It seems when the genetic explanation is employed, it’s meant in the sense that Huntingtons or Downs is genetic - which autism is not (the majority of the time)
This claim doesn't make much sense. Gene expression is primarily a function of genomic accessibility which is mostly a function of a dynamic interaction between the genome and development cues anticipated by the genome.
Additionally, there have been enormous efforts to find things like "maternal effects" on ASD outcomes. The latest and best work shows these associations are familial confounding, meaning these effects don't exist.
If the process of neurodevelopment was so sensitive to diffuse exposures from the environment, it would be quite hard for the genome to faithfully reproduce typically neurodevelopment >95% of the time.
Ahhhh, yes. And no. We must think beyond just de novo mutations (which is itself under-researched... no reason to believe they are always random). There are transcription factors and epigenetic layers to consider.
No, this is well studied. Transgenerational epigenetic inheritance (TGEI) is a fairytale pioneered by enterprising researchers looking to make a splash and media publications that like Lamarckian ideas for obvious reasons (genetics feels icky and deterministic to them). Neuro-geneticist Kevin Mitchell has several lay summaries of the issues with TGEI claims and research. There is also a similar Substack piece by Razib Kahn, a veteran genetics journalist and tech entrepreneur.
Alternatively, it is well-known that de novo mutations, typically in the paternal germline, are responsible for a significant portion of severe autism cases. This is often identified by whole exome sequencing (WES). However, these molecular diagnostic approaches have limitations and cannot identify ALL types of genetic lesions and whatever estimates we have for de novo mutations causing (severe) autism are under-estimates.
This paired with the extremely high heritability figures, familial and syndromic cases, genetic models that share pathways, sorting on polygenic risk among parents, the early onset of the phenotype, and the absence of measured environmental effects all unambiguously point to a genetic origin.
Honey I’m not talking about transgenerational epigenetic inheritance. That you would bring it up reflects your ignorance of these matters. I am however pointing to *direct* germline effects, whether they reside in the nucleotide sequence itself or in the apparatus that regulates gene expression. Autism has been emphatically shown to not travel down family trees like other genetic diseases. Instead its heritability is by and large limited to recurrence among siblings (just like my kids). So it behooves us to ask — quelle shenanigans in the pool of parental germ cells? It’s really not that hard.
Watch my Harvard talk on lmk your further knee-jerk criticisms.
Again, a direct germline effect is a genetic effect (you're literally talking about genetic effects when you say whether it "resides in the nucleotide sequence itself or the apparatus that regulates gene expression" - where do you think the epigenetic program and TFs originate?... The answer is the genome like I said in my original comment).
If you can identify some other substrate for the transfer of developmental information from the parental germline to a zygote please identify it. Transcriptions factors, metabolic enzymes and nutrients, and the packaging of the sperm and egg genomes are not players that actors that drive disease. They are directed by a genomic programs and the laws of physics. There is nothing passed on in the egg or sperm that can predictably, systematically, and durably disrupt neurodevelopment.
"Autism has been emphatically shown to not travel down family trees like other genetic diseases"
Uh, this is very much not true. Your actual family itself shows a horizontal pattern of inheritance with affected sibs (this is a familial pattern of disease implicating genes as a cause of disease; it is very similar to the pattern seen with autosomal recessive diseases). Plus, it has been shown that parents with high polygenic scores for autism tend to pair up and thus have children with polygenic scores that often exceed the "liability threshold" for a diagnosis.
The reasons vertical transmission of autism (which does happen typically unaffected mother to affected son) is so rare is that severe autistic individuals essentially never have children and high functioning cases are highly polygenic so their offspring have a greater chance of regressing to the mean (aka normal neurodevelopment) than inheriting the same risk threshold.
Your project here seems to be imagining things happening in germlines that don't happen.
A fascinating and enlightening report. I hope the researchers take note and act upon it. Jill, I specialise in learning disabilities here in Germany. However, I'm planning an online course for parents in the USA - starting in April. The methodology I employ is grounded in the biology of the brain, the results for dyslexia and dyscalculia (and ADHD) are measurably excellent. Interested? Please see my pitch for schools: https://joekennedy-education-consultant.com for more information. Joekenn77@googlemail.com
Recent research shows that genetic factors are the leading cause of autism spectrum disorder (ASD), accounting for approximately 80% to 90% of the risk. This includes both inherited genetic mutations and spontaneous (de novo) changes in DNA. Key genes like CHD8 and NRXN1 are involved in brain development and have been strongly linked to ASD.
No you are very much mis-reading the literature. Autism is 50-90% HERITABLE. That does not mean it's necessarily genetic. We should be concerned about other sources of the heritability, including de novo mutations and other molecular defects.
I just published a really long post about different theories that can cause autism ... I agree with a lot of what you've written here. Re transcription issues:
-- You might like Christopher Badcock's "The Imprinted Brain". He argues that gene imprinting, with an excess of maternal genes being silenced and an excess of paternal genes being expressed, is related to autism. He also discusses Mary Lyon's work on "lingering Lyonization", which is essential when imprints on the mother's X chromosome fail to "reset" during recombination and passed down to children, increasing autism risk, especially in males.
-- Environmental toxins and nutritional deficiencies are probably a huge factor.
-- Maternal stress during pregnancy is a major predictor of autism in children, as are traumatic experiences in the mother's childhood. I'm guessing this could cause transcription issues.
-- Some genes are more vulnerable to environmental, nutritional, and stress related factors. There are a couple common MTHFR mutations which have negative interactions with folic acid (synthetic folate) in prenatal vitamins and fortified foods, especially in combination with low sunlight exposure and low Vitamin D. Leads to lower levels of glutathione and an impaired ability to detox, and so would be a reason why autistic people have been found to have higher levels of heavy metals in their bodies.
Very interesting. What is the epidemiological evidence that women with MTHFR mutation are at higher risk for having children with autism or other defects?
Seems to mostly be anecdotal, but there's a lot of anecdotal evidence. Needs to be researched.
I suspect these mutations are not harmful on their own, only in combination with folic acid and other modern toxin exposures. I'm guessing there's such a high prevalence of them because they were originally adaptive. Specifically, I'm guessing they were an adaptation to having a lighter skin tone in hotter / sunnier climates (the highest prevalence of these mutations seems to be in Jewish people and Southern Europeans, e.g. Italians and Spanish people), especially in combination with a low-folate diet. Sunlight depletes folate levels, and while dark skinned people are protected against this, light skinned people aren't. These mutations cause you to use folate more slowly, so it would be protective in that sense.
You've read it!! That's great, I think Badcock is really on to something and I wish more people were aware of his work. His follow-up, "The Diametric Mind" is also really good.
Regarding folic acid, oh man, it's kind of complicated and still pretty speculative, so needs to be researched more. I wrote an 8,000 word essay about it. Basically, certain MTHFR mutations cause the body to break down folate (and folic acid) more slowly. While you can't overdo it on folate, the way our bodies use folic acid is a little different, and it can start to accumulate with high consumption (which is likely during pregnancy if you are taking a prenatal vitamin with folic acid and eat fortified foods). Our bodies actually prefer folic acid to folate, so high folic acid intake can block our body's from using folate from natural food sources too. This can cause a "functional folate deficiency" where the symptoms of folate deficiency (linked to autism) present despite high folic acid intake. Causes methylation issues. Folic acid and other synthetic vitamins also seem to be related to disordered eating (e.g. ARFID) so there's indirect effects as well.
In addition to autism, seems to be highly related to the increase in tongue ties in children, rising rates of certain cancers, allergies, asthma, and other conditions as well. Seems to be related more to high functioning autism than lower-functioning (at least in lieu of other factors), and also to gender dysphoria in autistic people.
The introduction of prenatal vitamins with folic acid correlates with the uptick in autism of children born in the 1980s or later, and the introduction of folic acid fortified in various common foods (e.g. many wheat products) in the late 1990s correlates with the next big uptick.
There's also good evidence that prenatal vitamins with synthetic vitamins (and which are frequently contaminated with heavy metals etc) can cause or worsen morning sickness, and thus adversely affect maternal diet during pregnancy.
Here's the essay -- it's a long read, and pretty speculative, but I tried my best to lay out the evidence.
Thanks for this article...exhaustive work. I have been exploring the incidence of cerebral folate deficiency and have just convinced our physician to do a trial of leucovorin for my non-verbal, profoundly autistic grandson. It appears low risk/high reward...unlike many of the other treatments suggested. Do you have experience with this?
I'm sorry, I don't! But low risk/high reward sounds good. I haven't heard of leucovorin though. I'm skeptical of pharmaceutical solutions in general, but each case of autism is unique. I have a longer article with as many causes of autism as I was aware of and some ways to address them, if you want --
And I thought I did a rather exhaustive look at autism research!! I did a quick scan of your article. You are beyond comprehensive.
I'm also not a big fan of pharmaceuticals..although I know they have been helpful for some. Leucovorin is folinic acid..the bioavailable form of folate that can cross the blood brain barrier. 30-70% of ASD kids have been shown to have cerebral folate deficiency. This can be confirmed with lumbar puncture or measurement of folate receptor autoantibodies. Both tests are difficult to do. The drug has been around for 70 years and has a long established safety profile.
You have to treat the nutrient deficiencies that are causing low appetite and picky eating first -- folate is one of them, so for short-term use until enough he eats enough folate-rich foods in his diet it sounds good! Grass-fed beef mixed with liver and heart is a good option for stuff like hamburgers.
You also need to get Vitamins B1, B12, and D in him. Also more zinc (low zinc can screw up sense of taste). Get him outside (in the morning, no sunscreen), ideally barefoot on grass. Look into a good multivitamin -- I haven't used any myself, but I see lots of positive reviews of these two:
The course will start on 8th May. It is really about stimulating and activating specific areas of the brain; you might find it usefull. I would like to invite you as a guest, free of charge.
It’s my understanding that while rare it’s possible for someone to be nonverbal (at least at times) and profoundly autistic (extremely sensitive/sensory issues) without having an intellectual disability. It seems to me that very often the ocasional but not consistent assumption of ID going along with autism but not being identified makes for a lot of confusion and disagreement. I wish there was a way to ask people to be more clear about this. I’ve read some summary of academic papers suggesting that the heritability of autism with and without ID is different. Unfortunately I don’t remember the details.
I have not yet met such a person. I have seen people with mutism (perhaps mistaken for autism) without ID. But those like my kids—nonverbal autistic—don’t have secret cognitive normalcy. It’s not a locked-in syndrome. Read amy Lutz’s book Chasing the Intact Mind.
The jury is out on this topic for me. I know that there is disagreement in the Speech and Language camps about facilitated communication but the number of stories of children believed to be intellectually disabled who find a voice through facilitated communication and go on to do amazing things. If you haven't heard it...listen to Elizabeth Bonkers...the "retard" (as called by her principal) who went on to give the valedictorian speech at Rollins University
I’m not even talking about facilitated communication but autistic people that can and do type (by themselves) but don’t often speak and people that can speak sometimes but not other times.
Very interesting piece. I see a relatively small number of subscribers so I will take a chance here. I’m a retired nurse. This is the first I’ve encountered this. If I understood, our DNA is relatively passive. At various moments when cell development is indicated a portion of the DNA strand needs to pass on genetic instruction to our RNA (transcription) and the RNA is responsible for the subsequent cell development.
A “genetic” cause for autism would indicate a problem in the DNA itself and an “environmental” cause would reveal itself in a more direct link (what the anti vaxers are pushing). You are proposing (or are you sharing others’ proposal?) that autism is likely the result in failed transcription between DNA and RNA when brain/neuro cell development is indicated.
Moving forward if we can learn the trigger for this disruptive transcription could be groundbreaking. Or have I misunderstood?
Are there other conditions that may actually be due to similar problems with transcription? I have a few autoimmune “illnesses” and you’ve piqued my curiosity.
I'm proposing glitches at the germline level that lead to dysregulated transcription during offspring development. You can watch my Harvard presentation for an example of this at jillescher.com
genetic mutations cause transcription problems and enviromental toxcins can cause genetic mutations
its still genetic, it's wildly heterogenous, but it's genetic
It seems when the genetic explanation is employed, it’s meant in the sense that Huntingtons or Downs is genetic - which autism is not (the majority of the time)
This claim doesn't make much sense. Gene expression is primarily a function of genomic accessibility which is mostly a function of a dynamic interaction between the genome and development cues anticipated by the genome.
Additionally, there have been enormous efforts to find things like "maternal effects" on ASD outcomes. The latest and best work shows these associations are familial confounding, meaning these effects don't exist.
If the process of neurodevelopment was so sensitive to diffuse exposures from the environment, it would be quite hard for the genome to faithfully reproduce typically neurodevelopment >95% of the time.
You obviously did not read my piece. I'm not talking about maternal effects, at all. Just germline-level effects.
So then your title means what exactly? Germline-level effects are called genetic effects. What's passed on from the germline is the genome...
Ahhhh, yes. And no. We must think beyond just de novo mutations (which is itself under-researched... no reason to believe they are always random). There are transcription factors and epigenetic layers to consider.
No, this is well studied. Transgenerational epigenetic inheritance (TGEI) is a fairytale pioneered by enterprising researchers looking to make a splash and media publications that like Lamarckian ideas for obvious reasons (genetics feels icky and deterministic to them). Neuro-geneticist Kevin Mitchell has several lay summaries of the issues with TGEI claims and research. There is also a similar Substack piece by Razib Kahn, a veteran genetics journalist and tech entrepreneur.
Alternatively, it is well-known that de novo mutations, typically in the paternal germline, are responsible for a significant portion of severe autism cases. This is often identified by whole exome sequencing (WES). However, these molecular diagnostic approaches have limitations and cannot identify ALL types of genetic lesions and whatever estimates we have for de novo mutations causing (severe) autism are under-estimates.
This paired with the extremely high heritability figures, familial and syndromic cases, genetic models that share pathways, sorting on polygenic risk among parents, the early onset of the phenotype, and the absence of measured environmental effects all unambiguously point to a genetic origin.
Honey I’m not talking about transgenerational epigenetic inheritance. That you would bring it up reflects your ignorance of these matters. I am however pointing to *direct* germline effects, whether they reside in the nucleotide sequence itself or in the apparatus that regulates gene expression. Autism has been emphatically shown to not travel down family trees like other genetic diseases. Instead its heritability is by and large limited to recurrence among siblings (just like my kids). So it behooves us to ask — quelle shenanigans in the pool of parental germ cells? It’s really not that hard.
Watch my Harvard talk on lmk your further knee-jerk criticisms.
Again, a direct germline effect is a genetic effect (you're literally talking about genetic effects when you say whether it "resides in the nucleotide sequence itself or the apparatus that regulates gene expression" - where do you think the epigenetic program and TFs originate?... The answer is the genome like I said in my original comment).
If you can identify some other substrate for the transfer of developmental information from the parental germline to a zygote please identify it. Transcriptions factors, metabolic enzymes and nutrients, and the packaging of the sperm and egg genomes are not players that actors that drive disease. They are directed by a genomic programs and the laws of physics. There is nothing passed on in the egg or sperm that can predictably, systematically, and durably disrupt neurodevelopment.
"Autism has been emphatically shown to not travel down family trees like other genetic diseases"
Uh, this is very much not true. Your actual family itself shows a horizontal pattern of inheritance with affected sibs (this is a familial pattern of disease implicating genes as a cause of disease; it is very similar to the pattern seen with autosomal recessive diseases). Plus, it has been shown that parents with high polygenic scores for autism tend to pair up and thus have children with polygenic scores that often exceed the "liability threshold" for a diagnosis.
The reasons vertical transmission of autism (which does happen typically unaffected mother to affected son) is so rare is that severe autistic individuals essentially never have children and high functioning cases are highly polygenic so their offspring have a greater chance of regressing to the mean (aka normal neurodevelopment) than inheriting the same risk threshold.
Your project here seems to be imagining things happening in germlines that don't happen.
A fascinating and enlightening report. I hope the researchers take note and act upon it. Jill, I specialise in learning disabilities here in Germany. However, I'm planning an online course for parents in the USA - starting in April. The methodology I employ is grounded in the biology of the brain, the results for dyslexia and dyscalculia (and ADHD) are measurably excellent. Interested? Please see my pitch for schools: https://joekennedy-education-consultant.com for more information. Joekenn77@googlemail.com
Recent research shows that genetic factors are the leading cause of autism spectrum disorder (ASD), accounting for approximately 80% to 90% of the risk. This includes both inherited genetic mutations and spontaneous (de novo) changes in DNA. Key genes like CHD8 and NRXN1 are involved in brain development and have been strongly linked to ASD.
No you are very much mis-reading the literature. Autism is 50-90% HERITABLE. That does not mean it's necessarily genetic. We should be concerned about other sources of the heritability, including de novo mutations and other molecular defects.
I prefer fact to conjecture.
I just published a really long post about different theories that can cause autism ... I agree with a lot of what you've written here. Re transcription issues:
-- You might like Christopher Badcock's "The Imprinted Brain". He argues that gene imprinting, with an excess of maternal genes being silenced and an excess of paternal genes being expressed, is related to autism. He also discusses Mary Lyon's work on "lingering Lyonization", which is essential when imprints on the mother's X chromosome fail to "reset" during recombination and passed down to children, increasing autism risk, especially in males.
-- Environmental toxins and nutritional deficiencies are probably a huge factor.
-- Maternal stress during pregnancy is a major predictor of autism in children, as are traumatic experiences in the mother's childhood. I'm guessing this could cause transcription issues.
-- Some genes are more vulnerable to environmental, nutritional, and stress related factors. There are a couple common MTHFR mutations which have negative interactions with folic acid (synthetic folate) in prenatal vitamins and fortified foods, especially in combination with low sunlight exposure and low Vitamin D. Leads to lower levels of glutathione and an impaired ability to detox, and so would be a reason why autistic people have been found to have higher levels of heavy metals in their bodies.
Very interesting. What is the epidemiological evidence that women with MTHFR mutation are at higher risk for having children with autism or other defects?
Seems to mostly be anecdotal, but there's a lot of anecdotal evidence. Needs to be researched.
I suspect these mutations are not harmful on their own, only in combination with folic acid and other modern toxin exposures. I'm guessing there's such a high prevalence of them because they were originally adaptive. Specifically, I'm guessing they were an adaptation to having a lighter skin tone in hotter / sunnier climates (the highest prevalence of these mutations seems to be in Jewish people and Southern Europeans, e.g. Italians and Spanish people), especially in combination with a low-folate diet. Sunlight depletes folate levels, and while dark skinned people are protected against this, light skinned people aren't. These mutations cause you to use folate more slowly, so it would be protective in that sense.
Super interesting, thanks for sharing, it didn't know that background.
Yes I’ve read Imprinted Brain. Good thinking! I’m super interested in these ideas.
How could folic acid in an MTHFR mutation scenario cause autism. Explain?
You've read it!! That's great, I think Badcock is really on to something and I wish more people were aware of his work. His follow-up, "The Diametric Mind" is also really good.
Regarding folic acid, oh man, it's kind of complicated and still pretty speculative, so needs to be researched more. I wrote an 8,000 word essay about it. Basically, certain MTHFR mutations cause the body to break down folate (and folic acid) more slowly. While you can't overdo it on folate, the way our bodies use folic acid is a little different, and it can start to accumulate with high consumption (which is likely during pregnancy if you are taking a prenatal vitamin with folic acid and eat fortified foods). Our bodies actually prefer folic acid to folate, so high folic acid intake can block our body's from using folate from natural food sources too. This can cause a "functional folate deficiency" where the symptoms of folate deficiency (linked to autism) present despite high folic acid intake. Causes methylation issues. Folic acid and other synthetic vitamins also seem to be related to disordered eating (e.g. ARFID) so there's indirect effects as well.
In addition to autism, seems to be highly related to the increase in tongue ties in children, rising rates of certain cancers, allergies, asthma, and other conditions as well. Seems to be related more to high functioning autism than lower-functioning (at least in lieu of other factors), and also to gender dysphoria in autistic people.
The introduction of prenatal vitamins with folic acid correlates with the uptick in autism of children born in the 1980s or later, and the introduction of folic acid fortified in various common foods (e.g. many wheat products) in the late 1990s correlates with the next big uptick.
There's also good evidence that prenatal vitamins with synthetic vitamins (and which are frequently contaminated with heavy metals etc) can cause or worsen morning sickness, and thus adversely affect maternal diet during pregnancy.
Here's the essay -- it's a long read, and pretty speculative, but I tried my best to lay out the evidence.
https://thecassandracomplex.substack.com/p/down-the-folic-acid-rabbit-hole
Thanks for this article...exhaustive work. I have been exploring the incidence of cerebral folate deficiency and have just convinced our physician to do a trial of leucovorin for my non-verbal, profoundly autistic grandson. It appears low risk/high reward...unlike many of the other treatments suggested. Do you have experience with this?
I'm sorry, I don't! But low risk/high reward sounds good. I haven't heard of leucovorin though. I'm skeptical of pharmaceutical solutions in general, but each case of autism is unique. I have a longer article with as many causes of autism as I was aware of and some ways to address them, if you want --
https://thecassandracomplex.substack.com/p/what-causes-autism
And I thought I did a rather exhaustive look at autism research!! I did a quick scan of your article. You are beyond comprehensive.
I'm also not a big fan of pharmaceuticals..although I know they have been helpful for some. Leucovorin is folinic acid..the bioavailable form of folate that can cross the blood brain barrier. 30-70% of ASD kids have been shown to have cerebral folate deficiency. This can be confirmed with lumbar puncture or measurement of folate receptor autoantibodies. Both tests are difficult to do. The drug has been around for 70 years and has a long established safety profile.
You have to treat the nutrient deficiencies that are causing low appetite and picky eating first -- folate is one of them, so for short-term use until enough he eats enough folate-rich foods in his diet it sounds good! Grass-fed beef mixed with liver and heart is a good option for stuff like hamburgers.
You also need to get Vitamins B1, B12, and D in him. Also more zinc (low zinc can screw up sense of taste). Get him outside (in the morning, no sunscreen), ideally barefoot on grass. Look into a good multivitamin -- I haven't used any myself, but I see lots of positive reviews of these two:
https://shopsubluna.com/
https://firstday.com/
Hi Jill,
The course will start on 8th May. It is really about stimulating and activating specific areas of the brain; you might find it usefull. I would like to invite you as a guest, free of charge.
May I ask a personal question about your autistic kids?
Be my guest
Do they have an intellectual disability?
Yes they have nonverbal profound autism.
It’s my understanding that while rare it’s possible for someone to be nonverbal (at least at times) and profoundly autistic (extremely sensitive/sensory issues) without having an intellectual disability. It seems to me that very often the ocasional but not consistent assumption of ID going along with autism but not being identified makes for a lot of confusion and disagreement. I wish there was a way to ask people to be more clear about this. I’ve read some summary of academic papers suggesting that the heritability of autism with and without ID is different. Unfortunately I don’t remember the details.
I have not yet met such a person. I have seen people with mutism (perhaps mistaken for autism) without ID. But those like my kids—nonverbal autistic—don’t have secret cognitive normalcy. It’s not a locked-in syndrome. Read amy Lutz’s book Chasing the Intact Mind.
The jury is out on this topic for me. I know that there is disagreement in the Speech and Language camps about facilitated communication but the number of stories of children believed to be intellectually disabled who find a voice through facilitated communication and go on to do amazing things. If you haven't heard it...listen to Elizabeth Bonkers...the "retard" (as called by her principal) who went on to give the valedictorian speech at Rollins University
I’m not even talking about facilitated communication but autistic people that can and do type (by themselves) but don’t often speak and people that can speak sometimes but not other times.
Very interesting piece. I see a relatively small number of subscribers so I will take a chance here. I’m a retired nurse. This is the first I’ve encountered this. If I understood, our DNA is relatively passive. At various moments when cell development is indicated a portion of the DNA strand needs to pass on genetic instruction to our RNA (transcription) and the RNA is responsible for the subsequent cell development.
A “genetic” cause for autism would indicate a problem in the DNA itself and an “environmental” cause would reveal itself in a more direct link (what the anti vaxers are pushing). You are proposing (or are you sharing others’ proposal?) that autism is likely the result in failed transcription between DNA and RNA when brain/neuro cell development is indicated.
Moving forward if we can learn the trigger for this disruptive transcription could be groundbreaking. Or have I misunderstood?
Are there other conditions that may actually be due to similar problems with transcription? I have a few autoimmune “illnesses” and you’ve piqued my curiosity.
I'm proposing glitches at the germline level that lead to dysregulated transcription during offspring development. You can watch my Harvard presentation for an example of this at jillescher.com