This is a very interesting post, thank you. I have a lot of experience with mental disorders simply by being caretaker and child to people with them, but the name game--"what do we call this disorder?"--is always difficult. I have a lot of sympathy for people who are trying to refer to something but simply don't have the right words.
"Autism" has certainly become a wastebasket diagnosis. I expect that will change if we ever develop the ability to actually treat different subtypes, rather than simply try to mitigate the symptoms.
"BPD" in my limited experience looks like someone stuck at a middle or high school development level with respect to relationships. This would be difficult to diagnose at a younger age because they would at most just look like elementary school kids who have trouble socializing and get their feelings hurt if a friend doesn't play with them.
The way conditions are defined and talked about certainly leaves a lot to be desired... I know one woman (a classic "karen" type, though largely reformed) who has been diagnosed with a whole slew of conditions (ADD, depression, anxiety, bi-polar, BPD, autism) over the years/in an attempt to figure out what's wrong with her. She suffered both physically abusive spouses and a neglectful childhood. Our ability to diagnose and treat people even when they and everyone around them recognizes there's an issue is really primitive.
I wonder if there are any medical treatments that help mitigate some of the effects of Lesch-Nyhan’s syndrome, besides tooth-removal?
There are some people with Lesch-Nyhan who have been really helped by deep brain stimulation. I'm not sure if it scaled up well -- when you're talking about things this rare you basically have to read tea leaves into 15-year-old articles -- but it *has* had miraculous results for some people, and "any results at all" for others.
Trying to spot "childhood BPD" is a thing a few people have tried, with mixed results in terms of "does this correspond to an adult BPD diagnosis at follow-up". That might be the wrong thing to look at -- the biggest obvious concern is that the "childhood BPD" versions are usually diagnosed in boys, and adult BPD proper is usually diagnosed in women, so there's a discontinuity there. I'll probably write more on that later.
I assume it's all de novo mutation? That should make prevalence estimates feasible just on the basis of "number of de novo mutations per foetus" * "odds of one hitting that specific gene", right?
Being an X-linked recessive, women are usually unaffected, so "inherited from carrier mother" is...relatively common? I don't know about hard ratios ("2/3rds from carrier, 1/3rd de novo" has gone around, but at the relevant sample sizes that'd honestly be guesswork). However, any given family's mutation seems pretty much unique even when they're inherited.
Not every mutation on the relevant gene causes classical Lesch-Nyhan. Some cause the severe kidney issues and physical disabilities, but not the self-mutilation. Some cause...very little? *Every* genetic disorder, once you drill deep down enough, has a long tail of "people have some vaguely related mutation and also are not completely from a 1950s propaganda family photo, does the former cause the latter". (The medical sociologist Daniel Navon has some interesting takes here.) It's not clear how large a proportion "Lesch-Nyhan syndrome" is of "every conceivable mutation on the associated gene that accordingly gets called a Lesch-Nyhan variant in sufficiently expansive papers". There are probably mutations that have been found in both classical LNS and variants.
My thinking was that if approx no males with the full syndrome have kids, which seems probable (especially before modern medicine to treat the kidney aspects) then the only way female carriers exist is relatively recent de novo mutations in their line?
That seems to be the case, yeah -- it's apparently one of those mutations that 'disappears' quickly (families with multiple brothers with Lesch-Nyhan exist, but I can't recall hearing of any with an uncle and nephew). The significant physical health problems make this a bit tricky to be sure of, though -- once you go back far enough, "serious kidney issues" would often be fatal before any more distinctive symptoms. There are more than a few theoretically-but-not-usually heritable syndromes where this is a known problem (velocardiofacial syndrome, which is strikingly common and often-but-not-always involves severe heart defects, is a big one), but Lesch-Nyhan is so rare we can assume it's not showing a VCFS pattern.
In practice, phenotypic uncertainty about what mutations would cause Lesch-Nyhan proper and what would cause an unrelated disorder makes working out a true "theoretical prevalence" from de novo mutation rate a bit tricky. We also don't know if it's a mutation with a high miscarriage risk -- it could be? I don't intuit this well for single-gene disorders. If it is, that would decrease prevalence compared to raw mutation rate.
This is a very interesting post, thank you. I have a lot of experience with mental disorders simply by being caretaker and child to people with them, but the name game--"what do we call this disorder?"--is always difficult. I have a lot of sympathy for people who are trying to refer to something but simply don't have the right words.
"Autism" has certainly become a wastebasket diagnosis. I expect that will change if we ever develop the ability to actually treat different subtypes, rather than simply try to mitigate the symptoms.
"BPD" in my limited experience looks like someone stuck at a middle or high school development level with respect to relationships. This would be difficult to diagnose at a younger age because they would at most just look like elementary school kids who have trouble socializing and get their feelings hurt if a friend doesn't play with them.
The way conditions are defined and talked about certainly leaves a lot to be desired... I know one woman (a classic "karen" type, though largely reformed) who has been diagnosed with a whole slew of conditions (ADD, depression, anxiety, bi-polar, BPD, autism) over the years/in an attempt to figure out what's wrong with her. She suffered both physically abusive spouses and a neglectful childhood. Our ability to diagnose and treat people even when they and everyone around them recognizes there's an issue is really primitive.
I wonder if there are any medical treatments that help mitigate some of the effects of Lesch-Nyhan’s syndrome, besides tooth-removal?
There are some people with Lesch-Nyhan who have been really helped by deep brain stimulation. I'm not sure if it scaled up well -- when you're talking about things this rare you basically have to read tea leaves into 15-year-old articles -- but it *has* had miraculous results for some people, and "any results at all" for others.
Trying to spot "childhood BPD" is a thing a few people have tried, with mixed results in terms of "does this correspond to an adult BPD diagnosis at follow-up". That might be the wrong thing to look at -- the biggest obvious concern is that the "childhood BPD" versions are usually diagnosed in boys, and adult BPD proper is usually diagnosed in women, so there's a discontinuity there. I'll probably write more on that later.
Great writing, very happy I found this blog. Keep it up.
That syndrome sounds truly horrifying.
I assume it's all de novo mutation? That should make prevalence estimates feasible just on the basis of "number of de novo mutations per foetus" * "odds of one hitting that specific gene", right?
Being an X-linked recessive, women are usually unaffected, so "inherited from carrier mother" is...relatively common? I don't know about hard ratios ("2/3rds from carrier, 1/3rd de novo" has gone around, but at the relevant sample sizes that'd honestly be guesswork). However, any given family's mutation seems pretty much unique even when they're inherited.
Not every mutation on the relevant gene causes classical Lesch-Nyhan. Some cause the severe kidney issues and physical disabilities, but not the self-mutilation. Some cause...very little? *Every* genetic disorder, once you drill deep down enough, has a long tail of "people have some vaguely related mutation and also are not completely from a 1950s propaganda family photo, does the former cause the latter". (The medical sociologist Daniel Navon has some interesting takes here.) It's not clear how large a proportion "Lesch-Nyhan syndrome" is of "every conceivable mutation on the associated gene that accordingly gets called a Lesch-Nyhan variant in sufficiently expansive papers". There are probably mutations that have been found in both classical LNS and variants.
My thinking was that if approx no males with the full syndrome have kids, which seems probable (especially before modern medicine to treat the kidney aspects) then the only way female carriers exist is relatively recent de novo mutations in their line?
That seems to be the case, yeah -- it's apparently one of those mutations that 'disappears' quickly (families with multiple brothers with Lesch-Nyhan exist, but I can't recall hearing of any with an uncle and nephew). The significant physical health problems make this a bit tricky to be sure of, though -- once you go back far enough, "serious kidney issues" would often be fatal before any more distinctive symptoms. There are more than a few theoretically-but-not-usually heritable syndromes where this is a known problem (velocardiofacial syndrome, which is strikingly common and often-but-not-always involves severe heart defects, is a big one), but Lesch-Nyhan is so rare we can assume it's not showing a VCFS pattern.
In practice, phenotypic uncertainty about what mutations would cause Lesch-Nyhan proper and what would cause an unrelated disorder makes working out a true "theoretical prevalence" from de novo mutation rate a bit tricky. We also don't know if it's a mutation with a high miscarriage risk -- it could be? I don't intuit this well for single-gene disorders. If it is, that would decrease prevalence compared to raw mutation rate.