Mitochondrial Dysfunction Linked to Autism

Megan Brooks

January 31, 2011

January 31, 2011 — Mitochondrial dysfunction (MD) is more common in children with autism and autism spectrum disorder (ASD) than the general population, a comprehensive systematic review and meta-analysis of relevant research confirms.

Mitochondrial dysfunction "may play a significant role in contributing to the symptoms of autism and is generally underrecognized in these children," Daniel A. Rossignol, MD, of the International Child Development Resource Center, Melbourne, Florida, told Medscape Medical News.

Dr. Daniel A. Rossignol

"Testing for mitochondrial dysfunction is available, and early treatment might lead to better long-term developmental outcomes," said Dr. Rossignol, who coauthored the review with Richard E. Frye, MD, PhD, of the University of Texas in Houston.

The report was published online January 25 in Molecular Psychiatry.

Commenting on the study Cecilia Giulivi, PhD, professor of biochemistry and metabolic regulation, at the University of California, Davis, who was not involved in the analysis, said, "At this point, it looks like there is a higher incidence of mitochondrial disease in autism, much higher than we suspected."

She noted, however, that testing for MD "is not a trivial task [and] we need more research to come up with a consensus of diagnostic tests to run. In addition, maybe other metabolic syndromes should be looked into," Dr. Giulivi said.

The primary objectives of the analysis were to identify features of MD in the general population of children with ASD and compare characteristics of MD in children with ASD and concomitant significant and severe MD with that of ASD children without MD and non-ASD children with MD.

They included 68 relevant published articles in a qualitative synthesis, including 18 studies with a total of 112 children with ASD and MD.

Genetics Not the Culprit

The results showed the prevalence of MD in the general population of children with ASD is approximately 5% (95% confidence interval [CI], 3.2% – 6.9%), which is 500% higher than the general population prevalence of 0.01%. For a variety of reasons, "this 5% value is most likely an underestimation," Dr. Rossignol said.

It also appears that one-third or more of children with autism may have some type of dysfunction in their mitochondria. On the basis of laboratory testing, the prevalence of abnormal biomarker values of MD, including lactate, pyruvate, carnitine, and ubiquinone, was high in children with ASD, much higher than the prevalence of MD. Some of these markers correlated with the severity of ASD.

Most of the 112 children with ASD and MD (79%) had no an identifiable genetic abnormality that could account for the MD.

"The mitochondrial dysfunction and disease reported in autism are related to a genetic abnormality in only 1 out of 5 children; meaning that a majority of these children have something else contributing to this dysfunction, which might include multiple environmental factors, such as toxins, oxidative stress, inflammation, and decreased levels of antioxidants," said Dr. Rossignol.

"Clearly, mitochondrial function is a ripe area of research when investigating the biological mechanism(s) of action of environmental toxicant exposures and indigenous abnormalities associated with ASD," the study authors write.

Loss of Social Skills

Children with ASD and MD had some distinct characteristics compared with the general population of children with ASD. In 12 studies, "children with autism and mitochondrial problems were more likely to lose acquired skills compared to children with autism in general," said Dr. Rossignol. However, it was not clear whether MD contributed to or caused the reported regression.

In addition to a higher prevalence of developmental regression (52%), seizures (41%), motor delay (51%), and gastrointestinal abnormalities (74%), such as reflux and constipation, also appear to be significantly more common in children with ASD and MD relative to children with just ASD.

Currently, "testing for mitochondrial problems in children with autism is rarely done, and we feel that testing should be routine, especially in children with regression or loss of skills," said Dr. Rossignol. "This is important because early recognition of mitochondrial problems in autism might lead to better outcomes in children with autism."

Dr. Rossignol and Dr. Frye note in their report that published studies looking at treatment for ASD and MD are limited. However, some studies have suggested that treatment with mitochondrial cofactor supplementation, including antioxidants, carnitine, coenzyme Q10, and B vitamins, may improve mitochondrial function and behavior in some children with ASD.

"A therapeutic trial of mitochondrial cofactors and antioxidants may be reasonable in children with ASD/MD," the study authors conclude. Carnitine, they say, may be particularly helpful in children with ASD because carnitine deficiency has been implicated in ASD, and some studies have reported improvements with the use of carnitine in ASD.

The researchers emphasize, however, that systematic studies documenting the efficacy of this and other potential treatments for MD in children with ASD are generally lacking.

Need for Longitudinal Studies

A small study by Dr. Giulivi and colleagues showed that impaired mitochondrial function and mitochondrial DNA abnormalities, including overreplication and deletions, were more common in children with autism than in typically developing children (Giulivi et al. JAMA. 2010;304:2389-2396).

"According to our study and those of others, there is evidence for MD in typical autism and ASD," Dr. Giulivi said. "However, I don't think that we know the role of this MD, meaning if it is related to the etiology (cause) or consequence of another underlying altered pathway.

"In any case [cause or consequence], a decline in mitochondrial function [below the threshold for a given tissue] and especially in highly aerobic tissues, such as brain, will have an impact on cellular energy and, in addition, maybe on other mitochondria-dependent pathways, such as heme metabolism," Dr. Giulivi noted.

She also made the point that most studies to date have been cross-sectional and therefore, "unless it is a longitudinal one, we cannot assess the role of MD in ASD and autism."

Dr. Rossignol and Dr. Frye point out that many of the studies they reviewed had a number of limitations, including "small sample sizes, referral or publication biases, and variability in protocols for selecting children for MD workup, collecting mitochondrial biomarkers, and defining MD." Only 39% of the ASD/MD studies reviewed noted the criterion used for diagnosing MD.

They agree with Dr. Giulivi that further studies are needed to further define the role of MD in ASD.

This research was funded in part by the Autism Research Institute and the Jane Botsford Johnson Foundation. Dr. Rossignol has 2 children with ASD and is a practicing primary care physician who treats ASD children with standard and integrative treatments. Dr. Frye provides expert testimony for children with MDs who may have been injured from vaccines. Funds from such testimony are used to support research on the biological basis of neurodevelopmental disorders. Dr. Giulivi has disclosed no relevant financial relationships.

Mol Psychiatry. Published online January 25, 2011.

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