Clinical Biomarkers

The powerful genetic and molecular biology tools that have brought so many advances in medicine over the past decades have been somewhat stymied by autism’s heterogeneity. Not only does the disorder present itself differently from one child to the next, but known genetic mutations account for only a small percentage of autism cases (usually those in which the autistic features are part of a larger syndrome such as Angelman or Fragile X). Moreover, emerging evidence suggests that a specific genetic background (chromosomal aberrations, point mutations, etc.) is insufficient to produce a specific autistic phenotype – other factors, such as environmental toxins, oxidative stress, and neuroinflammation, play a significant role in its development. Autism thus may result from complex interactions between environmental factors and genetic backgrounds. At the cellular level, such interactions can be manifested via imbalances of critical metabolites, the small molecules essential for proper cellular functions. Indeed, mitochondrial dysfunction, carnitine deficiency, abnormalities in cholesterol metabolism and other metabolic defects have been reported in autism.

Despite all the strides we have made over the past two decades, we know the cause of only 10-20% autism cases. For the majority of idiopathic autism cases, there are thus no suitable models to study the molecular mechanisms underlying their phenotypes. Fortunately, we now have new tools that enable us to translate in vivo findings to mechanistic studies in vitro.  In these sets of projects, we utilize these tools and start from the discrepancies of in vivo neurological findings in idiopathic autism patients to develop a bench model of the patient-specific disease. To identify diagnostic and prognostic markers of autism, we use multimodal imaging of patients with de novo autism and their healthy siblings. To study the molecular mechanisms underlying the observed findings in vivo, we use induced pluripotent stem cells (iPSCs) technology to derive neuroprogenitor cells and neurons from the selected patients and their healthy siblings. The principal goal of these projects is to elucidate the framework of idiopathic autism in the context of gene-metabolome networks and neuronal connectivity.