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Mitochondrial Dysfunction Identified in Autistic Children

Talan, Jamie

doi: 10.1097/01.NT.0000393955.80388.e3
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LEAD STUDY AUTHOR CECILIA GIULIVI (right) and a lab member look for mitochondrial dysfunction in samples from autistic children

LEAD STUDY AUTHOR CECILIA GIULIVI (right) and a lab member look for mitochondrial dysfunction in samples from autistic children

In a small study, investigators reported evidence of mitochondrial abnormalities across several tests compared to healthy controls.

Children with typical autism are more likely to have impaired mitochondrial function, confirming earlier studies reporting a similar link, according to study by investigators at the University of California-Davis (UC-Davis).

The researchers, led by Cecilia Giulivi, PhD, a mitochondrial expert who is a professor in the Department of Molecular Biosciences at UC-Davis, said that it is impossible to know whether the abnormalities identified are a cause or an effect of the disease process.

Reported in the Dec. 1 Journal of the American Medical Association (JAMA), the small study included 10 children with autism and 10 healthy age-matched controls. The children were randomly selected from Northern California subjects who previously had participated in the 1,600-participant Childhood Autism Risk from Genetics and the Environment (CHARGE) Study and who also consented to return for a subsequent study known as CHARGE-BACK, conducted by the UC Davis Center for Children's Environmental Health and Disease Prevention.

Dr. Giulivi and her colleagues collected plasma as well as lymphocytes and granulocytes from the children — between 2 and 5 years old — with severe language and behavior deficits and the controls.



The scientists isolated DNA from lymphocytes and looked for mitochondrial DNA abnormalities, mitochondrial dysfunction, and oxidative stress in children. As part of their analysis of mtDNA deletions, they compared cytochrome b (CYTB) to nicotinamide adenine dinucleotide (NADH) dehydrogenase 1 (ND1) genes, as well as NADH dyhdrogenase 4 (ND4) to ND1. The mean mtDNA copy number was not significantly different between the groups, but half of the children with autism had mtDNA overreplication, which led to a higher mean value than the healthy controls (239 vs. 179).

“Differences in mitochondrial DNA parameters between control children and those with autism could stem from either higher oxidative stress or inadequate removal of these harmful species,” the researchers wrote.

The children with autism had evidence of mitochondrial abnormalities across several tests compared to the controls. The mitochondria of the autistic children had reduced nicotinamide adenine dinucleotide oxidase activity, an average of 4.4 versus 12 for the normal controls (p=.001). Six of the 10 autistic children also had lower complex I activity and eight of the 10 had higher plasma pyruvate levels than the controls. By contrast, only two of 10 had higher lactate than the control children. The mitochondria from the autistic sample also had higher rates of hydrogen peroxide production compared to controls.But with all of these findings there is still no indication, at least from this study, whether these mitochondrial abnormalities are “a cause or a consequence of another process that accompanies autism,” said Dr. Giulivi. Altered energy metabolism, she explained, “may influence the social and cognitive deficits in autism.

“Mitochondrial dysfunction could greatly amplify and propagate brain dysfunction, such as that found in autism, given that the highest levels of mitochondrial DNA abnormalities are observed in post-mitotic tissue with high energy demands (such as the brain),” said Dr. Giulivi.

The plasma pyruvate and lactate-to-pyruvate ratios suggest pyruvate dehydrogenase (PDHC) deficiency and indeed when they looked at PDHC complex activity they found half the levels in autistic children than in the controls. Defects in PDHC lead to problems in energy metabolism because pyruvate is one of the main fuels for mitochondria.

These mitochondrial problems can create less capacity for the cells to produce ATP, the energy currency of the cell that pays for all cellular work. In the brain, as well as heart, ATP only comes from mitochondria. (Outside of the brain, lymphocytes can take their energy from mitochondria and other independent pathways.)

“We will expand the number of patients and controls to a larger population in terms of a cross-sectional and longitudinal studies to try to understand the basis for the mitochondrial dysfunction,” Dr. Giulivi said. “It is possible that we are facing a combination of genetic and environmental stressors.”

Investigators participating in the UC Davis Center for Children's Environmental Health and Disease Prevention, an interdisciplinary project jointly funded by the National Institute of Environmental Health and the U.S. Environmental Protection Agency, have access to an enormous amount of data collected on these children.

The Center is conducting several large studies with a specific focus on understanding how environmental exposures influence susceptibility and the severity of autism. Scientists have asked questions about prenatal care, birth and diet, as well as collecting maternal milk and exposures such as dust in their homes.

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Salvatore DiMauro, MD, the Lucy G. Moses Professor of Neurology at Columbia University Medical Center, said that “people have been talking about mitochondrial dysfunction in autism for years and this sample is extremely small. I don't quite understand what the fuss is all about.”

Still, he added, the authors of the JAMA study were not exaggerating any of their findings. “I must give the authors credit for being cautious in their conclusions,” he said.

Richard Kelley, MD, PhD, director of the Division of Metabolism at the Kennedy Kreiger Institute at Johns Hopkins Medical Institutions, and his colleagues published a paper in PLoS One in November 2008 and had very similar findings, especially with regard to complex I deficiency.

“Although a deficiency of mitochondrial complex I may be the most identifiable cause of regressive autism,” he continued, “the relatively mild biochemical abnormalities often are missed by routine metabolic testing.”

“I have been working with autism for 25 years and in some cases, maybe 20 to 30 percent,” he continued. “I see in the plasma amino acid profiles, specific patterns that signal abnormalities of mitochondrial function, most often complex I deficiency.”

Dr. Kelley noted that mitochondria are exquisitely sensitive to stress and these children may be born with mild mitochondrial abnormalities that may not cause problems until the system is taxed by some environmental hit, most probably infection and inflammation. He said that his clinic uses a comprehensive, non-invasive approach to screen for mitochondrial dysfunction.



Dr. Giulivi said that her study did not address the question of causality, but she noted the investigators are designing experiments to figure out how early the mitochondrial dysfunction occurs and exactly how it alters the development of brain circuits involved in autism spectrum disorders.

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Giulivi C, Zhang YF, Pessah IN, et al. Mitochondrial dysfunction in autism. JAMA 2010; 304(2): 2389-2396.
    ©2011 American Academy of Neurology