June 2010- It was 1943 when a now-extinct journal, The Nervous Child, published “Autistic Disturbances of Affective Contact,” describing 11 cases of “Kanner Syndrome.” The author was Johns Hopkins child psychiatrist Leo Kanner, whose encounter in 1938 with Donald T.—a 5-year-old brought to his Baltimore clinic from Forest, Miss.—led him to investigate a “behavior pattern not known to me or anyone else theretofore.”
Universally known now as autism, this common, complex neurobiological disorder that inhibits a person’s ability to communicate and develop social relationships today affects not 4 in 10,000, which was Kanner’s estimate, but 1 in 110. The prevalence of autism increased 57 percent from 2002 to 2006. The Centers for Disease Control and Prevention have called it a national public health crisis.
Rebecca Landa, director of
the Center for Autism and
Related Disorders at the
Kennedy Krieger Institute and
professor of psychiatry at
The rise of autism—described by some as epidemic—is attributable at least in part to public- and pediatrician-aimed awareness campaigns, according to early-detection specialist Rebecca Landa, director of the Center for Autism and Related Disorders at the Kennedy Krieger Institute and a professor of psychiatry at Johns Hopkins, whose ongoing research shows the benefits of early intervention.
Diagnosable medical conditions and single-gene defects, such as fragile X syndrome, together account for fewer than 10 percent of cases. What causes the remaining 90-plus percent of causes is unknown. Autism’s apparent escalation and baffling causes have fueled shrill and divisive controversies. But since a seminal twins study published in 1977, it’s clear that autism is a heritable condition: Siblings of an autistic child are at increased risk, none more dramatically so than identical twins.
“Autism is probably the most heritable of the common diseases,” says Gary Goldstein, president of Kennedy Krieger Institute and a professor of neurology and pediatrics at Johns Hopkins University School of Medicine.
“Its genetic link is probably the tightest of all the complex diseases such as diabetes, schizophrenia, and depression, which run in families but cannot be attributed to a single gene like classic Mendelian diseases.”
Piece by piece, researchers at Johns Hopkins and elsewhere are discovering genetic mutations associated with autism. Recent findings support an emerging consensus within the scientific community that autism is caused in part by many “rare variants,” or genetic changes found in less than one percent of the population, according to the Autism Genome Project.
Gary Goldstein, president of Kennedy
Krieger Institute and a professor of
neurology and pediatrics at Johns
Hopkins University School of Medicine
A study published in Nature in October 2009 by a Hopkins-led international team showed several genetic links to autism, chief among them a variant of semaphorin 5A, a signaling molecule whose protein product controls nerve connections in the brain.
This finding, suggesting that autism could result from differences in how nervous system connections are made in the brain, came on the heels of a Hopkins team having collared a strikingly common, single-letter variation in a culprit gene called contactin-associated protein-like 2, a protein known to affect a certain class of neurons at the synapse — the connecting point between two nerve cells.
“Our attempt, from the classical human genetic paradigm, has been to collaboratively collect a very large group of similarly diagnosed patients who can be studied using the most powerful tools we have to try to understand which genes are likely involved in autism,” says Aravinda Chakravarti, a professor in the Institute of Genetic Medicine and investigator in both the semaphorin and contactin studies.
The discovery of so-called autism genes holds no practical value—yet—for the thousand patients of Kennedy Krieger’s autism center, one of the largest in the nation. Gene hunting doesn’t have immediate payoffs for patients.
In fact, the genetics of autism is anything but clean, Goldstein says. It now seems naïve, he adds, to have thought there might be a handful of autism genes, each tidily conferring a 20 percent risk, thereby allowing for a neat predictive test.
Genes, by themselves, probably don’t cause autism, Goldstein says, and wouldn’t make good targets for therapy.
Aravinda Chakravarti, a professor
in the Institute of Genetic Medicine
Most likely, it’s a combination of genetic variants—deletions, duplications and/or insertions—spread across the genome that makes an individual susceptible to some provocateur: an epigenetic, environmental or immunological factor (Please see sidebar) that tips the balance and causes a disorder on the very wide spectrum defined as autism.
Goldstein cites a study published June 9, 2010 in Nature, which found that for every 1,000 copy number variations (predominantly deletions, or pieces of chromosome missing) in the general, or control, population, the autistic group had 1,200: an increase by 1.2-fold. Though not useful today to an individual with autism, the research is nonetheless exciting, he says, because when scientists looked at the genes statistically associated with autism compared to controls, they found them clustering together in pathways relating to synapses, thereby implicating a neural pathway as potentially important in autism. This pathway—a collective of protein products manufactured by genes—is inherently more targetable for therapy than a gene.
Synapses are always establishing new connections as we experience life, Goldstein points out. In other words, the brain is “plastic.” It’s not a done-deal at birth, or six months, or six years, but constantly being formed. Goldstein holds out hope that the search for genes may ultimately lead to a pharmaceutical fix for a dysfunctional synaptic pathway, and that, in turn, would allow autistic kids to be more receptive to the already effective educational and behavioral interventions pioneered by Landa.
“Saying why this mutation leads to this disease is important. That’s the part we don’t get yet.”
--by Maryalice Yakutchik