Wednesday, December 1, 2010

New Study on Mitochondrial Dysfunction in Autism

A new study by Cecilia Giulivi and colleagues confirms that the mitochondria are dysfunctional in autism. This study once again shows that the defective mitochondria make it difficult for children with autism to handle the oxidative stress of day to day environmental challenges. The research paper was published in the recent issue of the Journal of American Medical Association Vol: 304, Number 21, Page: 2389. December 1, 2010.

The researchers from the University of California at Davis studied the mitochondrial function in children aged 2-5 years with established diagnosis of autism and compared them to age matched but genetically unrelated typically developing children. They used the data from the CHARGE (Childhood Autism Risk From Genes and Environment) study in California, which was a population based, case controlled investigation.

Mitochondria are small organelles that are responsible for the energy production needed for the cell’s function. It has been suggested that the mitochondrial dysfunction may influence the social and cognitive deficits and the altered energy metabolism may affect the processes highly dependent on energy such as neurodevelopment.

Unlike previous studies, where the mitochondria from muscle tissue were analyzed, the authors of this study studied the mitochondria from the blood samples of these children. They studied the oxidative activity of the mitochondrial enzyme NADH, hydrogen peroxide production, plasma pyruvate and lactate levels, deletions and over-replications of the mitochondrial DNA.

The results show that the oxidative activity in the mitochondria of children with autism was one third (4.4 vs 12) that of the typical children, and the mitochondrial dependent oxygen consumption was impaired. “The increased oxygen reactive species production observed in this study is consistent with the higher ratio of oxidized NADH to reduced glutathione in the cells and the mitochondria of the children with ASD, supporting the concept that these cells from children with autism present higher oxidative stress”, the authors note.

80% of the affected children had three times higher level of pyruvate in the plasma. This was considered to be due to the deficiency of PDHC (pyruvate dehydrogenase complex). PDHC deficiency could contribute to brain dysfunction. Since the gene encoding the PDHC is located on the X chromosome, mutation in the X-linked gene may explain the 4:1 ratio of autism between boys and girls.

The study also showed that the children with autism had twice the mitochondrial rates of hydrogen peroxide production. “ Thus the mitochondria in autism had a lower oxidative phosphorylation capacity but also contributed to the overall cellular oxidative stress”, the authors commented.

Of the children with autism, 20 % had deletions and 50 % had over-replication of the genes in the mitochondria. It is hypothesized that the over replication of the mitochondrial DNA may be an attempt by the cell to overcome the defective mitochondria in the cells.

The authors state that “whether the mitochondrial dysfunction in children with autism is primary (genetic and possibly causative factor) or secondary to as-yet unknown (environmental injury) event, remains the subject of future work”.

The funding for this study was provided by University of California, MIND Institute Gift Funds, National Institute of Environmental Health Sciences, and Autism Speaks. The study is published in JAMA, December 1, 2010, The abstract of the article can be accessed here: Abstract

Khalid Rehman, M.D.

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