The autism family album
Griffin Hatcher, diagnosed with autism, has now almost completed his first year of public school.
by Sylvia Wrobel
Emory geneticists and clinicians are working with families to unravel autism and its triggers one gene at a time.
At 18 months, Griffin Hatcher had missed some common developmental milestones. He wasn't speaking by 2. At 3, he consistently ignored other children, preferring to lie on the ground and look at the spinning wheels of his toy car. His pediatrician said the boy was fine. So did another doctor. But Griffin's parents, Molly and Brent Hatcher, insisted on a referral.
When the Hatchers arrived at developmental pediatrician Amy Pakula's office, their journey, self-described as an "unpredictable, ever-changing, never-ending process of having a child with autism," picked up speed. Pakula, on faculty at Emory and Marcus Autism Center, told them that while she could offer no cure for autism, they could work together to tackle the problems it produced.
Treatment with Prozac caused neighbors to ask why the boy suddenly seemed less anxious and more engaged. Griffin's days filled with therapy—for speech, the activities of daily life, social interactions, and even occupational therapy on horseback. Following an individualized program prepared by Pakula, the 4-year-old entered a special preschool near his Flowery Branch home, where he could mix with typical kids.
Griffin Hatcher (right) has autism. His brother, Davis (left), does not. With an individualized program developed by an Emory developmental pediatrician, Griffin is able to engage more with people and the activities of daily life. He now attends a public elementary school near his home in Flowery Branch, Georgia.
"Amy never sugar-coated anything, and she went after every problem decisively and aggressively," says Brent, a lawyer. "We felt a tremendous sense of relief and direction, like we now had a team."
When it was time for public school, Pakula prepared another program, outlining in detail the support Griffin would need, including a paraprofessional to accompany him to some classes. It was up to the Hatchers to persuade the school system to accept—and pay for—this plan. They requested detailed reports from everyone who had worked with Griffin, and an outreach specialist from the Emory Autism Center reviewed their case. Griffin's therapists attended the successful meeting with school officials.
Now almost through his first year of public school, Griffin can read, his handwriting is improving, and he performs better socially. On weekends, he asks to go to school. He enjoys his brother Davis, a typical 3-year-old. Abstract thought remains hard, but his memory for details is almost photographic. In downtime, he navigates the computer, playing with his toy guitar to mimic the musicians he finds on YouTube.
The journey, however, remains a challenge. Prozac often keeps Griffin (and his parents) awake much of the night. The Hatchers have to guess when their son is sick or in pain, since he never tells them. They smile pleasantly while friends fret that their children didn't make the football team or get an A. They deal daily with a condition that needs continuous intervention but is not well reimbursed by insurance companies.
The Hatchers are eager to contribute to autism research. Griffin's diagnosis is pervasive developmental disorder, not otherwise specified. Although he has undergone genetic testing for all causes of autism spectrum disorders currently known, nothing has surfaced. On Pakula's recommendation, the family participates in a project at Emory and Marcus that searches for any characteristics to distinguish different varieties of autism and any genes, exposures, or combinations that could explain them. Both parents have spent hours in interviews, giving family histories, submitting to head and ear measurements, being photographed, recalling the smallest of details such as what Molly ate during pregnancy. All of their responses, like their DNA, are now part of a national database that is collecting information on families who have one child with autism.
Molly Hatcher says before their journey with Griffin began, "I used the word 'hope' so casually, to refer to whether it would rain or what I might get for my birthday. Now it means we will learn more about autism and that things will get better for Griffin and others with autism spectrum disorders."
When autism was first described in the 1940s, the blame often was assigned to emotionally distant "refrigerator" mothers who failed to properly bond with their babies. That long-disproved theory—and the pain and guilt it caused so many parents—was one of medicine's most shameful mistakes, says Emory psychiatrist and geneticist Joseph Cubells.
Today, the only known causes of autism are genetic. Increasingly precise genetic assessments, like those being developed at Emory, are correcting another earlier misconception: autism is not a single disorder, any more than cancer or mental illness is. Rather it is a neurobiologically diverse group of autism spectrum disorders (ASDs).
How many are there? Emory geneticist David Ledbetter says that scientists could end up identifying 100 or more different kinds, each with a different genetic basis and each accounting for just a small percentage of total cases. His research, and that of colleague Christa Lese Martin, focuses on genes or chromosomal events that by themselves produce a specific ASD. So far scientists have found at least 15 of these, including the fragile X gene discovered by Emory genetics chair Stephen Warren. Most geneticists now believe that many ASDs result from the interaction of multiple faulty genes, many not yet discovered. To complicate the impact even further, some of these genes are likely to be "susceptibility" genes that not only must interact with each other but also with one or more environmental triggers.
Complicated, says Ledbetter, but encouraging. "We are just beginning to understand how specific genotypes can result in different autistic phenotypes [similar patterns of cognitive, linguistic, and behavioral problems]. That has immense implications for diagnosis and personalized intervention—both behavioral, and eventually, pharmaceutical."The family array
The idea of using genetics to define a disorder is not new. In the 1960s, after scientists found the extra chromosome that causes Down syndrome, they began to discover chromosomal imbalances characterizing specific syndromes almost monthly. Today, thanks to the vast amount of genetic information available from the Human Genome Project and to new high-throughput cytogenetic microarray technology, a similar renaissance is occurring for autism. For example, Emory scientists developed one such technology, EmArray, now used in a clinical laboratory consortium of more than a dozen U.S. laboratories and 40 additional labs in Canada, Europe, and South America.
Microarrays are glass slides or silicon chips to which nucleic acid probes are chemically attached. With these arrays, scientists can examine thousands of genes simultaneously, detecting both chromosomal additions and deletions and subtle differences in genes and gene expression.
The Emory Genetics Laboratory each year provides microarray genetic testing for more than 2,000 children with developmental delays referred by physicians from across the country. Of those, approximately 400 are related to autism. The Emory lab was one of the first to use cytogenetic microarray testing for autism. Using this technique and the current state of knowledge about genetic bases, a specific genetic diagnosis for autism can be identified in 5% to 8% of cases. For others, such as Griffin Hatcher, a specific genetic diagnosis remains elusive.
Behind the Science
Joseph Cubells was one of the first scientists to point to a connection between a deletion syndrome known as 22q11 and autism.
Christa Lese Martin performs studies that identify specific chromosome duplications in families who participate in an autism gene bank.
Stephen Warren discovered the fragile X gene can cause one form of autism and is now working to identify a drug treatment for the faulty gene.
David Ledbetter believes scientists could end up identifying more than 100 different kinds of autism, each with a different genetic basis.
Knowing where to look
But maybe not for long. Families who are willing to share medical information and genes are invaluable to progress in understanding autism, says Ledbetter. The Autism Genetics Resource Exchange (AGRE) was the first collaborative gene bank for autism. More than 1,000 families—a majority of "multiplex" families with two or more children diagnosed with ASD—have contributed clinical and genetic information, including DNA samples, from both affected and unaffected family members to the gene bank. Warren serves on the Autism Speaks board, while Ledbetter serves on AGRE's scientific board. Ledbetter, Christa Martin, and a colleague from UCLA perform cytogenetic and molecular studies that identify specific chromosome duplications among families who participate in the gene bank.
The CDC has been tracking and monitoring the prevalence of autism since 1996. See cdc.gov/ncbddd/autism/actearly for a list of developmental milestones and early signs of autism spectrum disorders.
The NIH provides an extensive description of the various forms of autism at nimh.nih.gov/health/publications/autism/.
The Emory Autism Center (EAC), with the largest staff of specialized autism providers in Georgia, offers diagnosis, family support, and treatment and serves as a vital source of professional training. Last year, the center provided clinical care to more than 840 children and adults and strategies for families to reinforce learning at home and in the community. The center's specialists also consult with community physicians and community and state entities.
The center's Walden Lab School frequently is cited as one of the nation's top five models of early autism intervention, based on integrating children with autism into classes with typically developing toddlers, preschoolers, and pre-kindergarteners. The EAC's Monarch Program provides training and consultation services to schools K–12 that want to improve their educational programs for students with autism. More recently, the EAC has developed services for adolescents and adults, including Asperger's support groups.
Research at the EAC focuses on early intervention, including teaching and social conditioning, work that has changed how autism is treated across the country. EAC researchers also collaborate with the CDC, investigating reports of increased autism prevalence.
A second repository—the Simons Foundation Autism Research Initiative (SFARI)—focuses on "simplex" families, who have one child with ASD. The initiative collects clinic-based assessments and genotyping on the child with ASD as well as the parents and unaffected siblings. Among other research, the initiative sponsors a family collection study led by Martin and conducted by Emory's genetics department, the Emory Autism Center, and Marcus Autism Center (an affiliate of Children's Healthcare of Atlanta that works with children with developmental disabilities and collaborates with Emory, Georgia Tech, and others). As the only SFARI program in the Southeast, Emory is recruiting 150 families from those seen in Atlanta facilities or found through local autism support groups, school psychologists, and other community activities. In all, SFARI hopes to recruit 2,000 simplex families.
As an example of their power and cooperation, the databases are allowing Warren and his colleagues to conduct a study to determine whether genetic variations on the X chromosome play a larger-than-suspected role in causing autism. One reason to think they might is the four-fold excess of males with autism, a pattern that could arise because males, with only one copy of the X chromosome, would be more likely than females to be affected by X-linked mutations. Another reason is that the X chromosome is home to a large number of genes (including fragile X), whose mutations are known to cause problems with brain development.
The study, funded by the Simons Foundation, looks at the entire X chromosome of 300 autistic males, using microarray-based genomic selection technology developed by Emory geneticist Michael Zwick. The ambitious three-step process begins with identification of all deletions, duplications, and gene variations on each boy's X chromosome. Next comes a resequencing (or comparison to the human genome) of the coding portion of every gene, thus detecting any variations in how each gene "codes" or instructs for the production of the protein that carries out the function of the gene. Finally, the research focuses on epigenetic changes, processes outside the gene itself that could influence gene expression, explaining why what looks like the same variation could have different effects from one person to another.
Each week, Amy Pakula sees a dozen new referrals of babies and children with suspected autism at Emory and Marcus Autism Center. She follows more than 500 of these patients throughout the year. Part of her challenge is to take each child's genetic and developmental status and to create an intervention tailored for that child.
"I am the person who personalizes the science to practical services," Pakula says. "We are just beginning to learn that certain combinations of autistic problems cluster together in children with specific genotypes. As research continues, we may learn that certain treatments and behavioral management strategies work better in some of those groups than others."
That's why she recommends that families undergo genetic testing for known causes and why she encourages families to participate in family databases.
"I cannot do my job in the clinic without the geneticists, and they cannot gather the data they need without the help of the families we see," Pakula says.
Not just for kids
Most autism research and organizations focus on children. But these kids grow up. Every week psychiatric geneticist Joseph Cubells sees a handful of autistic adults, and he suspects some people with the most severe cases went undiagnosed in earlier eras and today are either confined to mental institutions or among the homeless.
Although Cubells sees many patients with Asperger's (a form of autism with normal, sometimes above normal, language and intellectual development), most of his ASD patients come from physician referrals for co-existing psychiatric problems, from depression to psychosis. The challenge of getting feedback from often linguistically impaired patients, coupled with a paucity of research on psychotropic medications in adults with ASD, makes his job a big one. Many patients arrive already taking a potentially toxic mix of four or five prescriptions accumulated over the years by a series of clinicians desperate to do something.
"One of the rewards of working with adults with autism," says Cubells, "is that it almost invariably involves working with families. Patients whose families stay involved generally do better."
Families also are helping researchers learn what to expect from patients with similar genotypes, says Cubells. Take, for example, the deletion syndrome known as 22q11, for which Cubells and colleagues at Emory and Children's Healthcare of Atlanta have developed a new clinic. Affecting one birth in 4,000, the chromosomal anomaly is second only to Down syndrome in frequency of occurrence but far more variable. It's one of the 15 or so known causes of autism, and more than a third of patients with the deletion have an autism diagnosis. An even higher number exhibit autistic-related problems of communication, social interaction, and stereotypic behavior.
An unknown number of people with the 22q11 deletion are "clinically silent," at least in early years, but they may develop serious heart, renal, immunologic, and endocrine disorders. Schizophrenia also may emerge in up to 30% of these adults, something not seen in other forms of ASD.
A study by Cubells, co-investigator Opal Ousley, and other Emory and Children's researchers was one of the first to point to an overlap between the 22q11 deletion abnormality and autism. Currently, the researchers are comparing autistic features in patients known to have 22q11 deletion syndrome with autistic features in patients with other chromosomal disorders that show a high rate of autism, such as fragile X. It is already known that the deletion is often characterized by poor early language development. "If these studies show other systematic characteristics, we'll be closer to understanding the relationship between specific genes and certain behaviors," says Cubells.
That could lead to better diagnosis. For example, Ousley already is working on possible biomarkers for this form of autism and others as well as specialized behavioral and educational interventions. Eventually, scientists believe this genetic understanding could identify drug targets to counteract the actions of a specific genetic change.
The fragile X hope
There's a long way to go before that happens, but Stephen Warren sees hope. He may be on the verge of identifying a drug treatment to compensate for a faulty fragile X gene, known to cause one form of autism. Five percent of people with autism carry this gene. Furthermore, 30% of people with fragile X meet the criteria for autism in the Diagnostic and Statistical Manual, the bible for practitioners diagnosing psychiatric disorders, and 80% of those with fragile X show autistic traits, such as repetitive behaviors.
More autism resources
An affiliate of Children's Healthcare of Atlanta, Marcus Autism Center works with children with autism and related disorders. Marcus Autism Center diagnoses and treats children with a wide range of neurologic problems, including autism spectrum disorders. They work with parents to find ways to help children cope with their disability, including carefully managed therapy to teach children to circumvent barriers posed by the disability.
The Early Intervention Program is an evidence-based program for children, age 18 months to 8 years, with autism spectrum disorders, providing intervention services for families who share a goal of transitioning children into public or private school systems. The Pediatric Neurodevelopmental Center provides evaluation and treatment for childrenby developmental pediatricians, child and adolescent psychiatrists, social workers, and others.
The Marcus School offers educational programs for children who exhibit aggressive and destructive behaviors, helping them learn to modify behaviors so they can participate in neighborhood schools and enjoy a better quality of life at home. Marcus and Children's collaborate closely with Emory, Georgia Tech, and others to provide autism resources for the community.
For more information
Emory Autism Center
Emory Genetics Laboratory
Marcus Autism Center
Soon after discovering the fragile X gene, Warren discovered the protein it produced. That enabled him to develop the first biologic diagnostic test and better explain why fragile X could have such a wide range of effects, depending on how much protein is produced by the damaged gene.
It also allowed him to identify a compound that causes fruit flies with a fragile X-like disorder to give up their fragile X-type behaviors and develop more normal biochemistry and brain wiring (Nature Chemical Biology, April 2008). Getting a drug from the lab to patients can take as long as 15 years, so Warren deliberately tested only compounds that already had survived FDA safety testing. With that hurdle eliminated, he anticipates clinical trials could begin in humans within the next two years. If the compound works as well in humans with fragile X as it has in the insect model, this treatment could open the door for many other forms of ASDs.
When autism was first recognized, moms got the blame. Today, say Emory researchers, mothers and fathers deserve much of the credit for advances in understanding this disorder. As advocates, lobbyists, spokespersons, and almost universal participants in the family-initiated AGRE and SFARI programs, families touched by autism are research's biggest supporters.
The unusually strong alliance of scientists, clinicians, and families comes at a time of incredible new research tools, says Warren. For understanding autism, it's the perfect storm. The Human Genome Project and technology that can spot differences in individual genomes, such as EmArray and Zwick's genomic selection microarray, enable scientists to take data provided by families and chip away at autism, one ASD subset, one chromosomal irregularity, one gene, at a time. What they are finding may help personalize treatment and, eventually, as Warren's fruit flies suggest, mitigate, even prevent its problems.