The mission of the Seaver Autism Center for Research and Treatment is to discover the causes of autism spectrum disorders (ASD) and to develop breakthrough interventions. The Center functions as a collaborative effort that combines psychiatry, psychology, neurology, molecular genetics, and neuroimaging into an integrated series of unique research programs. The Center also includes the Seaver Autism Clinical Program, which provides state-of-the-art assessment and treatment in ASD.
Genetics in the Service of Patient Care
Within the past 12 months there have been major changes in the understanding of the etiology of ASD. The Seaver Autism Center has been a founding site of several large genetic consortia, including the Autism Genome Project (AGP) and the Autism Case Control (ACC) study. These initiatives have identified several new causal genetic loci underlying specific cases of ASD. This has led to a profound shift in our thinking, such that ASD can now be conceived of as having multiple independent causes where in many cases the cause can be largely attributed to a specific etiological event. This perspective, called the “multiple rare variant hypothesis,” raises both great challenges and great opportunities. One challenge is that this complexity may necessitate studying and/or treating different forms of ASD differently. The opportunities are that with these rare causal variants, it becomes possible to give a medical diagnosis for some cases of ASD, to have more predictive power regarding risk of recurrence in siblings, and to think about novel targeted therapeutic approaches.
To take a concrete example from recent work carried out at the Seaver Autism Center, we identified the cause of ASD in a boy as a novel mutation in the PTEN gene. Once this mutation was identified, it could be concluded that this was the cause of the ASD, which immediately led to genetic counseling opportunities. The mother of the child was pregnant but, once she was informed by genetic counselors that the mutation in her affected child occurred spontaneously and would not recur, her concern about her unborn child was ameliorated. Furthermore, PTEN mutations are associated with tumor syndromes, and as a result of identifying the mutation, a surveillance program could be put into place.
With such causal genetic variants, one can explicitly model them in mouse and other model systems. For example, several groups have mutated the mouse PTEN gene and studied neurobiology and behavior of these mice, which should ultimately lead to therapies based on the insights learned from these animal models. The most dramatic example of such an approach is the recent large-scale clinical trial in Fragile X Syndrome (FXS). FXS accounts for approximately 2% of ASD cases. Detailed analysis of mouse and other models of FXS gave rise to a hypothesis that over-expression of a glutamate receptor in the synapse underlies some of the cognitive deficits in the disorder. As a result of this hypothesis, drugs that targeted this receptor were tried in mice and other model organisms that had mutations that mimic FXS, and these drugs were shown to correct some of the cellular and behavioral deficits observed in the mice. Since January 2008, there is now a large-scale clinical trial in FXS with a drug targeting the metabotropic glutamate receptor.
In another example of progress, one of the most exciting breakthroughs in the last 12 months in regenerative medicine is the ability to take skin cells (fibroblasts) and revert them to stem cells using a procedure now called the Yamanaka protocol. These cells, called induced pluripotent stem cells (iPSCs), can then be differentiated into other cells including neurons (brain cells). This allows us, for the first time, to examine neurons from patients to tease out molecular and cellular deficits. Rather than looking at gene expression or methylation in blood cells that may have no relevance to processes in the brain, we can look at these processes directly in brain cells. This procedure may have important implications for the study of ASD that we are actively pursuing.
Opportunities at the Seaver Autism Center
In recognition of these advances and an ever-changing field, we have introduced state-of-the-art genetic testing to clinical practice and research at the Seaver Autism Center. As part of this, we have partnered with the Department of Genetics and Genomic Sciences and the Institute of Personalized Medicine at Mount Sinai School of Medicine to translate the research findings from the Seaver Autism Center and from other laboratories around the world into genetic tests to supplement behavioral assessments in ASD. The Seaver Autism Center has always positioned itself to be a leader in defining the standard of care in ASD. It is our vision that using state-of-the-art molecular genetic, neurobiological, and clinical resources, we are now posed to make significant breakthroughs in identifying genetic subtypes of ASD and developing targeted treatments.
In addition to genetic and neuroimaging studies, we are currently conducting important studies examining novel therapeutics, including social skills group therapy, oxytocin, and LUMINENZ-ATTM. Our Clinical Program continues to offer Assessment & Evaluation Services, including diagnostic testing, neuropsychological testing, academic testing, and psychiatric evaluations. Evaluation can include genetic analyses. In addition, we offer comprehensive Treatment Services, including medication management, social skills groups, parent training sessions, cognitive behavior therapy, and a sibling support program. And as part of our commitment to education and community care, we also have a Community Outreach & Training Program that provides lectures and workshops to parent groups, agencies, and schools. Finally, the Seaver Autism Center hosts an annual conference to address current scientific trends and discoveries that will be held this year in April, 2010.
Dr. Joseph D. Buxbaum, PhD, is Director at the Seaver Autism Center for Research and Treatment and the G. Harold and Leila Y. Mathers Professor at the Departments of Psychiatry, Neuroscience, and Genetics and Genomic Sciences at Mount Sinai School of Medicine in New York.