Sunday, October 19, 2014

Autism: The Truth is (not) Out There

Parents of a child affected by autism naturally want to know the cause. Autism can dramatically disrupt the typical childhood pattern of cognitive, behavioural and social development. At the most severe end, the child may require care for the rest of their lives. Even at the milder end, it may make mainstream education impossible and exclude many opportunities available to typically developing children. Any parent would hope that knowing the cause could lead to better treatment and management options for their child.

Unfortunately, until very recently, it has not been possible to identify causes in individual children (with rare exceptions). Science and medicine had apparently failed to solve this mystery. (I say “had”, because, as we will see below, this is no longer true). The typical experience of children and their parents in the health system has been one of frustration, often with a long diagnostic odyssey, limited options for medical intervention and a struggle to obtain access to specialised educational services – all during a critical period in the child’s development. Given this frustration, it is understandable that a variety of alternative theories of autism causation have become popular. should beware, however – while such theories appeal to those common frustrations, they generally have no scientific support whatsoever. Many of these are not just non-scientific, but actively anti-scientific in nature. They tend to be based on anecdote, narrative and outright speculation, rather than the scientific method (objective assessment of empirical evidence). Many play to conspiracy theories, casting scientists and doctors as pawns of Big Pharma, for example, and those proposing alternative theories as brave mavericks fighting against the establishment to get The Truth out there.

Ironically, the truth is that many of the people pushing alternative theories are looking to make money off them – often by taking advantage of vulnerable parents. Not all, by any means, but very often a commercial interest is not hard to find (such as selling costly diets or supplements or even more dangerous supposed “treatments”; claims that alternative therapies like homeopathy can cure the condition; pricey seminars; or a new book to promote)*. Alternative theories for autism and the treatments that go with them are big business.

The other irony is that these theories actively ignore our growing knowledge of the real causes of autism, which are clearly mainly genetic. The Truth is known but it’s not out there. Scientists have done a poor job of communicating the extraordinary advances made in the last few years in understanding the genetic causes of autism. (Even many scientists and doctors seem unaware of these advances, in fact). This leaves a void that can be filled by theories that are highly speculative or sometimes frankly bizarre, and that are also either unsupported or flatly contradicted by available evidence.

The unusual suspects old psychoanalytical theory that autism is caused by “cold parenting” has long since been discredited, but still pops up every now and then (and is still quite prevalent in France and Argentina, for some reason). It is often espoused by people who also happen to offer psychological courses that purport to realign this relationship and thereby ameliorate the condition. Bizarrely, this theory has been resurrected in modern form by neuroscientist Susan Greenfield, who has suggested that autism is caused by overuse of digital technology and immersion in social media, with a concomitant withdrawal from direct human contact. The refrigerator mother has been replaced by the unfeeling screen of the iPad.

This technophobic notion is largely incoherent and has no supporting evidence. (When asked for evidence, Greenfield has described her own theory as follows: "I point to the increase in autism and I point to internet use. That is all.”). The fact that autism is typically diagnosed by two or three years of age, well before most kids have Facebook or Twitter accounts, rather fatally undermines the idea. class of theories propose that autism is caused not by an impoverished psychosocial environment, but by a toxic physical environment. There is no shortage of potential culprits: fluoride in the water, mercury in dental amalgam, vaccinations, genetically modified food, herbicides, pesticides, food allergies, microwaves, cell phone towers, traffic fumes, even toxins in everyday items like mattresses and dental floss.

(These days, many of these are given a pseudoscientific gloss by invoking the magic of “epigenetics”, a term now so corrupted as to be worse than useless).

A driving factor behind all of these theories is the fact that rates of autism diagnoses have been increasing steadily in some countries for the past couple decades. This has led some to declare “an autism epidemic”, with the obvious connotation that something in the environment must be causing it.

This premise is flawed, however, as it assumes the rate of diagnosis mirrors a real rise in the rate of the disease. In fact, the rise in diagnosis rates can be largely explained by better recognition of the condition among doctors and broader awareness among the general public, and by diagnostic substitution, whereby children who previously would have been given a general diagnosis of mental retardation are now more commonly diagnosed with ASD. After all, prior to 1943, no one was diagnosed with autism because the term had not yet been applied to this childhood condition. The gradual rise in autism diagnoses following that period could hardly be thought of as signaling a sudden epidemic. The criteria used by psychiatrists to define the condition have changed multiple times over the years, including in the most recent version of the DSM, and each change leads to a change in the number of children who fit under this diagnosis. The label is thus artificial and changeable and its application has also varied widely over time. There is no reason to think these variations reflect changes in the rate of the condition itself.

There is, moreover, no evidence linking any of the potential environmental factors listed above to autism. In fact, in many cases, there is very strong evidence disproving any such link. (See here and here for a discussion of the absence of any link with vaccination, for example). Regrettably, however, some of these stories simply refuse to die.

Undead memes
Part of their persistence may arise from the way they are framed as anti-mainstream theories – for many adherents this inoculates them against scientific critiques or counter-evidence, due to mistrust of the scientific establishment or a lack of acceptance of the scientific method as a means of objectively discovering the truth. It is, moreover, very difficult to counter emotive personal anecdotes and highly publicised but methodologically flawed studies (some of which have later been retracted or even shown to be fraudulent), with, for example, dry statistical data showing no epidemiological link to vaccines or fluoride or dental floss or any other supposed environmental toxins. one sense, such arguments grant too much credibility to these theories by allowing the battle to be fought solely on their turf. It puts the onus on scientists to disprove each new theory. (This is like arguing with creationists by trying to disprove the existence of Noah’s ark, instead of simply presenting the positive evidence for evolution by natural selection). The problem with this is that negative findings are simply not very compelling, psychologically, regardless of the statistical strength of the conclusion. It’s too easy to misinterpret what is really strong evidence that something is not the case as merely the absence of evidence that it is (which would leave it an open question, requiring “more research”). This means the “is not” side is at a disadvantage in an “is too”/“is not” argument. 

In my opinion, the strongest counter-argument is one that is often not mentioned in such discussions – the positive evidence for genetic causation. Instead of expending so much effort trying to prove “it’s not that”, we can simply say “it’s this – look”. There is really no explanatory void to fill. We know what causes autism, in general, and we are identifying more and more of the specific factors that cause it in individuals.

Autism is genetic
The evidence that autism is largely genetic is overwhelming – in fact, it is among the most heritable of common disorders. This has been established through family and twin studies that look at the rate of occurrence of the disorder (or statistical “risk”) in relatives of patients with autism. If one child in a family has autism, the risk to subsequent children has been estimated to be between ~10-20%, far higher than the 1% population average. If two children are affected, the risk to another child can be as high as 50%.

Now, you might argue that this does not prove genetic influences, as environmental factors may also be shared between family members. Twin studies have been designed for precisely that reason. Here, we compare the risk to one co-twin when the other has a diagnosis of autism, in two cases: when the twins are identical (or monozygotic, sharing 100% of their DNA) versus when they are fraternal (or dizygotic, sharing 50% of their DNA). This design is so powerful because it separates genetic effects from possible environmental ones. Genetic effects should make identical twins more similar than fraternal twins, while environmental effects should not differ between these pairs. results are dramatic – if one of a pair of identical twins is autistic, the chance that the other one will be too is over 80%, while the rate in fraternal twins is less than 20%. (Even in cases when the co-twin does not have a diagnosis of autism, they very often have some other psychiatric diagnosis, again much more so in identical than fraternal co-twins). These results, which have been replicated many times, show that variation across the population in risk of autism is overwhelmingly due to genetic differences. Crucially, these results are not consistent with an important role for variable environmental factors in the etiology of the disorder – these should affect identical and fraternal twins equally. Similarly, full siblings of someone with autism are at ~2 times greater risk than half-siblings, again consistent with genetic but not with environmental causation.

These kinds of analyses answer the question: in a given population at a given time, why do some people get autism while others don’t? The answer is unequivocal – this is overwhelmingly down to genetic differences.

Finding mutations in specific genes
The fact that autism is largely a genetic disorder has been known for decades. What has not been known is the identity of the specific genes involved, with the exception of a couple examples, involving genes associated with syndromes in which autistic symptoms are common, such as Fragile X syndrome or Rett syndrome. These syndromes are caused by mutations in specific single genes and account for 3-4% of all autism cases. However, the vast majority of cases were left unexplained, and not for want of looking.
This apparent failure to find the specific genes involved clearly has led to the impression that genetics can not explain the condition and that other factors must therefore be involved. This is not the case at all – even if we remained completely ignorant of specific causes, the fact that autism is extremely highly heritable would remain just as true. As it happens, the failure to find specific causes had a technical reason – it was simply very difficult to discover the kinds of mutations that cause the condition. This is because such mutations are individually very rare in the population and because there is not just one gene involved, or two, or even ten, but probably many hundreds.

These mutations are now detectable thanks to new technologies that allow the entire genome to be surveyed (either for changes to single letters or bases of DNA or for deletions or duplications of bits of chromosomes). Using these technologies, it has been possible to find over a hundred different genes (or regions of chromosomes) in which a mutation can lead to autism. Collectively, the known causes now account for 20-25% of cases of autism.

It is worth emphasising that point: doctors and clinical geneticists can now ascribe a specific genetic cause to perhaps a quarter of individual autism patients. This is a vast increase from even a few years ago and new risk loci are being discovered at an ever-increasing rate. There is every reason to think we are only at the beginning of these discoveries as we have really just begun to look. Again, regardless of how many cases we have explained currently, the very high heritability of autism remains a fact – the important factors in the vast majority of the remaining cases will still be genetic. Far from being a failure, modern genetics has been extraordinarily successful at uncovering specific causes of autism.

Autism can be genetic, but not inherited
One common objection to the idea that autism is a genetic condition is that so many cases of autism are sporadic – they occur in a family where no one else has autism. How could it be the case that the condition is genetic if it is apparently not inherited? This situation can arise when the condition is caused by a new mutation – a change in the DNA that occurs in the generation of sperm or egg cells (mostly sperm, as it happens). These occur all the time – this is how genetic variation enters the population. Most of the time these “de novo” mutations have no effect, but sometimes they disrupt an important gene and can result in disease. When they disrupt one of the many hundreds of genes important for brain development, they can result in autism.

It has been estimated that as many as half of all autism cases are caused by de novo mutations. By comparing the sequence of an affected child’s genome with that of their parents it is possible to tell whether a mutation was inherited or arose de novo. This is obviously important information in assessing the risk in that family to future offspring – in the case of a de novo mutation, this should not be higher than the population baseline risk. By contrast, if the mutation was inherited, then risk to subsequent children may approach 50%.

Another important finding is that the effects of such mutations are more severe in males than in females. Not all carriers of the known disease-linked mutations actually develop autism. Some develop other disorders, while some are apparently healthy and unaffected (or at least have no clinical diagnosis). This means people can be carriers of such a mutation but not have autism themselves. This is especially true for females. In cases where a pathogenic mutation in an autism patient was inherited from an unaffected parent, that parent is twice as likely to be the mother as the father. Also, the mutations observed in female patients who do have a diagnosis of autism tend to be much more severe than those observed in male patients. These data are consistent with a model where the male brain is more susceptible to the effects of autism-causing mutations than the female brain. This can explain why an apparently unaffected couple can have multiple children with autism.

These genetic findings also highlight a fundamental point: autism is not a single condition. The clinical heterogeneity has always been acknowledged (leading to the use of the term autism spectrum disorder), but it is now also clear that is also extremely heterogeneous from an etiological point of view. Autism is really an umbrella term – it refers to a set of symptoms that can arise as a consequence of probably hundreds of distinct genetic conditions.

Defining new genetic syndromes
Those distinct conditions were never obvious before, because we had no way to distinguish between people who carry mutations in different genes. But now genomic technologies can identify people with the same mutations and are allowing clinicians to define new syndromes, which may be characterised by a typical profile of symptoms. For example, mutations in a gene called CHD8 are a newly discovered, very rare cause of autism, but enough cases have now been studied to define a symptom profile, showing for example that these patients are at especially high risk of co-morbid gastrointestinal problems (found at higher rate in autism generally, but not in all cases). Knowing the cause in individuals can thus provide important information on prognosis, common co-morbidities, even responsiveness to medications.
The application of genetic testing in cases of autism should spare many children and parents the diagnostic odyssey that many currently suffer through. A definitive diagnosis can bring important benefits in terms of how families think of and deal with the condition. Indeed, support groups have arisen for many rare genomic disorders, allowing parents to compare experiences with other families with the same condition. On the other hand, as described in a recent review on this topic: “we should balance our enthusiasm for finding a genetic diagnosis with the recognition that autistic traits represent one aspect of a diverse behavioral spectrum, and work to avoid any potential stigmatization of the patient and family through identification of genetic susceptibility”.

The use of genetic information in clinical management is likely to become increasingly important in the near future as we learn more about newly discovered syndromes and their underlying biology. This kind of personalised medicine is already happening in other fields, such as oncology. One can hope that its application in psychiatry will go a long way towards transforming the experiences in the health service of autism patients and their parents and reducing the frustrations that arose when we were effectively operating in the dark.

This is a positive message of real success in science that is already changing how we think about disorders like autism and that is likely to completely transform the practice of psychiatry, especially for neurodevelopmental disorders. Scientists need to do a better job of getting that truth out there.  

*(For the record, I declare no such conflicts myself).

 Thanks to Dorothy Bishop, Svetlana Molchanova and Emily Willingham for helpful comments on this post.