Perception, Reality, and Lesch-Nyhan Syndrome

inventing behavioural phenotypes from first principles

Nash Jones is a young boy from New Zealand, which means his family’s accent sounds uncanny valley to me, and probably indistinguishable from Australian to you. He is the only person in New Zealand with Lesch-Nyhan syndrome. His parents note that no practitioner they’d seen in the whole country had ever worked with someone with Lesch-Nyhan before. But it so happened that when he was a baby experiencing a strange health crisis, someone at the hospital had done her thesis on it, and wondered if this boy with kidneys full of stones was the zebra to end all zebras.

No one is sure just how rare Lesch-Nyhan is. The traditional quote is 1 in 380,000 males, but this seems to be a drastic overestimate. The realistic maximum is in the neighbourhood of one in a million. Population prevalence in the UK is about one in two million. The population of New Zealand is just above five million, implying the UK number is closest to the truth. As an X-linked recessive (this is X-linked recessives week for the blog, I guess) where patients don’t tend to reproduce, it’s functionally unheard of in women.¹

No one cares about disorders that affect one in five million people. Lesch-Nyhan syndrome is the exception. It’s an archetypal example in medical genetics textbooks. It’s namedropped in the DSM entry on intellectual disability. People write theses on it. Research on Lesch-Nyhan led to the creation of one of the most fundamental concepts in genetic disorder research, the “behavioural phenotype” — distinctive behavioural and personality traits associated with a particular disorder.

People care about Lesch-Nyhan syndrome because the behavioural phenotype is constant extreme self-mutilation, forever.

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The DSM-5 entry on “Intellectual Disability” — which ten years ago was “Mental Retardation” — names four specific syndromes. They are Down syndrome, Rett syndrome, Sanfilippo syndrome (rendered for some insane reason as “San Phillippo syndrome”), and Lesch-Nyhan syndrome. Down’s is extremely common, if you’re normed on genetic disorders and therefore consider 1/800 “extremely common”. Rett syndrome is maybe about a tenth, twentieth of that, and still one of the most common causes of severe intellectual disability. Sanfilippo — which they couldn’t even get the name of right — is around 1/70,000, and one of the more common childhood-onset dementias, which are so rare no one knows they exist. Lesch-Nyhan is massively rarer than Sanfilippo. But they could get the name right. Everyone gets the name right.

People think they know a few things about Lesch-Nyhan. They know how to spell it, which is not a given — Anglophones seem to pick eponyms by finding the surnames least familiar to us (I have to look up “Creutzfeldt-Jakob” every time). They know it has the behavioural phenotype to end all behavioural phenotypes. They “know” boys with Lesch-Nyhan self-mutilate relentlessly, that they don’t stop biting or hitting themselves. They “know” they do it to others, too, attacking their parents and caregivers. They “know” it causes a few other things, some nondescript “kidney issues”, a level of intellectual disability that, going by clips of boys in wheelchairs unable to speak or move their limbs, must be profound.

“Genetic Russian Roulette” describes the general knowledge of it well:

we’ll come back to that last one

There’s truth to this, but it misses what makes Lesch-Nyhan really interesting.

Lesch-Nyhan, again, is as rare as disorders get. It is the outlier to end all outliers. The list of people whose careers saw significant clinical experience with Lesch-Nyhan is…Nyhan.² People thus talk about it through games of telephone. They simplify it in the process into a “comprehensible” disorder, something that looks like “intellectual disability + self-injury” they’ve seen elsewhere. It doesn’t.

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“Nyhan himself found a number of Lesch-Nyhan boys while visiting state institutions for developmentally disabled people. When I asked him how long it took him to diagnose a case, he said, “Seconds.” He went on, “You walk into a big room, and you’re looking at a sea of blank faces. All of a sudden you notice this kid staring at you. He’s highly aware of you. He relates readily to strangers. He’s usually off in a corner, where he’s the pet of the nurses. And you see the injuries around his lips.””
—Richard Preston, “An Error in the Code”, for The New Yorker (2007)

People in the past wouldn’t have thought people with Lesch-Nyhan were possessed by demons out of being superstitious idiots who don’t understand medicine. They would’ve thought people with Lesch-Nyhan were possessed by demons because people with Lesch-Nyhan are possessed by demons.

Boys with Lesch-Nyhan develop their compulsion towards self-mutilation in toddlerhood. This is not to say they are diagnosed at that age. From an earlier point, they have dystonia — involuntary rigid movements, limiting their ability to use their limbs — and dysarthria — slurred or incomprehensible speech, generally accompanied by swallowing problems. They have “orange sand” in their urine, solid uric acid crystals visible in a diaper. They can develop life-threatening kidney stones, as Nash Jones did. These can lead a child to medical attention, to genetic testing, to the artificial creation of a nightmarish limbo where parents watch their happy, thriving sons knowing everything will soon change.

It’s dramatic, when it comes. Boys wake up screaming in the night, wailing inconsolably, because something that is not them has taken up residence in their hands. Hands are the enemy. When I was watching the video of Jones, I was struck, constantly, by the lack of restraints on his hands. Every other depiction of Lesch-Nyhan focuses on gloves and mittens, desperate attempts to imprison the demons. When boys with Lesch-Nyhan have their hands free, they attack themselves relentlessly, ripping teeth and ears, prying out eyes, biting their fingers down to the bone. One boy described by Nyhan (1976) had given himself a cleft palate — tore a hole in the roof of his mouth.

The boys are horrified by this. They desperately wish to avoid it. They scream when their gloves are removed, beg someone to put them back on. With time they learn to look away, tear their gaze from the terror of their hands. This only lasts so long; eventually they have to warn whoever’s studying the damage that if the gloves don’t go back on, they’re going to bite their fingers off. It’s not an empty threat. The doctor can see that — the tips are already missing.

The interesting thing is, these restraints don’t always have to be particularly strong. They usually are; some caregivers construct practical straitjackets. But some boys are assuaged by socks or lightweight mittens, as long as they’re taped securely. Sometimes the possession is isolated to fingers, not the whole hand, and only those fingers need restricting. Nyhan describes these patients as “basically very gentle people, on whom, as it were, an irresistible impulse has been grafted” (p. 245).

Hands are the primary locus of Lesch-Nyhan self-mutilation, but not exclusively. Severe damage to the lips is nearly universal in Lesch-Nyhan syndrome. The lips are close to the teeth; the teeth are natural weapons. The severity of the dystonia means biting oneself elsewhere is usually not primary, but there is flesh right next to the teeth, and the demon, such as it is, wants flesh. There are adults with Lesch-Nyhan who still have lips. They don’t have teeth.

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There’s more to Lesch-Nyhan than physically injuring yourself.

On a personality level, people with Lesch-Nyhan are not aggressive. Research consistently describes them as friendly, funny, and engaging. They get along with others; they love and are loved. Anderson et al. (1992), looking into the personality and cognitive profile of boys with Lesch-Nyhan, presented almost a Fifties stereotype of the “all-American boy” — kids whose lives were marked by playing with their friends, watching baseball (“one boy was the acknowledged neighborhood expert on the current baseball season”, p. 194), and socializing. Oh, and biting their fingers off.

And yet, aggression is an archetypal feature of Lesch-Nyhan syndrome. This is less often about physical harm to others, because your hands are distracted with yourself. It can be, yes — but it’s often emotional. Nyhan states deadpan that “four-letter Anglo-Saxon expressions are common” (Nyhan, 1973, p. 43). In his later 1976 paper, he gives an anecdote of a boy who played nurses at his institution against one another, lying that they were gossiping about one another behind their backs. These are often directed against those the patient cares about most, dedicated specifically, so it seems, to twisting a knife into one’s heart.

This is not done to hurt the other party. It is part of the self-mutilation.

A special issue of the Matheny Bulletin — the newsletter for a residential facility with unusually many residents with Lesch-Nyhan — made the point that it would be better termed “emotional self-harm”. Hurting others is characteristic of Lesch-Nyhan precisely because of the extraversion and empathic sensitivity of those with it. They want very deeply to befriend those around them, be thought highly of by them, and to be of the world. They are sensitive to precisely what will hurt someone. They have an irresistible drive to suffer, to make things as bad for themselves as they possibly can. So they hurt those they care about, precisely to make their family and friends think worse of them — to see themselves rejected.

Like other Lesch-Nyhan self-harm, this is unwanted. Robey & Balboni (2021) discuss the lengths boys would take to prevent it — realizing they were about to kick or spit on someone, and telling them to stand back. People with Lesch-Nyhan routinely warn newcomers about the risk, pleading with them to understand that they never really mean it. One of the two men with Lesch-Nyhan who Preston met for his New Yorker piece had worked selling flowers; he carried business cards that told customers about Lesch-Nyhan, and handed them out after he, say, told them to eat shit.

This complex emotional self-harm appears elsewhere. As boys with Lesch-Nyhan grow up and develop cognitive and emotional maturity, the demon repurposes it for itself. The Matheny Bulletin gives an anecdote of a boy who loved films, but turned down cinema invitations to deprive himself of his hobby. People playing video games with switches (buttons that allow severely physically disabled people to perform complex acts) would reduce the number of switches used to worsen their own performance. They would work at length on creative projects, then destroy them upon completion. A man with Lesch-Nyhan who gave speeches to medical students (described in Robey & Balboni) mentioned that he had lied about how much pain he was in after a surgery in order to experience overmedication-related complications.

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One of the things people “know” about Lesch-Nyhan syndrome is that it causes severe intellectual disability. (If you’re really unlucky, one of the things they “know” is that it looks like autism.) This underlies a lot of the ways people flatten Lesch-Nyhan into something “like other disorders”. Self-injury and aggression in severe ID are ideas people broadly understand, so Lesch-Nyhan is presumably a “severe ID + self-injury + aggression” syndrome. This is aided by the severe physical disabilities it causes; someone who can’t walk, has serious limb dystonias and trouble eating, and is difficult to understand when they talk seems like they must have comparably serious cognitive problems.

This is the part of the telephone game that leads to the most serious misunderstandings, because Lesch-Nyhan clearly does not cause severe intellectual disability. None of the above would be possible if it did. People with very limited cognitive abilities are not able to make 5D-chess self-torture prisons.

Cognitive testing in Lesch-Nyhan is a joke. You can’t realistically give an IQ test to someone who has severe dystonia, who can’t use his hands, who would stab himself in the neck if you gave him a writing implement, and who will give the wrong answer to questions in the hopes you’ll think worse of him. You have to rely on clinical impression (which is, in practice, bigger to how people think about intelligence anyway), or tests adapted so heavily their validity is questionable.

The impression is that while Lesch-Nyhan is an intellectual disability syndrome, it’s a relatively mild one with large error bars. Matthews et al. (1995) reviewed a number of testing attempts and themselves tested the boys at Matheny, finding an average in the upper end of the mild intellectual disability range. This seems to decline a little over time (Matthews et al., 1999), which is typical of intellectual disability syndromes (representing ‘growing into deficit’ rather than a decline in actual intelligence); it stays clearly in the same mild ID range, and there are still people who test well above the 70 threshold for intellectual disability.

Some studies imply much higher averages. The previously-mentioned Anderson et al. (1992) comprised 42 participants — clearly a substantial chunk of everyone alive in America with Lesch-Nyhan at the time. But even large samples can be questionably representative, and we run into that problem here; 33 of the 42 were living at home, while many boys with Lesch-Nyhan end up in residential care environments from young ages simply because of the difficulty of managing those symptoms in a normal house. They can be thought of as probably the most cognitively high-functioning subset of the Lesch-Nyhan population in the US in the early Nineties, if we assume milder or absent intellectual disability is a motivating factor for people to keep kids at home. But it’s a very, very small population.

Of all 42 participants, only one was felt to have an unambiguous intellectual disability.

This was based on school grade-level equivalents for reading and mathematics (writing is out of the cards). It’s a little optimistic; most were performing below grade level, and mild ID in kids routinely looks like “below grade level, but not shockingly” rather than more severe delays. It was also from parent report, and you might expect that to be biased, but parental bias in disability is tricky — parents routinely overreport their childrens’ disabilities as well as underreport, and they seem at least consistently accurate in “knowing if your child is intellectually disabled or not”.

Nonetheless, ~15% were performing at grade level for reading or mathematics. Two boys were performing above grade level. Most subjects “older than 4” (the median age in the study was 12) were at least literate and numerate, and it occurs to me we don’t tend to expect neurotypical five-year-olds to be prolific readers either. Some chunk of the remaining percentage would have mild intellectual disabilities that are obscured by a simple grade-based assessment, but there clearly has to be a significant minority of the Lesch-Nyhan population with normal-range intelligence.

Two of the participants didn’t have true Lesch-Nyhan syndrome — they had a mutation in the same gene and severe kidney problems, but lacked the characteristic self-mutilation. This happens sometimes, and tends to be called a “Lesch-Nyhan variant” despite the rather obvious clinical differences. If we exclude these boys and assume, conservatively, that they were in the more scholastically able subset, the numbers adjust downwards a bit, but many non-Lesch-Nyhan mutations are also associated with intellectual disability, so this can’t be a certain assumption.

It’s worth pointing out here that Anderson et al. (1992) and Matthews et al. (1995) are contemporaries — both addressing the very small pool of “boys with Lesch-Nyhan syndrome in the United States in the early-mid 1990s”. Given the former mostly focuses on boys living at home, and the latter is a census of an institution, we can synthesize them. Testing is difficult to such a degree that interpreting results is difficult, but mild intellectual disability pops out as somewhere around typical. There are exceptions well below — but also exceptions well above. Christie et al. (1982) concurs with both; of nine children who had taken IQ tests of some description, most were in the mild ID range, three below, and one boy had an IQ of 101. Notably, he performed below grade level at school, which has some implications for Anderson.

Because Lesch-Nyhan is vanishingly rare, people don’t tend to get opportunities to reassess telephone-game wisdom. A relatively large chunk of people with severe intellectual disabilities struggle with self-injury or aggression, in ways that look absolutely nothing like and have absolutely nothing in common with Lesch-Nyhan. Single paragraphs in a textbook are not a good place to express nuance. Lesch-Nyhan is the only thing nearly as rare as it that will get any paragraphs in a textbook at all, and when they’re right next to the other “aggression syndrome” one, misunderstandings get baked in.

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A similar problem is “differential diagnosis”. Because Lesch-Nyhan ends up in textbooks as “the self-injury syndrome”, people end up putting it as a differential diagnosis possibility for any boy who has some sort of disability-related self-injury. The worst of this routes through autism; “severe autism” is a wastebasket diagnosis for various sorts of “introverted disabled kids with short tempers or challenging behaviours”, and boy, does that not look anything at all like Lesch-Nyhan.

I jump at the chance to read all sorts of shit about how you should destroy your furniture before calling the cops on your schizophrenic child or whatever, because 1. I have something wrong with me that makes me want to read that, and 2. a lot of people insist disability/neurodivergence self-advocates are just ignoring the parents and caregivers of people in difficult situations, and I want to make very sure that I’m not. Accordingly, I read some time ago about half of a book by a mother who involuntarily subjected her eleven-year-old autistic son to ECT. One point that stood out to me was that, shortly prior, someone tested him for Lesch-Nyhan syndrome — described as a “disease caus[ing] mental retardation and self-injurious behavior (primarily biting)”. At the time, I knew relatively little about Lesch-Nyhan outside the textbook version, but it’s still a recognizable enough name I made a note of it.

When you find out more, it becomes clear the idea of mistaking Lesch-Nyhan for autism is risible. Some autistic people self-harm in stereotyped ways (or, for that matter, self-harm in the ways other people self-harm), and some autistic people go through periods of being aggressive or violent towards others, for various complex reasons. Neither of these look even a little bit like Lesch-Nyhan. In fact, Lesch-Nyhan is remarkably non-autistic; the ‘aggression’/emotional self-harm component is based on a uniquely strong sensitivity to other people, their emotions, and what they think of you. It is, as Nyhan said, the syndrome diagnosable by how affectionate and extraverted people are before you even notice the wounds.

You can’t have an eleven-year-old with unrecognized Lesch-Nyhan syndrome, because he’d have been dead for six years. You can’t have an autistic eleven-year-old with unrecognized Lesch-Nyhan syndrome, but…

…autism diagnosis is terrible. I can actually comprehend, in a “comprehending the horrors of the Great Old Ones” way, how you’d end up making that mistake. Williams syndrome is a rare genetic disorder marked by a distinctive behavioural phenotype of “extremely outgoing”, “loves people and socializing”, “trusts everyone immediately”, and “makes aggressively strong eye contact”. 15% of people with Williams syndrome are diagnosed with autism.

But Lesch-Nyhan fails the Williams Test. In fact, it might fail it worse than Williams syndrome itself. The prevalence of Williams syndrome is about 1 in 7,500. It does have some interesting overlap with the more subtle/non-social features of autism, though may I suggest they’re caused by something else? Because Williams syndrome is a chromosomal disorder, it’ll be picked up on by a chromosomal microarray without either a specific gene test or the very recent clinical introduction of WES/WGS, and because it’s relatively common and one of the milder intellectual disability syndromes, it’ll pop up in a meaningful fraction of kids being assessed for “developmental eccentricity NOS”. Lesch-Nyhan is an incredibly distinctive single-gene disorder with “one person in all of New Zealand”-tier prevalence. It’s a bit overkill to treat as first-line differential diagnosis.

This misconception comes both from the failures in how we think about autism and the failures in how we think about Lesch-Nyhan. Autism diagnosis is messy, and unlike the impression you’d get from people whining about diagnosis-seeking or Asperger’s, it’s a lot messier at the low end. Lesch-Nyhan is incredibly unlike any of the more common things that look a little like it in a single textbook paragraph, but it’s so rare as to never disabuse you of the notion.

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People really, really want to connect the behavioural phenotypes of genetic syndromes to the same neurotype-clusters that pop up in the general population. This is strongest for autism, the most childhood-diagnosable of them, which is why people talk about autism and Williams syndrome as comorbidites without being roundly mocked. Some genetic disorders — most famously fragile X — really do have behavioural phenotypes that resemble idiopathic autism, but even this is tricky and far from totally intersecting.

I’m not a fan of this phenomenon. While the behavioural phenotypes of genetic disorders are not wholly discontinuous from “people be acting ways” — a lot of genetic disorders are pretty common and subtle, and almost all have a broad spectrum — at some point the continuity breaks. It seems better understood to me as a metaphor than a literal statement of actual reality.

Lesch-Nyhan fails the autism metaphor. It does not look like autism. It does not look like any “severe ID + self-injury + aggression” disorder, because it is not one. (Neither is autism, but wastebaskets are wastebaskets.)

But it dawned on me what the metaphor is — and it highlights vividly just how this is a metaphor, rather than the literal diagnosis everyone makes in practice, because Lesch-Nyhan is so obviously discontinuous and so obviously not this.

What does a person who relentlessly hurts themselves and others, despite desperately not wanting to, and while wanting dearly to be loved and included and respected by the people they care about (and are hurting) have? Borderline personality disorder.

BPD is a wastebasket diagnosis nearly as bad as autism is, but I think there’s a “real BPD” underlying it that is developmental in exactly the same way — that is a childhood-onset developmental disorder and a lifelong neurotype (these are different ways to think about one thing). This is not to say borderline-personality-disorder is lifelong, because most people recover (an impression you would not get from how people talk about it). But “getting past the problem stage in your life where you fit BPD criteria” and “having a fundamentally different personality and worldview” are not synonyms. Attempts at finding the “borderline syndrome of childhood” generally conclude relatively few children who fit criteria for a BPD-equivalent are diagnosed with BPD as adults — I think a large chunk of this is because we haven’t actually constructed any equivalents, but there’s also a component of “the diagnostic category of BPD isn’t quite finding the neurotype” involved.

I like this metaphor, because it fits in a strange and visceral sense, and because it shows just how obviously the comparison is a metaphor that has absolutely no resemblance to reality. There is clearly nothing shared between BPD and Lesch-Nyhan. But there is something you see in the background when you look in the mirror, that you never noticed before it was reflected.

The same holds for demonic possession. People with Lesch-Nyhan are possessed by demons. We know they are not. We know it’s a single-gene disorder with particular predictable symptoms. But they are possessed by demons. There is a hostile and alien force living in their body that finds new ways to force them to suffer. They exist clearly separate of it. They talk about this. They know this.

There’s something to be said for fiction-that’s-truer-than-truth. Lesch-Nyhan syndrome is nothing like BPD and does not involve being possessed by literal demons, but you’ll be a lot more accurate about what it is if you correct in the “BPD syndrome” and “possessed by demons” directions than the “intellectual disability + self-injury syndrome” extrapolated from textbooks. There are a lot of common intellectual disability + self-injury syndromes. That’s exactly Lesch-Nyhan’s problem.

1. It’s happened, though. Girls with Lesch-Nyhan syndrome are technically carriers — they only have one mutated X — but they have extreme skewed X-inactivation, such that none or practically none of their normal X chromosomes are active in any cells. One girl had a monozygotic twin without Lesch-Nyhan — there’s twin discordance for you!

2. Lesch was a med student in Nyhan’s lab when an unusual patient came through. He later went into cardiology.