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The sooner the diagnosis, the better the outcome
BOSTON—Aimed at identifying autism before a child's language and developmental milestones are delayed, Boston Children's Hospital researchers have developed a prototype blood test for the disorder that they hope will result in a faster and earlier diagnosis.
The preliminary results of the blood test, described Dec. 5 in the online journal PLOS ONE, led to a diagnosis of autism in about two-thirds of patients before clear symptoms begin to appear. Studies have shown the average age of an autism diagnosis is four-and-a-half years old, although parents begin suspecting autism at an average age of 19 months.
"Since brain biopsy isn't a viable option for research, we asked ourselves whether blood could serve as a proxy for gene expression in the brain," says Dr. Isaac Kohane, director of the Boston Children's Hospital Informatics Program (CHIP). "We found that it could, though we and others were initially skeptical."
Dr. Sek Won Kong, a CHIP investigator, and his research team analyzed blood samples from 66 male patients with autism from Boston Children's and other hospitals and the Autism Consortium of Boston, then compared them with 33 age-matched boys without autism. Using microarrays, they looked for RNA signatures reflecting differences in gene activity or expression between the two groups.
Analyzing the blood samples, Kong and colleagues flagged 489 genes as having distinct expression patterns in the autism group, then narrowed this to a group of 55 genes that correctly identified or ruled out autism in 76 percent of samples. They validated their findings in a second group of 104 male and female patients with autism and 82 controls, achieving an overall classification accuracy of 68 percent (73 percent for males and 64 percent for females).
The gene signature approach, which Boston Children's Hospital has licensed exclusively to SynapDx of Southborough, Mass., can potentially diagnose autism far more often than the genetic tests currently available. Those tests look for variety of autism-related mutations—from small "spelling" changes to lost or extra copies of a gene or genes, or wholesale chromosome abnormalities. However, the known mutations account for fewer than 20 percent of autism cases.
Kohane stresses that the test was not intended as a general screening tool, but as an aid to help provide guidance after suspecting autism—and would not supplant behavior testing.
"It's clear that no single mutation or even a single pathway is responsible for all cases," Kohane says. "By looking at this 55-gene signature, which can capture disruptions in multiple pathways at once, we can say with about 70 percent accuracy, 'this child does not have autism,' or 'this child could be at risk,' putting him at the head of the queue for early intervention and evaluation. And we can do it relatively inexpensively and quickly."
Kohane also believes autism can develop in ways other than genetics. The 55 genes for which expression was altered also suggest more than one path to autism, he says. He and his team found that based on their genetic signatures, subjects with autism clustered into four subgroups marked by changes in different biological pathways. Synaptic pathways, specifically long-term potentiation pathways—which are essential for memory and learning—and neurotrophic pathways signal neurons to survive, develop and grow.
Most current theories of autism focus on disordered synapses, says Kohane, speculating that brain development in autism may be impaired by abnormal immune responses to infections and other stressors prenatally or during infancy.
"In our sample, about half of the autism cases had some sort of alteration on immune pathways, synaptic pathways or both," Kong states.
For example, chemokines (inflammatory chemical messengers that recruit immune cells to fight infections) have been found to be overexpressed in some neurocognitive disorders, and animal studies have found that prenatal infections are associated with autism-like features in offspring, notes Kohane.
"We know that if a mother has rheumatoid arthritis or the father has type 1 diabetes, there is an increased risk of autism in the child," Kohane says. "Studies have also found an increase in autoimmune disease, just as autism is increasing."
Kohane's next step in studying the efficacy of the RNA blood analysis will be to conduct a sibling study.
"Our research is of siblings in the Boston area to test whether the siblings of autism patients have a higher tendency to develop autism," he says. "We know identical twins have a 70 to 90 percent of both being diagnosed with autism. There is believed to be a 20- to 30-percent chance of finding autism in a sibling of a child diagnosed with autism."
The results of this study will be available in 2013, he says.