Mitochondrial dysfunction in autism

May combine two claims.

Eight of 10 children with autism had higher pyruvate levels, but only 2 had higher lactate levels compared with controls.

“Eight of 10 cases had higher pyruvate levels but only 2 cases had higher lactate levels compared with controls.”

• Also stated in: § RESULTS · plain

  “Two of 10 children with autism had high lactate levels and 8 had high pyruvate levels.”

May combine two claims.

Succinate oxidase, cytochrome c oxidase, and adenosine triphosphatase activities in children with autism were not different from control values.

“However, the values for succinate oxidase, cytochrome c oxidase, and adenosine triphosphatase activities in children with autism were not different from the control values (Table 2).”

May combine two claims.

Low NADH oxidase activity was the most common deficiency (8 of 10), followed by succinate oxidase (6 of 10), ATPase or complex V (4 of 10), and complex IV or cytochrome c oxidase (3 of 10).

“Using the control values to define a reference range (set at 99% CI) for the individual data, low NADH oxidase activity was the most common deficiency (8 of 10), followed by succinate oxidase (6 of 10), adenosine triphosphatase or complex V (4 of 10), and complex IV or cytochrome c oxidase (3 of 10) (Table 2).”

May combine two claims.

Mitochondrial DNA overreplication was found in 5 of 10 children with autism, with a mean mtDNA-to-nuclear-DNA ratio of 239 versus 179 in controls (P=10−4).

“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).”

• Also stated in: § RESULTS · plain

  “However, 5 of 10 children with autism presented mtDNA overreplication leading to a higher mean value of 239 (95% CI, 217-239) compared with 179 (95% CI, 165-193) for control children (P=10−4).”

May combine two claims.

Deletions at the cytochrome b segment were observed in 2 of 10 children with autism, with a mean cytochrome b-to-ND1 ratio of 0.80 versus 0.99 in controls (P=.01).

“Two of 10 children with autism presented deletions at the segment of cytochrome b (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), whereas there were no deletions at the segment encoded by ND4 (Table 3).”

May combine two claims.

No statistically significant differences were found in mean glycemia or lactate levels between children with autism and controls.

“No statistically significant differences were found in the mean values for glycemia or lactate level between cases and controls.”

May combine two claims.

The increased reactive oxygen species production observed is consistent with the higher ratio of oxidized NADH to reduced glutathione in lymphoblastoid cells and mitochondria from children with ASD, supporting higher oxidative stress in these cells.

“The increased reactive oxygen species production observed in this exploratory study is consistent with the higher ratio of oxidized NADH to reduced glutathione in lymphoblastoid cells and mitochondria from children with ASD,33 supporting the concept that these cells from children with autism present higher oxidative stress.”

• cites [33] James SJ Rose S Melnyk S Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism FASEB J 2009 23 8 2374 2383 19307255 PMC2717775Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Cases and controls had similar age, sex, and ethnicity, although controls were more likely to be nonwhite.

“Cases and controls had similar age, sex, and ethnicity, although controls were more likely to be nonwhite.”

May combine two claims.

Ten group comparisons were made; 6 were significant at α=.05 and 2 at α=.005 using Bonferroni correction.

“Ten group comparisons were made in this study; of these comparisons, 6 were significant at the α level of .05 and 2 were significant at the α level of .005 (ie, using the conservative Bonferroni correction).”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

The possibility of type I errors should be considered.

“Second, the possibility of type I errors should be considered.”

May combine two claims.

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

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

Probably not a substantial claim: may not pass S3 (load-bearing).

The differences between cases and controls could represent confounding due to possible associations between mitochondrial dysfunction and race, which differed by case-control status.

“Fourth, the differences observed between our cases and controls could represent confounding effects due to possible associations between mitochondrial dysfunction and race, which also differed by case-control status.”

May combine two claims.

Increased reactive oxygen species production induced by dysfunctional mitochondria could elicit chronic oxidative stress that enhances mtDNA replication and possibly mtDNA repair.

“Increased reactive oxygen species production induced by dysfunctional mitochondria could elicit chronic oxidative stress that enhances mtDNA replication, and possibly mtDNA repair.”

Classified as probably not a substantial claim. May combine two claims.

Although skeletal muscle can tolerate this shift in metabolism, consequences for brain function could be devastating due to its heavy reliance on mitochondrial oxidative phosphorylation.

“Although skeletal muscle can tolerate this shift in metabolism, consequences for brain function could be devastating due to its heavy reliance on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes.7,29”

• cites [7] Schapira AH Human complex I defects in neurodegenerative diseases Biochim Biophys Acta 1998 1364 2 261 270 9593927Not checked yet

  Not checked in the free run.

• cites [29] Erecinska M Nelson D Silver IA Metabolic and energetic properties of isolated nerve ending particles (synaptosomes) Bioenergetics 1996 1277 1-2 13 34 8950370Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Experiments were run in triplicate and repeated at least 2 times in independent experiments unless noted otherwise.

“Experiments were run in triplicate and repeated at least 2 times in independent experiments unless noted otherwise.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

Caution should be exercised in generalizing the findings to a larger population.

“Nevertheless, caution should be exercised with regard to the generalization of findings in a larger population.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The higher mtDNA copy number could represent a compensatory mechanism to increase wild-type mtDNA templates and maintain normal mitochondrial transcript levels.

“The higher mtDNA copy number could represent a compensatory mechanism to increase the number of wild-type mtDNA templates and maintain normal levels of mitochondrial transcripts.35”

• cites [35] Williams RS Mitochondrial gene expression in mammalian striated muscle J Biol Chem 1986 261 26 12390 12394 3745193Not checked yet

  Not checked in the free run.

May combine two claims.

Demographic and clinical data for the larger CHARGE study population were comparable with the subset, except the 10 autism cases were somewhat higher functioning.

“Demographic and clinical data for the larger CHARGE study population were comparable with those for the subset used in this study, except that the 10 cases with autism were somewhat higher functioning than the cases with autism from the original CHARGE study sample; therefore, the case-control differences in cognitive and adaptive scores were somewhat attenuated (TABLE 1).”

Classified as probably not a substantial claim. May combine two claims.

Controls were screened for ASD with the Social Communication Questionnaire, and those above cutoff were fully assessed with the ADI-R and ADOS.

“The Social Communication Questionnaire was used to screen for ASD among those recruited as general population controls. Children who scored above the screening cutoff were fully assessed using the ADI-R and the ADOS.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The investigators attempted to achieve comparable age, sex, and race/ethnicity across groups to minimize confounding.

“We also attempted to achieve comparable age, sex, and race/ethnicity across groups to minimize confounding socio-demographic factors that may be surrogates for genetic, epigenetic, or cultural background.”

May combine two claims.

A lactate-to-pyruvate ratio of 12 corresponds to an oxidized NADH to reduced NADH ratio of 750:1, and a ratio of 6 corresponds to 1500:1.

“The lactate-to-pyruvate ratio reflects the redox state of the cytosolic compartment,28 such that a lactate-to-pyruvate ratio of 12 (as in controls) indicates a ratio of oxidized NADH to reduced NADH of 750:1 and a lactate-to-pyruvate ratio of 6 (as in autism) indicates a ratio of oxidized NADH to reduced NADH of 1500:1.”

• cites [28] Krebs HA Pyridine nucleotides and rate control Symp Soc Exp Biol 1973 27 299 318 4148884Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Children from the general population scoring at 71 or above on both Mullen and Vineland scales and without ASD qualified as typically developing controls.

“children from the general population scoring at 71 or above on both of these scales who did not have an ASD qualified as typically developing controls.”

May combine two claims.

None of the children had been previously diagnosed with a genetic syndrome or had indications of genetic syndromes.

“Fifth, none of the children in this study had been previously diagnosed with a genetic syndrome or had any indications of genetic syndromes as determined by developmental pediatricians at the Medical Investigations of Neurodevelopmental Disorders Institute.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Alternatively, the mtDNA abnormalities could result from defective replication and/or repair of mtDNA of primary genetic or secondary oxidative-damage origins.

“Alternatively, these mtDNA abnormalities could result from defective replication and/or repair of mtDNA of primary (genetic36) or secondary (oxidative damage to single base pairs inflicted by free radicals37) origins.”

• cites [36] Zeviani M Spinazzola A Carelli V Nuclear genes in mitochondrial disorders Curr Opin Genet Dev 2003 13 3 262 270 12787788Not checked yet

  Not checked in the free run.

• cites [37] Giulivi C Boveris A Cadenas E Hydroxyl radical generation during mitochondrial electron transfer and the formation of 8-hydroxydesoxyguanosine in mitochondrial DNA Arch Biochem Biophys 1995 316 2 909 916 7864650Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The study protocol followed the Declaration of Helsinki and was approved by the institutional review board; written informed consent was obtained from a parent.

“The study protocol follows the ethical guidelines of the Declaration of Helsinki15 and was approved by the institutional review board of the University of California, Davis, School of Medicine. All participants enrolled in the study had written informed consent provided by a parent.”

• cites [15] World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects 8 11 2010 http://www.hpci.ch/files/documents/guidelines.hh_gl_helsinki.pdf. Accessibility verifiedNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Inferences about a cause-and-effect association between mitochondrial dysfunction and typical autism cannot be made in a cross-sectional study.

“Sixth, inferences about a cause and effect association between mitochondrial dysfunction and typical autism cannot be made in a cross-sectional study.”

May combine two claims.

The cases in this substudy were somewhat higher functioning than those from the original study, lessening the difference with controls.

“Third, the cases in this substudy were somewhat higher functioning than those from the original study, lessening the difference with controls.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Some complex activities above the control interval in 2 cases might represent an attempt to compensate for low PDHC activities or other mitochondrial dysfunction.

“Some complex activities were found above the control interval in 2 cases (Table 2 and eTable 2 at http://www.jama.com). This might represent an attempt to compensate for the low PDHC activities (or other mitochondrial dysfunction), as has been observed in other mitochondrial disorders.30”

• cites [30] Barrientos A In vivo and in organello assessment of OXPHOS activities Methods 2002 26 4 307 316 12054921Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The number of individuals assessed for mitochondrial activities was relatively small, although the sample size based on statistical power was adequate.

“First, the number of individuals in which mitochondrial activities were assessed was relatively small, although the sample size (based on statistical power for discovery of effects) was adequate.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Defects in genes other than those tested could have been present in these samples.

“Nevertheless, defects (other than deletions) in genes (other than those tested) could have been present in these samples as recently reported in another study of ASD.38”

• cites [38] Pinto D Pagnamenta AT Klei L Functional impact of global rare copy number variation in autism spectrum disorders Nature 2010 466 7304 368 372 20531469 PMC3021798Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

A final CHARGE study diagnosis of autism required meeting ADI-R criteria on communication, social, and repetitive behavior domains and scoring at or above the ADOS cutoff for autistic disorder.

“A final CHARGE study diagnosis of autism was defined as meeting criteria on the communication, social, and repetitive behavior domains of the ADI-R and scoring at or above the cutoff for autistic disorder on the ADOS (module 1, 2, or 3).”

May combine two claims.

Differences in mtDNA parameters between control children and children with autism could stem from either higher oxidative stress or inadequate removal of harmful species.

“Differences in mtDNA parameters between control children and those with autism could stem from either higher oxidative stress33 or inadequate removal of these harmful species.34”

• cites [33] James SJ Rose S Melnyk S Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism FASEB J 2009 23 8 2374 2383 19307255 PMC2717775Not checked yet

  Not checked in the free run.

• cites [34] Ming X Johnson WG Stenroos ES Genetic variant of glutathione peroxidase 1 in autism Brain Dev 2010 32 2 105 109 19195803Not checked yet

  Not checked in the free run.