Mitochondrial Dysfunction More Common in Children With Autism

Deborah Brauser

December 02, 2010

December 2, 2010 — Impaired mitochondrial function and mitochondrial DNA (mtDNA) abnormalities, including overreplication and deletions, are more common in children with autism than in typically developing children, new research suggests.

"We are really excited about this. Mitochondrial dysfunction or mitochondrial deficit has been a recurring question in the autism field," lead study author Cecilia Giulivi, PhD, professor in the Department of Molecular Biosciences at the University of California, Davis, told Medscape Medical News.

"We wanted to answer this question using an epidemiologically well-defined group of children and looking at different biomarkers of this dysfunction from lymphocytes, which you can get from a simple blood draw without having to do any muscle biopsies. And we found that 50% to 80% of the children with autism had one or more of these biomarkers," explained Dr. Giulivi.

Although the investigators urge caution in regards to a cause and effect association and in generalizing the findings from this exploratory study of just 20 children, they note that mitochondrial dysfunction "could greatly amplify and propagate brain dysfunction such as that found in autism."

Dr. Giulivi added that children with mitochondrial diseases may present conditions such as exercise intolerance, seizures, and cognitive decline. "Many of these characteristics are shared by children with autism. That's why clinicians should ask questions about these symptoms, such as about exercise cramping and pains or vision or hearing problems. Most parents just don't know enough to provide this information on their own."

The study was published in the December 1 issue of the Journal of the American Medical Association.

Biomarkers Evaluated

Dr. Cecilia Giulivi

Dysfunction in mitochondria is already associated with several neurological conditions, including Parkinson's disease, Alzheimer's disease, schizophrenia, and bipolar disorder.

"Mitochondria are the main powerhouse of the cell; cells take all of their energy from it. And one of the main tissues affected by mitochondrial dysfunction is the brain," said Dr. Giulivi.

In 2003, the Childhood Autism Risks from Genetics and Environment (CHARGE) study was launched to evaluate "modifiable factors in autism etiology and markers of biological dysregulation that may provide mechanistic clues," write the researchers.

This ongoing study recruited children from 22 counties in northern California and parts of Los Angeles County between the ages of 2 and 5 years who were diagnosed as having autism, as well as age-, sex-, and ethnically matched, typically developing children (healthy controls).

For this subanalysis, the investigators assessed peripheral blood lymphocytes from 10 of the children with full spectrum autism (as diagnosed on both the Autism Diagnostic Inventory–Revised and the Autism Diagnostic Observation Schedule) and 10 of the healthy controls from CHARGE (90% male in both groups) for either mitochondrial dysfunction or mtDNA abnormalities.

The main outcome measures included "oxidative phosphorylation capacity, mtDNA copy number and deletions, mitochondrial rate of hydrogen peroxide production, and plasma lactate and pyruvate," write the study authors.

Overreplication for this study was defined as "mean values of the ratio of mtDNA to nuclear DNA that were significantly higher and different from the mean control values."

Analysis of mtDNA deletions included comparisons of cytochrome b (CYTB) to nicotinamide adenine dinucleotide (NADH) dehydrogenase 1 (ND1) genes, as well as NADH dyhdrogenase 4 (ND4) to ND1.

Hydrogen peroxide production and individual pyruvate dehydrogenase complex (PDHC) activity were both determined with the following formula: nanomoles x [minutes x milligrams of protein]−1.

Significant Dysfunction

Results showed that "the reduced...NADH oxidase activity (normalized to citrate synthase activity) in lymphocytic mitochondria from children with autism was significantly lower compared with controls" (mean, 4.4 vs 12; P = .001), researchers report, a finding that signifies far less oxygen consumption.

"A 66% decrease is significant," said Dr. Giulivi in a release. "When these levels are lower, you have less capability to produce adenosine triphosphate to pay for cellular work. Even if this decrease is considered moderate, deficits in mitochondrial energy output do not have to be dismissed, for they could be exacerbated or evidenced during the perinatal period but appear subclinical in the adult years."

The autism group also had significantly higher mean plasma pyruvate levels than did the healthy controls (0.23 vs 0.08 mM, P = .02), leading to a lower lactate-to-pyruvate ratio (6 vs 12, P = .002) and lower PDHC activity (mean, 1.0 vs 2.3; P = .01).

They also had higher mitochondrial rates of hydrogen peroxide production at complex 1 (0.15 vs 0.07, P = .03) and complex 3 (0.34 vs 0.16, P = .02).

"As a result of having levels twice as high as those of [the healthy controls], the cells of children with autism were exposed to higher oxidative stress," explained Dr. Giuvili.

In addition, 8 of the children in the autism group had high pyruvate levels, but only 2 had higher lactate levels. A total of 6 had "complex 1 activity below control range values."

Although the mean mtDNA copy number was not significantly different between the groups, half of the children with autism had mtDNA overreplication, which led to a higher mean value than the healthy controls (239 vs 179).

"Usually, when you have more copies of [mtDNA], you're trying to overcome some kind of damage or dysfunction, especially to oxidative stress. This was actually the first test we did, and we were really surprised and excited about this higher number," explained Dr. Giulivi.

Of the 5 autistic children who had overreplication, 2 also had deletions in the ratio of CYTB to ND1. No deletions in mtDNA genes were found in the healthy controls.

The investigators note that, overall, their study observed defective or abnormal lymphocytic mitochondria in the children with autism based on their findings of low PDHC activity accompanied by low lactate-to-pyruvate ratios, impaired complex I alone or in combination, enhanced rate of hydrogen peroxide production, and mtDNA overreplication and/or deletions.

Study limitations cited included the small number of study participants and that "inferences about a cause and effect association between mitochondrial dysfunction and typical autism cannot be made in a cross-sectional study.

"More research is needed to understand the molecular causes of [this disorder] and how this and other neurometabolic defects may contribute to autism or related phenotypes," the study authors write.

Dr. Giulivi noted that her team plans to extend the study to more children and would like to also look at the parents and unaffected siblings of these children. "In the extended studies, we want to look for unique biomarkers for autism. Are any of the activities that we measure unique to autism or can they be found in other neurological diseases or syndromes?

"Autism is essentially diagnosed with behavioral problems. If we can do something to find the biomarkers before the behavioral problems show up, that would be really good for early diagnosis, intervention therapies, and more," she concluded.

The study was funded in part by Autism Speaks, the 2008 Medical Investigations of Neurodevelopment Disorders Institute Pilot Research Grant, the MIND Institute Gift Funds, and grants from the National Institute of Environmental Health Sciences. The study authors have disclosed no relevant financial relationships.

JAMA. 2010;304:2389-2396.

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