Call me a glutton for punishment, but despite the hornet’s nest that I wrote myself into a couple of weeks ago, I’ve a second post on autism for this Science Tuesday. The controversy over the MMR vaccine and the alleged links to autism and the passions that it evokes inspired me to keep on reading the scientific literature on autism research. Coincidentally, a major article was published in this week’s Science addressing the hanging question asked by a number of  rightly concerned parents is, “If the MMR vaccine doesn’t cause autism then what does?”

As you might expect, that’s not an easy question to answer. As is the case with most complex disorders there is no one “cause”. Autism isn’t like tuberculosis, there’s not a bacteria that causes the disease. In fact,most researchers believe that “autism” is not a discrete disorder, rather “autism is a clinically defined pervasive developmental disorder with phenotypically diverse neuropsychiatric symptoms and characteristics. These manifest as a spectrum of social and communicative deficits, stereotypical patterns and disturbances of behaviour.”¹ This spectrum of symptoms is collectively described as autism spectrum disorders (ASDs) and range from severe mental retardation often accompanied by seizures to milder . Symptoms of ASDs usually become apparent in children by three years old, but are often detectable by 14 months. This is one of the reasons that the unsubstantiated ‘link’ between autism and the MMR vaccine is so persistent, the age at which the vaccine is given is often the age at which symptoms become apparent.

There has been extensive research into the neuropathology and neurobiology of ASDs and a number of changes to the nervous system are associated with autism. These include aberrations in brain growth, neuronal patterning and cortical connectivity as well as changes in structure and function of synapses and dendrites.² The cause of these morphological changes, and thus autism, is not so clear. The short answer is ASDs are primarily genetic disorders, but there may be environmental factors that are involved as well. For the long answer, read on.

Genes: This is the big one. In the case of autism, as with many complex traits, the heritability of the trait can be estimated. Heritability refers to the proportion of phenotypic variation that is attributable to genetic variation. If a particular trait’s heritability is 100% then the trait is due entirely to genetic variation, if the heritability is 0% then the trait is due entirely to environmental variation.  By some estimates, heritability of autism spectrum disorders exceeds 90%. Twin studies support a strong genetic component and sibling recurrence risk – the chance of a younger sibling of an autistic child having autism, exceeds 15%. When compared with the rates in the general population (1 in 500 for “autism” and 1 in 150 for ASDs) there is little doubt that a big piece of the puzzle rests in our genes.³

The problem is that autism is not caused by a mutation in a single gene. Nearly 30 individual genes have been identified as playing a role in ASDs, including genes involved in synapse function, neuron adhesion, endosomal trafficking, neuronal activity regulation and other biological processes. The paper that inspired this post is the most recent study into genetic factors causing autism. A group led by Christopher Walsh at Harvard used “homozygosity mapping” to isaolate several genes that were associated with autism. Homozygosity mapping involves study families in which parents share ancestors, which increases the risk of children accumulating harmful recessive mutations. This is the reason that inbreeding is a social taboo.

Walsh’s group found a number of different mutations in autistic children from these families, a number of which were associated with large deletions of parts of the genome or chromosomal rearrangements. A subset of these could be associated with mutations in autistic children with unrelated parents, lending support to the hypotheses that defects in these genes cause ASDs. Interestingly, some of the genes identified by Walsh’s group and others are also associated with other neurological disorders including Fragile X syndrome, Rett syndrome and epilepsy.

As a geneticist, it is a temptation to end this post here. To declare that the cause of autism is a series of mutations in the genome that induce changes in brain morphology and the spectrum of symptoms that we call autism. Unfortunately, that would be ignoring part of the equation. Some researchers think that the 90% heritability estimate is high, and even if it is not the environment still plays a role in autism.

Environmental factors: There has been a wealth of research into the role of environmental toxins in causing autism and this school of thought is the one that supports the MMR-autism link. The argument here is that the massive increase in autism in the last couple of decades points to an environmental influence for which genetics alone can not account. Researchers are looking most closely at the usual suspects – heavy metals like arsenic, lead and mercury. There is some evidence to support an association between even low level exposure to toxic heavy metals and neurological issues ADHD and lower IQs. This association led to the scare regarding the mercury containig thimerosal in the MMR vaccines. However, repeated studies have found that autism diagnoses continue to rise even after the removal of thimerosal from the vaccine.

A second interesting line of research looks at a different type of environmental influence – maternal viral infections in autism in children. Since the mid-90’s researchers have known that a strong correlation exists between maternal influenza infection, particularly in the second trimester, and the likelihood of having autistic children. Recent research has involved attempting to discern the reason for this phenomena by using animal models. A recent paper describes a mouse system in which adult progeny of virally infected mothers display a number of ASD symptoms. Beyond the potential causative effects of virus infection, a mouse model would be of great utility for neuropathology, epidemiology and potentially development of treatments for autism.

Finally, when thinking about the enviromental influences on autism, it’s important to explore the role of the environment on genetics. Many of the types of genetic changes that have been identified as causative in autism are indicative of some sort of DNA damage – DNA damage that may result from exposure to an environmental toxin. Many scientists, and I count myself in their number, feel that the recent autism ‘epidemic’ is due primarily to improved screening and diagnosis. In other words, prior to the 1980’s, many people suffering from autism were diagnosed as “slow” or misdiagnosed with another type of mental retardation. Unfortunately, there is no way to quantify this hypothesis.

The alternative is that there is one or more environmental components that we increasingly exposed to that is causing more frequent incidents of autism. Perhaps these environmental factors are acting as a DNA mutagen – a compound that causes DNA changes. If that is the case, we must consider timing. Autistic children bearing causative mutations were born with those mutations. They originated either de novo at a very early stage of development, possibly as a result of exposure to some toxin in utero, or they came from the parents.

The take home message is that researchers do not know what causes autism in children. Most evidence supports that genetics plays the dominant role, but if in fact the frequency of autism is rising, then there are very likely some compounds in our environment that play a role. My Ph.D. supervisor always told me that as scientists we can never “prove” the truth, only disprove falsehoods. That’s where we are with the causes of autism. Researchers have disproved the falsehood that the MMR vaccine causes autism. However, they can’t assuage parents anxieties by collaring the culprit.

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1: Schmitz and Rezaie. The neuropathology of autism: where do we stand? Neuropathology and Applied Neurobiology 2008; 34: 4 -11

2: Pardo and Eberhart. The Neurobiology of Autism. Brain Pathology 2007; 17: 437 -447.

3: Sutcliffe. “Insights into the Pathogenesis of Autism. Science 2008; 321: 208-9.

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