Autoantibodies not implicated in cases of autism?

Contrary results are a common feature of the autism peer-reviewed research landscape. No sooner does one group publish the next 'big thing' when it comes to the singular term 'autism' than seemingly opposite results follow suit.

So it is with the paper under discussion today by Simran Kalra and colleagues [1] (open-access) who concluded that: "The idea that autoantibodies represent an underlying cause or are biomarkers for autism pathophysiology is not supported by this report."

Autoantibodies by the way, are part of the process whereby the body's immune system fails to recognise self as 'self' and mounts a response against the body's own tissue. It's a topic that has been discussed quite extensively with the autism spectrum in mind (see here for example) as part of a wider scientific debate about a role for immune function in at least some autism (see here).

The Kalra paper is open-access but a few details might be useful:

• "Serological analysis was performed on typically developing children (n = 55), developmentally delayed children without autism (n = 24) and children diagnosed with autism (n = 104)." I believe this cohort of children were part of a larger study titled: 'Clinical and Immunological Investigations of Subtypes of Autism'.
• Based on an interesting analytical method - Luciferase Immunoprecipitation Systems (LIPS) - used as an alternative to the more traditional ELISA methods, researchers initially set about looking for the presence of "autoantibodies against GAD65." GAD65 by the way, is part and parcel of the mechanism for synthesising GABA (see a previous post on this topic). They then extended the study focus to look for antibodies "against several other autoimmune-associated autoantigens, candidate neurological autoantigens, and viral proteins."
• Results: well, when comparing study samples against samples from three people with diagnosed type 1 diabetes where GAD65 autoantibodies were to be expected to be present (and indeed were): "testing of serum from the typically developed children..., developmentally delayed children... and children with ASD... demonstrated no seropositive autoantibodies to GAD65." 
• Likewise when comparing autism samples with samples from "three positive control samples from subjects with systemic lupus erythematosus" for Ro52 - one of the anti-Ro antibodies found in cases of SLE - there was again nothing of note to see. Collectively the authors conclude that: "These findings rule out the possibility that GAD65 and Ro52 autoantibodies are biomarkers in ASD [autism spectrum disorder]."
• Among the other results reported is an interesting remark when it comes to a retrovirus called XMRV. For those in chronic fatigue syndrome / myalgic encephalomyelitis circles, XMRV will probably be remembered for all the wrong reasons (see here) albeit with not all questions completely answered (see here). Kalra et al found nothing in terms of seropositivity when it came to autism and XMRV (and another target, mouse mammary tumor virus (MMTV)). They do however caution that "additional studies are needed to determine if other infectious agents, or the body's response to such infections agents, might play a role" in some autism.

These results are interesting. As per my opening comment on contrary results being part and parcel of autism research, the lack of GAD65 antibodies detailed is in direct contrast to previous findings such as those produced by Rout and colleagues [2] for example. Whilst there may be various reasons for the difference in findings including a role for the analytical method used, I was drawn to one comment made by Rout et al suggesting that there may be a subgroup of children with autism and/or ADHD (attention-deficit hyperactivity disorder) where further characterisation may be needed. That also reduced levels of GAD65 mRNA levels have been reported [3] in relation to autism (with appropriate caveats regarding tissue used for study) does not mean that GAD65 is off the research menu just yet.

The lack of XMRV antibody findings reported by Kalra et al in relation to their autism group is not necessarily new news. Previous studies such as the one from Satterfield and colleagues [4] basically said as much.

There are of course quite a few other types of autoantibodies and/or antibodies to infective agents that perhaps require more study using the technique utilised by Kalra and colleagues with autism in mind. The various contributions in this research area from the Saudi-Egyptian research tag-team that crop up on this blog every now and again (see here and see here) might be a next port of call. Anti-brain antibodies detailed by other teams might also receive the same treatment (see here). Who knows, researchers might also consider putting a little more flesh on the bones of all that folate receptor autoantibody research that is crying out for independent replication (see here) or even antimitochondrial antibodies (see here). Quite a few areas to consider.

As for the infection side of things and realising the important contribution that at least one of the authors on the Kalra paper has made to another area of research (Swedo and PANDAS/PANS) I can think of quite a few research studies to be done. My growing interest in enterovirus and autism (see here) or even enterovirus and ADHD (see here) is again requiring some further investigation. Perhaps a little more 'out there' are the ways and means that the methods detailed by Kalra might also be transferable to more ancient retroviruses such as the HERVs that have been discussed before on this blog (see here) with autism and various other conditions in mind (see here).

Music: John Newman - Come And Get It.

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[1] Kalra S. et al. No evidence of antibodies against GAD65 and other specific antigens in children with autism. BBA Clinical. 2015. August 8.

[2] Rout UK. et al. Presence of GAD65 autoantibodies in the serum of children with autism or ADHD. Eur Child Adolesc Psychiatry. 2012 Mar;21(3):141-7.

[3] Yip J. et al. Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: an in situ hybridization study. Autism Res. 2009 Feb;2(1):50-9.

[4] Satterfield BC. et al. PCR and serology find no association between xenotropic murine leukemia virus-related virus (XMRV) and autism. Mol Autism. 2010 Oct 14;1(1):14.

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Kalra, S., Burbelo, P., Bayat, A., Ching, K., Thurm, A., Iadarola, M., & Swedo, S. (2015). No evidence of antibodies against GAD65 and other specific antigens in children with autism BBA Clinical DOI: 10.1016/j.bbacli.2015.08.001

The autisms, case reports and two 'intervention' options

I'm looking at two papers today which I'd like to think cover the title of this post pretty well dealing with the plurality of autism - the autisms - and the idea that intervention or management-wise, there is no 'one size fits all' when it comes to the autisms.

First up are the findings reported by Ziats and colleagues [1] who presented results for a child - "A 4-year-old male with autism and two episodes of neurodevelopmental regression" - who was also found to have a "mutation in the TMLHE gene, which encodes the first enzyme in the carnitine biosynthesis pathway, and concurrent carnitine deficiency." Supplementation with carnitine (see here) seemed to lead to some interesting changes in the developmental profile for this boy such that: "the patient's regression ended, and the boy started gaining developmental milestones."

Accepting that this was another example of the N=1 and autism (see here) I was rather interested in these results having previously blogged about issues with the TMLHE (trimethyllysine hydroxylase) gene in relation to autism (see here). The source of that previous post was the paper from Patricia Celestino-Soper and colleagues [2] (open-access) who concluded that: "TMLHE deficiency is a risk factor for autism" and quite a bit more should be done to screen for such issues. I wouldn't disagree with those sentiments (see here).

Next up are the results reported by Serret and colleagues [3] (open-access) who presented findings based on two participants "diagnosed with autism spectrum disorders in childhood and presented regression with catatonia features and behavioural disorders after a stressful event during adolescence." Further: "both patients presented mutation/microdeletion of the SHANK3 gene, inducing a premature stop codon in exon 21." Issues with SHANK3 have been reported in relation to autism previously.

Authors reported that: "lithium therapy reversed clinical regression, stabilized behavioural symptoms and allowed patients to recover their pre-catatonia level of functioning, without significant side effects." Further: "These cases support the hypothesis of a specific SHANK3 phenotype" and that lithium might hold some favour in improving clinical presentation in those cases.

Again, I was interested in the Serret findings with the caveat about their also using the case study approach in their paper. Lithium is an interesting compound that has graced this blog a few times in relation to its potential 'anti-suicide' correlating properties (see here) and as a possible management tool when it comes to the presentation of mood disorders comorbid to a diagnosis of autism (see here). Accepting that lithium has its own potential side-effects profile, the idea that cost-benefits might be calculated and if so deemed more benefit and less cost subsequently applied to 'some' autism, is an interesting prospect.

Reiterating my opening paragraph, what the Ziats and Serret papers serve to tell us is that within 'the autisms' there may be many different roads to a diagnosis of autism and that under the diagnostic label of 'autism', genetics, biochemistry and subsequent intervention/management strategies may vary from person to person. As I've said before, receipt of a diagnosis of autism (when it is eventually received) should be a starting point for further inquiry not the 'finishing line'.

That comorbidity - if I can still call it that - might also be a 'target' for analysis and investigation is also an important point raised and further asks more questions about the value of intervening on said comorbidity and the possible knock-on effects on the presentation of more core autism symptoms (see here). Y'know something like what is emerging in the body of research looking at anxiety and autism (see here).

With the body of work linking this, that and t'other to autism I'm starting to think that some further resources might be needed to pull all the available peer-reviewed information together in terms of what factors have been linked to those 'autisms'. I've always been very partial to autism research looking at inborn errors of metabolism (IEMs) as a starting point for investigations (see here) given both the data on overlap and even the idea that some of the various interventions for specific IEMs might hold promise for 'some' autism (see here). Analysis of things like rare genetic variations also being linked to the appearance of autism (see here) ties into the IEM investigations and perhaps represents the next tier of evaluation, bearing in mind the reduced costs of things like whole genome sequencing these days set within the perspective of personalised medicine (see here). Environment, bearing in mind the range of factors this might cover, should also be included in any diagnostic work-up based on the evolving science connecting something like infection to autism onset for some (see here and see here). There are various tests that could be performed covering a whole slew of potential infective agents (see here).

This is just a rough-and-ready idea of where autism research and practice could go with this but much like the pathways to diagnosing and managing bowel issues when comorbid to autism for example (see here), a general diagnostic roadmap is perhaps indicated...

Music: Years & Years - King.

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[1] Ziats MN. et al. Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation. Am J Med Genet A. 2015 May 5.

[2] Celestino-Soper PB. et al. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Proc Natl Acad Sci U S A. 2012 May 22;109(21):7974-81.

[3] Serret S. et al. Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports. BMC Psychiatry 2015, 15:107.

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Ziats MN, Comeaux MS, Yang Y, Scaglia F, Elsea SH, Sun Q, Beaudet AL, & Schaaf CP (2015). Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation. American journal of medical genetics. Part A PMID: 25943046




Serret, S., Thümmler, S., Dor, E., Vesperini, S., Santos, A., & Askenazy, F. (2015). Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports BMC Psychiatry, 15 (1) DOI: 10.1186/s12888-015-0490-1

Maternal complement C1q and offspring psychosis

"In conclusion, exposure to maternal C1q activity during pregnancy may be a risk factor for the development of schizophrenia and psychosis in offspring". That was the primary observation made by Emily Severance and colleagues [1] at Johns Hopkins, extending their scientific interest in immune system involvement being potentially linked to psychiatry [2].

"Serve the public trust, protect the innocent,
uphold the law"

I've already talked about Dr Severance's previous research forays into complement factor C1q and psychiatry on this blog (see here) and how C1q seropositivity was pretty significantly associated with both recent and non-recent onset schizophrenia in their cohort. Said complexing of C1q also turning up food components (gluten and casein) as potentially being involved [3] which has rumbles of Dohan's hypothesis [4] mixed in.

The most recent Severance paper takes things another stage further by trying to "determine if maternal C1q was associated with offspring schizophrenia and psychosis". Archived serum samples provided during pregnancy were therefore analysed for 55 "matched case-control" pairs of mothers - mothers with offspring who went on to develop psychoses as adults and those with offspring who were asymptomatic from such psychiatric issues. "IgG markers of C1q, bovine milk casein, egg ovalbumin, and wheat gluten were measured". Authors reported that: "C1q was significantly elevated in case mothers" and in that case group, where offspring developed psychoses: "C1q was significantly correlated with antibodies to both food and infectious antigens: gluten..., herpes simplex virus type 2..., and adenovirus".

Accepting that the total number of participants included in this latest trial was relatively small, also relying on archived samples collected as part of the US Collaborative Perinatal Project (CPP) [5], these are interesting results. That both food and infectious agent antigens seemed to correlate with C1q adds to other interesting work by Dr Severance and colleagues on, for example, the protozoan Toxoplasma gondii potentially joining forces with food antigens (see here) in some fashion. I don't know enough about the processes potentially involved in any relationship to provide any definitive answers as to the hows and whys but one hazards a guess that something like an effect on gastrointestinal barrier function might play some role [6].

This and other research from people such as the late Paul Patterson [7] continue to drive home the notion that maternal infection, or rather the immune processes and consequence of infection during pregnancy, seem to be able to influence later life outcomes for offspring. We still need to know more about the specific biological processes involved in any relationship including the rising scientific star that is epigenetics [8] (something covered in a recent blog post) and also how subsequent life events (whether biological, social or psychological) contribute to any psychiatric diagnosis. Whether for certain people or groups of people, there may be some merit at looking further at gastrointestinal (GI) functions (see here) or even dietary changes (see here) is perhaps something else worth investing a little more research time and effort into too...

Ben Folds Five to close...

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[1] Severance EG. et al. Maternal complement C1q and increased odds for psychosis in adult offspring. Schizophrenia Res. 2014. 4 September.

[2] Severance EG. et al. Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res. 2014 Jul 14. pii: S0920-9964(14)00319-3.

[3] Severance EG. et al. Complement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia. Neurobiol Dis. 2012 Dec;48(3):447-53.

[4] Dohan FC. Genetic hypothesis of idiopathic schizophrenia: its exorphin connection. Schizophr Bull. 1988;14(4):489-94.

[5] Klebanoff MA. The Collaborative Perinatal Project: a 50-year retrospective. Paediatr Perinat Epidemiol. 2009 Jan;23(1):2-8.

[6] Nouri M. et al. Intestinal barrier dysfunction develops at the onset of experimental autoimmune encephalomyelitis, and can be induced by adoptive transfer of auto-reactive T cells. PLoS One. 2014 Sep 3;9(9):e106335.

[7] Brown AS. & Patterson PH. Maternal infection and schizophrenia: implications for prevention. Schizophr Bull. 2011 Mar;37(2):284-90.

[8] Tang B. et al. Epigenetic changes at gene promoters in response to immune activation in utero. Brain Behav Immun. 2013 May;30:168-75.

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Emily G. Severance, Kristin L. Gressitt, Stephen L. Buka, Tyrone D. Cannon, & Robert H. Yolken (2014). Maternal complement C1q and increased odds for psychosis in adult offspring Schizophrenia Research : 10.1016/j.schres.2014.07.053