Autism Spectrum and Neurodevelopmental Disorders

Clinical Update for Psychiatrists

By Wendy Froehlich, MD and Lawrence K. Fung, MD, PhD | December 11, 2012

Dr Froehlich is a Pediatrician and Child and Adolescent Psychiatrist and Dr Fung is a Child and Adolescent Psychiatry Fellow in the department of psychiatry and behavioral sciences at Stanford University in California. Drs Froehlich and Fung report no conflicts of interest concerning the subject matter of this article.

With recent advancements in the understanding of cellular mechanisms and biological pathways involved in specific genetic syndromes associated with ASDs, novel therapeutics are also being developed and targeted for specific genetic disorders. For example, the affected gene in fragile X syndrome codes for a negative regulator of the metabotropic glutamate receptor mGluR5. Thus, disturbance of the gene leads to enhanced excitatory activity at this receptor. mGluR5 antagonists such as AFQ056 are showing promising results in preliminary clinical trials of individuals with full mutations of FMR1.^62,63

In addition to altered activity at the mGluR5 receptor, animal models of fragile X syndrome also demonstrate abnormalities in GABA physiology.⁶⁴ GABA_B receptor agonists, such as arbaclofen, are being tested with encouraging findings in patients with fragile X syndrome.⁶⁵ In tuberous sclerosis, a genetic disorder associated with a defect in tumor suppressor genes regulating the mTOR pathway, dysregulation of mTOR leads to multiple organ tumors and an increased risk of autism. The mTOR inhibitor rapamycin has been shown to have beneficial effects against tumors in humans, and there are ongoing trials investigating the effects of rapamycin on cognition, behavior, and neurological symptoms.⁶⁶

Syndrome-specific treatments such as the examples described above may eventually prove beneficial not only for the original syndrome in which they are trialed but also for other syndromes caused by genes disrupting similar or overlapping biological pathways.

Conclusion and future directions

Knowledge about the underlying biology of ASDs is rapidly advancing through genetic, neuroimaging, and environmental studies while concurrent investigations are focusing on improving detection, diagnosis, and treatment. With improvements in technology, scientific techniques are beginning to combine various study methodologies that complement each other.

On the cellular level, the development of induced pluripotent stem cell technology allows researchers to engineer neurons and other human cell lines by genetically reprogramming cells from tissues such as skin. This technology creates a unique opportunity to study human neurons directly and is being used to investigate genetic syndromes associated with autism. In addition to establishing neuronal phenotypes throughout development, it also allows researchers to test potential pharmacological agents that may reverse cellular abnormalities.^67,68

On the circuit level, further defining neurocircuitry by linking molecular biomarkers with neuroimaging (eg, MRI coupled with positron emission tomography with specific radioligand for molecular target) will likely lead to new insights, thus setting the stage for improved circuit-based and molecular-based treatment strategies for specific symptoms. Finally, future research may begin to focus more on gene-environment interactions, epigenetics, and not only early diagnosis and improved treatment but also prevention.

Pages: 1 2 3 4

Also in this Special Report

Treatment of Traumatic Stress Disorder in Children and Adolescents

The Adolescent Brain Is Different

Traumatic Brain Injury in Children and Adolescents

Developmental Psychopathology Comes of Age

Autism Spectrum and Neurodevelopmental Disorders

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Autism Spectrum and Neurodevelopmental Disorders

Clinical Update for Psychiatrists

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