Genomic instability not linked to autism?

An eyebrow was raised upon reading the findings reported by Penelope Main and colleagues [1] concluding that: "it appears unlikely that genomic instability is a feature of the aetiology of autism." Based on results derived in part from "the cytokinesis-block micronucleus cytome (CBMN-cyt) assay" [2] looking at markers of DNA damage, authors reported very little to see in their small cohort of children with autism (n=35) compared with siblings (n=27) and asymptomatic controls (n=25) although with the requirement for: "replication using a larger cohort".

"Nah. I don't need one. I got a Donk".

Of equal interest to this blog was the discovery that there was no significant difference in B vitamins - outside of vitamin B2 - nor homocysteine (the 'big H') levels across the study groups. As regular readers might already know, I've covered homocysteine a few times on this blog with autism in mind (see here for example). Indeed, this authorship group have talked around this topic previously (see here).

Although no expert on the whys and wherefores of the CBMN-cyt assay outside of reading through the Fenech paper [2] and other material around the subject, I gather that this is quite a widely used method for measuring DNA damage covering: "(a) micronuclei (MNi), a biomarker of chromosome breakage and/or whole chromosome loss, (b) nucleoplasmic bridges (NPBs), a biomarker of DNA misrepair and/or telomere end-fusions, and (c) nuclear buds (NBUDs), a biomarker of elimination of amplified DNA and/or DNA repair complexes".

A quick trawl of the other research literature in this area reveals that this is not the first time that members of this group have looked at DNA damage with autism in mind as per another paper by Main and colleagues [3] (including Michael Fenech on the authorship list). On that occasion, lymphoblastoid cell lines (LCLs) from an even smaller group of children with autism and their asymptomatic siblings (N=6 pairs) were analysed for the possible presence of "increased DNA damage events" following artificial challenge to an oxidative stressor (hydrogen peroxide) among other things. They concluded: "(i) that LCLs from children with autism are more sensitive to necrosis under conditions of oxidative and nitrosative stress than their non-autistic siblings and (ii) refutes the hypothesis that children with autistic disorder are abnormally susceptible to DNA damage." The issue of oxidative stress and autism has been discussed quite a bit in the research literature (see here).

I would tend to agree that this is still an area of autism research deserving of further investigations on the basis of that proposed oxidative stress link. I might be further showing my incompetence in this area of endeavour by also referring you back to the paper by Shuvarikov and colleagues [4] and their suggestion that HERV (human endogenous retrovirus) elements may: "mediate other recurrent deletion and duplication events on a genome-wide scale" on the basis of their findings in relation to particular types of de novo deletions including autism as part of the clinical presentation. HERVs are something I've been quite interested in for some time now, with autism (see here), attention-deficit hyperactivity disorder (ADHD) (see here) and myalgic encephalomyelitis (ME) (see here) in mind. Other retrotransposons have also cropped up in more recent times too (see here). The relationship with DNA methylation taps into the rising star discipline that is epigenetics (see here) and potentially back to the reason why homocysteine was included in the most recent Main paper (see here for my lovely hand-drawn picture of the methylation cycle). Certainly with all the recent continued interest in de novo mutations potentially linked to autism [5] it strikes me that further scrutiny of this area is perhaps warranted.

Music then... Emeli Sandé - Next To Me.

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[1] Main PA. et al. Lack of Evidence for Genomic Instability in Autistic Children as Measured by the Cytokinesis-Block Micronucleus Cytome Assay. Autism Res. 2014 Nov 4. doi: 10.1002/aur.1428.

[2] Fenech M. Cytokinesis-block micronucleus cytome assay. Nat Protoc. 2007;2(5):1084-104.

[3] Main PA. et al. Necrosis is increased in lymphoblastoid cell lines from children with autism compared with their non-autistic siblings under conditions of oxidative and nitrosative stress. Mutagenesis. 2013 Jul;28(4):475-84.

[4] Shuvarikov A. et al. Recurrent HERV-H-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays. Hum Mutat. 2013 Oct;34(10):1415-23.

[5] Iossifov I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014 Oct 29. doi: 10.1038/nature13908.

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Main PA, Thomas P, Angley MT, Young R, Esterman A, King CE, & Fenech MF (2014). Lack of Evidence for Genomic Instability in Autistic Children as Measured by the Cytokinesis-Block Micronucleus Cytome Assay. Autism research : official journal of the International Society for Autism Research PMID: 25371234