Mitochondrial Dysfunction and autism. Brief Q and A with lead author

13 Dec

Mitochondrial Dysfunction was thrust back into the news again earlier this month when a team from UC Davis led by Professor Cecilia Giulivi discovered:

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

In itself this is a fascinating development and the first true look at whether autistic children were more likely or not to have mtDNA dysfunction(s).

However, as ever in the world of autism, the world of the anti-vaccinationists are never far behind. This passage from Harold Doherty demonstrates this bizarre need to always conflate the two:

The Poling family was successful in advancing a vaccine injury claim on behalf of their daughter Hannah Poling to the point of settlement by US authorities. Hannah’s father is Dr. Jon Poling, a practicing neurologist in Athens, Georgia, and clinical assistant professor at the Medical College of Georgia. He reviewed his daughter’s case in the Atlanta Journal-Constitution on April 11, 2008. In his comments Dr. Poling explained how mitchondrial dysfunction was related to his daughter’s case and to the existence of a possible mitochondrial dysfunction subgroup of autism disorder. He also discussed, as a medical doctor who expressly recognized the importance of vaccines in preventing serious diseases, the need for public health authorities to abandon fear tactics and conduct research to restore confidence in public health authorities and vaccines

In order to try and staunch the upcoming flood of misunderstandings and false statements like those implied by Doherty (and John Poling whom other mtDNA specialists such as John Shoffner clearly don’t trust on the issue), I contacted Professor Giulivi and asked her three simple questions about the study she is lead author of. She supplied three simple answers.

KL: Do you think, based on available science (including your paper) that vaccines cause autism?

CG: We do not have any evidence for this in our study. Our study was cross-sectional not longitudinal so it cannot point to any cause (not just vaccines), meaning we do not have anydata supporting one way or another.

KL: If so, why is this? Does it follow (in your opinion) that mitochondrial dysfunction can be triggered by a vaccine?

CG: Again, please see (1).

KL: Do you believe your own paper adds weight to any opinion regarding autism causation by any means?

CG: No. At this point we do not know if it is mainly genetic, environmental or a combination of both. Again, with a cross-sectional study you get a snapshot of the situation but not how you got to that situation.

There you have it. The lead author of the study everyone is raving about is very carefully pointing out that the study in question does not add weight to _any_ hypothesis of autism causation, let alone vaccines.

16 Responses to “Mitochondrial Dysfunction and autism. Brief Q and A with lead author”

  1. brian December 13, 2010 at 21:35 #

    Mitochondrial issues in individuals with ASD may well be a result rather than a cause of ASD. Let’s take this step by step:

    Rett syndrome, an ASD-like syndrome that can cause profound disability following 6 to 18 months of apparently normal postnatal development, is caused by mutations in the MECP2 gene.

    Rett syndrome is commonly associated with apparent mitochondrial dysfunction, including “ultrastructural alterations in the mitochondria and decreased respiratory chain enzyme activity.” [Am J Med Genet. 2002 Aug 15;111(3):238-42]

    The MECP2 gene product is a regulatory protein that affects the expression of myriad other genes, including genes affecting neurodevelopment as well as some mitochondrial genes such as CO1 (cytochrome oxidase subunit 1). [Mol Cell Biol. 2006 July; 26(13): 5033–5042; BMC Neurosci. 2010; 11: 53.]

    MECP2 gene expression is commonly abnormal in the brains of individuals with ASD. [Epigenetics. 2006; 1(4): e1–11; Hum Mol Genet. 2004 Mar 15;13(6):629-3] Therefore, the question raised by the report of mitochondrial abnormalities in individuals with ASD is something of a chicken-and-egg issue: which came first.

    The role of MECP2 in neurodevelopmental disorders is reviewed in Curr Psychiatry Rep. 2010 April; 12(2): 127–134; the role of MECP2 in Rett syndrome and ASD was reviewed in Epigenomics. 2009 October 1; 1(1): 119–130.

  2. Roger Kulp December 13, 2010 at 23:54 #

    Here’s the article

    Here’s the data

    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 × [min × mg protein]?1 vs 2.3 [95% CI, 1.7-2.9] nmol × [min × 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 × [min × mg of protein]?1 vs 0.16 [95% CI, 0.12-0.20] nmol × [min × 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).

    Seems pretty clear to me.These are tests that could be duplicated on anyone.

  3. Brian B December 13, 2010 at 23:59 #

    I’m glad this study is receiving so much public attention, it speaks volumes for the progress it is raising on an awareness level.

    That’s why Dr. Mark Hyman of the HuffingtonPost received the BAZI Brilliant badge for his efforts in spreading information about the latest breakthrough in autism research.

    More here:

  4. Kev December 14, 2010 at 08:47 #

    Brian B – you might want to read this before handing out quasi-awards:

  5. RAJ December 14, 2010 at 11:36 #

    Rett Syndrome represents the confusion in the general public and the science media about the concepts of genetic vs heritabilty.

    99.5% of Rett Syndrome cases are de novo mutations not present in either parent.

    With the exception of Fragile X Mental Retardation Syndrome, the single gene disorders are primarily the consequence of a de novo mutation not present in either parent. In the single gene disorders lumped together as ‘Single Gene Autism Spectrum Disorders)the majority of children with an identified genetic mutation, have a de novo mutation (Tuberous Scerosis, Downs Syndrome, CHARGE, Angelmans Syndrome, Pradi-Willis Syndrome, Klinefelter Syndrome, Williams Syndrome, Turner Syndrome, Timothy Syndrome)

    Improving technology has reached the point where sub-microscopic genetic anomolies can be identified. The excitement over of finding copy number variations throughout the genome in autism samples using this improved technology which is greater than found in population norms is important however non-specific CNV’s greater than population norms has also been found in all the developmental disorders (Autism, schizophrenia, ADHD, intellectual disability).

    CNV’s can be inherited but most cases are de novo mutations.

    It is important to keep the facts in mind when you hear the behavioral geneticist claims that autism is the most heritable of the developmental disorders.

    The geneticists claims that autism is 90% heritable is based on a single small UK twin study that has many flaws in the study design.

  6. Prometheus December 14, 2010 at 21:26 #

    RAJ again trying to make the point that autism is genetic but not neccessarily inherited:

    “The geneticists claims that autism is 90% heritable is based on a single small UK twin study that has many flaws in the study design.”

    Some of this is a semantic issue, as “old-school” geneticists called a trait “heritable” if it could be passed on to subsequent generations (as copy number variations and other mutations can be). This is actually different from saying that the trait is/was “inherited”. So, the twin study that RAJ excoriates does show that autism is 90% “heritable” without claiming that the autistic person “inherited” it from their parents.

    Clear? There is a difference.

    It is also clear, from research into familial autism clusters, that there are forms of autism that are not only heritable but inherited. In addition, having one autistic child is associated with an increased risk of subsequent children being autistic. So, it isn’t all just random one-time occurences.

    Perhaps if we said that autism is 90+% genetically determined with a small, but probably non-zero contribution from “environmental” factors (“environmental” being used in its broadest possible sense, such as genetic imprinting), RAJ wouldn’t feel compelled to post the same objection every time there is an article about the genetics of autism.

    It really is time for parents to free themselves from guilt about their autistic children – it’s not their fault, even if it was their genes. And, since – as RAJ has commented time after time – “99.5% of Rett Syndrome cases are de novo mutations not present in either parent.”, it’s not even the parents’ genes, it’s just random chance.


    • Sullivan December 14, 2010 at 22:28 #


      Isn’t there also an inherent bias in claiming that Rett syndrome or Down Syndrome is mostly non-inherited. My guess is that a large fraction of those with either Rett or Down syndromes do not go on to be parents.

      RAJ also saddens me in that he hasn’t kept up with the autism twin study literature. He is encouraged to look through Pubmed and this blog to find recent studies. My guess is that he will be happy he did.

  7. RAJ December 15, 2010 at 02:46 #

    “RAJ also saddens me in that he hasn’t kept up with the autism twin study literature. He is encouraged to look through Pubmed and this blog to find recent studies. My guess is that he will be happy he did”.

    Skip the pejorative insults Sullivan and trying reading the entire articles rather than the abstracts you accept without questioning.

    I have kept up with the twin studies and the 1995 UK twin study is full of logical flaws and wrong assumptions. This study has driven the autism agenda since it was published and there isn’t a genetic article that doesn’t reference this study and begin with the statement that autism is 90% heritable.

    Among the flaws is that the authors couldn’t find a single pair of DZ twins concordant for autism in all of the UK which is implausible since recurrance rates in siblings has been report as between 2 – 6%. Again this study reported more significantly more MZ twin pairs than DZ same sex twin pairs when there should have been an equal number of MZ and DZ twin pairs.

    Despite claims that this was a population based study, the twins were all recruited through flyers sent to clinicians, special schools and parent organizations which is notorius for a bias towards recruiting concordant MZ twins who are always more likely to generate interest. The twins in the study concordant for autism was notable for the high rates of severe mental retardation and seizures and dysmporhic features not generally found in such high rates as was reported in this study.

    This was a genetic study and all pairs with an identified cause were disqualified from participating. One pair each with congenital rubella syndrome, Downs Syndrome and Williams Syndrome. None of those disorders are the consequence of genetic mutations inherited from either parent. In Downs syndrome over 98% of the children do not inherit their mutations from either parent. Williams Syndrome, same thing, there are a few cases of the Williams Syndrome mutation being inherited from a parent but for the vast majority the mutation is not inherited from either parent. So, in in those cases that were disqualifed none had a genetic mutation inherited from either parent. Rather puzzingly they did include a pair of twin sisters positive for the Fragile X mutation when they should have been disqualified.

    The classical twin study design does not segregate MZ concordance rated by placentation status. About 2/3’s of MZ twin pregnancies are monochorionic (same prenatal environment) but 1/3 are dichorionic (seperate placenta) and do not share the exact same prenatal environment as do all virtually all DZ twin pairs.

    It is intriguing that they found a concordance rate of 60% in MZ twins which is exactly the same 60% that Davis et al reported in schichophrenia only the 60% concordance rate in schizophrenia was found in MZ twins who were monochorionic. Concordance rates in dichorionic MZ twins was 10.7, the same as has been frequently reported in schizophrenia in DZ twin pairs.

    If autism is heritable the concordance rates should be identical in both monochorionic and dichorionic twins. All twin studies in autism have employed the classical twin study method and no twin study in autism has ever seperated concordance rates of MZ twins by chorion type.

    The classical twin study design simply ignores any environmental component by conveniently invoking the equal prenatal assumption.

    If autism is 90% heritable without any environmental component then concordance rates for MZ monochorionic twins autism should be exactly the same as concordance rates in MZ dichorionic twins.

    This question can’t be settled until twin studies report concordance rates in MZ twins by chorion type, which may be coming sooner than you think.

    • Sullivan December 15, 2010 at 03:37 #

      “Skip the pejorative insults Sullivan and trying reading the entire articles rather than the abstracts you accept without questioning.”

      Sorry RAJ, it was as nice as I could make it. You present yourself as a semi-expert in the field and your response still shows you don’t know what I was referring to. If you want to consider it “pejorative”, that is an impression of yours, and not the intent, however.

      I will add–You have built a nice straw man in your ignorance of recent results.

      (note–edited after submission)

  8. Prometheus December 15, 2010 at 04:22 #


    RAJ has been on this hobbyhorse for quite some time and I remain at a loss to understand what he’s trying to say. For example:

    “If autism is 90% heritable without any environmental component then concordance rates for MZ monochorionic twins autism should be exactly the same as concordance rates in MZ dichorionic twins.”

    Heritability (H^2 or “broad sense heritability”), which encompasses not only allelic (genetic) inheritance but also imprinting and epistasis, can be approximated from twin studies using Falconer’s equation:



    rMZ = monozygotic twin correlation
    rDZ = dizygotic twin correlation

    The narrow-sense heritability (h^2), which is allelic (genetic) heritability, can be approximated by looking at the correlation between siblings compared to the correlation between adopted children:

    h^2 = rSib – rAd


    rSib = correlation between siblings
    rAd = correlation between adopted children (or between adopted children and natural children)

    I bring up all of this tedious mathematics in order to show that when geneticists talk about “heritability” they are often not talking about whether a trait is strictly genetic and they are almost never talking about whether a trait was inherited.

    Perhaps this is why I can’t seem to understand what RAJ is talking about. He talks a lot about monochorionic and dichorionic monozygotic twins as though not sharing a placenta (dichorionic) would make a significant difference in exposure to “environmental factors”. As far as external environmental factors, the mother’s blood supplies both placentas via the uterine and (to a much lesser extent) ovarian arteries, so any difference in what the fetuses are exposed to would be random, varying and insignificant.

    As for “internal” environmental factors, the reality is that the differences between sharing or not sharing a placenta are swamped by variations in placental blood supply and vascular quality, both of which appear to be largely due to random factors. If RAJ is claiming that these environmental factors are determining or influencing autism, he’ll need more than twin studies to prove that. Monochorionic twins can have very different blood supplies due to disparate umbilical vessel calibre and dichorionic twins can have very similar blood supplies and vice versa.

    I’ve tried for some time to get RAJ to clearly state his argument, but I can’t seem to get any closer to it. Maybe I’m just not smart enough to understand it or maybe RAJ isn’t explaining it very well.


  9. Prometheus December 15, 2010 at 04:43 #

    Oh, one final point. If a trait (like autism) is “90% genetic”, then it would be ridiculous to say, in the same sentence, that there is “no environmental component” – the part that isn’t genetic is either random or environmental and it’s hard to separate the two.

    And to answer Sullivan’s question, people with Rett’s syndrome or Downs syndrome can pass it on to their offspring. By classical genetics, they’d have about a 50% chance of having children with that condition (assuming that their mates don’t have the condition and assuming that the Downs syndrome is due to an extra copy of chromosome 21 without translocations).

    As a practical matter, most people with severe developmental disorders don’t usually have children, but there are cases where, because of poor supervision or abuse, people with Downs syndrome have had children.

    Another question that comes up in terms of genetic counseling is whether parents who have had an autistic child should be advised against having more children. If the autism was due to a de novo mutation, they are not at significantly increased risk, but it is not a trivial matter to make that determination without doing extensive (and expensive) genetic evaluation. Again, there are numerous cases of familial autism, where the parents show no overt signs of autism yet autistic children are born in multiple generations. Clearly, the genetics of autism are not as clear yet as we might like.


  10. Prometheus December 15, 2010 at 04:55 #

    OK, OK, one last comment.

    Part of RAJ’s issue may be that he has placed too much weight on a single paper – Davis, Phelps and Bracha (1995). I haven’t been able to find a single paper since 1995 (and only three up to that point) which deals with the subject.

    However, I did find a paper that RAJ needs to read:

    Machin G., Non-identical monozygotic twins, intermediate twin types, zygosity testing, and the non-random nature of monozygotic twinning: a review. Am. J. Med. Genet. C Semin. Med. Genet. 2009 May 15;151C(2):110-27.

    He may have to pay to get it, but it will definitely be worth the cost. It may let him get down from his hobbyhorse at long last.



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