Mitochondrial dysfunction in autism. JAMA 2010

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Mitochondrial dysfunction in autism. JAMA 2010


Giulivi C, Zhang Y-F, Omanska-Klusek A, et al. Mitochondrial dysfunction in autism. JAMA 2010 Dec 1;304(21):2389-2396.






Vol. 304 No. 21, December 1, 2010


Preliminary Communication


Mitochondrial Dysfunction in Autism

Cecilia Giulivi, PhD; Yi-Fan Zhang, BS; Alicja Omanska-Klusek, MS; Catherine Ross-Inta, BS; Sarah Wong, BS; Irva Hertz-Picciotto, PhD; Flora Tassone, PhD; Isaac N. Pessah, PhD

JAMA. 2010;304(21):2389-2396. doi:10.1001/jama.2010.1706

Context  Impaired mitochondrial function may influence processes highly dependent on energy, such as neurodevelopment, and contribute to autism. No studies have evaluated mitochondrial dysfunction and mitochondrial DNA (mtDNA) abnormalities in a well-defined population of children with autism.

Objective  To evaluate mitochondrial defects in children with autism.

Design, Setting, and Patients  Observational study using data collected from patients aged 2 to 5 years who were a subset of children participating in the Childhood Autism Risk From Genes and Environment study in California, which is a population-based, case-control investigation with confirmed autism cases and age-matched, genetically unrelated, typically developing controls, that was launched in 2003 and is still ongoing. Mitochondrial dysfunction and mtDNA abnormalities were evaluated in lymphocytes from 10 children with autism and 10 controls.

Main Outcome Measures  Oxidative phosphorylation capacity, mtDNA copy number and deletions, mitochondrial rate of hydrogen peroxide production, and plasma lactate and pyruvate.

Results  The reduced nicotinamide adenine dinucleotide (NADH) oxidase activity (normalized to citrate synthase activity) in lymphocytic mitochondria from children with autism was significantly lower compared with controls (mean, 4.4 [95% confidence interval {CI}, 2.8-6.0] vs 12 [95% CI, 8-16], respectively; P = .001). The majority of children with autism (6 of 10) had complex I activity below control range values. Higher plasma pyruvate levels were found in children with autism compared with controls (0.23 mM [95% CI, 0.15-0.31 mM] vs 0.08 mM [95% CI, 0.04-0.12 mM], respectively; P = .02). Eight of 10 cases had higher pyruvate levels but only 2 cases had higher lactate levels compared with controls. These results were consistent with the lower pyruvate dehydrogenase activity observed in children with autism compared with controls (1.0 [95% CI, 0.6-1.4] nmol x [min x mg protein]–1 vs 2.3 [95% CI, 1.7-2.9] nmol x [min x mg protein]–1, respectively; P = .01). Children with autism had higher mitochondrial rates of hydrogen peroxide production compared with controls (0.34 [95% CI, 0.26-0.42] nmol x [min x mg of protein]–1 vs 0.16 [95% CI, 0.12-0.20] nmol x [min x mg protein]–1 by complex III; P = .02). Mitochondrial DNA overreplication was found in 5 cases (mean ratio of mtDNA to nuclear DNA: 239 [95% CI, 217-239] vs 179 [95% CI, 165-193] in controls; P = 10–4). Deletions at the segment of cytochrome b were observed in 2 cases (ratio of cytochrome b to ND1: 0.80 [95% CI, 0.68-0.92] vs 0.99 [95% CI, 0.93-1.05] for controls; P = .01).

Conclusion  In this exploratory study, children with autism were more likely to have mitochondrial dysfunction, mtDNA overreplication, and mtDNA deletions than typically developing children.


Author Affiliations: Department of Molecular Biosciences, School of Veterinary Medicine (Drs Giulivi and Pessah, Mr Zhang, and Mss Omanska-Klusek, Ross-Inta, and Wong), Departments of Public Health Sciences (Dr Hertz-Picciotto) and Biochemistry and Molecular Medicine (Dr Tassone), School of Medicine (Drs Hertz-Picciotto and Tassone), and Center for Children's Environmental Health and Disease Prevention (Drs Hertz-Picciotto and Pessah), and Medical Investigations of Neurodevelopmental Disorders Institute (Drs Hertz-Picciotto, Tassone, and Pessah), University of California, Davis.


© 2010 American Medical Association.