Reassessing the role of mitochondrial DNA mutations in autism spectrum disorder.

12 Apr

Autism and mitochondrial medicine have become a very hot topic in recent years. What the connections are between autism and mitochondrial disorders has yet to be clarified. Mitochondria are little structures within cells that produce much of the energy required. Mitochondria have their own DNA (mtDNA) in addition to the nuclear DNA (nDNA) of the cell. nDNA is what most people think of when we hear “genes” or DNA. Given the focus on mitochondrial dysfunction and autism, it is natural to consider the question: are there mutations in the mtDNA which increase the risk of autism?

A new paper takes a look at the question. They studied 148 patients with ASD and found, well, no support for a link to mtDNA mutations. Here is the abstract:

BMC Med Genet. 2011 Apr 6;12(1):50. [Epub ahead of print]
Reassessing the role of mitochondrial DNA mutations in autism spectrum disorder.
Alvarez-Iglesias V, Mosquera-Miguel A, Cusco I, Carracedo A, Perez-Jurado LA, Salas A.
BACKGROUND: There is increasing evidence that impairment of mitochondrial energy metabolism plays an important role in the pathophysiology of autism spectrum disorders (ASD; OMIM number: 209850). A significant proportion of ASD cases display biochemical alterations suggestive of mitochondrial dysfunction and several studies have reported that mutations in the mitochondrial DNA (mtDNA) molecule could be involved in the disease phenotype.

METHODS: We analysed a cohort of 148 patients with idiopathic ASD for a number of mutations proposed in the literature as pathogenic in ASD. We also carried out a case control association study for the most common European haplogroups (hgs) and their diagnostic single nucleotide polymorphisms (SNPs) by comparing cases with 753 healthy and ethnically matched controls.

RESULTS: We did not find statistical support for an association between mtDNA mutations or polymorphisms and ASD.

CONCLUSIONS: Our results are compatible with the idea that mtDNA mutations are not a relevant cause of ASD and the frequent observation of concomitant mitochondrial dysfunction and ASD could be due to nuclear factors influencing mitochondrion functions or to a more complex interplay between the nucleus and the mitochondrion/mtDNA.

PMID: 21470425 [PubMed – as supplied by publisher]Free Article

This is consistent with previous studies, as noted in a recent review article which was itself summarized at The Thinking Person’s Guide to Autism by Emily Willingham as Mitochondrial Disease and Autism: Linked?

Ms. Willingham noted there:

Thus, tracking down mitochondrial dysfunction in the context of ASD to a specific mutation has remained an elusive goal. Two scenarios are likely for this lack of mutational findings: (1) there are mutations, but we just haven’t found them yet; or (2) the environment is largely responsible for any mitochondrial dysfunction that abnormal marker levels might indicate.

This paper is available as a free manuscript online. Here is the

Although it is widely accepted that some forms of ASD appear concomitantly with the impairment of mitochondrial energy metabolism, there are reasons to believe that the cause of these mitochondrial disorders does not systematically rest on mutations or variants in the mtDNA molecule. Pathogenic mtDNA mutations have been reported in ASD patients, but this seems to be the exception rather than the rule. It is more likely that the real causes of mitochondrial deficiencies in some ASD cases are due to the intervention of several nuclear factors acting alone (additively or epistatically) or through a complex interplay with mtDNA variants. For the time being, while the cause for mitochondrion dysfunction in ASD remains unclear, there is no reason to indicate systematic screening for mtDNA mutations in ASD patients unless a mitochondrion disorder is suggested by a clear phenotype.

What is also interesting to me is the table of characteristics of the study subjects. In particular, there is a big difference in the percentage with epilepsy and dimorphism between adults and children:

Mitochondrial dysfunction is listed as mild and somewhat infrequent (about 10%). Not the very high prevalences of mitochondrial dysfunction that some have suggested are present in autitics. This does beg the question: should this genetic study be performed on those with some measure of mitochondrial dysfunction?

This doesn’t mean that mitochondrial dysfunction isn’t an important area for autism research, or that a genetic study such as this shouldn’t be done on a larger group with some measure of mitochondrial dysfunction.

Of course it would be great to hear that there is something definitive in this study. As in, “this is it!” rather than “this probably isn’t it”. Mitochondrial DNA mutations “probably isn’t it” when it comes to the etiology of ASD in most people.

11 Responses to “Reassessing the role of mitochondrial DNA mutations in autism spectrum disorder.”

  1. passionlessDrone April 12, 2011 at 16:37 #

    Hi Sullivan –

    It just gets weirder and weirder.

    My thoughts are, it looks like they searched for ‘well known’ mutations in mtDNA. I would note with small amusement that Hannah Polings mutation was undocumented, and by these standards, would have failed to show up.

    IIRC, the Giulivi study (a much smaller study), which purported to find changes in mtDNA, didn’t look for well known mutations, so much as differences in the number of mtDNA and whether or not there were additions or deletions to the code; which I think would be acquired due to problems during replication opposed to inherited mtDNA problems.

    Regarding epilepsy, I thought (?) that in many cases, onset of seizures happened in adolescence or early adulthood, which might speak towards the discrepancy.

    Regarding dismorphism, if what we are witnessing in our children ins a new phenomena, I don’t think it would necessarily be unusual for different age cohorts to have differences in this regard.

    Also, it looked to me like the adult cohort were all institutionalized individuals; I didn’t see anywhere that severity was notated for the children. If they were the more common mixture of the spectrum of ASD, that could also provide some problems.

    Nice article.

    – pD

    • Sullivan April 12, 2011 at 20:22 #


      It is getting pretty strange, isn’t it. Nice catch that the adults were institutionalized. Somehow that passed by me.

  2. brian April 12, 2011 at 23:09 #

    I thought that the paper linked below was more interesting and more thorough than the newer article that is the subject of this post:

  3. brian April 13, 2011 at 00:24 #

    Ah! I’d forgotten that you had already blogged about it.

    Strangely, I still expect that mitochondrial issues should be common in ASD, since dysregulation of the expression of the regulatory protein MeCP2 (MECP2 mutations cause Rett syndrome) is apparently quite common in the brains of autistic individuals and affects the expression of mitochondrial respiratory chain proteins (mitochondrial problems are common in children with Rett syndrome, as are the sort of metabolic issues found in the Giulivi study.)

  4. daedalus2u April 13, 2011 at 00:25 #

    Pd, there are two main classes of autism, the type that runs in families and the type that is sporadic. The type of autism that has dysmorphic features tends to be the sporadic type and tends to be associated with CNVs. The type that is familial tends to not be associated with dysmorphic features and the genetics is (so far) completely impenetrable with no single gene accounting for more than a few percent of causation.

    It is not clear if there is an adverse phenotype associated with the mitDNA mutation that Hannah Poling has. Her mother has the same mutation (T2387C) with no apparent symptoms. It is on the 16s ribosome, which is part of the complex that synthesizes other proteins, not one of the proteins in the respiration chain.

    I have looked and have not been able to find a reference stating that this change is pathological and what the pathology looks like.

  5. passionlessDrone April 13, 2011 at 02:18 #

    Hi Daedulus2u –

    The type of autism that has dysmorphic features tends to be the sporadic type and tends to be associated with CNVs.

    As I think about this, that makes a lot of sense. Again, not trying to antagonize anyone, it does seem likely that carriers of genes that cause dismorphism are less likely to reproduce. Very clever. Thank you.

    It is not clear if there is an adverse phenotype associated with the mitDNA mutation that Hannah Poling has. Her mother has the same mutation (T2387C) with no apparent symptoms.

    I have looked and have not been able to find a reference stating that this change is pathological and what the pathology looks like.

    Yeah, that was part of the joke.

    At the time of the whole Hannah Poling thing, the narrative was that she had an underlying genetic defect that her vaccinations interacted with which resulted in her developmental changes. The fact that, indeed, there were no referenes indicating that the change was pathological wasn’t a problem, because, as the narrative went on, the mtDNA region was so highly conserved, and so important, any mutations could manifest as mitochondrial disease.

    If that is true, searching for ‘well known’ mutations in mtDNA, isn’t necessarily that meaningful if our goal is to understand the capacity for mutations to serve as predispositions to autism. If, on the other hand, our concern lays with mutations that are already known to have pathological adverse phenotypes, our ability to super impose a pre-existing genetic condition over Hannah Polings developmental regression disipates.

    – pD

  6. livsparents April 13, 2011 at 03:05 #

    I just hope that they don’t use the idea that ‘mitochondrial dysfunction is not a major cause of autism’ to attempt to deny the idea that autism could be an indicator of mitochondrial dysfunction. If the larger subset (autism) has a higher incidence of the smaller subset of mitochondrial issues than the public at large, we need to understand that and investigate. I just don’t want to hear that DevPeds or PedNeurologists are ignoring potential mito issues because “mitochondrial issues don’t cause autism”.

    There seem to be quite a few mitochondrial issues within our community , not a lot of knowledge about it and as a result, seemingly too many undiagnosed or misdiagnosed children. Once the DNA testing’s costs come down to earth over the next half dozen years, it really should be a ‘standard’ test for all those on the spectrum.

  7. Roger Kulp December 4, 2015 at 14:32 #

    Mitochodrial disease may not be a CAUSE of autism,but it is increasingly seen as a common comorbidity,just like seizures and GI diseases.This showed up in my PubMed feed this morning.

    nnov Clin Neurosci. 2015 Sep-Oct;12(9-10):29-32.
    Autism in the Son of a Woman with Mitochondrial Myopathy and Dysautonomia: A Case Report.
    Brown BD1, Rais T1.
    Author information

    The relationship between autism spectrum disorders and mitochondrial dysfunction, including mitochondrial myopathies and other mitochondrial diseases, is an area of ongoing research. All autism spectrum disorders are known to be heritable, via genetic and/or epigenetic mechanisms, but specific modes of inheritance are not well characterized. Nevertheless, autism spectrum disorders have been linked to many specific genes associated with mitochondrial function, especially to genes involved in mitochondrial tRNA and the electron transport chain, both particularly vulnerable to point mutations, and clinical research also supports a relationship between the two pathologies. Although only a small minority of patients with autism have a mitochondrial disease, many patients with mitochondrial myopathies have autism spectrum disorder symptoms, and these symptoms may be the presenting symptoms, which presents a diagnostic challenge for clinicians. The authors report the case of a 15-year-old boy with a history of autism spectrum disorder and neurocardiogenic syncope, admitted to the inpatient unit for self-injury, whose young mother, age 35, was discovered to suffer from mitochondrial myopathy, dysautonomia, neurocardiogenic syncope, Ehler-Danlos syndrome, and other uncommon multisystem pathologies likely related to mitochondrial dysfunction. This case illustrates the need for a high index of suspicion for mitochondrial disease in patients with autism, as they have two orders of magnitude greater risk for such diseases than the general population. The literature shows that mitochondrial disease is underdiagnosed in autism spectrum disorder patients and should not be viewed as a “zebra” (i.e., an obscure diagnosis that is made when a more common explanation is more likely).

    Researchers,and too many autism advocates,tend to look at autism in a “vacuum”,when for many it is a syndromic disorder,where multiple medical,or mental,health conditions interact,and effect each other.


  1. Mitochondrial disease and Vaccines – Vaxopedia - September 18, 2016

    […] Reassessing the role of mitochondrial DNA mutations in autism spectrum disorder. […]

  2. What is Mitochondrial Autism? – VAXOPEDIA - October 8, 2018

    […] Reassessing the role of mitochondrial DNA mutations in autism spectrum disorder. […]

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this: