Although metabolic processes have been implicated in the pathogenesis of other neurological disorders, far less attention has been given to the investigation of potential metabolic dysfunction in autism. In 2007, Autism Speaks awarded a grant to Ved Chauhan, Ph.D., to allow him to organize a special colloquium highlighting metabolic issues in autism. Held on March 3rd in conjunction with the annual American Society for Neurochemistry conference, five speakers presented their perspectives on the evidence for a metabolic component in autism to an audience of approximately 150 researchers.

Jay Gargus, M.D., Ph.D., began the special session by speaking about mitochondrial dysfunction, opening his talk with a commentary on the Federal Government's recent settlement of one autism case with mitochondrial dysfunction, and MMR vaccine, and the timely nature of the meeting. Recent studies have shown that a subset of autistic subjects is associated with mitochondrial energy deficiency that is identified as impairment in fat and carbohydrate metabolism. This type of mitochondrial defiency is similar, but more subtle than those seen in classic mitochondrial defects. Mild mitochondrial dysfunction has also been found in the subset of autistic patients with a genetic defect on chromosome 15. Dr. Gargus also discussed rare cases of familial autism associated with sudden infant death syndrome (SIDS) or associated with abnormalities in cellular calcium homeostasis.

The second speaker, Martha Herbert, M.D., Ph.D., discussed the involvement of whole body systems, rather than only the brain, in the development of autism. Both the brain volume and tissue changes that she and others have described appear to occur postnatally, and Dr. Herbert suggested that they may be related to immune activation and oxidative stress. She presented a model for how these neuropathological changes in early brain development may be due to postnatal consequences of metabolic disturbances. In this case, the structural brain changes in autism (e.g. brain enlargement) would be the outcome of chronic metabolic disturbances (e.g. brain immune activation) rather than the primary locus of developmental disturbance. Moreover, such metabolic disturbances may be persisting beyond the most sensitive windows of brain development and chronically impacting nervous system function.

Abha Chauhan's, Ph.D., talk focused on the role of oxidative stress, immune abnormalities and inflammatory reactions in the development of autism. Oxidative stress is a process that occurs when the generation of free radicals during normal metabolic processes in the cell overwhelms the normal defense mechanisms and leads to damage or death of the cells. Dr. Chauhan suggested a potential mechanism linking oxidative stress with immune abnormalities, inflammation, mitochondrial dysfunction, impaired energy metabolism and excitotoxicity, leading to clinical symptoms and pathogenesis of autism. She presented the evidence that autistic subjects have increased oxidative stress, and that their immune response and/or inflammatory response may be compromised. She also discussed that environmental and genetic factors may increase vulnerability to oxidative stress in autism. Dr. Chauhan's studies have shown that there is increased peroxidation of lipids, and decreased serum levels of anti-oxidant proteins, namely, ceruloplasmin (copper transport protein) and transferrin (iron transport protein) in autism. In their studies, a correlation was observed between reduced levels of these proteins and regression in children with autism. Dr. Chauhan also presented evidence that suggests an imbalance in immunoglobulins levels and altered serum levels of inflammatory proteins in children with autism.

Jill James, Ph.D., focused her comments on glutathione metabolism. Glutathione is important for protecting biological molecules from oxidation. Dr. James reported altered levels of glutathione in the blood and lymphoblasts from children with autism. She also spoke about regulation of normal reduction /oxidation homeostasis and cellular methylation, and the finding that levels of molecules controlling the methylation reaction are altered in autism. Such impairment could create a fragile state with a reduced ability to detoxify environmental exposures. Dr. James emphasized that individualized treatment strategies directed toward correcting metabolic imbalance may improve some autistic behaviors.

To conclude the session, S. Hossein Fatemi, M.D., Ph.D., spoke about the role of neurodevelopmental genes in the etiology and treatment of autism. His laboratory has studied autism using several approaches including postmortem analyses and animal models. He discussed three different findings pertaining to autism: (1) Disruption in the Reelin (an important secretory glycoprotein responsible for normal layering of the brain) signaling system, (2) Altered expression of apoptotic proteins, proteins that promote cell death, in different regions of autistic subjects, and (3) Elevated levels of glial fibrillary acidic protein (GFAP), a protein indicative of cellular injury, and perturbed neuronal migration processes. He also talked about altered expression of phosphodiesterases, which play an important role in controlling the levels of important intracellular signaling molecules, in the brains of autism. Through his multi-disciplinary approach to studying autism, Dr. Fatemi's laboratory has identified several potential genes that may form the basis of novel therapeutic avenues for treatment of autism.

Through presentation of these data at such a large international conference, the goal was to promote broader exploration in autism by investigators specializing in neurochemistry and related subjects. To this end, all of the speakers spoke of the clinical relevance of clarifying metabolic dysfunction in autism, especially emphasizing the importance of developing research to address the functional impact of metabolic changes, and of clinical practices to recognize the metabolic consequences of subtoxic environmental insults. Autism Speaks would like to thank Dr. Ved Chauhan for his efforts in organizing and chairing this conference.