The world’s worst disease

June 5, 2008 2:29 PM

While many ailments are considered terrifying, Lesch-Nyhan is the stuff of nightmares. An extremely rare genetic neurological disorder with no cure, it often compels its victims to self-mutilate, even when they understand that doing so causes them harm. Richard Preston used Lesch-Nyhan as a plot device in his best-selling thriller The Cobra Event, and went on to write a fascinating article about the disease, its sufferers, and its implications for human behavior in the New Yorker. [PDF].

Inspired by this question in the green and ericb’s follow-up answer. Related articles on PubMed. Previous mentions of Lesch-Nyhan on the blue.

I’ve described Lesch-Nyhan as a talking point in classroom debates over the ethical implications of genetic analysis and intervention: it is the quietest and saddest moment I have in a classroom.

posted by Bora Horza Gobuchul (35 comments total)

Just whoa. That New Yorker article creeps me out. But the worlds worst disease?
Dying of rabies?
Fatal familial insomnia? Pancreatic cancer?
posted by lalochezia at 3:26 PM on June 5, 2008

Fascinating stuff. Almost makes credible the idea that we're all in possession of a "death drive," or Thanatos, in psychoanalytical language. Otherwise how could a few simple mutations cause a suite of behaviors that are not merely non-functional, but positively self-destructive in a very specific and targeted way, as if an already extant capacity were just modulated up several-fold?
posted by decoherence at 3:58 PM on June 5, 2008 [1 favorite]

Terrifying and heartbreaking.
posted by Unicorn on the cob at 4:09 PM on June 5, 2008

I have nothing to add except :-(
posted by turgid dahlia at 4:17 PM on June 5, 2008

Addendum for clarity: lalochezia, it wasn't my intention to have a gross-out debate over the title of the "world's worst disease", and in retrospect I might have considered another approach to my lead-in. To me, Lesch-Nyhan is "the worst" because its sufferers (mostly males) are born with the disease, often suffering it from infancy, rather than contracting it accidentally, and despite the mental retardation that is usually a co-symptom, know that what they are doing to themselves is wrong, and wish to stop it, but are unable to control their compulsion for self-mutilation. In the worst cases, they will literally eat themselves alive. (Although I was encouraged to find that deep-brain electrical therapy is a recent approach that appears to show some promise).

In that sense, fatal familial insomnia is similar, in that the "I-function", the neurological sense of self, remains intact through the progress of the disease. Further research yielded this short paper, which you might find interesting.
posted by Bora Horza Gobuchul at 4:21 PM on June 5, 2008

I saw an LN kid last year. He was 12 and strapped down into a heavy duty wheelchair, muzzled, and giggly. Growth retarded for his age but happy as a clam otherwise.

decoherence: "How could a few simple mutations cause a suite of behaviors that are not merely non-functional, but positively self-destructive in a very specific and targeted way, as if an already extant capacity were just modulated up several-fold?"

How does your theory account for Angelman, Cri cu Chat, or Prader-Willi? I'm having trouble understanding how goal-directed behaviour such as you describe can be encoded in genes, or in the absence or mutation of specific proteins. It also seems that the emergence or persistence of such a complex desire would be selected against by evolution.
posted by meehawl at 4:30 PM on June 5, 2008

I think this is more like extremely bad argument with a loved one than extreme case of nail-biting or other physical tic. You know that what you're saying is just making it all worse, but you have to say it, the ugliest, most injuring thought that comes to mind. Excition and inhibition are all mixed up. Only in this case the one you want to hurt and know that you don't want to hurt is yourself, and hurting is not words but actual hurting and you're permanently in that state.

Mind checks out for possible risks and threats and somehow that list gets inverted, what is usually inhibited gets excited and the most improbable and damaging acts get to be the ones that are sent for body to act on.

I think that many of us get scared by their thoughts, why we find ourselves thinking the very worst things that could happen or what we could do. Probably to double check that we shouldn't do them accidentally. These poor people can't avoid acting them out. Cognitively interesting, as there are infinite amount of boring, inconsequential possibilities and this seems to prove that mind automatically seeks out for the very worst and the best possible outcomes and actions.
posted by Free word order! at 4:55 PM on June 5, 2008

Ah Lesch-Nyhan. Just some of that medical school fodder that gets beaten into young doctors. I can still remember way way too much about something that I'm sure I'll never see in practice.
posted by i_am_a_Jedi at 4:59 PM on June 5, 2008 [1 favorite]

What a great New Yorker article. Lesch-Nyman is like super-Tourettes with a mean(er) streak.

I have a guess about the cause of the neurological symptoms. I think they are a side effect of the body's attempt to cope with the metabolic problems produced by the enzyme deficiency at the root of Lesch-Nyman.

The enzyme in question helps recycle DNA. Because Lesch-Nyman sufferers cannot recycle the DNA, its breakdown products (certain purines) accumulate, ultimately turning into more uric acid than the body can get rid of. I would guess that the body copes with this problem by reducing processes which produce broken down DNA as much as possible.

One of the main things which produces DNA breakdown products is apoptosis, or programmed cell death, so that gets turned way down.

It's become fairly clear that one of the ways a person gets rid of undesirable behaviors of at least certain very dangerous kinds, such as biting off one's fingers, is by killing off neurons in the brain which are associated or have come to be associated with them. Essentially, the brain prunes itself in the normal course of development. But if Lesch-Nyman sufferers have greatly reduced capacity for apoptosis in the brain, they don't do this, and the awful behaviors remain a constant threat.

Reduced Apoptosis might also make their behavior stay pretty immature. James Elrod and Jim Murphy are the most child-like plus thirtys I have ever heard of.
posted by jamjam at 5:03 PM on June 5, 2008 [1 favorite]

meehawl: It's certainly not "my theory," just idle speculation. But just as random gene mutations don't typically lead to creatures sprouting wings or functional appendages where previously they had none at all, they also don't typically lead to brand new sets of seemingly purposive behaviors. Mutations generally work on some underlying trait -- either rendering it completely inoperative, or tweaking slightly so that it becomes maladaptive, as in the other diseases you've listed.

So how then to explain the very coherent and seemingly purposive nature of the behaviors in Lesch-Nyhan? It's not just that they can't eat, or cry in a weird way -- they're actually harming themselves and people closest to them in what seem like very rational, intentional, directed ways. What's the mechanism? I don't know. Interesting to speculate about though.
posted by decoherence at 5:11 PM on June 5, 2008

Great article.
posted by Artw at 5:20 PM on June 5, 2008

Stealth marketing for The Happening?

Also, who at the New Yorker thought it was a good idea to typeset that entire article in a sans-serif font?
posted by vsync at 5:39 PM on June 5, 2008

(Please do not mention The Happening, or remind me that M. Night Shyamalan exists. Thank you!)
posted by Artw at 5:50 PM on June 5, 2008

Coincidentally, I just finished Richard Preston's Panic in Level 4 last week. It works pretty well as a collection of anecdotes about the people he's encountered and their different problems, including a chapter about two men with Lesch-Nyhan. It probably isn't as rich in detail as his other writing, though I have no basis for comparison. Good travel reading.
posted by Inspector.Gadget at 5:57 PM on June 5, 2008

One boy, known as J.J., ended up living in Nyhan's research unit for a year, when he was eleven. He was a gregarious child, whose hands seemed to hate him. Over time, his fingers had got inside his mouth and nose and had broken out and removed the bones of his upper palate and parts of his sinuses, leaving a cavern in his face. He had also bitten off several fingers. [...] Occasionally, a man with the disease flings his head backward with such force that his neck is broken.

Interesting. Maybe this could be one of the physiological bases which inspired myths of demonic possession?
posted by aeschenkarnos at 6:11 PM on June 5, 2008

decoherence, I think the whole point is that the potential for those behaviors exists in all of us, and may even be a necessary basis for creativity. But in the LN patients those impulses are uncontrolled. It's not that LN creates the behaviors, but that it prevents the patients from keeping them in check as the rest of us do.
posted by localroger at 6:29 PM on June 5, 2008

Stealth marketing for The Happening?

Unlikely, unless they've been stealth marketing for The Happening since the 1970's. Not everything is "stealth marketing". Very few things are. I wonder when "perceiving wildly inappropriate events as possibly stealth marketing for one or more products" will end up in the DSM.
posted by aeschenkarnos at 6:32 PM on June 5, 2008

If anything it's stealth marketing for The Cobra Event, which actually sounds worse.
posted by Artw at 6:57 PM on June 5, 2008

localroger: That's more or less exactly what I was saying. The fact that LN manifests itself not in a jumble of random, dysfunctional behaviors, but in a seemingly coherent set of purposive behaviors makes me think there's some single underlying mechanism that's affected. Either there's a "self-destructive behavior regulator" which has gotten out of whack, or LN effects some sort of impulse reversal, as someone above alluded to. Either case would incredibly fascinating and revealing.
posted by decoherence at 7:31 PM on June 5, 2008

The New Yorker is still killing it. I got that article today from the askme post, really fascinating. The first thing I thought about was that weird death urge, the drive the car off the cliff, stab yourself in the guts kind of feeling that sometimes comes over me, being a human is super fucking weird. Those poor fuckers, I'm glad that someone documented how well they managed to live.
posted by Divine_Wino at 7:47 PM on June 5, 2008

aeschenkarnos: Interesting. Maybe this could be one of the physiological bases which inspired myths of demonic possession?

Given the extreme rarity and the poor survivability, I tend to think not. Back when those sort of myths formed, population levels were so low that you'd only have one case or so per generation per area. The vast majority of those would quickly die of the physical effects and poor health before they even reached an age where they could manifest the psychological aspects. Not to mention that a lot of societies back then would have just abandoned the child when they found out they were too weak to walk.
posted by Mitrovarr at 8:14 PM on June 5, 2008

Terrifying indeed. I am once again amazed by human resilience.

And once again fascinated by the degree to which our "selves" appear, more and more, to be governed by crude matter. Well, stupefyingly intricately organized matter.
posted by flotson at 8:15 PM on June 5, 2008

THE POWER OF THE DISEASE COMPELS YOU!!!!!!
posted by blue_beetle at 9:10 PM on June 5, 2008 [1 favorite]

Mitrovarr Given the extreme rarity and the poor survivability, I tend to think not. Back when those sort of myths formed, population levels were so low that you'd only have one case or so per generation per area.

That's all you need for a legend: the cyclops, for instance, almost certainly came from cases of holoprosencephaly. Any individual child need not have lived, but not knowing why they die so early, people would assume that one could survive to adulthood.

The vast majority of those would quickly die of the physical effects and poor health before they even reached an age where they could manifest the psychological aspects. Not to mention that a lot of societies back then would have just abandoned the child when they found out they were too weak to walk.

In stone age societies, sure; but by the Dark Ages, it's feasible, particularly among upper or middle class families in Europe. Keeping a kid alive, fed and watered on a diet that reduces his bladder troubles, restrained from biting and stabbing at himself, it could be done. He wouldn't be a large or healthy child; even with the strength of madness, two friars could restrain him easily enough. As an adult, the way he cries out alternately curses and demands to be tortured most harshly, and pleas for restraint and mercy, this would be indistinguishable (and the distinction meaningless) from demonic possession to the medieval mind. I'd bet there are multiple cases of this in the medical and religious writings of 10th to 16th century Europe.
posted by aeschenkarnos at 11:36 PM on June 5, 2008

All I know is, my son and daughter (twins, under three years) are very different people; while they're both happy and intelligent and curious and thoughtful, one of them laughs, giggles and goes "whee" when the plane we're flying in hits turbulence -- and the other takes a great amount of pleasure in small amounts of self-inflicted pain, pulling on hair or hitting themselves lightly in the head with objects.

And I wasn't even slightly worried about this, until reading this thread, so goodbye good night's sleep and hello long night searching wikipedia and scaring myself. Sigh.
posted by davejay at 12:06 AM on June 6, 2008

As an adult, the way he cries out alternately curses and demands to be tortured most harshly, and pleas for restraint and mercy, this would be indistinguishable (and the distinction meaningless) from demonic possession to the medieval mind. I'd bet there are multiple cases of this in the medical and religious writings of 10th to 16th century Europe.

If anything, I suspect it would be perceived as the opposite: extreme piety bordering on sainthood. The medievals, remember, were a lot less solicitous for their health and safety than we are, and medieval saints and mystics indulged in the entire spectrum of self-mutilation: flagellation, deliberate starvation, immobility (there was an entire class of saints who sat on pillars their whole lives), and direct contact with the diseased. Catherine of Siena, among many other saints, drank pus and ate leper scabs.

Be careful about making the really mundane and obvious link between demonic possession and mental disorders. The medievals were religious, but they weren't idiots. The mentally ill weren't, as far as I know, considered any more demonic than anyone else (it was often believed that mental illness was a punishment from God, but, assuming that it began from birth, it was generally a reflection on the parents and not on the ill person). Not to mention that if you believe in all kinds of supernatural shit, your idea of normality and abnormality is going to be a lot more flexible; there're a lot of things wrong with Foucault's Madness and Civilization, but he's right when he points out that the reification of the line between healthy and insane is a product of the early modern period.
posted by nasreddin at 2:36 AM on June 6, 2008

Davejay, according to the articles the crystals in the urine are the major sign. If he has none of that at all, it's extremely unlikely.
posted by aeschenkarnos at 2:42 AM on June 6, 2008

Nasreddin, I think there's a long tradition of epileptics being considered possessed.
posted by parudox at 3:29 AM on June 6, 2008

Nasreddin, I think there's a long tradition of epileptics being considered possessed.

Yes, definitely. But I'm not sure this is the same thing.
posted by nasreddin at 3:59 AM on June 6, 2008

I especially love the New Yorker writer's description of driving at full speed across a lake bed with two LN patients in tow and their laughter as the vehicle sinks below its axles in the clay.
posted by rongorongo at 4:33 AM on June 6, 2008

Terrifying.
posted by greytape at 6:22 AM on June 6, 2008

This is truly fascinating.

But the worlds worst disease?

I too feel the "worst disease" bit is a stretch. In the world of horrid diseases, this is truly a bad one, but it's no Progeria.
posted by Pollomacho at 6:45 AM on June 6, 2008

Over time, his fingers had got inside his mouth and nose and had broken out and removed the bones of his upper palate and parts of his sinuses, leaving a cavern in his face. He had also bitten off several fingers. [...] Occasionally, a man with the disease flings his head backward with such force that his neck is broken.

Fuck. That takes "don't pick at your scabs" to a new, terrifying level. I'd be interested in knowing how their brains can shut down the body's natural shock mechanism to such enormous trauma, and (likely) enormous pain.
posted by Civil_Disobedient at 9:25 AM on June 6, 2008

Fibrodysplasia ossificans progressiva, which turns any injury to bone, is pretty weird and nasty, but it doesn't have the involuntary actions component that makes Lesch-Nyhan so scary.
posted by Artw at 9:35 AM on June 6, 2008

I guess I was not expressing myself clearly earlier. What I meant is that there are many diseases that knock out elements of the nigrostriatal pathway and lead to very stereotyped and distinctive behavioural changes. The high serum urate levels created by LN is one of this diseases. I do not see hidden "subconscious" urges revealed in the pathology of these diseases, but merely derangements of some of the sub-cortical processing elements of our brains that are involved in originating or repressing actions. Or to take a different approach, if disease or injury wipes out part of someone's pre-frontal cortex then, depending on the location and extent, you will probably see some very typical behaviour changes. Many frontal lobe syndromes convert a person into a semblence of a much more apathetic, amiable and relaxed, less driven individual. Damage other areas and, through disinhibiton, you can get a person more prone to hypersexuality, hyperorality, or risk taking. And then there is the whole phenomenon of perseverent behaviour. In these, as well, I do not see latent drives being revealed but simple cognitive disarray.
posted by meehawl at 4:11 PM on June 6, 2008