The New Mito-Autism Study in JAMA

A new study was released today in JAMA which looked at, in part, mitochondrial DNA overreplication in a sample of ten autistic children between the ages of 2 and 5 and ten matched controls.  Giulivi et al. found that 5 of the 10 autistic children and 2 of the control children had mitchondrial DNA overreplication.

In a previous post here, the question was raised of how autism is diagnosed in the samples being studied. This new study allows an opportunity to look at how carefully the sample is selected and controls matched to the sample.

For example, "The recruited children were aged 2 to 5 years and resided with a biological parent in a well-defined catchment area of more than 22 counties in northern California and parts of Los Angeles County, California." The controls were "sampled from birth files with frequency matching to the projected distribution of sex, age, and geographic area among cases of autism. Environmental, lifestyle, reproductive, maternal medical, and detailed demographic information was collected through an extensive telephone interview with the primary caregiver. Participants’ mothers classified parents into race and ethnicity categories identical to those used in the US Census and these same categories were used to define child race and ethnicity."

What about the autism diagnosis and making sure the recruited children really were on the spectrum and what was known about their functional levels? The authors stipulate precisely the means through which diagnoses were made and the scorings used: "Diagnoses were confirmed through clinical examinations using the Autism Diagnostic Inventory-Revised (ADI-R)9 and the Autism Diagnostic Observation Schedule (ADOS)." The authors "selected 10 individuals who met criteria for full syndrome autism on both the ADI-R and ADOS and 10 typically developing control children." The authors even took into account the diversity of the spectrum: "Because ASD represents a fairly diverse phenotype, we studied children meeting criteria for full syndrome autism and neurotypically developing children (controls) without a clinical diagnosis of full syndrome autism, ASD, or developmental delays." The authors continue, "We also attempted to achieve comparable age, sex, and race/ethnicity across groups to minimize confounding sociodemographic factors that may be surrogates for genetic, epigenetic, or cultural background." In other words, the researchers took care to make the best selection they could for the controls so that their results would be as accurate as possible.

In part, the study revealed that "Defective or abnormal lymphocytic mitochondria in children with autism were observed in this exploratory study as determined by the following parameters:
(1) low PDHC activity accompanied by low lactate-to-pyruvate ratios,
(2) impaired complex I alone or in combination with other complexes (mainly complex V), 
(3) enhanced mitochondrial rate of hydrogen peroxide production, and
(4) mtDNA overreplication and/or deletions."

The authors (despite focus on press releases that don't always present an accurate portrait of a study) were careful to note the limitations of the study, as well: small sample size, potential of Type I errors, "cases in this substudy were somewhat higher functioning than those from the original study, lessening the difference with controls," "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," and "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."

Perhaps the most relevant limitation that the study authors themselves note is this: "inferences about a cause and effect association between mitochondrial dysfunction and typical autism cannot be made in a cross-sectional study. Several factors influence expression of mitochondrial respiratory insufficiencies in both the affected and general populations (ie, nuclear genetic
backgrounds,39 mtDNA heteroplasmy in different tissues,40 different energy thresholds within a given tissue or organ,41 and environmental factors42)."

People in the autism community have rejected studies with hundreds of thousands of children, crying foul. They have embraced case series with a dozen kids as proof of the MMR causing autism, all while insisting that the study doesn't say that at all. They have gone gaga over monkey studies (how many 14, 13, 12?). People in the autism community go beyond what the researchers themselves note are limitations in the study, ignore the caution, ignore the calls for more research ("More research is needed to understand the molecular causes of the mitochondrial dysfunction and how this and other neurometabolic defects may contribute to autism or related phenotypes.") and insist that answers are at hand.

We must be cautious. This is not the magic bullet. Half the sample did not have "mtDNA overreplication." Two of the controls did. Perhaps like epilepsy this is more likely to occur in the autistic population. With a sample of 10 and a control of 10, it would be inexcusable to speculate beyond this study and extrapolate its findings to all autistic individuals. Much more work remains to be done. The best that we can do, as members of this community, is to work to get the facts correct and not speculate wildly. We should recognize our limitations in understanding the details of the study, and we should never, ever leap to conclusions based upon a press release and an abstract.

Cecilia Giulivi; Yi-Fan Zhang; Alicja Omanska-Klusek; Catherine Ross-Inta; Sarah Wong; Irva Hertz-Picciotto; Flora Tassone; Isaac N. Pessah
Mitochondrial Dysfunction in Autism
JAMA. 2010;304(21):2389-2396.


Autism Mom Rising said...

People focus on studies whose outcomes they agree with and tear apart those they don't. It is a common occurance across much of Autism and this is not limited to one group or another.

All I know is that a good deal of these kids have medical illnesses and thank goodness research is being done into that.

DAN Docs have been routinely seeing kid's test results coming back with mito problems for almost a decade now. Good thing someone else is finally looking into it.

KWombles said...

Yes, that's true. Confirmation bias and disconfirmation bias work to keep people who already have their minds made up continuing along in that mindset. I did not tear this study apart. I did not dismiss it. I cautioned that it should not be used beyond what it was: a preliminary study.

You really want to tell me that DAN docs have been sending kids out for muscle biopsies on a routine basis?

There really aren't very many mito specialists out there and the research is still preliminary.

Mitochondrial disorders can be devastating and deadly. It isn't something I dismiss lightly and I certainly didn't here. One of the bloggers on the directory lost her two children to mito disorders.

Research is imperative, but we'd be a lot farther along as a community if folks didn't go beyond what studies actually say. :-)

KWombles said...

http://www.redorbit.com/news/health/1958597/cellular_energy_defects_discovered_in_autistic_children/ Does a nice job of writing about this study; doesn't overhype it, doesn't go beyond the study itself.

kathleen said...

I thought this was an interesting piece written by a physician on just what it takes to be a DAN! doc..


Science Mom said...

DAN Docs have been routinely seeing kid's test results coming back with mito problems for almost a decade now. Good thing someone else is finally looking into it.

No they haven't. DAN! doctors are not qualified to diagnose mitochondrial disorders. It is alarming that they would flippantly and inexpertly diagnose such a disease/disorder in order to 'treat' them. If a mito disorder is suspected, the responsible and ethical thing to do is to refer them to a specialist, not take matters into their own hands.

Chris said...

Kim: You really want to tell me that DAN docs have been sending kids out for muscle biopsies on a routine basis?

I read this study in the college library. What struck me was that they were relying on certain genes in the blood, and did not do muscle biopsies.

Also, this was done in UC Davis, the home of the MIND Institute. I am suspicious that they could only find ten children. I was reminded of the studies where monkeys go missing. I am wondering if there was some data manipulation going on.

Oh, and DAN! "doctors" checking for mitochondrial disorders looks about as accurate (and lucrative) as having parent acquired samples being sent to mail-order labs. Dubious at best, and sure way to ensure get cash from desperate parents.