Monday, 8 December 2014

Significantly shorter leukocyte telomere length in childhood autism

"These results provided the first evidence that shorter leukocytes telomere length is significantly associated with childhood autism." So said the results reported by Zongchang Li and colleagues [1] (open-access) based on quite a well-powered study (for an initial research foray anyway) looking at "110 autism patients (male 98 and female 12) and 129 healthy controls (male 98 and female 31)".
On the behalf of scientists everywhere,
I am ashamed to count you amongst us.

Quite a good introduction to telomeres can be found here and how: "Telomeres have been compared with the plastic tips on shoelaces, because they keep chromosome ends from fraying and sticking to each other, which would destroy or scramble an organism's genetic information." Because I couldn't have said it better myself, I won't try, other than to direct you to some of the other collected research on telomere length being related to all-manner of things including ageing [2], schizophrenia [3] and possibly even social environment [4].

The Li paper is open-access but here are a few pointers:

  • Based on the fact that: "increasing evidence has demonstrated that leukocytes telomere length is also associated with increased risk of some psychiatric diseases including schizophrenia, mood disorders and anxiety disorders" authors set about looking at leukocytes telomere length (LTL) in cases of paediatric autism compared with aged-matched asymptomatic controls. Clinical assessment of autism by the way, was based on DSM-IV criteria as well as assessment "using the childhood autism rating scale (CARS) and autism behavior checklist (ABC)."
  • Real-time PCR was the analytical weapon of choice for looking at relative telomere length (RTL) - "a modified version of the quantitative real-time PCR method originally described by Cawthon" [5] apparently - though I hasten to add, that I'm no expert on the ins-and-outs of this technique.
  • Results: "there was a significantly shorter leukocyte telomere length in patients with childhood autism" compared with controls. Taking it another way: "When participants were divided into long and short groups according to the median RTL value of healthy controls, we observed a significantly increased presence of autism for individuals with shorter RTL... compared with those with longer RTL." The age side of things also seemed to hold true for the Li results as per their results revealing: "a significant inverse correlation between RTL and age in controls". You will however note the 'in controls' part of that last sentence which did not hold [significantly] true for autism cases.
  • Interestingly, authors also reported that: "among the subjects with childhood autism those who received family training interventions have significantly longer RTL than those without family training interventions." They did find that clinical symptoms were decreased in those taking part in such intervention but drew back from suggesting a link given that lower clinical symptoms scores were also noted in those with "medication exposure" without any corresponding effect on RTL.
  • The conclusion: a bit of a first attempt looking at telomere length in relation to autism finding something potentially important but with the need for further, independent replication. Also, a little more investigation on the hows, whys and implications of such results are required.

The first thing that crossed my mind having read the Li paper was the the idea that shorter telomere length is related to DNA damage and "genomic instability" and how that might play out with regards to autism. Not so long ago on this blog, I discussed the recent paper by Penelope Main and colleagues [6] (see here) who, from a slightly different analytical perspective, concluded: "it appears unlikely that genomic instability is a feature of the aetiology of autism". Quite the contrast by all accounts.

That being said, Li et al do discuss the possibility that: "telomeric DNA was highly sensitive to be damaged by the oxidative stress" which does bring their results and other findings from Main and colleagues [7] potentially back into some sort of stellar alignment as linking back into quite a body of research talking about oxidative stress and autism in mind [8]. I say that acknowledging that there is much more research to do in this area but templates for such an association might already exist [9] in the peer-reviewed arena.

Again, perhaps showing my lack of insight into this area, a quick read around this topic also pointed to another possible area of interest when it comes to telomeres and autism: telomerase. This enzyme which apparently might serve as a bit of a double-edged sword when it comes to reversing ageing (see here) but also being a key expression ingredient in tumor cells (see here), has something of an important effect on telomeres with regards to prevent shortening. As far as I can ascertain, the sum total of current research on telomerase and autism is zero aside from peripheral discussion of issues with genes such as PINX1 noted in some cases of autism and it's described inhibition of telomerase activity [10]. I'd be minded to suggest that looking at the activity of telomerase as well as telomere length might be an important part of any future scientific inquiry with autism in mind.

I might also suggest that further research inquiry be focused on the possible ways and means that telomere length might be affected by intervention as per the possible effects from family intervention detailed in the Li data. I'm not specifically talking about the psychological aspects, which I'll leave others to decide whether they're important or not, but rather other data on for example, how exercise might show a beneficial effect on telomere length [11] and whether this might be pertinent to at least some cases of autism (see here). Dare I also even mention the possible relation between vitamin D and telomeres [12] again in light of some recent findings with autism in mind, bearing in mind correlation is not the same as causation?

Finally: a paradox... The 'Leukocyte Telomere Length and the Father’s Age Enigma' [13]? Older fathers apparently pass on longer telomeres to their offspring, but older paternal age is also apparently a risk factor for autism. OK, the Li paper looked at telomere data in children with an average age of about 4 years so there may be some scope for factors to affect telomere length in the time from entry into the world. They also did report on father and mother age for autism participants (see here) but not for controls so unfortunately we can't say too much more on that topic. Again, perhaps something to be looked at in subsequent studies?

Music to close: Street Fighting Man by the Stones (with hat-tip to Fantastic Mr Fox).

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[1] Li Z. et al. Shorter telomere length in peripheral blood leukocytes is associated with childhood autism. Sci Rep. 2014 Nov 17;4:7073.

[2] Müezzinler A. et al. A systematic review of leukocyte telomere length and age in adults. Ageing Research Reviews. 2013; 12: 509–519.

[3] Kota LN. et al. Shortened telomere in unremitted schizophrenia. Psychiatry Clin Neurosci. 2014 Nov 27. doi: 10.1111/pcn.12260.

[4] Mitchell C. et al. Social disadvantage, genetic sensitivity, and children’s telomere length. PNAS. 2014; 111: 5944–5949.

[5] Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res. 2002 May 15;30(10):e47.

[6] 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.

[7] 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.

[8] Rossignol DA. & Frye RE. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front Physiol. 2014 Apr 22;5:150.

[9] Yu WY. et al. Short telomeres in patients with chronic schizophrenia who show a poor response to treatment. J Psychiatry Neurosci. 2008 May;33(3):244-7.

[10] Zhou XZ. et al. The telomerase inhibitor PinX1 is a major haploinsufficient tumor suppressor essential for chromosome stability in mice. J Clin Invest. 2011 Apr;121(4):1266-82.

[11] Ludlow AT. et al. Do telomeres adapt to physiological stress? Exploring the effect of exercise on telomere length and telomere-related proteins. Biomed Res Int. 2013;2013:601368.

[12] Richards JB. et al. Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women. Am J Clin Nutr. 2007 Nov;86(5):1420-5.

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ResearchBlogging.org Li Z, Tang J, Li H, Chen S, He Y, Liao Y, Wei Z, Wan G, Xiang X, Xia K, & Chen X (2014). Shorter telomere length in peripheral blood leukocytes is associated with childhood autism. Scientific reports, 4 PMID: 25399515