A New Genetic Model For Autism

In 2007, I made a link filled comment about autism at Colorado Confidential summing up the key points about what we know and do not know about the causes of the condition. I was going back over some of those links, and one of the papers I'd cited to earlier had been cited to by a number of other articles later.

Of particular interest was a paper in the Proceedings of the National Academy of Sciences (a very reputable scientific body) setting out a hypothesis that would comprehensively explain a large share of all autism cases. In a nutshell, here is what is proposed (except as noted this comes solely from the paper cited as explained by me as an educated layman):

1. People receive genes in pairs, one part of each pair from a father and one from a mother. (This statement defines the term "gene" as I am using it in this post.)

2. There is probably a single primary "autism gene" and this gene is probably not on either the X or the Y chromosome. A single copy of an autism gene in a boy results in a near 100% chance that the boy will have an an autism spectrum disorder (ASD). The exact manifestation rate depends upon the assumptions made and the model used. It is likely is that the chance of developing ASD if the autism gene is present is close to high end of that range, and that there is little or no environmental impact on whether or not a boy develops some form of ASD.

3. Other genes, called "modifier genes" determine, at least to some extent, how severely the autism will manifest in that boy, but do not prevent a boy from having some sort of ASD. Full fledged autism, therefore, as opposed to a more mild ASD, is due both to the presence of an autism gene, and the absence of modifier genes. There isn't enough data in this study to understand the nature of these modifier genes in boys.

4. It is also entirely possible that some modifier genes in boys are environmentally triggered, or the environmental can impact the severity, but the the mere presence or absence of ASD is not greatly impacted by environment. (This is from my own general understanding of this area of genetics.)

5. Sometimes a mutation in a parent's particular sperm or particular egg cell will cause a parent who does not have an autism gene to pass an autism gene onto a child. These mutations in autism gene free parents account for about two-thirds of all autism cases. About 6.7-7.7 in one thousand newborn girls are autism gene carriers with no autism symptoms, about 2.3-3.3 in one thousand newborn girls have an ASD and about 1% of newborn boys have an ASD.

6. These mutations most commonly appear in the sperm of older fathers, with the risk rising greatly by paternal age 40, when they are 5.75 times as likely as for fathers under age 30. Advancing maternal age is not linked to ASD after adjusting for paternal age. Advancing paternal age was also associated with some of the male-female sex ratio in autism. The sex ratio in the offspring with autism of fathers younger than 40 years was noticeably higher than the sex ratio of the offspring with autism of fathers older than 40 years. (This statement integrates data from a separate source.)

7. About 6.6 per 1,000 children whose parents both lack the autism gene (i.e. two thirds of children who either have autism or are carriers for the gene) receive one as a result of a mutation on a gender neutral basis, rather than inheriting it from a parent who has the gene.

8. The number of autism gene mutations rate per 1000 births to fathers in the appropriate age group is about 2.9 for fathers 15-29, about 5.7 per father aged 30-39and about 25.8 for fathers 40+.

These numbers from the the Israeli Israeli data in the "separate study" cited above (including a few details from outside the abstract available here), with some adjustments. I attributed part of each age group's to genes directly inherited from a parent by reducing the autism rate for each age group by the one-third of the total population autism rate. This provides a mutation rate for fathers 30-39 that is double that of fathers aged 15-29, and a mutation rate for fathers age 40+ that is roughly nine times that of fathers aged 15-29. Then, I fitted this data to the American autism incidence rate which is about 25% higher than in the Israeli study. In doing so, I used data from the National Vital Statistics Reports for 1980-2004 and census bureau population figures that shows that currently about 50% of newborns have fathers 15-29, about 40% have fathers 30-39, and about 10% have fathers age 40+.

9. My calculations above in connection with other information in this post, suggest that about a third of autism cases are due to non-age related mutations of in sperm or egg cells of parents who don't have an autism gene, about a third of autism cases are due to age regulated mutations in sperm cells of fathers aged 30 or more who don't have an autism gene, and about a third of autism cases are a result of inheriting an autism gene from a parent, usually a carrier mother or a mild ASD symptom parent of either sex.

10. My calculations also suggest that age based autism gene mutations are becoming more common due to the aging demography of fatherhood. In 1980, this model would suggest that 39% of mutatation based autism was attributable to parental age, in 1990, it had risen to 47%, in 2000 to 52%, and based upon the latest data available (2004 fatherhood rates and 2006 population figures), about 54% now. Put another way, older fatherhood can account for an approximately 33% increase in overall autism incidence rates since 1980 to the present, even disregarding entirely autism caused by girls who become carriers for autism because of a mutation in a parent's gene line and then have autistic children as a result. This is nothing near the epidemic increases in autism incidence that have been reported, but autism was only added to the standard diagnositic pyschiatric manual in 1980, and Asperger's syndrome was only separately added in 1994, so there are serious measurement and diagnosis issues associated with surging autism levels (which isn't to say that real prevalance isn't changing, only that we can't be sure from the data that we have now.)

11. It is possible that autism causing mutations in the sperm of older men reflect vulnerability to a sperm mutation only in certain situations, and that the mutation itself will not happen very frequently, in the absence of some environmental exposure experienced by the father that has the mutation. (This statement is based upon my own general understanding of and reading about how genetics and the environment interact.)

12. Girls can also have an autism gene. But, there is probably a "modifier gene" or "modifier genes" that prevent autism from arising at all in about 70% of girls. Thus, in girls, autism arises from both the presence of an autism gene and the absence of a modifier gene or genes.

13. The main modifier gene that protects girls from autism is probably on the X chromosome, and one probably needs to have two copies of this X based modifier gene to prevent autism from arising at all. About 70% of females (some studies would put the number closer to 77% which in turn would impact the other numbers) have two anti-autism modifier genes. About 84% of men, and 13.5% of women have a single anti-autism modifier gene. About 2.5% of women and 16% of men have no anti-autism modifier genes. (I have created in this paragraph the simplest model of a modifier gene that would fit the modifier gene model and data they described in the paper which was a matter that they did not explore. More complex mechanisms with similar effects are possible alternatives.)

14. We don't know whether or not the modifier genes that prevent autism when present in pairs in girls have any impact on the severity of an ASD in either boys or girls.

15. It wouldn't be surprising if the presence of a single anti-autism modifier gene was quite important in determining how severely an ASD would manifest (e.g. producing Asperger's syndrome rather that full fledged autism.) If true, one would expect only 12-16% of both boys and girls with an ASD to have pure autism cases, and would expect sibling studies and family studies to show patterns of heritability for severe v. less severe versions ASD in families with multiple cases. In fact, the percentage of ASD individuals with pure autism is on the order of 16%-25%, consistent with this theory, and the sibling and family studies do show the sibling and inheritance effects in autism severity when multiple people in a family have an ASD. (This theory is my own, although obvious from the suggestion of the paper.)

16. The anti-autism gene that prevent autism from manifesting in many women is probably not the only modifier gene relevant to ASD severity in either boys or girls.

17. About one-third of all autism cases involve a parent who has the autism gene and passes the gene they have onto a child. Usually, this parent is a mother with no autism symptoms, but more rarely, they could also involve a parent with a ASD condition, usually one that is mild or even subclinical (i.e. autism like symptoms too subtle to diagnose as even a mild ASD spectrum condition). In the usual case, where the mother has one copy of the autism gene, and the father has none, about half of the boys born to the mother (regardless of the father of the particular child) will have an ASD, and on average, about 15% of the girls born to parents with this genetic profile will have an ASD.

Analysis

While this hypothesis is based only upon a medium sized study (a few thousand children with autism in family relationship), its relatively simply hypothesis is a compelling and plausible explanation consistent with inheritance patterns that are well established in many vaguely similar genetic conditions. We won't have proof positive until a particular gene is found in almost everyone with autism, but this study points a clear finger at what we should be looking for and explains neatly how it can persist despite the fact that it impacts the future reproductive abilities of those who have the gene and manifest its effects.

The first place to look for a cause of rising autism incidence is in paternal age trends. A rise in the percentage of fathers over age 40 would strongly point towards that as an important cause of rising ASD incidence. Moreover, this would happen in two ways. First, older fathers would be having more sons born with ASD than younger fathers. Second, older fathers would be having both more daughters born with ASD than younger fathers, but also more daughters carrying the ASD gene have have sons of their own who are much more likely to have ASD. Modeling the projected incidence rise based upon increasing numbers of older fathers would be quite a precise and easy exercise, that would make it quite easy to determine the magnitude of ASD incident due instead to either changes in diagnostic standards or changing environmental exposures, or both.

Second, if there is an environmental impact on ASD prevalence, exposures to parents and not to children is the place to look. There are multiple known environmental mutagens. If older fathers have had increased exposure to these mutagens, that would be a very plausible culprit.

More Progress On A Genetic Model For Autism

New studies that link specific locations in the genome with autism largely confirm previous studies (see also here regarding the heritability of Asperger's Syndrome).

Studies of identical twins show that when one twin has autism, about 90 percent of the time the other twin will too. Autism affects about one in every 100 children in the United States and is more common in boys. . . the new study shows that people with autism had the same number of deletions [ed. i.e. places where DNA is usually present] as people in a healthy control group did. However, people with autism tend to have deletions that remove parts or all of genes, while healthy people carry deletions on stretches of DNA that don’t contain genes.

“You and I may have just as many deletions in our genomes, but since they don’t hit genes, we don’t have autism. . . . This is a natural part of being a human being. We get mutations. Most of the time it’s not a problem, but sometimes it hits a gene involved in autism.” . . .

Many of the people with autism had more than one spot in the genome where they were missing large chunks of DNA, each about 30,000 base pairs long.

Each of the specific variants was rare on its own, with even the most common found in less than 1 percent of people in the study. Often, people with autism inherited the rare variants from their parents, but just under 6 percent of them had new deletions not found in their parents. Such new mutations may account for some sporadic cases of autism. . . . “Most individuals with autism are genetically unique," . . . Although each person with autism appears to have a distinct set of genetic variations, the genes affected by the variants tend to affect similar biological processes. . . .

Some of the deleted genes had a strong link to autism, meaning that missing just a single copy is enough to push a person across the autism threshold. . . . Other genes had to be inherited along with more deletions or other genetic factors for autism to develop.

One gene strongly linked to autism in the new study is called DDX53-PTCHD1, and is located on the X chromosome. Women — who have two X chromosomes — may carry a deletion of the gene on one of their X chromosomes, but a healthy copy of the gene on the other X chromosome is enough to cover for the missing copy. Problems may arise if a woman passes the X chromosome with the deleted gene on to a son. With no healthy copy of the gene (the Y chromosome doesn’t carry the gene) to compensate, he will get autism.

Researchers also identified several genes involved in forming connections, called synapses, between brain cells. . . .

All together, the new study identified 25 places in the genome that may help in diagnosing autism. . . . Even with the new findings, scientists are able to explain genetic causes for only about 10 percent of autism cases. . . . “What causes autism in the other 90 percent of cases is still on the table[.]”

1. Autism has a strong genetic component.

2. Autism involves a variety of genetic causes, a significant number of which are either new mutations in the child's generation, or are asymptomatic until combined in rare ways with other genes. The present as a single syndrome only because they all impact genes related to brain function.

3. Some important element of autism genetics is linked to an X chromosome genetic factor.

4. Vaccination does not cause autism.

The genetic model of autism shows some similarity with schitzophrenia and bipolar disorder, which seems to be the cumulative result of large numbers of more or less random variations in the genome, rather than having a single or dominant particular gene allele as a cause. But, while schitzophrenia and bipolar disorder seem related to the total number of these random variations in the genome, autism seems more related to where these variations are located, rather than their overall frequency.

Second Trimester Fevers Increase Autism Risks 40%

A new study finds that fevers in pregnant women during the second trimester increase the risk of a child with autism by 40%. The magnitude of this effect closely matches estimates from previous independent studies. The sample size is 95,000 (which is just barely big enough to measure these effects), while most other fevers are not as definitvely associated with autism risk.

The link is strongest in the second trimester, when a single fever is associated with a 40 percent increase in autism risk. Three or more fevers after the first trimester triples the risk of having a child with autism, according to the study, which appeared 13 June in Molecular Psychiatry. 

The findings support the idea that a pregnant woman’s immune response, which often includes fever, can disrupt brain development in the fetus, says lead researcher Mady Hornig, associate professor epidemiology at the Columbia University. 

The study is inconclusive on whether drugs that lower fever mitigate the risk, but the results hint that they might, says Sarkis Mazmanian, professor of biology at the 

California Institute of Technology. . . .

15,701 of the mothers reported on a health questionnaire that they’d had one or more fevers while pregnant. The team followed all of the participants’ children until they reached age 9, on average, and found that 583 received an autism diagnosis.

The timing of the fever matters for autism risk, the researchers found. Compared with the 40 percent increase in the second trimester, having a fever in the first trimester carries a 34 percent increase in the risk of autism, but that result is not statistically significant. Having a fever in the third semester has no effect on autism risk.

The researchers also found a dose-response relationship for fever: The increase in risk ranges from 30 percent throughout pregnancy for one or two episodes of fever, to more than threefold for three or more episodes in the second trimester and beyond.

Still, the vast majority of women who have a fever during pregnancy do not have a child with autism and the absolute increase in risk is small. Even among mothers who had three or more fevers, only 5 out of 308 children (about 1.6 percent) have autism, compared with 376 of 65,502 children (about 0.6 percent) whose mothers reported no fevers. . . .

Hornig’s team examined whether medications that lower body temperature would reduce the risk. More than 5,600 women took acetaminophen for fever during their second trimester. The team found an association between acetaminophen use and a decrease in autism risk, but it was not statistically significant. Only 161 women took ibuprofen during the second trimester, and none of them have a child with autism. (About half of pregnant women use acetaminophen at least once, but doctors generally advise against ibuprofen use during pregnancy.) . . .

A 2013 study led by Hertz-Picciotto found that drugs that lower fever mitigate the increase in autism risk associated with fever. 

The mechanism for fevers to cause autism in a fetus might include autoimmune responses and/or inflammation (which aren't mutually exclusive - inflammation is one type of autoimmune response).

Autism has a strong genetic component, although it appears that a lot of the risk comes from de novo mutations that were not present in either of the parents when they were born. It also appears that women have protective genes that are absent in men that mitigate autism symptoms or prevent them from arising.

Baseline autism spectrum disorder risk is on the order of 1% of all births (comprising a large share of symptoms previously classified as cognitive developmental disorders not otherwise classified), so it is closer to 1.4% percent for pregnant women who have fevers in the second trimester (a scenario consistent with the notion that the anatomical systems that develop in this time period during gestation are the ones that are associated with autism).

But, if the 40% figure is to be applied on a case by case basis, rather than across the board (which isn't clear from the media report that I link) the concern may be much more of a concern in pregnancies where this is a high risk of autism (e.g. in cases where the father is middle aged or older, where there is a family history of sub-clinical autism-like personality traits, and where the fetus is male), than in pregnancies where no autism risk factors are present. 

On the other hand, if this is an across the board increase in risk, that does not interact with other risk factors, then second trimester fevers may be the main source of risk in otherwise low autism risk pregnancies, while it is a minor consideration relative to other risk factors in high autism risk pregnancies.

This is one of only a handful of well documented environmental causes of autism, which has a strong genetic component. Another is exposure of the parents to agricultural chemicals (before conception in the case of fathers and during gestation in the case of mothers).

Prenatal Risk Factors For Autism?

A New York Times opinion piece from last week by a research who argues for prenatal effects in the womb as a cause of some share of autism cases in a trade non-fiction book. Some of the key observations and evidentiary points from the scientific literature that the author is advocating for regarding the pressing health issue are as follows:

At least a subset of autism — perhaps one-third, and very likely more — looks like a type of inflammatory disease. And it begins in the womb. . . . In autistic individuals . . . [i]nflammatory signals dominate. Anti-inflammatory ones are inadequate. A state of chronic activation prevails. And the more skewed toward inflammation, the more acute the autistic symptoms.

Nowhere are the consequences of this dysregulation more evident than in the autistic brain. Spidery cells that help maintain neurons — called astroglia and microglia — are enlarged from chronic activation. Pro-inflammatory signaling molecules abound. Genes involved in inflammation are switched on. . . .

A population-wide study from Denmark spanning two decades of births indicates that infection during pregnancy increases the risk of autism in the child. Hospitalization for a viral infection, like the flu, during the first trimester of pregnancy triples the odds. Bacterial infection, including of the urinary tract, during the second trimester increases chances by 40 percent.

The . . . mother’s attempt to repel invaders — her inflammatory response — seems at fault. . . .Inflaming pregnant mice artificially — without a living infective agent — prompts behavioral problems in the young. In this model, autism results from collateral damage. It’s an unintended consequence of self-defense during pregnancy.

Yet to blame infections for the autism epidemic is folly. . . . the epidemiology doesn’t jibe. . . . Better clues to the causes of the autism phenomenon come from parallel “epidemics.” The prevalence of inflammatory diseases in general has increased significantly in the past 60 years. As a group, they include asthma, now estimated to affect 1 in 10 children — at least double the prevalence of 1980 — and autoimmune disorders, which afflict 1 in 20. Both are linked to autism, especially in the mother. One large Danish study, which included nearly 700,000 births over a decade, found that a mother’s rheumatoid arthritis, a degenerative disease of the joints, elevated a child’s risk of autism by 80 percent. Her celiac disease, an inflammatory disease prompted by proteins in wheat and other grains, increased it 350 percent. Genetic studies tell a similar tale. Gene variants associated with autoimmune disease — genes of the immune system — also increase the risk of autism, especially when they occur in the mother. . . .

Mothers of autistic children often have unique antibodies that bind to fetal brain proteins. A few years back, scientists . . . injected these antibodies into pregnant macaques. (Control animals got antibodies from mothers of typical children.) Animals whose mothers received “autistic” antibodies displayed repetitive behavior. They had trouble socializing with others in the troop. In this model, autism results from an attack on the developing fetus. . . .

A mother’s diagnosis of asthma or allergies during the second trimester of pregnancy increases her child’s risk of autism. . . . Amniotic fluid collected from Danish newborns who later developed autism looked mildly inflamed. . . .

Why are we so prone to inflammatory disorders? . . .

[P]eople living in environments that resemble our evolutionary past, full of microbes and parasites, don’t suffer from inflammatory diseases as frequently. . . . Generally speaking, autism also follows this pattern. It seems to be less prevalent in the developing world. Usually, epidemiologists fault lack of diagnosis for the apparent absence. A dearth of expertise in the disorder, the argument goes, gives a false impression of scarcity. Yet at least one Western doctor who specializes in autism has explicitly noted that, in a Cambodian population rife with parasites and acute infections, autism was nearly nonexistent.

For autoimmune and allergic diseases linked to autism, meanwhile, the evidence is compelling. . . . asthma and autism follow similar epidemiological patterns. They’re both more common in urban areas than rural; firstborns seem to be at greater risk; they disproportionately afflict young boys. In the context of allergic disease, the hygiene hypothesis — that we suffer from microbial deprivation — has long been invoked to explain these patterns. . . . it should apply to autism as well. (Why the male bias? Male fetuses, it turns out, are more sensitive to Mom’s inflammation than females.)

A few points of context and emphasis are in order here:

* A variety of past data has already established a very strong genetic component to autism associated with rare rather than common genetic variants (sometimes in the form of deletions and copy number variants, rather than specific SNPs), in a particular complex of genes with particular functions. A majority of all autism cases probably have a genetic basis, although the particular mutations that are involved in any particular case vary widely. Non-genetic pre-natal causes are, at most, an important cause of only a minority of autism case.

* The autoimmune hypothesis offered above is not exclusive of genetic causes. In a significant share of the up to one third of pre-natal inflamation associated cases cited, the inflamation has a genetic component. In those cases where there is not a genetic component, the mechanism described sounds like an epigenetic effect in many cases. Epigenetic effects can be hereditary, although unlike true genetic effects, they usually persist for only a few generations and can be induced during someone's lifetype by means other than mutations.

* Childhood vaccination does not cause autism. Few cases of non-causation are better established.

* Even in cases where the environmental effects described above are at work, autism is still congenital, i.e. present at birth. Indeed, all of the evidence of maternal inflamation during pregnancy increasing autism risk involved the first two-thirds of the pregnancy, with a significant share of that risk attributable to early parts of the pregnancy when the mother may not even know that she is pregnant. Autism has not been convincingly linked in published scientific studies to the child's diet or parenting styles, for example.

* Controlling inflamation during pregnancy poses its own risk, and can't be limited to the period when people know that they are pregnant alone since the high risk period is front loaded. Many, if not all, anti-inflammatory drugs may present their own risks to a fetus during pregnancy. The author of the article quoted above argues for a comprehensive rethinking of our public health measures to address the problems associated with an overly hygenic environment, without definitively proposing a single solution. But, this calls for a balancing analysis. Lack of hygene causes deadly and unpleasant diseases. Excessive hygene can promote succeptibility ot excessive autoimmune responses. Even though Cambodia has lower rates of autoimmune disorders and autism, very few people would trade that benefit for the overall public health harms associated with its relative lack of hygene. Some level of excessive autoimmune disfunction may be a price worth paying for a reduced incidence of infectious disease agents.

* Autism is the fever of mental health conditions. It is a common symptom of a disorder with a non-specific cause. Indeed, this is more than just an analogy. Autism symptoms, like fevers, appear to be associated with inflamation.

* Regardless of the epidemiology of autism, if a large subset of autism cases involve an autoimmune inflamation mechanism, then early diagnosis and treatment designed to reach that mechanism, particularly during period key to brain development, such as anti-inflammatory drugs, in theory, might be effective. Treatments designed to selectively reverse epigenetic methylation of a child's genome related to autoimmune function also look like a promising avenue to investigate. But, please don't rely on me in turning to a totally unproven theory as a medical treatment without advice from a doctor. I'm a lawyer with a solid background in mathematics who stays abreast of the literature, not a doctor.

* Universal health care has collective public health benefits. One reason that really good population genetic and epidemiological studies often come from Scandinavia is that countries like Denmark have comprehensive national medical records in a well indexed form that is linked to other data about the patients that can be used for medical research. Strict American medical privacy and human subjects research laws make these kinds of studies almost impossible to conduct in the United States with the same level of rigor and statistical power. Nothing has more statistical power than a complete data set for an entire national population.

Autistic Kids Tend To Have Nerdy Parents

Background Features of the Broad Autism Phenotype (BAP) are disproportionately prevalent in parents of a child with autism, highlighting familial patterns indicative of heritability. It is unclear, however, whether the presence of BAP features in both parents confers an increased liability for autism. The current study explores whether the presence of BAP features in two biological parents occurs more frequently in parents of a child with autism relative to comparison parents, whether parental pairs of a child with autism more commonly consist of one or two parents with BAP features, and whether these features are associated with severity of autism behaviors in probands.

Method Seven hundred eleven parents of a child with an autism spectrum disorder and 981 comparison parents completed the Broad Autism Phenotype Questionnaire. Parents of a child with autism also completed the Social Communication Questionnaire.

Results Although parental pairs of a child with autism were more likely than comparison parental pairs to have both parents characterized by the presence of the BAP, they more commonly consisted of a single parent with BAP features. The presence of the BAP in parents was associated with the severity of autism behaviors in probands, with the lowest severity occurring for children of parental pairs in which neither parent exhibited a BAP feature. Severity did not differ between children of two affected parents and those of just one.

Conclusions Collectively, these findings indicate that parental pairs of children with autism frequently consist of a single parent with BAP characteristics and suggest that future studies searching for implicated genes may benefit from a more narrow focus that identifies the transmitting parent. The evidence of intergenerational transmission reported here also provides further confirmation of the high heritability of autism that is unaccounted for by the contribution of de novo mutations currently emphasized in the field of autism genetics.
 

 From here.

The result confirms previous studies along the same lines (the Broad Autism Phenotype was defined in 2004). As noted here:

Some of the common symptoms of broad autism phenotype include being shy socially, having a hard time making friends, the inability to read body language, having an obsessive behavior, being compulsive, and preferring routine to spontaneous actions.

Obviously, "broad autism phenotype" is a term of art, but in ordinary plain English, I'm hard pressed to think of a word that describes  it better than "nerdy" (other than the more derogatory term "dweeby").

Many mental health conditions are associated with a family history of individuals who have subclinical symptoms of mental conditions themselves, often similar in kind to the person who has them.

This study doesn't explore the nature v. nuture nature of the intergenerational transmission of autism spectrum symptoms, but a variety of other evidence suggests that genes are far more important than parenting in this regard (although the Early Start Denver Model of treatment, which is basically a nuture oriented approach, has shown some positive results).  At a minimum, the consensus view is that autism is either purely genetic, or flows from a (genes x environment) interaction for which some genetic component is almost always necessary.  Autism like symptoms with a purely environmental cause would probably be classified as a subtype of child abuse symptom rather than as autism per se._

Key Piece of Genetic Autism Puzzle Discovered

Boys shows signs of autism spectrum disorders more often than girls. But, autism is strongly hereditary. What's going on? The most parsimonious assumption is that there are one or more X chromosome linked genes that are protective against problems created by autism causing genes elsewhere in the genome.

The DIA1R gene (which stands for "deleted in autism one related" because it influeces the expression of the autosomal DIA1 gene on chromosome 3 which is "deleted in autism") seems to fit the bill:

[M]utations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR. . . . [DIA1 and DIA1R synthesize two very similar] signal peptides for targeting to the secretory pathway [probably for the same system in the brain]. Both genes are ubiquitously expressed, including in fetal and adult brain tissue.

Another similar X linked gene with the same kind of protective role that was previously discovered was DDX53-PTCHD1.

Since girls have two X chromosomes and since one protective gene seems to provide at least some benefit even if that girl also has a deleted DIA1R gene, girls are more likely to have some protection from their deleterious autism related genes. But, a boy with a deleted DIA1R gene in his one X chromsome lacks to XLMR/autism spectrum disorder protective trait and shows more autism spectrum disorder or retardation symptoms. A girl with some, but not all of the protective X linked genes, may sometimes not be symptom free but may still experience a milder autism spectrum disorder (e.g. Asperger's) than a boy who lacks more of these protective genes.

Since this basic genetic model involving autosomal autism causing traits that frequently arise by novel mutation and X linked protective genes was proposed in 2007, scientists have identified at least the two key X linked protective genes described above and have gained some insight into what at least one of them does. Researchers have also in the last three and a half years, increasingly come to conclude that there is not a single primary autism causing gene, although all of the known autism causing genes do appear to be dominant rather than recessive in effect.

Researchers also know that the gene DIA1, and probably other genes appear to contribute to autism, but that there also appear to be a whole host of other autism causing mutations. About two-thirds of these arise from new mutations in sperm cells that are not present in the parent, while the other third are inherited from a less symtomatic mother or a mildly symptomatic father, or both.

The brain chemistry system that genes like DIA1R and DDX53-PTCHD1 protect is apparently highly prone to malfunction from a large number of other genes, none of which is predominant as a cause of autism, perhaps because the process impacted is intricate and delicate, without these protective genes. But, we actually have only a dim idea of precisely which process or processes in the brain that autism disrupts, and in general. We know what happens when this process, whatever it is, goes wrong, in great detail, but not why a problem with this process causes this effect. This is, of course, unfortunate, since it is hard to treat autism in people who have it already until we have a better idea of what is broken that causes these symptoms. But, the more we can pin down the genes produce autism spectrum disorders, the more we can engage in a narrow and targeted effort to understand how this process in the brain works and what these genes do to disrupt its normal functioning.

More Evidence That Subclinical Autism Traits Are Associated With Autism Genes

A recent large genome wide association study identified risk factor genes for autism and noted that even among people not diagnosed with autism, that these risk factor genes were associated with subclinical levels of autism symptoms.

This confirms previous hints along the same lines in a 2013 study, a 2012 study, a 2010 study, and an earlier one in 2004 (discussed with the 2013 study).

Also, there is no doubt that there is a significant genetic component to autism spectrum disorders that is inherited from one's biological parents (see, e.g., here looking at sibling rates and this twin study).  Stephen Hsu's take on this study includes excerpts from it that explains that there are many known specific genes that are risk factors for ASD.

But, oversimplified genetic models of the condition's prevalence fitted to the data also strongly suggest (particularly based on the link between prevalence and advanced parental age) that a very substantial share of all autism cases involve mutations that are novel to the child and not present in either parent's genome. My crude estimate in 2008 which nonetheless is still a pretty good fit to the data eight years later suggests that:

[A]bout a third of autism cases are due to non-age related mutations of in sperm or egg cells of parents who don't have an autism gene, about a third of autism cases are due to age regulated mutations in sperm cells of fathers aged 30 or more who don't have an autism gene, and about a third of autism cases are a result of inheriting an autism gene from a parent, usually a carrier mother or a mild ASD symptom parent of either sex.

This estimate may be high, but is order of magnitude correct.  For example, a 2014 study comparing whole genomes of individuals with ASD and their family members, found "de novo" mutations contributed to 30% of cases of male ASD and 45% of cases of female ASD (see also this 2015 study).  Indeed, the cause of seriously developmental disabilities, in general, is roughly similar to the pattern observed in ASD spectrum disorders.

Also, one thing that we do know beyond any reasonable doubt is that vaccination does not cause autism.

A weak capacity for empathy is often considered a diagnostic symptom of autism. But, even if this is true, empathy can cause its own problems and can lead to bad moral decision-making by people in leadership positions. It isn't unreasonable to think that some level of neurodiversity is beneficial to our society, even if the most severe cases of autism are something no one should have to experience.

Autism and mtDNA?

A new study finds a link between mtDNA clades and autism prevalence. While there is a plausible biochemical mechanism by which this link could arise, based upon other work I've seen on inheritance patterns in autism, I'm quite skeptical of the result.

The current study analyzed these mtDNA lineages among 1,624 patients with autism and 2,417 healthy parents and siblings, representing 933 families in the Autism Genetic Resource Exchange (AGRE). Using data from genome-wide association studies on this AGRE cohort previously performed by the Center for Applied Genomics at CHOP, they determined patterns of functional mtDNA variants associated with ASD risk that emerged over human history. 

The study team found that individuals with European haplogroups designated I, J, K, O-X, T and U (representing 55 percent of the total European population) had significantly higher risks of ASD compared to the most common European haplogroup, HHV. Asian and Native American haplogroups A and M also were at increased risk of ASD. 

These findings support the idea that an individual already predisposed to ASD based on their mitochondrial haplogroup may develop the disease when additional genetic variants or environmental insults occur that lower mitochondrial function, impair OXPHOS, and alter brain activity.

Among the reasons to be skeptical: the p-value is only 0.04 so it looks like p-hacking by carefully choosing results bins after the fact; the sample size is exaggerated because the samples are not independent, the characterization of the mtDNA haplogroups involved is non-standard (mtDNA haplogroup O is Australian aboriginal, so a European haplogroup O-X makes no sense; there is no mtDNA haplogroup HHV and instead there are two separate ones H and HV); the odds ratios aren't huge; mtDNA clades are strongly ancestry informative and could be tracking differences in diagnosis rates or ancestry correlated autosomal traits; these are very broad categories that aren't phylogenically coherent.

More evidence of p-hacking in this paper flows from the fact that a 2013 study with a similar design and only modestly smaller sample size found no significant association between mtDNA haplogroup and autism risk and did not show the autism-mtDNA links for  any of the specific haplogroups reported on in the 2017 paper, despite having a similar, although moderately smaller sample size in terms of independent individuals (818 cases and 1641 controls). The abstract of that paper and its citation are as follows:

Despite the increasing speculation that oxidative stress and abnormal energy metabolism may play a role in Autism Spectrum Disorders (ASD), and the observation that patients with mitochondrial defects have symptoms consistent with ASD, there are no comprehensive published studies examining the role of mitochondrial variation in autism. Therefore, we have sought to comprehensively examine the role of mitochondrial DNA (mtDNA) variation with regard to ASD risk, employing a multi-phase approach. In phase 1 of our experiment, we examined 132 mtDNA single-nucleotide polymorphisms (SNPs) genotyped as part of our genome-wide association studies of ASD. In phase 2 we genotyped the major European mitochondrial haplogroup-defining variants within an expanded set of autism probands and controls. Finally in phase 3, we resequenced the entire mtDNA in a subset of our Caucasian samples (∼400 proband-father pairs). In each phase we tested whether mitochondrial variation showed evidence of association to ASD. Despite a thorough interrogation of mtDNA variation, we found no evidence to suggest a major role for mtDNA variation in ASD susceptibility. Accordingly, while there may be attractive biological hints suggesting the role of mitochondria in ASD our data indicate that mtDNA variation is not a major contributing factor to the development of ASD.

Hadjixenofontos, A, et al., "Evaluating mitochondrial DNA variation in autism spectrum disorders." 77(1) Ann Hum Genet. 9-21 (2013 epublished November 6, 2012) doi: 10.1111/j.1469-1809.2012.00736.x. (Open access).

Another lack of association between ASD and mtDNA variation was found in a 2011 study. The 2011 and 2013 studies combined have as large a sample size, if not larger, than the 2017 paper.

So, two of three studies have found a lack of association and the one that did find the association has a p value of 0.04 which is not statistically significant after considering look elsewhere effects given that at least three such studies have been done.

Background on sibling shared autism risk can be found here. All siblings with the same mother have the same mtDNA. The odds ratio for siblings of ASD affected individuals to have an ASD is 9.4-14.7 which is much greater than the odds ratio associated with sharing an mtDNA haplogroup.

Ideally, mtDNA associations would be studied at maximal sub-haplogroup detail, in light of a phylogeny of the haplogroups implicated, and excluding cases where a de novo mutation was likely such as in cases of advanced paternal age, as well as cases where a paternal inheritance was likely due to sub-clinical or clinical ASD symptoms in the father.

The abstract and citation to the new paper are as follows:

Importance Autism spectrum disorders (ASD) are characterized by impairments in social interaction, communication, and repetitive or restrictive behavior. Although multiple physiologic and biochemical studies have reported defects in mitochondrial oxidative phosphorylation in patients with ASD, the role of mitochondrial DNA (mtDNA) variation has remained relatively unexplored. 

Objective To assess what impact mitochondrial lineages encompassing ancient mtDNA functional polymorphisms, termed haplogroups, have on ASD risk. 

Design, Setting, and Participants In this cohort study, individuals with autism and their families were studied using the Autism Genetic Resource Exchange cohort genome-wide association studies data previously generated at the Children’s Hospital of Philadelphia. From October 2010 to January 2017, we analyzed the data and used the mtDNA single-nucleotide polymorphisms interrogated by the Illumina HumanHap 550 chip to determine the mtDNA haplogroups of the individuals. Taking into account the familial structure of the Autism Genetic Resource Exchange data, we then determined whether the mtDNA haplogroups correlate with ASD risk. 

Main Outcomes and Measures Odds ratios of mitochondrial haplogroup as predictors of ASD risk. 

Results Of 1624 patients with autism included in this study, 1299 were boys (80%) and 325 were girls (20%). Families in the Autism Genetic Resource Exchange collection (933 families, encompassing 4041 individuals: 1624 patients with ASD and 2417 healthy parents and siblings) had been previously recruited in the United States with no restrictions on age, sex, race/ethnicity, or socioeconomic status. Relative to the most common European haplogroup HHV, European haplogroups I, J, K, O-X, T, and U were associated with increased risk of ASD, as were Asian and Native American haplogroups A and M, with odds ratios ranging from 1.55 (95% CI, 1.16-2.06) to 2.18 (95% CI, 1.59-3) (adjusted P < .04). Hence, mtDNA haplogroup variation is an important risk factor for ASD. 

Conclusions and Relevance Because haplogroups I, J, K, O-X, T, and U encompass 55% of the European population, mtDNA lineages must make a significant contribution to overall ASD risk.

Dimitra Chalkia, et al., "Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders" JAMA Psychiatry. (Published online August 23, 2017). doi:10.1001/jamapsychiatry.2017.2604

Hereditary Component of Autism Underestimated

Estimates of the extent to which autism is hereditary are probably underestimates, because in many families where some children are diagnosed with autism, and others are not, the children not diagnosed frequently have subclinical autism symptoms.

Approximately one in five siblings of children with autism who don’t meet criteria for the disorder display mild or “subclinical” autism traits. . . . These traits consist of language delays, the use of odd or repeated phrases and other unusual speech qualities and difficulties interacting with others. Most such children come from families with at least two other youngsters who have an autism spectrum disorder.

Four times as many boys as girls meet psychiatric criteria for autism. But the inclusion of mild autism traits narrows that ratio to three boys for every two girls. . . .

[The study] assessed signs of autism in 2,920 children from 1,235 families participating in a national online research registry. Each family in the registry includes at least one child with an autism spectrum disorder and at least one biological sibling. Data came from questionnaires completed by parents.

Their responses indicated that 134 families, or 11 percent, had more than one child diagnosed with autism. About one in four families, including nearly all of those with multiple autism cases, also contained siblings with mild symptoms.

Among mildly affected boys and girls, 20 percent had received a diagnosis of language delay or speech problems early in life, double the prevalence in the general population.

The study is J.N. Constantino et al. Sibling recurrence and the genetic epidemiology of autism. American Journal of Psychiatry, in press, 2010. doi:10.1176/appi.ajp.2010.09101470.

Second of Irish Twins At Higher Risk For Autism

A new study on autism risk finds that the second child of a pair of children born in close succession (the old rub was that children born less than a year apart were "Irish twins"), have a heightened risk for autism, even controlling for known risk factors like advanced paternal age that could confound the correlation. Presumably, such a risk would be due to pre-natal environment, rather than any genetic factor.

[T]he risk of an autism diagnosis in a second-born child rose more than three-fold when the child was conceived within 12 months of the birth of the first baby . . . second-borns conceived between 12 and 23 months after a first child was born had twice the risk of being diagnosed with autism compared to babies conceived a full three years after an older sibling was born. . . . For the new study, researchers scrutinized birth records from 662,730 second-born children from California, all of whom were born between 1992 and 2002 and none of whom had an older sibling with autism. By age 6, 3,137 of the second-borns had received a diagnosis of autism, according to data provided by California’s Department of Developmental Services. Of those, 2,747 occurred in children born less than 36 months after their siblings[.]

Similar risk factors have been identified for schizophrenia, which like autism, is also associated independently with advanced paternal age, suggesting again that both conditions may have a similar disease model for an epidemiology perspective. Given these findings, I'd be willing to guess that bipolar disorder, which also seems to have a similar disease model, also has an elevated "Irish twin" risk.

Given the fact that it isn't uncommon for autistic children to have siblings with subclinical autistic traits, a factor that tends to understate the degree to which autism is hereditary, the other possibility that comes to mind is a genes x environment interaction. It may be that many of the second children diagnosed with autism actually did share genes with an older system that pre-disposed each to autism, but that in utero stresses associated with a swift second pregnancy caused the autism-like symptoms to cross the line from sub-clinical to clinically diagnosable as a result, while autism traits expressed only at a subclinical level in the first child of the pair.

One Form of Autism Cured In Mice

Aside from being eaten by cats, having incredibly short life spans, and being dissected for no fault of your own, mice have it really good. They always get the benefits of cutting edge medical science. This time, a way to reverse advanced autism in mice has been discovered.

It isn't a general cure. It applies to a mouse form of a kind of autism found in one in 10,000 to 15,000 girls. Boys are swiftly killed by the disease. The most recent data shows that 1 in 150 children have an autism spectrum disorder and it is more common in boys than in girls - so only a fraction of 1% of autism cases are directly impacted by the discovery. Treatment was easier to devise in this kind of autism than others because scientists know precisely what causes this form of autism, a defect in the operation of specifically identified genes. This is a particularly nasty version of autism, however:

After its outset—usually within 18 months of birth—young girls suffering from the illness begin to display asocial symptoms similar to those of autism. RS [Rett Syndrome] primarily affects the nervous system and can eventually lead to problems with speech and movement, often leaving patients with a stiff gait or confined to a wheelchair. Symptoms can also include tremors and irregular breathing.

The scientists treated the mice with tamoxifen, a breast cancer drug, with great results.

All of the symptoms . . . were erased in the female mouse model. . . . "It's like a dream result, to me," marvels biologist Rudolf Jaenisch of the Massachusetts Institute of Technology's Whitehead Institute. "Even if you have the disease—and these animals were almost moribund—you can still rescue them."

There is no known cure for inappropriate use of similes by biologists at this time, perhaps because mice are not known to suffer from that disorder.

Don't try this at home with your Rett Syndrome afflicted child. While scientists eventually got a good result with a proper dosage of the drug, the trial and error process to determine the proper dose of the drug killed a lot of mice.

But, the good news is that one autism spectrum disorder may be headed for a cure in the foreseeable future.

All Three Candidates Miss Vaccine-Autism Point

In a disappointing development, all three candidates in the Presidential race: McCain, Obama and Clinton appear grossly uninformed about the state of the science on the alleged link between autism and vaccines (the research says "none" and thimerosal in childhood vaccines has been specifically ruled out), let alone the public health risks that result from that lack of knowledge (fewer vaccinated kids is a public health risk).

Saying you know and being wrong is obviously a bad thing.

McCain:

Sen. John McCain, R-Ariz., declared that "there's strong evidence" that thimerosal, a mercury-based preservative that was once in many childhood vaccines, is responsible for the increased diagnoses of autism in the U.S. -- a position in stark contrast with the view of the medical establishment.

But, sometimes turning an "I don't know" statement into a "we don't know" statement is the wrong answer, although politicians love to use the phrase when they lack information. Obama and Clinton misstated science in this way:

Obama:

"We've seen just a skyrocketing autism rate. Some people are suspicious that it's connected to the vaccines. This person included. The science right now is inconclusive, but we have to research it."

Clinton:

Senator Hillary Clinton, in response to a questionaire from the autism activist group A-CHAMP, wrote that she was "Committed to make investments to find the causes of autism, including possible environmental causes like vaccines." And when asked if she would support a study of vaccinated vs. unvaccinated children, she said: "Yes. We don't know what, if any, kind of link there is between vaccines and autism - but we should find out."

We can only hope that the candidates become better informed before they make policy decisions in this area.

Note: Two legal cases pressing an autism-vaccine link have made headlines recently.

One involved the highly unusual case of a thimersol preserved vaccine being administered to a pregnant woman in a manner pre-approved by the FDA and made headlines for abusive litigation tactics the Plaintiffs' lawyer directed at a blogger. Childhood vaccines, of course, are generally not administered in utero.

The other involved a similarly highly unusual case of a vaccinated child with a rare metabolic disease in addition to autistic symptoms, in which a vaccine compensation board chose to make an award rather than allow further expert witness and research intensive litigation in the unique case. The advocates for the child had argued that the combination of the vaccine and the metabolic disease may have had some connection to the autism symptoms. The child advocate's argument suggested that the extensive research showing a lack of an autism-vaccine link might to be applicable to a specially vulnerable child with a metabolic disease.

The Genetics Of Autism and ADHD

A new study compared the genetic profiles of people diagnosed with an autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and people diagnosed with both disorders. Both conditions are highly heritable. 

The study used large data set with 23,583 subjects (with ADHD and/or one of four subtypes of autism spectrum disorder) and 42,201 controls, apparently mostly from the national health records of Denmark and possibly also from 23andMe data. The study excluded individuals with a moderate to severe mental retardation from both its subjects and its controls.

The study finds seven genes that are associated with both disorders, and five genes that distinguish between the disorders which are also associated with educational attainment, neuroticism and regional brain volume. 

The Paper And Its Abstract

Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental conditions, with considerable overlap in their genetic etiology. We dissected their shared and distinct genetic etiology by cross-disorder analyses of large datasets. 

We identified seven loci shared by the disorders and five loci differentiating them. All five differentiating loci showed opposite allelic directions in the two disorders and significant associations with other traits, including educational attainment, neuroticism and regional brain volume. 

Integration with brain transcriptome data enabled us to identify and prioritize several significantly associated genes. The shared genomic fraction contributing to both disorders was strongly correlated with other psychiatric phenotypes, whereas the differentiating portion was correlated most strongly with cognitive traits. Additional analyses revealed that individuals diagnosed with both ASD and ADHD were double-loaded with genetic predispositions for both disorders and showed distinctive patterns of genetic association with other traits compared with the ASD-only and ADHD-only subgroups. 

These results provide insights into the biological foundation of the development of one or both conditions and of the factors driving psychopathology discriminatively toward either ADHD or ASD.

Manuel Mattheisen, et al., "Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups" Nat Genet (September 26, 2022). https://doi.org/10.1038/s41588-022-01171-3 (closed access).

The Data Set

The data set was apparently a national health care record system for Denmark in which there were 2,304 cases with both ADHD ad an autism spectrum disorder, 11,964 ADHD cases without an autism spectrum disorder, and 9,315 cases with an autism spectrum disorder without ADHD, although some of the data may also have been from the 23andme consumer genetic profiling company (a data set that would include me, my family, and a number of my extended family members). Also:

Controls were randomly selected from the full control cohort to roughly match a 1:4 ratio in cases and controls. . . . we excluded individuals with a moderate to severe mental retardation (ICD10: F71-F79) from both the case and control cohort.

Autism spectrum disorder cases were further categoried into four subtypes: childhood autism (cha, ICD10 F84.0); atypical autism (ata, ICD10 F84.1); Asperger’s syndrome (asp, ICD10 F84.5); and pervasive disorders, unspecified and others (pdm, ICD10 F84.8+9). 

It appears that ADHD cases were not subtyped, which is something of a shame. There is good reasons to think that the genetic basis of ADHD predominantly inattentive type (i.e. without hyperactivity), has a different genetic basis than ADHD combined type (and ADHD predominately hyperactive which probably overlaps heavily with the combined type). This level of information ought to have been available although empirically efforts to further subtype ADHD probably wouldn't have been available in the data. See, e.g, prior posts at this blog from September 8, 2012, April 3, 2012, and October 18, 2017 (Genetics of ADHD hyperactivity/impulsivity and inattention dimensions are quite different),

A Key Figure From The Paper

A figure from the closed access paper:

Fig. 2: Comparison of PRS profiles across ADHD and ASD subtypes for 15 traits and/or phenotypes that have shown significant genetic correlations with ADHD and ASD in the past.

Peer Review

The relatively new practice of disclosing comments from the peer review of the paper, provides some interesting insights although it is rather technical and difficult to evaluate without an open access manuscript to reference it to for the most part. Some notable comment state:

A serious limitation of this study is that the design relies on the common psychiatric nosology that in particular for ASD and ADHD has been problematic, surely in the past when only one of both diagnosis was allowed. Given the high comorbidity between ADHD and ASD, and among other psychiatric disorders in general, plus the fact that recent research shows that ‘genes do not respect diagnostic classifications’ (see CDG publications) I would rather see a focus on the shared genetic findings for ADHD and ASD, in aiming to find general genetic/biological vulnerabilities for trans diagnostic neurodevelopmental problems, instead of relying on a classification system that has surely proven its value in clinical practice but does not seem to guide biological underpinnings of those disorders.

and

Concerning the used sample, I would appreciate getting some more details on the assessment of comorbid ASD and ADHD in the respective cohort. While some of the individuals might have been diagnosed under DSM-IV, which did not allow a comorbid diagnosis of ADHD, I wonder if and how this was accounted for in the datasets. In light of the cited Meta-study 25-32% of ASD individuals do fulfill the criteria for ADHD. In this study, the comorbid cohort accounts for 10% of the sample (assuming they were from both the ASD and the ADHD cohorts).

The responses gave rise to a table regarding the shared risk genes:

The Sociology of Brain Disorder Treatment

There are two medical specialties that deal with brain disorders and conditions. One is neurology. The other is psychiatry. Where does one draw the line between the two?

Neuroskeptic compares the number of articles on particular conditions in leading academic journals for each specialty (Neurology and the American Journal of Psychiatry), to look empirically at how the line has been drawn within the medical profession.

The division doesn't seem to be very strongly linked to the extent that a condition is biologicallly based. As he notes:

Schizophrenia, which is probably considered "the most neurological" psychiatric disorder, is in fact the least talked about in Neurology.

Both mental retardation and autism are middle ground between the two specialties, with mental retardation leaning towards neurology, and autism leaning towards psychiatry.

Eyeballing the data, one way to think of the way that the conditions have been allocated is that psychiatrist deal with conditions that influence your personality and social interactions, other than pure cognition, while neurologists deal with other conditions and conditions that impact pure cognition.

This explains the mental retardation v. autism divide, for example. While both have a cognitive function element, explaining the neurological interest in both conditions, what distinguishes an autism diagnosis from a mental retardation diagnosis that is not autism is the diagnostic and treatment focus on how autism affects personality, social interaction and empathy, particularly in the case of autism spectrum disorders like Asperger's, where IQ is often in the normal range.

The gray area for ADHD, likewise, can be explained as a product of the lingering ambiguity over whether to think of the condition as a personality disorder that is a cogential part of who someone is, or as a developmental disorder of something large is part of a larger cognition process.

Psychaitry is concerned with "who you are" while neurology is concerned with "what you are" even though there isn't obviously any fundamental difference between the kind of brain functions that lead to schizophrenia and those that lead to congential epilepsy. The looming question behind Neuroskeptic's post is whether the divide says more about perhaps unfounded biases about mental health that pervade even the supposedly enlightened medical profession, than it does about science.

There are other ways to see the distinction, of course. One is that neurologists deal with issues that are believed to be exclusively "hardware" issues, while a core issue for psychiatrists is to parse "hardware" from "software" issues and address each appropriately. Some conditions may not neatly fit that divide today simply because historical ambiguity led a condition to be assigned to one category or the other, and given that all of the physicians involved have a similar allopathic medical background and training, there is no compelling reason to upset the apple cart of institutional and funding and bureaucratic arrangements based on the distinction at this point, even if it isn't terribly logical.

In the same way, no one is urgently pushing to have responsibility for counterfeiting enforcement removed from the duties of the United States Secret Service even though this doesn't logically have much to do with is primary responsibility to provide bodyguard protection to the President and other senior federal officials and candidates, because the skill set for the two tasks is similar.

Still, the divide has a strong impact on treatment modality. Neurologists use drugs and sometimes surgery, while seeing little place for therapy. Psychiatrists, while also prescribing drug treatments, recognize the value of psychological talk therapies as a complementary treatment modality to a much greater extent.

A footnote to the post in the study is also interesting:

"Gathering" this data took me 15 minutes. 20 years ago, it would have taken... well, you'd have had to read and manually categorize 30,000 abstracts. Even at 2 minutes per abstract (bare minimum) that's, er, 1000 man-hours of work.

There Are Two Distinct Forms Of Autism Syndrome Disorders

Autism Spectrum Disorder (ASD) cases can be clustered into two types based upon the risk factor genes involved. This division coincides with a distinctions between severe symptoms and less severe symptoms. The two clusters appear to have distinct causes. Basically, it appears that there are two different conditions that happen to have symptoms that resemble each other. 

Knowing what causes a particular individual's ASD could be critical in figuring out what kind of therapies or symptom management strategies are likely to work best for a particular individual.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disease primarily characterized by deficits in verbal communication, impaired social interaction and repetitive behaviors. It exemplifies profound clinical heterogeneity, which poses challenges in diagnosis and treatment. Genetic studies have pointed to hundreds of presumptive causative or susceptibility genes in ASD, making it difficult to find common underlying pathogenic mechanisms and suggesting that multiple different genetic etiologies for ASDs influence a continuum of traits. 

Deep phenotyping analysis allowed for re-categorization of genetic variants. Our previous analysis suggested the existence of two significant subgroups within the existing ASD classification. To investigate this hypothesis in greater detail we have performed in-depth analysis using phenotypic and genetic data from Autism Genetic Resource Exchange (AGRE) and Autism Genome Project (AGP). Our initial findings on both phenotypic and genetic data (1,262 cases and 2,521 controls using familial transmission disequilibrium test) suggest existence of two groups that range in severity. Findings were replicated in a validation dataset. Genetic risk scores (GRS) were used to sum up the total effect of several single-nucleotide polymorphisms characteristic of the two clusters. The high discriminatory ability of the genetic risk score to define cluster 1 from cluster 2 case group at different combinations of sensitivity and specificity was assessed and clearly demonstrates strong signal with AUC being 0.74. There is a significant signal differentiating the 2 clusters relying on non-genetic risk factors and even greater signal when using both non-genetic risk factors and GRS. The detection and validation of the two groups allowed us focus on convergence of findings at the pathway level. ASD heterogeneity was leveraged via large scale pathway analysis within those two categories, which led to identification of a driver gene set across significant pathways. The significant pathways in cluster 1 (severe, affected = 300) include autoimmune disease, vitamin B6 metabolism, whereas in cluster 2 (non-severe, affected = 921) included oxytocin signaling pathway, WNT signaling pathway and glutamatergic synapses (all at P < 0.001). We envision that systematic study of all genomic pathways obtained given a set of redefined categories will yield profound findings for ASD even in the absence of strong individual variant information.

S. Smieszek and J.L. Haines., "Autism redefined: Genomic pathway approach to autism spectrum disorder." ASHG Conference Presentation 33 (October 2016).

Autism Diagnosis Stable By Fourteen Months Of Age

The findings suggest that an ASD diagnosis becomes stable starting at 14 months of age and overall is more stable than other diagnostic categories, including language or developmental delay.

From here (citing this article in JAMA Pediatrics). The abstract from the referenced article is as follows:

Importance Universal early screening for autism spectrum disorder (ASD) in primary care is becoming increasingly common and is believed to be a pivotal step toward early treatment. However, the diagnostic stability of ASD in large cohorts from the general population, particularly in those younger than 18 months, is unknown. Changes in the phenotypic expression of ASD across early development compared with toddlers with other delays are also unknown. 

Objectives To examine the diagnostic stability of ASD in a large cohort of toddlers starting at 12 months of age and to compare this stability with that of toddlers with other disorders, such as developmental delay. 

Design, Setting, and Participants In this prospective cohort study performed from January 1, 2006, to December 31, 2018, a total of 2241 toddlers were referred from the general population through a universal screening program in primary care or community referral. Eligible toddlers received their first diagnostic evaluation between 12 and 36 months of age and had at least 1 subsequent evaluation. 

Exposures Diagnosis was denoted after each evaluation visit as ASD, ASD features, language delay, developmental delay, other developmental issue, typical sibling of an ASD proband, or typical development. 

Main Outcomes and Measures Diagnostic stability coefficients were calculated within 2-month age bands, and logistic regression models were used to explore the associations of sex, age, diagnosis at first visit, and interval between first and last diagnosis with stability. Toddlers with a non-ASD diagnosis at their first visit diagnosed with ASD at their last were designated as having late-identified ASD. 

Results Among the 1269 toddlers included in the study (918 [72.3%] male; median age at first evaluation, 17.6 months [interquartile range, 14.0-24.4 months]; median age at final evaluation, 36.2 months [interquartile range, 33.4-40.9 months]), the overall diagnostic stability for ASD was 0.84 (95% CI, 0.80-0.87), which was higher than any other diagnostic group. Only 7 toddlers (1.8%) initially considered to have ASD transitioned into a final diagnosis of typical development. Diagnostic stability of ASD within the youngest age band (12-13 months) was lowest at 0.50 (95% CI, 0.32-0.69) but increased to 0.79 by 14 months and 0.83 by 16 months (age bands of 12 vs 14 and 16 years; odds ratio, 4.25; 95% CI, 1.59-11.74). A total of 105 toddlers (23.8%) were not designated as having ASD at their first visit but were identified at a later visit. 

Conclusions and Relevance The findings suggest that an ASD diagnosis becomes stable starting at 14 months of age and overall is more stable than other diagnostic categories, including language or developmental delay. After a toddler is identified as having ASD, there may be a low chance that he or she will test within typical levels at 3 years of age. This finding opens the opportunity to test the impact of very early-age treatment of ASD.

There is no rigorously evidence validated treatment of autism at any age, although there are approaches which are used to manage the symptoms. Also, it is worth noting that autism is a syndrome of similar symptoms that tend to appear together but almost certainly has multiple distinct causes (mostly de novo genetic mutations) that all affect the same neurological sub-systems of the body in similar ways. 

So, a cure to one cause of autism wouldn't necessarily be a cure to most cases of autism. 

Are Autism And Schizophrenia Inverses Of Each Other?

People's brains change in a person's late teens and early twenties when they experience "synaptic pruning" that strengthens frequently used connections in the brain while trimming away superfluous ones.

In schizophrenia, this process goes overboard and the brain compensates by treating random noise as signals, which leads to hallucinations. People with autism apparently don't trim enough which impairs learning. Thus, it could be that both conditions involve defects in the same process in opposite directions.

These findings may suggest new treatments targeting GABA receptors for "normalizing" synaptic pruning in diseases such as autism and schizophrenia, where synaptic pruning is abnormal. Research has suggested that children with autism may have an over-abundance of synapses in some parts of the brain. Other research suggests that prefrontal brain areas in persons with schizophrenia have fewer neural connections than the brains of those who do not have the condition.

From here.

On the other hand, it seems odd that autism would have a very early childhood onset if it is really related to synaptic pruning.  But, there are also other developmental periods besides late puberty when synaptic pruning occurs, and perhaps an earlier time period is implicated in autism.

Autism May Be Related To Human Level Intelligence

Autism may be related to the human specific evolution of higher intelligence: 

Researchers discovered that autism’s prevalence may be linked to human brain evolution. Specific neurons in the outer brain evolved rapidly, and autism-linked genes changed under natural selection. These shifts may have slowed brain development in children while boosting language and cognition. The findings suggest autism is part of the trade-off that made humans so cognitively advanced.

Vaccines Do Not Cause Autism

The evidence that vaccines do not cause autism is overwhelming. Also, measles is no joke. It is not a merely uncomfortable childhood experience. In 2002, there were 600,000 children who died from the disease.

The death rate is far lower in the developed world than the third world due to widespread vaccination (a 96% vaccination rate for kindergarteners in the United States) which prevents the disease from spreading in isolated breakouts usually from contact with non-U.S. persons from places that have lower vaccination rates. Of course, even in the majority of developed world cases where measles infections do not kill, the infection is nothing anyone would wish on a child. It is not a major killer in the United States (on average about ten deaths per year distributed unevenly in connection with epidemic outbreaks), but it is almost completely avoidable with a safe and effective shot.

Independent research has found no link between the childhood MMR vaccination and either autism or Crohn’s disease (a chronic inflammatory bowel disease). This should encourage parents to follow the advice of their family doctor and have their children immunised with the triple dose vaccine.

Measles, mumps and rubella can be serious diseases with potentially fatal consequences. Using single dose vaccines would leave children exposed to the risk of infection for longer periods.

A colossal amount of work has been done by GPs and their primary health care teams to convince parents of the value of vaccination. MMR is an extremely safe vaccine and has been used worldwide for nearly 30 years. Over 500 million doses have been used in over 90 countries. . . By protecting their own children, parents are also protecting other people’s children from the serious health risks associated with the illnesses of measles, mumps and rubella.

Vaccination levels for MMR fell following adverse publicity in 1998 after the publication of a paper suggesting an association with the MMR vaccine and autism and inflammatory bowel disease. Dr Andrew Wakefield suggested that if there was a link between MMR and these conditions, the risk might be avoided by giving three separate doses one year apart.

No independent studies, however, have been able to find any evidence of a link between the MMR vaccine and autism or bowel disease.

From the British Medical Association.

Study: Autism Basically The Inverse of M.S.

NPR has a story that indicates that autism may be basically a function of too much mylenination (the body's natural nerve insulation), while M.S. is too little, according to a new study.

On the bright side, we are much further along in finding medical treatments for M.S., than for autism for which treatment has been basically intractable, and the new understanding of autism may shed light on how to treat it derived from M.S. research.