Talk:Lesch-Nyhan syndrome

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Contents

[edit] Old entries

Larsie (& Taxman), you have done a great job in creating this detailed article.

I disagree with the comment "Haldane's rule predicts a 2/3 chance that she is a carrier and a 1/3 chance that the son has a new germline mutation". I don't believe that Haldane makes any reference to the incidence of new mutations. Also, is it really necessary to include such a detailed description of X-linked genetics? Why not just include a link. Axl 23:27, 8 Nov 2004 (UTC)

Correction to the above: apparently there are three Haldane's rules, one of which does make the prediction quoted. While the rule does make the prediction, in this case the prediction is wrong because the mutation rate in males exceeds the rate in females. Axl 14:11, 11 Nov 2004 (UTC)

[edit] My copyedit

I must compliment the previous authors on the large amount of work. The restructuring and copyediting I'm doing today has a lot to do with the overlap that has crept into the article. I've also changed a lot of terms that are POVish (malady, affliction). In all, I have not changed any facts, apart from the following:

  • Most women with gout do not carry a LNS mutation, and testing is never done unless this is in the context of a strongly suggestive history and fears that she may transmit this trait to her offspring.
  • Haldane's rule may not apply (as above). JFW | T@lk 21:01, 10 Nov 2004 (UTC)

i don't think all that copy editing did much except for make a mess of the article, the headings now don't exactly pertain to the paragraphs below them and the signs and symptoms is to long, it needs to be broken up. it also seems as though a lot of information was lost --Larsie 22:20, 10 Nov 2004 (UTC)

Please do not misunderstand me. The medical articles on Wikipedia all follow a style pattern which has been detailed on WikiProject "Clinical medicine"; please peruse this. The clinical pattern, whether in men or in women, belongs under "description" or "signs and symptoms", not in a seperate section.
You have done a lot of great work on this article, and it is still evolving further. Let's please cooperate on this. I think it is worthy of becoming a featured article when some more copyediting has been done (and certain redundancies removed). JFW | T@lk 11:49, 11 Nov 2004 (UTC)
Actually, I'm a bit annoyed that someone has removed perfectly good changes. Women with gout are not tested for LNS mutations. Period. They are tested to determine whether a second child may also develop LNS. JFW | T@lk 11:55, 11 Nov 2004 (UTC)
i think that the article should take whatever form that would be best accepted as a well written, informative, feature article. period. i think the best way to determine this is to read the reviews and make whatever changes necessary. --Larsie 19:57, 14 Nov 2004 (UTC)

[edit] Review articles

I have now included references to the original description of LNS, as well as its linkage to HPRT mutations. I also made a stub for HPRT. Sadly, no recent general review articles have been published. The closest I could get is one by Dr Nyhan himself in 1997 (PMID 9211189). If I can get access to the article fulltext I'll present relevant material here for discussion.

I will also look into the basic biochemistry. HPRT does not produce uric acid. Rather, it shunts DNA breakdown products back into new DNA synthesis. Defects of the gene lead to increased siphoning of the purine breakdown material into their "natural" metabolic sink, which happens to be uric acid. The important question is whether the shortage of "recycled" purines is important in the context of LNS. Old memories from medical school tell me that it is. JFW | T@lk 17:54, 11 Nov 2004 (UTC)

I'm done here. Perhaps I'll still add something about allopurinol. JFW | T@lk 20:21, 14 Nov 2004 (UTC)

[edit] X linked

I believe it is correct to say that LNS only affects males. Females carriers, even those with gouty symptoms, do not have the disease. Osmodiar 08:12, 24 Nov 2004 (UTC)

It's correct to say that the disease is extremely rare in females; it's NOT correct to say it only effects males. See Yukawa, T.; Akazawa, H.; Miyake, Y.; Takahashi, Y.; Nagao, H.; Takeda, E. : A female patient with Lesch-Nyhan syndrome. Dev. Med. Child Neurol. 34: 543-546, 1992. PubMed ID : 1612215 - Nunh-huh 08:21, 24 Nov 2004 (UTC)

OK, but I think it should be stressed that it is overwhelmingly a disease of males, to the point that a female case warrants a write up in a journal. I changed the wording in the introduction back to allow for the possibility of female patients. Perhaps a more detailed discusion of non random X inactivation, new mutations, and other possibilities (Turner syndrome?) could go under the "female" section. Osmodiar 09:09, 24 Nov 2004 (UTC)

[edit] Picture?

Would it be possible to get a picture of one of the custom wheelchairs used by LNS patients -- ie, with saddles, restraints, etc to minimize self-injury? Catherine\talk 08:17, 24 Dec 2004 (UTC)

[edit] Duplicate article

From Talk:Lesch-Nyhan Syndrome:

This article or section should be merged with Lesch-Nyhan syndrome
Although I didn't find anything on the internet, I wonder if this version might not be a copyright violation. BlankVerse ∅ 19:21, 18 Feb 2005 (UTC)

I've decided just to redirect without merge, as it's an obvious copy and paste (probably from someone's paper). sjorford →•← 11:11, 24 Feb 2005 (UTC)

[edit] Accuracy concerns

  • Major contributions were made to this article by User:Larsie, User:135.214.66.240, User:135.214.66.241. However, these users have made some prank edits to other articles. Can their contributions be checked carefully? I see that many other users have contributed and the article has been featured, but there is still a lingering concern. Thanks. -- Curps 22:02, 8 Mar 2005 (UTC)
My concerns are raised in Wikipedia:Votes for deletion/Lars Olsen (note "Lars Olsen" <--> "Larsie" coincidence), which I believe is a longstanding hoax article that he had a hand in creating. At the very least he engaged in shenanigans there. -- Curps 23:03, 8 Mar 2005 (UTC)
See also cryptic messages [1] [2] which seem to imply playing some kind of game, concern about it getting public or getting kicked off Wikipedia. -- Curps 23:05, 8 Mar 2005 (UTC)
I have no expertise whatsoever in the subject matter of Lesch-Nyhan syndrome, I'm just in the process of looking into User:Larsie's contribution history. He created Lesch-Nyhan syndrome only a couple of days after his edits to Lars Olsen and the above cryptic messages, hence I had some concern. -- Curps 23:06, 8 Mar 2005 (UTC)
Larsie is the principal author of the article. I'm no expert, but I (and others) read this article quite carefully during its FA candidacy. At the time, I found Larsie to be a serious and conscientious editor. I would be very surprised if User:Larsie has made any inappropriate edits to this article. You say he's made "prank" edits to other articles? Can you please elaborate?
User:135.214.66.241 made one edit, changing: "sibs" to "siblings". You are concerned about that?
User:135.214.66.240 made three edits. Two changed section headings from "What is the Prognosis?" to "Prognosis", and from "What research is being done?" to "Research" (neither section title now survives). The third added: These individuals unfortuneatly must be restrained to prevent the ability for self mutilation and rarely survive into adulthood. The vestigial remains of which read: Nearly all affected individuals need restraints to prevent self-injury, and are restrained more than 75% of the time. What concerns you about these changes?
I beleive that User:Jfdwolff is a knowledgable editor in this field, you might want to solicit his opinion.
Paul August ☎ 22:55, Mar 8, 2005 (UTC)
Curps, thanks for the explanation. Paul August ☎ 20:24, Mar 9, 2005 (UTC)

Thank you Paul. It's been a while I last copyedited the article, but I was generally under the impression that it was well sourced and structured. All I did was add some molecular biology and classical references. When I've got some time (I'm on night shift) I'll have a quick scan. JFW | T@lk 23:00, 8 Mar 2005 (UTC)

The article is factually accurate. Axl 19:31, 9 Mar 2005 (UTC)


[edit] First paragraph

It seems to me that part of wikipedia's goal is to allow anyone access to the information they need. To that end, it seems that the first paragraph is a little incomprehensible to those without a chemistry background. Is it possible to make the first paragraph a little more user-friendly, and maybe go into that kind of detail in a second paragraph? Verloren Hoop 21:28, 11 July 2006 (UTC)

[edit] De-feature?

This article's sourcing is miserable. It does not meet FA requirements. JFW | T@lk 21:45, 31 March 2007 (UTC)

I was just coming here to post the same query; I've been intending to submit this for review for some time, but thought I'd ask if anyone is willing/able/available to bring it to standard. SandyGeorgia (Talk) 03:33, 1 April 2007 (UTC)

[edit] Removed text added by IP to Self-injuring behavior

Removed the following inserted text:[3]

Compulsive behaviors also occur, the development of this type of behavior is sometimes seen within the first year, or in early childhood, but others may not develop it until later in life. In addition to the myriad forms of physical self-injury seen in LND, there is also a behavior abmnormality. This is discussed as aggressive behavior in much of the Lesch-Nyhan literature, but will be referred to as indirect self-injury or emotional self-injury here. Individuals with LND not only demonstrate a compulsion to injure themselves, they also compulsively attempt or otherwise abuse others, including those they care for the most, such as parents, teachers, and aides. Examples are kicking and head butting while being dressed or bathed, cursing without provocation, spitting or vomiting on care providers, and spilling drinks. After performing these behaviors, the individual will characteristically apologize profusely, only to shortly thereafter repeat the behavior. At Matheny, we have come to recognize these behaviors as indirect attempts at self-injury. These aggressive behaviors cause others to become angry, which may lead to the perpetrator being punished, or minimally feeling guilty. In any case, this can be interpreted as a form of self-injury, as the intent may not be to harm the other person, but to suffer the consequences.

I've taken this out because it adds to the already-existing problem of an uncited article, and has other issues as well. Why was the reference to coprolalia removed? What is the source for this text? Please see WP:RS and WP:MEDMOS). The text contains self-references to this Wiki article, so needs copyediting. There are also self-references to Matheny, which should be removed and sourced. The language is informal, not encyclopedic. (At Matheny, we have come to recognize ... ) The article is not on Matheny's website, so the text is out of place here. "These aggressive behaviors cause others to become angry" is editorializing. Perhaps some of the content here can be sourced, copyedited, and re-added. SandyGeorgia (Talk) 15:30, 12 April 2007 (UTC)

[edit] Oxidative stress induced by urate

The idea that other examples of pathogenesis due to urate-induced oxidative stress are not related to Lesch-Nyhans is clearly original research and contrary to the cites in the article. It is unsupported by any literature I know of. If there is, please cite it.

So, I'm going to involke my sole priviledge here as a "expert" to cite the literature and revert the revert. (Damn, I just hate getting into edit fights about stuff I am actually do work on.) Recently, it has become clear that oxidative stress induced by urate is a general mechanism of pathogenesis. Thus, other examples are quite relevant to the Lesch-Syndrome. The literature cited in the article clearly reflects this. The big puzzle with respect to this disease is the odd symptomology. This is ultimately related to it. Also, there has been criticism that the cites on this article are not current. This is an attempt to correct this.Pproctor 14:16, 27 May 2007 (UTC)

I have removed the section on oxidative stress to the talk page for discussion. Citation of Visser et al as supporting a oxidative model appears to misrepresent their data. Moreover, searching for "Lesch-Nyhan Syndrome oxidative stress" in Pubmed only returns two results, neither fully supporting this idea. This synthesis of data from other systems with the sparse mention of oxidative stress in the Lesch-Nyhan Syndrome literature appears to me to be original research as outlined in the Wikipedia:NOR policy (which I encourage you to read carefully). If you wish to replace this section in the LNS article it will require high-quality sources that address this specific question. TimVickers 03:24, 28 May 2007 (UTC)

Er, experts can cite their own work at arms length, as long as the cites meet the rules. Mine do. Also, you are entirely incorrect about the further cites not supporting the role for oxidative stress in hyperuricemic syndromes. It is a very big deal right now in pathogenesis in general, though it originated with the Lesch-Nyhan syndrome over three decades ago. How else do you explain (e.g.) the efficacy of SOD in hyperuricemic syndrome in Dalmatian dogs?. Also, the concept antedates the term "oxidative stress". So the older papers are not indexed under this on pubmed.

BTW, while we are playing competing experts here-- I'm and MD, PHD with a path residency. I published my first paper on uric acid and the possible physiological role of its redox properties in the journal Nature in 1970 [4]. Check it out. And yes, Ames' rediscovery [5] ten years later is generally cited. The Matthew effect at work, but a good screen for whether someone knows the uric acid literature or not. In research, there is a penalty for being too early.

Uric acid is now firmly established as the putative most important extracellular antioxidant in humans. It is the proxidant properties that likely cause the problems, in LNS, metabolic syndrome and so forth. Not my suggestion about the latter, BTW. likewise, how can anyone possibly claim papers in Nature, Stroke, PNAS, The CRC handbook of Free Radicals and Biomedicine, JBC, and so forth are "original research" or "speculation"?

As for its relevance to LNS-- In fact, I got into the uric acid "biz" after encountering a patient with LNS. This sugested that uric acid might actually be something more than the end product of purine metabolism. This was one of the first identifed cases after the first description of this syndrome. Has anyone else posting here actually seen a case of LNS or published any papers on it? Pproctor 14:06, 28 May 2007 (UTC)

Pproctor, I think it would be best to work through this before adding the text back in. I defer to Tim on the actual content, but as a layperson, I can't discern the connection between the text and LNS, so at any rate, if the text is kept, it will need some adjustment so that it is accessible to laypersons. Working this out on the talk page is the best option. SandyGeorgia (Talk) 14:58, 28 May 2007 (UTC)
Additional concerns regarding WP:WIAFA, 4 (stays tightly focused on the topic) and 1e, stability (reverts). It's unclear to me that this oxidative stress section is tightly focused on LNS? SandyGeorgia (Talk) 15:03, 28 May 2007 (UTC)
Restatement: urate-induced oxidative stress is now thought to play a role in the etiology of many diseases ( for which I give cites-- would not even think of doing OR). Again, I can enlarge on this ad nauseum, but it would overwhelm the article. Similarly, in the first world, atherosclerosis is the single major cause of death, while stroke is number four. Among several points I attmept to make is that, while itself a very rare disease, LNS is important if only because historically it was the first disease in which urate-induced oxidative stress was proposed as a pathogenic mechanism.Pproctor 16:42, 28 May 2007 (UTC)

Your expertise is unfortunately irrelevant here, as is mine, since Wikipedia cannot verify our identities. The part of the policy I think this section might have problems with is the section on synthesis of material. This problem would be avoided if you can find papers that address oxidative stress in LNS - not in other diseases. As I said above, the vast majority of the literature on this disease does not appear to mention oxidative stress as a possible pathophysiological mechanism, so I'm sure you can understand why I am sceptical of this proposal. TimVickers 15:06, 28 May 2007 (UTC)

First. I plead "not-guilty" WRT to this "expert" business. You-all started it. Perhaps inadvertantly, Georgia presented you as an "expert" on oxidative stress--- which you definitely are WRT Leschmania. Feeling thus freed to answer in kind, I replied to this assertion of your expertise with my own credentials. These are arguably more immediate to the subject at hand, me actually having seen a LNS patient and published papers on the disease and all. YMMV, natually.
Besides, it is not a hard rule. Otherwise, (e.g.) why the "expert-needed" tag? Similarly, one partial exception is when assertion of expertise cuts thru all the BS and there is objective proof of both identity and expertise. Georgia clearly took advantage of this in your case. Otherwise, she would not have cited you as an expert. Again, I just replied in kind. Likewise, I can prove who I am (e.g., the Peter Proctor of this Nature paper on uric acid [6]). I certainly would not question your undoubted ability to make pronouncements in the area of Leishmania oxidative metabolism, of which you make a point in your page.
As for the references to oxidative stress and LNS, the cites are quite specific. Read the titles. IIRC, the one you object to concerns CNS oxidative stress induced by hypoxanthine. This is the urate procursor that is produced at high levels in LNS.Pproctor 16:42, 28 May 2007 (UTC)
No, the one I was objecting to the section describing as experimental evidence for oxidative stress in LNS is PMID 11882343. This gives some indicators of increased oxidative stress but others indicating no change in redox balance. Their lack of SOD effect is also inconclusive. This paper can't fairly be described as demonstrating anything one way or the another, it is suggestive, but nothing more than that. More importantly, have you read the section in the NOR policy on the synthesis of material? This is the crux of the matter. TimVickers 16:55, 28 May 2007 (UTC)
The abstract of the paper you refer to states: "Overall, these data provide evidence for increased oxidative stress, but the failure to protect the knockout mice by over-expressing SOD1 argues that oxidative stress is not the sole process responsible for the loss of striatal dopamine."
True, the paper states that oxidative stress is "not the sole process" in LNS. Never said it was. Personally, I also favor some kind of dopaminergic thing, as we noted in another early paper (Proctor P, McGinness JE, "Levodopa side-effects and the Lesch-Nyhan syndrome" Lancet. 1970 Dec 26;2(7687):1367). As the paper you cite notes, involvement of dopaminergic pathways and oxidative stress are the standard models in LNS these days. <sarcasm=on> My extreme modesty stopped me before. But since you brought it up, I will now claim my clear discovery credit for the dopaminergic business too.<G><sarcasm=off> Seriously, the lesson here is to be careful with whom you differ with on Wikipedia and assertions of "expertise" don't mean much.Pproctor 18:44, 28 May 2007 (UTC)
If oxidative stress is indeed the standard model these days, could you provide a few citations for current reviews that discuss the oxidative model? That would solve this difficulty entirely. TimVickers 20:26, 28 May 2007 (UTC)
P.S. the paper PMID 17226099 seems more useful than the Bavaresco study you cite. TimVickers 20:36, 28 May 2007 (UTC)
Small chide-- I did not say oxidative stress was the "standard model". I said oxidative stress and something dopaminergic were the "standard model", as expressed in the paper you cited. I get into enough trouble for the things I actually say.
Anyway, thank you for this cite. BTW, I'm getting confused here-- did I cite it first or did you?. Anyway, it supports the case for oxidative stress in LNS, the issue here. As I note, the real hyperproduction in LNS is of hypoxanthine-- uric acid is the metabolic by-product. According to the usual and customary rules on wikipedia, all I need is just one valid literature reference to and there seem to be multiple ones.
Also, LNS is a pretty rare disease, of interest mostly because of the model it provides. While there is some recent literature on LNS and oxidative stress (which we have cited), things have moved on. Most recent work on oxidative stress due to purinergia is in major killer diseases such as (e.g.) metabolic syndrome, atherosclerosis, and stroke, for which there are lots of refs on pubmed.
This area is also (uh) confused. My favorite example is stroke, where some researchers claim uric acid-induced oxidative stress is causative in stroke, e.g.,[7], while others claim the exact opposite-- namely, that uric acid is neuroprotective and prevents stroke due to its antioxidant properties, e.g., [8]. An altogether delicious situation if you consider academic disputes as entertainment and have priority of discovery claims in both camps. My personal and definitely OR opinion is that "it depends". Pproctor 21:38, 28 May 2007 (UTC)

[edit] Reviews on LNS

Could you please provide a citation for recent review that discusses this oxidative model in LNS? I think I need to read about this to get a better grasp of how these papers fit into the field as a whole. TimVickers 22:11, 28 May 2007 (UTC)
To my knowledge, there are not any. Moreover, to my knowledge at least, there are not any general review articles on LNS, much less the subject of the role of oxidative stress in this disease. So we must rely on the primary sources, which are also scanty. This is far too obscure a disease to be of much interest except as it relates to human disease in general, for which it is an arguable model for some things such as dopaminergic lesions and (yes) purinergic oxidative stress. Both of which are also involved in far more significant human diseases. Simply-stated-- few people and funding agencies are interested and few researchers (if anyone) ever got tenure working on LNS.Pproctor 23:33, 28 May 2007 (UTC)
I can't access these at home, but there do seem to be quite a few recent reviews, PMID: 15711436, PMID: 12010614 and PMID: 10852837 (free full text). I suppose these will discuss the oxidative stress model in detail. I'll have a look at them tomorrow. Do you know of any papers or reviews on "purinergic oxidative stress"? I can't find any relevant papers using this term in Pubmed or even with Google. TimVickers 01:17, 29 May 2007 (UTC)
Thanks for the cites. Only one of these (Ghei et al) appears to be a general review on hyperuricemia. My wild guess is that it at least mentions oxidative stress, a very big thing in hyperuricemia pathogenesis these days. If he does not, he missed something. Not that this is unusual--many researchers don't know a whole lot beyond what they are immediatedly working on. Present company excepted, naturally. -- A medline search on "uric acid oxidative stress" draws 564 cites. Similarly, "radical uric acid" draws 631. "Radical urate" draws 505 cites, and so forth. Check it out.
Significantly, the paper by Nyhan [9] reviews dopaminergic mechanisms in LNS. As I noted above, we were the first to propose this. Shortly after publication, our 1970 Lancet paper was cited by Nyhan in a book chapter on LNS and is apparently where he first heard the idea, but it has now merged into the noise. Pproctor 15:22, 29 May 2007 (UTC)
A slightly later review article: PMID: 15660333
Kanellis J, Kang DH., "Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease." Semin Nephrol. 2005;25(1):39-42.
"Recent experimental findings have led to renewed interest in the possible role of uric acid in the pathogenesis of both hypertension and vascular disease. Often considered an antioxidant, biochemical and in vitro data indicate that noncrystalline, soluble uric acid also can react to form radicals, increase lipid oxidation, and induce various pro-oxidant effects in vascular cells. (emphasis-added) In vitro and in vivo findings suggest that uric acid may contribute to endothelial dysfunction by inducing antiproliferative effects on endothelium and impairing nitric oxide production. Proinflammatory and proliferative effects of soluble uric acid have been described on vascular smooth muscle cells (VSMCs), and in animal models of mild hyperuricemia, hypertension develops in association with intrarenal vascular disease. Possible adverse effects of uric acid on the vasculature have been linked to increased chemokine and cytokine expression, induction of the renin-angiotensin system, and to increased vascular C-reactive protein (CRP) expression. Experimental evidence suggests a complex but potentially direct causal role for uric acid in the pathogenesis of hypertension and atherosclerosis." Pproctor 15:49, 29 May 2007 (UTC)

Yes, there are lots of papers on uric acid's role as an antioxidant, but almost none on it acting as a pro-oxidant. Similarly, the Ghet at al review "Pathogenesis of hyperuricemia: recent advances." does not mention oxidative stress, neither does the Nyhan review. The Deutsch review does mention oxidative stress, in two sentences at the end of a section. From these reviews, the oxidative hypothesis really does not seem to be very significant in current research. I don't object to this idea being added to the article, perhaps as a few sentences at the end of the pathogenisis section, but it really shouldn't be given more weight than seen in other modern reviews. TimVickers 16:43, 29 May 2007 (UTC)

I would support reducing the entire section to one or two sentences if they clearly establish relevance to LNS. SandyGeorgia (Talk) 18:51, 29 May 2007 (UTC)
Science is not a democracy. While the effect was first proposed for LNS, the oxidative stress/purinergic disease people now mostly work on stroke, atherosclerosis, and metabolic syndrome, several orders of magnitude more important than LNS. This does not mean oxidative processes are considered unimportant in LNS, just that the present action is elsewhere. E.g., while retaining an interest, I departed this field long ago for much greener pastures.
Nyhan's review is specifically on dopaminergic processes on LNS, as is most of the literature. Would not expect mention of oxidative stress. The two processes are on different levels--- I ought to know, since I discovered them both, he says modestly<G>. Did I mention 6-HDA, considered an animal model for LNS? It destroys nerves by oxidative mechanisms. A whole other literature here that I have not mentioned. No point in confusing matters even more.
Also, while dating back to the early 1970's, the broader importance of purine-induced oxidative stress has only recently come to be appreciated. So most of the papers are quite recent, last 2-3 yers, in fact. In fact, as I note here, there is a current dispute in the literature about whether uric acid causes or prevents stroke.Pproctor 22:50, 29 May 2007 (UTC)

___________________________________________

I don't know if the text is going to stay, but there's no reason to have three different reference styles cluttering an FA, so I converted the refs to cite.php. Pproctor, I'm not sure citing your own Letter to the Editor rises to the level of reliable sources; isn't that like saying it's so because I said it's so? (added)SandyGeorgia

By historical accident, in some journals (e.g.) the Lancet and Nature, "letters to the editor" are the same thing as research papers, peer-reviewed and all. Typically, they also have a "correspondence" section for what you think of as "letters". As for the references, thanks for spiffing them. Personally, I don't go to all that trouble until I know a cite is going to stick.Pproctor 23:33, 28 May 2007 (UTC)
The classic Nature "letter to the Editor" is Wattson and Crick's paper describing the structure of DNA.Pproctor 15:54, 29 May 2007 (UTC)

I'm not finding your responses above are helping explain to me why the content is relevant and focused on LNS, but perhaps Tim is seeing it. Of course, considering your professed expertise in LNS, gosh, it would be nice if you cold cite the rest of the article — not just your own work — so it wouldn't be defeatured. SandyGeorgia (Talk) 22:23, 28 May 2007 (UTC)

The relevance is two-fold. First, historical--LNS is the first examle of purinergic oxidative stress playing an etiological role. So it is the precursor for similar findings in metabolic syndrome, atherosclerosis, and stroke, among other "killer-diseases". Second, tissues only go bad in certain limited ways. Now, researchers think the role for urate-induced oxidative stress in all these diseases involves common pathways. These are likely also involved in LNS, and vice versa. To avoid accusations of OR, I merely listed cites indicating that these other syndromes also involve urate-induced oxidative stress. However, I can (but did not) cite an invited review article I did for a CRC handbook which relates oxidative stress in LNS mchanistically to the etiology of atherosclerosis. Invited CRC reviews are way up the academic research food chain, BTW.
As for experts citing their own works-- this is very much allowed, as long as this is at arms length. I pretty much cited all the papers indicating a role for oxidative stress in LNS. This included some, but not all of my own papers on this issue. Again, research in this disease is very thin. There is also work I did on LNS which I did not cite -one example is the fact that we first proposed the generally-accepted role for dopaminergic pathways in this disease. When provolked, I noted this paper above to strengthen the point that I agree that oxidative stress is not the only thing going on in LNS, but let it lie in the article. Similarly, I list both our 1970 Nature paper and Ames' decade-later rediscovery of it WRT the evolution of high uric acid levels in humans. I could have legitimately omitted the Ames paper, which is the one generally cited by people that don't know better. Dr Ames is much more famous than I am.<G> Pproctor 23:33, 28 May 2007 (UTC)
Your efforts to help keep the article from being defeatured by citing all of it are greatly appreciated. SandyGeorgia (Talk) 00:04, 29 May 2007 (UTC)

[edit] Oxidative stress

Significantly, uric acid is a powerful reducing substance. As such, it is the single most important extracellular antioxidant, accounting for roughly half of the antioxidant ability of plasma. It may even partially substitute for ascorbic acid in human evolution.

However, like most strong reducing agents, uric acid can also act as a pro-oxidant, particularly at higher concentrations like those in LNS. Further, oxidation of purines by Xanthine oxidase to uric acid produces reactive oxygen species. Thus, free radicals, oxidative stress, and reactive oxygen species may play some role in the etiology of Lesch-Nyhan's syndrome.[1] Such processes also likely figure in other hyperuricemia syndromes such as that in dalmatian dogs, which responds to "Orgotein", a veterinary formulation of bovine liver superoxide dismutase. There is additional experimental support for oxidative stress in LNS.[2] While first proposed in the Lesch-Nyhan syndrome, uric acid-induced oxidative stress is also thought to contribute to the pathogenesis of other diseases such as metabolic syndrome[3] and stroke[4] by similar pathogenic mechanisms.

Likewise, strong reducing substances such as uric acid form Charge transfer complexes with neuromelanin in pigmented midbrain structures such as the substantia nigra and the locus ceruleus. The role of this in LNS is unknown, but it might be related to (e.g.) the extrapyramidal symptoms.

[edit] Compacted version

Uric acid is a reducing agent and usually acts act as an antioxidant in the body. However, uric acid can also act as a pro-oxidant, particularly at high concentrations like those produced in LNS. Thus, free radicals, oxidative stress, and reactive oxygen species may play some role in the etiology of Lesch-Nyhan's syndrome.[5]

Excellent, tightly focused on the subject at hand, and accessible. By the way, I'll be traveling the rest of the week, with limited internet access. SandyGeorgia (Talk) 19:49, 29 May 2007 (UTC)
OK by me on the condition we also note the putative role purinergic oxidative stress plays in (e.g.) metabolic syndrome, atherosclerosis, stroke etc. To physicians and med student types (who read this stuff) this is not irrelevant to the disease. I might also mention 6-HDA, the animal model.Pproctor 23:02, 29 May 2007 (UTC)
Why not add that more general material to the pro-oxidant article? That page is a bit on the thin side and general statements would fit better in the more general article. TimVickers 02:30, 30 May 2007 (UTC)

[edit] The "expert problem" rears its ugly head

You-all win. I give up. Again. The traditional medding with the efforts of expert editors that over and over screws up technical articles at Wikipedia. Again, I lodge my usual and customary useless protest. Far as I can tell, nobody here are physicians, have ever worked with LNS, or have much of a clue about the science. Similarly, there is also some artificial "concensus" asserted totally at odds with the guidelines, etc.. Such things rely mainly on the fact that people like me have better (and more profitable) things to do than argue with some lay person who does not know enough to understand what they do not understand. EOF.Pproctor 16:54, 17 June 2007 (UTC)

[edit] Dr. Seegmiller's Name

I am offering a small suggestion here, rather than just edit the text myself. I realize that to some this may be nit-picking. I am a physician (a pathologist) and worked in Dr. Seegmiller's lab at UCSD (Dr. Nyhan's lab was one floor above) on many of the issues discussed in this article. Dr. Seegmiller's name, as used in all of his professional citations and honors, was J. Edwin Seegmiller. Although it is true that his friends and close associates sometimes called him "J" (which I guess could become "Jay"), this was a nickname. Given his great contributions to this field, it just struck me as a little less than respectful to refer to him by his nickname. I will also add that I have no major problems with the article as written, considering the general audience of Wikipedia. For those who want to really dig into this, especially those with some background in biochemistry or molecular biology, read the chapter in The Metabolic and Molecular Bases of Inherited Disease (McGraw-Hill, 8th edition, Charles R. Scriver, ed.) Dfuerpo 00:16, 3 July 2007 (UTC)

[edit] Deep-brain stimulation treatment?

Hi. This is a bit far afield from any area of my own expertise, but I would imagine that the Taira case study involving deep-brain stimulation [10] as successful treatment of the behavioral symptoms warrants mention in this article, most likely in the "Treatment" section? While it's not a commercially available treatment, it seems to show some promise at the very least. Thoughts? S. Ugarte 03:07, 15 August 2007 (UTC)

[edit] Fencing Stance ?

Can somebody provide a cite to the "fencing stance" referred to in the main article Pproctor 04:15, 7 October 2007 (UTC)