial nephritis, with marked thickening of tubular basement membranes, and leads to progressive renal failure during adulthood.”

From http://www.ncbi.nlm.nih.gov/pubmed/11675411

That particular disorder aside, hyperuricemia (from what I understood) increases the risk of developing gout. Also:

“Hyperuricemia and gout have long been known to run in families. As well as an apparently multifactorial genetic component to classic gout itself, 2 rather unusual sex-linked single-gene disorders of purine biosynthesis or recycling have been defined: deficiency of the enzyme hypoxanthine-guaninephosphoribosyl transferase (HPRT), and overactivity of PPriboseP synthase. Both result in overproduction of urate, hyperuricemia, and secondary overexcretion that may lead to acute or chronic renal damage. Familial juvenile hyperuricemic nephropathy (FJHN) and autosomal-dominant medullary cystic kidney disease (ADMCKD) are more common but less well-defined hyperuricemic conditions resulting from a decrease in the fractional excretion of filtered urate, with normal urate production...”

http://www.ncbi.nlm.nih.gov/pubmed/15660329

Here is an interesting find (article from 1996) relating to pregnancy (and Doran’s mother and numerous miscarriages.)

“Hyperuricemia and pregnancy induced hypertension--reappraisal.

Serum uric acid estimation was done in forty primigravidae with pregnancy induced hypertension and twenty normotensive primigravida in the third trimester of pregnancy, at delivery and six weeks postpartum. The mean serum uric acid levels in normotensive women in the antenatal period and at delivery were 4.65 +/- 0.33 and 4.88 +/- 0.23 mg% and in mild PIH were 5.42 +/- 0.55, 6.14 +/- 0.76 mg%, respectively. Level of serum uric acid in mild PIH was significantly higher than normotensive women (P). In severe PIH, the mean serum uric acid levels were 6.65 +/- 0.60, 8.24 +/- 1.09 mg% in antepartum and at delivery respectively which was significantly more than control group and mild PIH group women (P). However, no differences was observed, in the serum uric levels between these groups during the postpartum period. Serum uric acid level of 5.5 mg or more was observed to be an indicator of PIH. Levels of serum uric acid did show a high positive correlation with the severity of PIH in relation to hypertension and proteinuria. Hyper uricemia (more than 5.5 mg% is associated with increased perinatal morbidity and mortality.”

http://www.ncbi.nlm.nih.gov/pubmed/8979621

From the same study:

“Many clinical and biochemical parameters have been used to detect pregnancy induced hyper­tension (PIH) and to assess its severity. Unfortunately most of the available parameters till date are neither specific nor always sensi­tive. In pre-eclamptic patients with mild pathologic lesions document­ed by renal biopsy, serum uric acid (SUA) was elevated. In more severe cases with azotemia SUA is disapproportionately higher. In chronic hypertensive vascular disease complicating pregnancy, SUA may be elevated but usually to the same degree as other nitro­genous end products. The patho­genesis of hyperuricemia in PIH has not yet been determined. Chesely and Williams stated that in PIH there was impaired glome­rular filtration rate and an increas­ed tubular reabsorption of uric acid, leading to impaired uric acid clearance, but Pollak and Nettles reported that decreased uric acid clearance was the result of en­hanced tubular reabsorption or inhibited tubular secretion or both. Slemons and Bogert first observ­ed an association between SUA concentration and the presence of PIH. Stander and Cadden were first to demonstrate a high corre­lation between the severity of PIH and concentration of SUA level. Though in early part of the 20^th century, studies seem to correlate the level of SUA with severity of FIH, no proper case control studies have been done subsequently. Hence this study was planned to find out the correlation between severity of PIH and SUA levels.”

http://www.indianjmedsci.org/article.asp?issn=0019-5359;year=1996;volume=50;issue=3;spage=68;epage=71;aulast=Mustaphi

This study is old – I’m not certain about its accuracy today – but it was written in 1996, based on information/knowledge from before that time. 1996, is not too late I think, for a more detailed world building in Dorne/the Martells; just saying that GRRM having access to such information (and using it as inspiration) is not too farfetched I think.

Also, anemia can be a cause for maternal mortality during childbirth – or complicate the childbirth. IIRC, anemia can be a symptom of hyperuricemia. Just the same:

Hyperuricemia is predictive for the development of both hypertension and coronary artery disease; it is increased in patients with hypertension, and, when present in hypertension, an elevated uric acid level is associated with increased cardiovascular morbidity and mortality.

http://www.ajkd.org/article/S0272-6386%2899%2970295-7/abstract?cc=y?cc=y

and:

Although many pregnant women with high blood pressure have healthy babies without serious problems, high blood pressure can be dangerous for both the mother and the fetus. Women with pre-existing, or chronic, high blood pressure are more likely to have certain complications during pregnancy tha those with normal blood pressure. However, some women develop high blood pressure while they are pregnant (often called gestational hypertension).

http://www.nhlbi.nih.gov/health/public/heart/hbp/hbp_preg.htm

thus hyperuricemia would (if I understood correctly) complicate childbirth and be a risk for both the mother's and child's health. Elia, we are told, was very ill after Aegon's birth.

...

So...the possibility that we are dealing with a genetic disorder (a cause for hyperuricemia in Doran and Elia) is only the first part of a whole. IF a genetic disorder was the cause of both Doran’s and Elia’s bad health... what consequences could it have on the story, if any? What sort of “plot point” could it account for?

Or is it complete crackpot and Elia's and Doran's health problems only coincidence?

I also wonder, though it might be pointless, about the origin of the Martell name. The common etymology indicates that Martell (Like Charles Martel) stems from the french Martel - hammer. Or is there also here a play with Mortel - mortal, deadly?

[Olligarchy]

Very interesting. It would explain a lot of things... though when did the trait enter into Martell genealogy?

[Greymoon]

Very interesting. It would explain a lot of things... though when did the trait enter into Martell genealogy?

I don't know about the when...but I wonder about the why mostly. I mean...if it's true what's the purpose of it, besides explaining Elia's frail health and difficult pregnancies and allowing a relationship between the two sort of afflictions, hers and Dorans...but beyond that?...

I wonder if anyone else was ill in the family? (Rhaenys? We’d have heard, certainly?)...

or if Elia was disliked at court for having "bad blood" or "cursed blood" or something of the like, if others realized the she wasn't the only Martell with a frail constitution and that it might have run "in the family"?

She was probably being looked down upon because of her health -- but the family factor would have made it worse, no?

[Mithras]

Elia's delicate health was due to her preterm birth. In Westeros, preterms births are said to be dangerous and such babies are not expected to live. It is a canon information.

[joluoto2]

Very interesting. It would explain a lot of things... though when did the trait enter into Martell genealogy?

Maybe with Princess Daenerys (if it comes from the Targs, though we have not heard of any such symptoms in the Targ lineage), could have come at any point in time. Could even be something from Rhoyne or something from the old Andal line of Martells.

[Greymoon]

Elia's delicate health was due to her preterm birth. In Westeros, preterms births are said to be dangerous and such babies are not expected to live. It is a canon information.

Elia was born preterm? Where is that mentioned please? (It's not that I don't belive you, just that I don't remember)

This would derail the above theory -- not entirely however, since there is still a genetic factor increasing the likeliness of gout developing and, hypertension (induced by hyperuricemia) could lead to difficult pregnancies (clue Doran's mother.).

[Olligarchy]

Maybe with Princess Daenerys (if it comes from the Targs, though we have not heard of any such symptoms in the Targ lineage), could have come at any point in time. Could even be something from Rhoyne or something from the old Andal line of Martells.

Was thinking Daenarys too. The Targs have a host of illnesses and her bringing it over to the Martells would serve as a fantastic analogy to them also ruining the Kingdom of Dorne by bringing them into the Seven Kingdoms!

[jet199]

Hypertension sounds like something that would have caused Elia to nearly die and cause maesters to recommend she have no more children. I assume if she had haemorrhaged or got an infection she would have actually died.

However people tend to recover quite quickly from hypertension so it wouldn't have left her bedridden unless that was just something recommended by over careful maesters. Of maybe she was a hypochondriac.

I would think it is a Martell gene as Mariya Martell seems to have a physique similar to Doran's.

I was wondering if this condition was related to any health benefits (such things often are, or they get selected out, for instance people with high cholesterol have, on average, higher intelligence and the most famous is sickle cell anaemia which prevents malaria) and apparently people with hyperuricemia have a decreased risk of Parkinson's disease. This might explain why Mariya was able to tell Aegon where to stick it even though she 80 and blind. This kind of fits with the culture of the Martells which is that they take lessons from their past which is passed down from the older generation who all have their wits very much intact.

[Greymoon]

Elia's delicate health was due to her preterm birth. In Westeros, preterms births are said to be dangerous and such babies are not expected to live. It is a canon information.

just found this (results and conclusion from a study on hyperuricemia and preterm births):

Results

Maternal hyperuricemia (uric acid one standard deviation greater than the appropriate gestational age) was independently associated with preterm birth (odds ratio (OR), 3.17; 95% confidence interval (CI), 2.1 – 4.79), small for gestational age delivery (OR, 1.28; 95% CI, 1.04 – 2.57), NICU admission (OR, 1.65; 95% CI, 1.12 – 2.94) and neonatal IVH (OR, 8.14; 95% CI, 1.11 – 87.1).

Conclusions

Maternal hyperuricemia in normotensive singleton pregnant women is significantly associated with preterm and SGA delivery and the development of neonatal IVH.

http://www.biomedcentral.com/1471-2393/14/104

If Elia's mother had hyperuricemia; this would fit with Elia's preterm birth (and the many miscarriages before that.)

[Mithras]

Elia was born preterm? Where is that mentioned please? (It's not that I don't belive you, just that I don't remember)

This would derail the above theory -- not entirely however, since there is still a genetic factor increasing the likeliness of gout developing and, hypertension (induced by hyperuricemia) could lead to difficult pregnancies (clue Doran's mother.).

“I was the oldest,” the prince [Doran] said, “and yet I am the last. After Mors and Olyvar died in their cradles, I gave up hope of brothers. I was nine when Elia came, a squire in service at Salt Shore. When the raven arrived with word that my mother had been brought to bed a month too soon, I was old enough to understand that meant the child would not live. Even when Lord Gargalen told me that I had a sister, I assured him that she must shortly die. Yet she lived, by the Mother’s mercy. And a year later Oberyn arrived, squalling and kicking."

[Greymoon]

“I was the oldest,” the prince [Doran] said, “and yet I am the last. After Mors and Olyvar died in their cradles, I gave up hope of brothers. I was nine when Elia came, a squire in service at Salt Shore. When the raven arrived with word that my mother had been brought to bed a month too soon, I was old enough to understand that meant the child would not live. Even when Lord Gargalen told me that I had a sister, I assured him that she must shortly die. Yet she lived, by the Mother’s mercy. And a year later Oberyn arrived, squalling and kicking."

Thanks ;)

[Oberoth]

Maybe Doran wouldn't have had such extreme problems if he toned down his food.

[The_Crannogman]

If both Doran and Elia both had birth defects due to their mothers ill health why doesn't Oberyn? Surely if he was the last child born he was at more risk than Doran of being born weak or with some defect as his mother was in very poor health and had suffered multiple medical set-backs but at the time of Doran's birth she would have been a lot healthier.

[Defeatarion]

If both Doran and Elia both had birth defects due to their mothers ill health why doesn't Oberyn? Surely if he was the last child born he was at more risk than Doran of being born weak or with some defect as his mother was in very poor health and had suffered multiple medical set-backs but at the time of Doran's birth she would have been a lot healthier.

Just luck I am assuming. Although I think he got the cockiness gene.

[Greymoon]

If both Doran and Elia both had birth defects due to their mothers ill health why doesn't Oberyn? Surely if he was the last child born he was at more risk than Doran of being born weak or with some defect as his mother was in very poor health and had suffered multiple medical set-backs but at the time of Doran's birth she would have been a lot healthier.

There's luck as Defeatarion pointed out, but also -- having a genetic predisposition for something, doesn't mean that one will be afflicted; it only means that the chances of developing a certain condition is increased. Think about breast cancer or heart failure, diabetes etc. there's often a genetic factor involved in these, but it doesn't mean that because you are at risk, you shall develop either. Some conditions can somewhat be prevented by a healthy life style -- in other cases leading an "unhealthy" life style can increase the risk. And in yet other cases, no matter what you do, it won’t change anything because you’re just unlucky. (Or especially lucky in the reverse case.) Also, every child inherits two sets of genes from their parents, because one sibling gets an unlucky combination doesn't mean that every child from the same parents would.

ETA: spelling

[Bloodmane]

Doran seems to have gout - by our medical definitions I mean. Gout is the major manifestation of hyperglycemia, possibly along with renal impairment, otherwise hyperglycemia is just a risk factor for certain diseases (like miscarriage/premature birth) or a component of certain syndromes (some but not all of genetic origin).
In Martin's world however diseases must not be judged by real-life medical notions. Of course a broken leg Is a broken leg, and lung wounds may kill you, but the major epidemics, while do resemble real-life medieval ones (greyscale - leprosy, pale mare - mostly cholera / possible other enteritis, spring sickness - flu) they are not identical. Also there are some (magic related) events that clearly defy real-life medical knowledge - Dany unburnt, possibly Gregor decapitated and alive(?) - but those I think would be also considered impossible by a master wearing the silver but not the Valyrian steel ring.
Doran's joint disease could be simple (not hereditary) gout, or as plausible a component of the "Martel disease" comprising (lets say) also a predisposition to miscarriage, premature birth, short stature, homely face...
By the way, in real-life "hereditary" does not necessary mean that every member of every generation should inherit the disease. We know that in Martin's world traits are inherited from mother and father and there are recessive and dominant traits (just read that dull book about the families of Westeros with descriptions of lords and ladies or whatever is its title), so at least Mendelian laws should be also be valid.

[Greymoon]

In Martin's world however diseases must not be judged by real-life medical notions. Of course a broken leg Is a broken leg, and lung wounds may kill you, but the major epidemics, while do resemble real-life medieval ones (greyscale - leprosy, pale mare - mostly cholera / possible other enteritis, spring sickness - flu) they are not identical. Also there are some (magic related) events that clearly defy real-life medical knowledge - Dany unburnt, possibly Gregor decapitated and alive(?) - but those I think would be also considered impossible by a master wearing the silver but not the Valyrian steel ring.

Doran's joint disease could be simple (not hereditary) gout, or as plausible a component of the "Martel disease" comprising (lets say) also a predisposition to miscarriage, premature birth, short stature, homely face...

Yes, but I find the possibility that we are dealing with hereditary condition extremely interesting. That there is enough documented knowledge about gout and hyperuricemia in real world, makes it sweeter because while I agree that there's often an element of fantasy in Westerosi ailments and healing, part of it is no less drawn directly from real world experience and knowledge. Greyscale and the pale mare, the spring sickness, etc. all seem to have their real world counterpart (to some extend).

Milk of the Poppy seems to be opium (tea? or pure latex diluted with something else?); tansy is also a real plant, and was in the Middle Ages used to induce abortion.

By the way, in real-life "hereditary" does not necessary mean that every member of every generation should inherit the disease. We know that in Martin's world traits are inherited from mother and father and there are recessive and dominant traits (just read that dull book about the families of Westeros with descriptions of lords and ladies or whatever is its title), so at least Mendelian laws should be also be valid.

I concur. Not every Targaryen has shown signs of madness. Not everyone of Cat's children has auburn hair and grey eyes. Martin's genetics are a bit skewed (the seed is strong... since when are blue eyes a dominant trait?) but they are no less....ruled by "some" laws IMO.