Tracing autism's roots

Move over vaccines. The most promising research into the disorder is emerging from the quest for the genes that underlie it.

By David Stipp, contributor

Do vaccinations cause autism?

Despite the fact that one major study after another has answered no since the issue came to the fore around 2000, 54% of parents of autistic children in a 2006 survey said the answer is yes. In fact, the parents named vaccines more frequently than any other suspected cause.

It's likely that even more parents blame vaccines now in the wake of the recent brouhaha about 9-year-old Hannah Poling. The government agreed that her family was entitled to a settlement from a federal vaccine injury fund based on their claim that childhood vaccinations aggravated a rare metabolic disorder in Hannah, triggering autism symptoms.

Anti-vaccine advocates hailed the decision as unprecedented support for their view that either thimerosal, a mercury-based preservative once widely used in vaccines, or the vaccines themselves, are behind many cases of the brain disorder.

Federal health officials countered that the Poling case says nothing in general about autism and vaccines - they're concerned about parents refusing immunizations for their kids. Hannah, they noted, has been diagnosed with a genetic defect in her mitochondria - energy dynamos within cells. The mitochondrial disorder can cause a form of autism, and its symptoms often aren't apparent until stress, such as a fever, overtaxes energy-deficient cells. Vaccinations occasionally induce fever, hence the ones Hannah got as a toddler may have combined with her disorder to bring on signs of autism. Or they might not have - Hannah had a history of ear infections, and the associated fever might have aggravated her mitochondrial disorder.
Complex genetics

The ruckus highlights one of the great ironies surrounding autism: While anti-vaccine groups and thousands of anxious parents are fixated on a single environmental factor - vaccines - as a possible cause of autism, most of the exciting insights on its causes in recent years have come from the study of its complex genetic underpinnings.

The quickening quest for genes underlying autism promises both to improve diagnosis and treatment, and to help resolve burning questions about the disorder, such as why surveys suggest it is three times more prevalent in New Jersey than in Alabama.

The central role genes play in autism became manifest after scientists realized about two decades ago that there are different forms of the disorder involving varied sets of genes. Called "autism spectrum disorders," or ASDs, they include Asperger's syndrome, which causes social deficits but not the cognitive delays usually associated with autism.

Using this broad definition in studies of twins, researchers have repeatedly shown that if one identical twin is diagnosed with autism, the other has about a 90% chance of developing an ASD. Geneticists have concluded from such studies that most, and perhaps the great majority, of ASDs involve a genetic component.

There is a new wrinkle to the genetic research however. Based on family studies, scientists have long characterized autism-linked genes as "heritable." But recent research shows a surprisingly large number of mutations tied to autism are "de novo" glitches that arise spontaneously in children whose parents don't carry them.

Such spontaneous mutations have come to light by studying so-called "structural changes" in the genome, which, if DNA's chemical letters were arranged in book form, would consist of largish mistakes such as duplicated and missing pages. A recent study that got much less attention than the Poling story showed that 7% of kids with autism carry structural changes not found in their parents, compared with less than 1% of such glitches seen in the general population.

"This is really exciting, and a lot of people haven't picked up on it yet," says geneticist Stephen Scherer, a co-author of the study at the Hospital for Sick Children in Toronto.
Spontaneous mutations

It's likely that many more such changes will be linked to ASDs as researchers examine a wider array of cases with new gene-scanning tools. Some researchers even theorize that the majority of autism cases stem from such spontaneous mutations.

Why would genes linked to autism be so mutation-prone?

Consider a mutation on chromosome 16 recently tied to autism. The glitch is in a DNA region containing so-called "morpheus" genes, which changed very rapidly as evolution produced ever brainier apes. The genes may well help shape cognitive capacities specific to apes and humans, including ones affected by autism.

Since fast mutation goes hand in hand with fast evolution, it's likely that the new autism-linked gene lies in a DNA "hotspot" prone to spontaneous mutation. In short, the same phenomenon that helped to rapidly evolve our braininess may contribute to autism.

For all geneticists' excitement about such discoveries, few if any of them rule out environmental contributors to autism, such as exposure to certain drugs, chemicals or infections during pregnancy. As Hannah Poling's case suggests, environmental factors may conspire with predisposing genes to bring on autism.

But pinpointing the culprits among the tens of thousands of possible environmental factors - everything from air pollutants to ultrasound examinations during pregnancy to multiple immunizations given to kids all at once - is a monumental problem that could take decades to solve with traditional human studies. Parents of autistic children can't wait that long.

But gene research is helping on this front too, by speeding the quest for environmental contributors. For instance, researchers are developing various mouse models of autism by mimicking mutations linked to the disorder in the rodents. Such animals are very useful for testing suspected environmental contributors to autism.
Early intervention

Genetics research should also help explode the myth that the effects of ASD-susceptibility genes are set in stone. By helping to identify the disorder during infancy, genetic tests promise to enable early intervention that wards off some of autism's worst effects. (Autism usually isn't diagnosed until speech delays or social deficits surface after infancy.)

By teaching parents how to bolster social engagement in babies with ASD-susceptibility genes - for instance, by removing distracting objects so that a parent's face is the most salient object in a baby's visual field - "you might even be able to prevent the full syndrome from emerging," says Geri Dawson, chief science officer of Autism Speaks, an advocacy group based in New York. Toronto's Scherer adds that his team's genetic research has already led to early interventions in several cases involving families participating in studies.

Tricky questions remain about interpreting tests for autism-linked genes. But several companies, such as Mukilteo, Wash.-based CombiMatrix, France's IntegraGen SA and Melville, N.Y.-based Population Diagnostics Inc., have already introduced such diagnostics or announced plans to develop them.

Over time such tests will enable ever more precise classification of autism cases according to underlying causes. Among other things, that should help researchers sort out what's driving the extraordinarily high prevalence observed in areas such as New Jersey. Even better, it will provide a way to detect the special vulnerabilities of kids like Hannah Poling before symptoms appear - and perhaps even keep such children out of harm's way.