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Progress in Understanding "Model" Syndromes May Lead to Breakthroughs in Understanding Autism

November 06, 2007

Eight months ago researchers in Scotland found that they could reverse the debilitating defects and certain death in mice carrying the Rett syndrome gene, well after the mice had regressed into the most severe stages of disease. Although the specific treatment approach was not one that is directly applicable to autism treatment, the successful "rescue" of adult animals taught us that developmental disorders, those that begin in infancy, apparently still have a potential to be reversed later in life.

Each time a new study such as this reports on successes in other developmental disorders, families ask whether the advances will have any impact on autism. Indeed, much can be gleaned from the multiple developmental disorders which share autism as a feature. Research into disorders with co-morbid autism is essential because it allows researchers to search for the commonalities that can explain the biological link to autism.

Autism is very common among patients with Rett syndrome, one of the five Pervasive Developmental Disorders. In Fragile X syndrome, approximately 30% of the affected individuals also have a diagnosis of autism, in Tuberous Sclerosis the number is closer to 50%, and in Timothy syndrome, a very rare disorder, it is upwards of 60%. Unlike autism, all of these are known to be single-gene disorders, and as research reveals the genes involved, the affected biological pathways are beginning to be uncovered. It is for this reason that many leading autism researchers are now exploring these disorders as "model disorders" for autism.

One research field that has the potential to significantly impact autism research is that of Fragile X, a complex neurodevelopmental disorder that shares several similarities and overlap with autism. An estimated 2-5% of autistic individuals carry the Fragile X mutation. In addition to the 30% of Fragile X individuals that receive a diagnosis of autism, almost all Fragile X individuals display at least some autistic features, including abnormal and repetitive behaviors, language disabilities, and social anxiety. In fact, autism presented by children with Fragile X is clinically indistinguishable from autism presented by children without Fragile X. Indeed, before the Fragile X gene was discovered, many children with Fragile X were lumped together with children with idiopathic autism (autism of unknown cause). Because of the similarities between Fragile X and autism, scientists have argued that at some level the two disorders share common underlying pathologies. Interestingly, this appears to include enlarged head size and brain white matter abnormalities, two of the most reproducible findings in idiopathic autism to date.

Yet, unlike the complicated etiology of autism, Fragile X results from the mutation of a single gene, FMR1. If we can understand how the loss of function of one gene can lead to autistic behaviors such as social communication deficits, it will help us better understand the biology of autism. In addition, since not all children with Fragile X have autism, this is also a scientific opportunity to better understand what factors other than the mutated gene might lead to autism in some individuals and only Fragile X syndrome in others.

Even more significantly, as the genes for these other syndromes are discovered, the impacted biological pathways, the molecular underpinnings, are rapidly being identified. Because specific proteins and molecules can provide targets for possible pharmaceutical interventions, researchers in these disorders are much further along in the development of potential targeted treatments. For instance, just like autism, scientists have thought for a long time there would be no cure for Fragile X. However, over just the past three years, research by Drs. Mark Bear and Susumu Tonegawa from Massachusetts Institute of Technology and many others have shown that at least in animal models, you can actually reverse the Fragile X and autistic symptoms with experimental compounds. Although the underlying disease-causing biological mechanisms may end up being different, given the similarities between the disorders, it gives the scientists much hope that perhaps we can do the same for autism too.

In summary, in short time the field of Fragile X has managed to move from complicated behavioral symptoms, to plausible molecular underpinnings, to the potential of therapeutic intervention. Given the complex biological and behavioral nature of autism, scientific progress in autism will require the continuous influx of new scientists and ideas from the many related disciplines. The scientific impact of research in related disorders such as Fragile X, Rett, Tuberous Sclerosis and others is of the highest significance - the developing links between autism and these disorders may finally provide autism researchers with a window into the etiology, underlying pathology, and treatment of autism. The hope this can inspire is priceless.