Evidence for an autoimmune aetiology of epilepsy?

With a title like that, I was bound to post about the paper by Mei-Sing Ong and colleagues [1] and their suggestion that: "Epilepsy and autoimmune disease frequently co-occur; patients with either condition should undergo surveillance for the other".

Capo di Noli @ Wikipedia 

United under the umbrella that is autism spectrum comorbidity (even possible phenotypes), I've talked quite a bit on this blog about epilepsy / seizure disorders (see here) and autoimmune conditions (see here), and how coexistence alongside the presentation of autism may be a potential route towards some overlapping or shared genetic or biochemical pathways being involved. It is indeed a coincidence that one of the authors on the Ong paper - Isaac Kohane - is one and the same with some autism [comorbidity] research in mind.

The Ong paper details the results of a a survey of health insurance claims in the US where authors "examined the relationship between epilepsy and 12 autoimmune diseases: type 1 diabetes mellitus, psoriasis, rheumatoid arthritis, Graves disease, Hashimoto thyroiditis, Crohn disease, ulcerative colitis, systemic lupus erythematosus, antiphospholipid syndrome, Sjögren syndrome, myasthenia gravis, and celiac disease". They reported that the risk of epilepsy was higher amongst those people with an autoimmune condition - all 12 of the autoimmune conditions looked at - and particularly when it came to risk for children. More chatter about this study can be found here.

Looking through many of those autoimmune conditions examined by Ong, the first thing that struck me was that many of those conditions have been talked about in research circles in the context of autism. Bowel conditions such as ulcerative colitis and Crohn's disease have certainly seen their fair share of discussion (see here) alongside the possibility of other bowel disease presentation in cases (see here). Coeliac (celiac) disease and autism... well, don't get me started. Antiphospholipid syndrome, or at least anti-phospholipid antibodies, have also been talked about in the context of autism too (see here). I could go on and on and on; reiterating that a diagnosis of autism is seemingly protective of nothing when it comes to other health issues, and quite a few of those health issues tend to fall into the autoimmune domain.

The next thing that struck me about that list of autoimmune conditions and indeed, how they might link into something like epilepsy, was the issue of food, and in particular gluten. Now, I'm not trying to make any sweeping generalisations here or anything like that, but outside of the classical relationship between coeliac disease and gluten, there is quite a bit of emerging evidence that gluten may be implicated in so much more including some overlap with autism. Don't believe me? Well, take type 1 diabetes as one example and papers like the one by Marietta and colleagues [2] on gluten modulating the incidence of type 1 diabetes (at least in mice). The paper by Sildorf and colleagues [3] even went as far as reporting on how a gluten-free diet was associated with clinical remission without insulin therapy for one boy with type 1 diabetes, bearing in mind no clinical or medical advice is given or intended from me on this issue. At this point I might also drop in a note about the various research being done on epilepsy, some epilepsy, and the use of a ketogenic diet (high fat, low carbohydrates which I assume impacts on gluten intake) as potentially being relevant here too.

Alessio Fasano, who has been mentioned on this blog before, summarised the possibility of a connection between gluten (gliadin) and type 1 diabetes quite nicely in one of his papers [4]. Indeed, following on from that paper and the notion that "loss of intestinal barrier function is necessary to develop autoimmunity", the question emerges: does the association between autoimmune diseases and epilepsy also suggest that gut permeability (a.k.a leaky gut) might be a feature of some cases of epilepsy? I don't want to get too bogged down with answering that question aside from reiterating that following on from the observations of Ong et al if it was eventually confirmed that there may be an autoimmune component to at least some cases of epilepsy, autism and particularly those cases of autism accompanied by a diagnosis of epilepsy, may very well represent one of the next stages in the evolution of this research topic.

Music to close. It's been a while since I've linked to an Elvis song, so here's Viva Las Vegas.

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[1] Ong MS. et al. Population-Level Evidence for an Autoimmune Etiology of Epilepsy. JAMA Neurol. 2014 Mar 31.

[2] Marietta EV. et al. Low incidence of spontaneous type 1 diabetes in non-obese diabetic mice raised on gluten-free diets is associated with changes in the intestinal microbiome. PLoS One. 2013 Nov 13;8(11):e78687.

[3] Sildorf SM. et al. Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Rep. 2012 Jun 21;2012.

[4] Visser J. et al. Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms. Ann N Y Acad Sci. 2009 May;1165:195-205.

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Ong MS, Kohane IS, Cai T, Gorman MP, & Mandl KD (2014). Population-Level Evidence for an Autoimmune Etiology of Epilepsy. JAMA neurology PMID: 24687183

Autism research at IMFAR 2014

So, here we go again as the annual IMFAR (International Meeting for Autism Research) meeting gets underway for 2014.

As in previous years (see here and see here), I am a watcher rather than an attender but do like to keep an eye on the conference because of the wealth of autism research talent it includes. That and also because the conference often provides a sort of 'heads-up' as to what might be appearing in the peer-reviewed literature over the coming months and hence future blogging material.

The on-line searchable program book is live (see here) but I'd like to draw your attention to a few abstracts which I found particularly interesting:

• The high prevalence of autism spectrum disorders among children with intellectual disabilities (see here).
• Psychiatric and medical conditions among adults with ASD (see here)
• Low endogenous fecal chymotrypsin: a possible biomarker for autism? (see here).
• Endogenous retrovirus expression in two mouse models of autism spectrum disorders (see here).
• Early characteristics of children who lose their autism diagnosis between age 2 and 4 (see here).
• Prevalence of obesity in autism spectrum disorders and associated risk factors (see here).
• The effectiveness of methylcobalamin and folinic acid treatment on adaptive behavior in children with autistic disorder (see here).
• Oxidative stress and immune cytokines in plasma of young children with autism spectrum disorder and recent language and/or social regression: a prospective case-control study (see here).
• Molecular analysis of inflamed ileocolonic tissue from GI symptomatic ASD children (see here).
• Placental features in ASD compared to controls: a community based cohort in Brooklyn (see here)
• Neonatal cytokines and chemokines and risk of autism spectrum disorder: the Early Markers for Autism (EMA) study (see here).
• Paternal age-related changes in DNA methylation from an autism-enriched cohort (see here)

There is a lot more research being presented, some of which I'm sure will be making headlines over the next few days. So, if you have a few hours free, head over to the conference website and see what's happening or if you're a Twitterererer, use #IMFAR2014 and follow proceedings there...

Gluten sensitivity and psychiatry reviewed

It's Coeliac Awareness Week here in the UK (see here) from 12-18 May 2014. With the rate of coeliac (celiac) disease going up according to the BBC website I thought it pertinent to talk today about something relevant to these issues.

So...

The review article by Genuis and Lobo [1] (open-access here) is the source material for today's short and quite descriptive post and their focus on how the protein gluten may be doing so much more than that currently recognised with the autoimmune condition coeliac disease in mind. To quote: "Emerging scientific literature contains several reports linking gluten sensitivity states with neuropsychiatric manifestations including autism, schizophrenia, and ataxia".

Wheat a minute... @ Wikipedia 

Gluten and its various metabolites, its intestinal and extra-intestinal effects, remains a primary interest of mine. Regular readers of this blog may already have come across other musings on the topic of this stuff, covering both my professional interest in gluten and autism, some autism (see here) and also a wider appreciation of its potential links to all manner of conditions and states (see here).

One of the advances currently being made when it comes to some of the research examination of gluten is the notion that non-coeliac gluten sensitivity (NCGS) may be an important one and by inference, coeliac disease is not the only manifestation of a gluten-related issue. My recent ramblings on the Simone Peters paper is testament to this.

The Genuis/Lobo paper covers quite a bit of the evidence so far for NCGS and the growing links between gluten and various conditions, including mention of some of the trailblazers in this field such as Mario Hadjivassiliou and colleagues (see here) and Faith Dickerson / Robert Yolken et al (see here). I'd also like to give a hat-tip to Emily Severance who is also an emerging force in this area (see here). The study by Jessica Biesiekierski and colleagues (see here) also gets a mention, which may very well go down as a classic study in this area of investigation. Even one of the authors of the paper - Stephen Genuis - has some research form in this area of investigation (see here).

There's little more for me to say about the Genuis/Lobo paper beyond the age-old requirement for a lot more research in this area. Outside of correlation not being the same as causation, I know some people still have a tendency to frown on this area of investigation, food as medicine and the like, particularly in light of the seemingly large number of conditions/states where gluten has been reported to have a potential effect breaking a cardinal rule of 'real science' (7. Does the claim involve multiple unassociated disorders? ). Assuming however that you see some commonalities across conditions like autism, schizophrenia and ataxia - or at least sub-groups of these quite heterogeneous conditions - and understand that comorbidity or an increased risk of certain comorbidity might be important to some people diagnosed with these conditions, you might see your way to taking a longer look at some of the peer-reviewed evidence hinting at some connection.

And now for some music. Smokey and the Bandit theme tune OK for you?

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[1] Genuis SJ. Lobo RA. Gluten Sensitivity Presenting as a Neuropsychiatric Disorder. Gastroenterol Res Pract. 2014;2014:293206.

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Genuis SJ, & Lobo RA (2014). Gluten Sensitivity Presenting as a Neuropsychiatric Disorder. Gastroenterology research and practice, 2014 PMID: 24693281

Neonatal jaundice and risk of autism?

The research of Mu-Hong Chen and colleagues from Taiwan appears on this blog quite a bit. Regular readers may already have read about the work of this group looking at various aspects on and around autism including the association with allergic and autoimmune conditions (see here) and the possibility of a link between asthma and ADHD (see here). Much of the strength of the data and results produced by this group lies in their examination of the National Health Insurance Research Database (NHIRD) which covers a large proportion of the Taiwanese population. Big data in action you might say, bearing in mind correlation and causation are not the same thing.

Chen Chengpo @ Wikipedia 

A further publication by Chen and colleagues [1] adds to the research collection from this group and their suggestion that: "Newborn exposure to hyperbilirubinemia was related to the increased risk of developing ASD [autism spectrum disorder], any developmental delay, and developmental speech or language disorder in later life". This conclusion was reached on the basis of an examination of some 2000 newborns presenting with neonatal jaundice compared with over 8000 matched controls without, following up on the subsequent rates of autism and other developmental diagnoses such as ADHD et al. Aside from the autism correlation, the authors also reported that phototherapy - treatment with light for newborn jaundice - was probably not going to be a significant factor in the suggested relationship. Just in case you need some more background about jaundice, I might refer you to quite a good, quite recent, overview (see here).

Hyperbilirubinemia leading to jaundice has been talked about a while back on this blog (see here). Since that post in early 2011, several other papers have been published which, on the whole, have suggested that jaundice might indeed be something to look at with autism risk in mind. The systematic review from Amin and colleagues [2] is quoted as suggesting: "jaundice, assessed by total serum bilirubin (TSB), was associated with ASD" based on data from several other research reports. Further, Mamidala and colleagues [3] reported that based on their analysis of pregnancy and birth-related variables in relation to autism offspring risk, the presence of neonatal jaundice was one of the more marginally significant associations found in their cohort. Even further, Froehlich-Santino and colleagues [4] talked about neonatal jaundice and autism risk in the context of sex differences: "jaundice was associated with an increased risk for ASDs in females".

Bearing in mind that not every study has reported a connection between neonatal jaundice and autism, or at least neonatal hyperbilirubinemia [5] and the quite high frequency of jaundice in newborns present in the population as a whole, one needs to treat any association with a degree of caution. That being said, data is data and results are results so some further inspection is perhaps indicated in this area.

When I posted the details of the Chen study to Facebook, it led to an interesting stream of comments and discussions about the meaning of the jaundice correlation and how it may play into some other areas in relation to autism. The genetic condition Gilbert's syndrome was mentioned as a function of jaundice being a primary manifestation there. This fairly common condition, affecting between 5-10% of the population, is not life-threatening (indeed might even be protective against the risk of other conditions). I was particularly interested in some of the biochemistry behind Gilbert's syndrome and the suggestion that the process of glucuronidation is affected in cases [6]. It jogged my memory of a recent post where I discussed the work of Stein and colleagues [7] and how reduced glucuronidation was observed in their cohort of children with autism, suggesting that sulphation might not be the only pathway with an autism connection.

Another commentator also posted an interesting question about how neonatal jaundice might also tie into the practice of breastfeeding and subsequently impact on autism risk. Just so you know, breastmilk jaundice is a recognised entity and is thought to be due to either inadequate milk intake leading to dehydration or components of breastmilk affecting the metabolism of bilirubin [8]. The discussion led to the paper by Mary Clark [9] and her opening line: "Breastfed infants are more likely to be jaundiced than infants who are formula fed" which subsequently led to the question: "does that mean that breastfeeding causes autism?". Now, I don't want to venture too far into the issue of 'bitty' and autism (see here) or make any sweeping generalisations about what may or may not be associated with the onset of autism but do feel that this question warrants more research attention. I note the paper from Al-Farsi and colleagues [10] who reported an "increased ASD risk is generally associated with suboptimal breast-feeding practices" and that's all I'm going to say on the matter at present.

If there is some take-home message from this post, it is that alongside the body of literature talking about the potential adverse effects of neonatal jaundice, hyperbilirubinemia [11] even in the very long term [12] it would perhaps be wise not to overlook some effect yet falling into the description of the autism spectrum, with the requirement for quite a bit more investigation.

Music then... since we are almost there, Summertime by Ella and Louis, best enjoyed looking out onto a sunny meadow sipping something cold and chatting about Eurovision.

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[1] Chen M-H. et al. Is neonatal jaundice associated with autism spectrum disorder, attention deficit hyperactivity disorder, and other psychological development? A nationwide prospective study. Res Autism Spec Disord. 2014; 8: 625-632.

[2] Amin SB. et al. Is neonatal jaundice associated with Autism Spectrum Disorders: a systematic review. J Autism Dev Disord. 2011 Nov;41(11):1455-63.

[3] Mamidala MP. et al. Prenatal, perinatal and neonatal risk factors of Autism Spectrum Disorder: a comprehensive epidemiological assessment from India. Res Dev Disabil. 2013 Sep;34(9):3004-13.

[4] Froehlich-Santino W. et al. Prenatal and Perinatal Risk Factors in a Twin Study of Autism Spectrum Disorders. J Psychiatr Res. 2014. March 29.

[5] Croen LA. et al. Neonatal hyperbilirubinemia and risk of autism spectrum disorders. Pediatrics. 2005 Feb;115(2):e135-8.

[6] de Morais SM. et al. Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome. Gastroenterology. 1992 Feb;102(2):577-86.

[7] Stein TP. et al. Autism and phthalate metabolite glucuronidation. J Autism Dev Disord. 2013 Nov;43(11):2677-85.

[8] Hargreaves T. & Piper RF. Breast Milk Jaundice. Arch Dis Child. Apr 1971; 46(246): 195–198.

[9] Clark M. Clinical update: understanding jaundice in the breastfed infant. Community Practitioner. 2013; 86: 42-45.

[10] Al-Farsi YM. et al. Effect of suboptimal breast-feeding on occurrence of autism: a case-control study. Nutrition. 2012 Jul;28(7-8):e27-32.

[11] Seidman DS. et al. Neonatal hyperbilirubinemia and physical and cognitive performance at 17 years of age. Pediatrics. 1991 Oct;88(4):828-33.

[12] Hokkanen L. et al. Adult neurobehavioral outcome of hyperbilirubinemia in full term neonates-a 30 year prospective follow-up study. PeerJ. 2014 Mar 4;2:e294.

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Chen, M., Su, T., Chen, Y., Hsu, J., Huang, K., Chang, W., Chen, T., & Bai, Y. (2014). Is neonatal jaundice associated with autism spectrum disorder, attention deficit hyperactivity disorder, and other psychological development? A nationwide prospective study Research in Autism Spectrum Disorders, 8 (6), 625-632 DOI: 10.1016/j.rasd.2014.03.006

Regression and autism continued (yet again)

I noticed a few weeks back that the topic of regression - developmental regression - with autism in mind resurfaced during a few media reports (see here and here). That last report by Jennifer Richler, who knows more than most about the research around regression and autism [1] particularly took my attention, and the implication that perhaps we need a little more investigation into this area with a focus on developmental trajectories and the small details which might reflect onset of the regressive phenotype(s) and indeed, any pre-regressive presentation. Whether also a history of developmental regression might affect age at diagnosis might be another question to be asked in light of the study findings from Mishaal and colleagues [2].

Journeys... @ Wikipedia 

It is therefore timely that the paper by Kern and colleagues [3] (open-access here) also appeared in my inbox recently talking about regression in relation to autism based on parental reports. The quote: "82 children (60.7%) were reported to have R[egressed]" was interesting because this seemed to be quite a high figure bearing in mind the participant group size (N=135).

My previous post on the topic of regression and autism highlighted the meta-analysis paper by Barger and colleagues [4] which at most set parent-reported regression in autism at around 40% of cases, bearing in mind how one goes about defining regression. Indeed, the recent paper by Goin-Kochel and colleagues [5] similarly found the rate to be around the 40% mark (36.9% overall) in their cohort of over 2000 children. Allowing for the assumption that rates of regression in cases of autism are a static entity and not subject to changes over time, the disparity between the figures is interesting.

I'm not on this occasion going to go through the Kern paper in excruciating detail because it is open-access. It is not altogether dissimilar from the earlier Richler paper in that parental report forms the crux of the observations and factors such as gastrointestinal (GI) issues were also included in the research mix. Where the two results separate is on a few main points: (a) Richler and colleagues included a control group; Kern et al did not, (b) Richler talks about: "no evidence that onset of autistic symptoms or of regression was related to measles-mumps-rubella vaccination"; Kern suggests: "The majority of parents reported that the regression was preceded by or was associated with vaccinations (57.3%) or another medically related event (11.0%)", and (c) Richler talks about children "who lost skills" had "more gastrointestinal symptoms than children with ASD and no regression"; Kern by contrast reports: "no significant relationship between the children’s age, gender, race, severity, or GI symptoms, and their membership in the D[elayed], DR [delayed and later regressed], or R[egressed] groups". I don't want to head too far into the discussions surrounding point (b) but will draw your attention to the paper by Woo and colleagues [6], who looking at data from the US VAERS (Vaccine Adverse Event Reporting System) observed that "The proportion of VAERS cases of autism with regression was greater than that reported in population-based studies, based on the subset of VAERS cases with medical record confirmation". I wonder if this might have something to do with the high rate of regression reported by Kerns et al also?

I was particularly interested in the differing results reported as a consequence of the presence of GI factors comorbid to core autism presentation with regression in mind. I note in the paper by Valicenti-McDermott and colleagues [7], they reported that "children with language regression more frequently exhibited an abnormal stool pattern" assuming that one equates abnormal stool pattern[s] as being the same as GI symptoms; well, functional GI symptoms at least. The paper from Mady Hornig and colleagues [8] (open-access here) adds to this sentiment with their observation that "Autism with GI disturbances is associated with elevated rates of regression in language or other skills and may represent an endophenotype distinct from other ASD". All of this kinda puts a new slant on the recent papers confirming an over-representation of GI issues in cases of autism (see here).

I'm intrigued by the notion that combined regression and GI issues might be a distinguishing endophenotype (sub-group) in the growing plurality of autism. Autism research is still feeling its way through the concept of regression outside of something like Heller's syndrome / CDD (and anti-NMDA receptor encephalitis and other viral infections in mind) and how such reports fit into the grand scheme of how and why autism comes about. As per some recent chatter on the early [behavioural] identification of autism, regression occurring in cases of autism is also a potential fly in the ointment for establishing very early indicators of autism, further compounded by the start-stop that accompanies child development. And then there is the issue of racial differences in the reported rates of regression in autism... already covered by some media just to complicate matters further.

More to do methinks.

To close, although Europe is braced for that annual get-together that is the Eurovision Song Contest tomorrow (Saturday 10th May 2014) I'm not gonna post to any of the past or present songs. Instead, some very motivational lyrics from Kiss. Thank God.

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[1] Richler J. et al. Is there a 'regressive phenotype' of Autism Spectrum Disorder associated with the measles-mumps-rubella vaccine? A CPEA Study. J Autism Dev Disord. 2006 Apr;36(3):299-316.

[2] Mishaal RA. et al. Age of autism spectrum disorder diagnosis is associated with child's variables and parental experience. Res Autism Spect Disord. 2014; 8: 873-880.

[3] Kern JK. et al. Evaluation of regression in autism spectrum disorder based on parental reports. N Am J Med Sci. 2014 Jan;6(1):41-7.

[4] Barger BD. et al. Prevalence and onset of regression within autism spectrum disorders: a meta-analytic review. J Autism Dev Disord. 2013 Apr;43(4):817-28.

[5] Goin-Kochel R. et al. Developmental regression among children with autism spectrum disorder: Onset, duration, and effects on functional outcomes. Res Autism Spec Disord. 2014; 8: 890-898.

[6] Woo EJ. et al. Developmental regression and autism reported to the Vaccine Adverse Event Reporting System. Autism. 2007 Jul;11(4):301-10.

[7] Valicenti-McDermott MD. et al. Gastrointestinal symptoms in children with an autism spectrum disorder and language regression. Pediatr Neurol. 2008 Dec;39(6):392-8.

[8] Hornig M. et al. Lack of association between measles virus vaccine and autism with enteropathy: a case-control study. PLoS One. 2008 Sep 4;3(9):e3140.

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Kern JK, Geier DA, & Geier MR (2014). Evaluation of regression in autism spectrum disorder based on parental reports. North American journal of medical sciences, 6 (1), 41-7 PMID: 24678477

Oxidative stress inducing mitochondrial dysfunction in autism?

Consider this post a sort of accompaniment to my recent chatter about the paper by Suzanne Goh and colleagues on brain lactate levels and mitochondrial dysfunction as a neurobiological subtype of autism (see here). Read on...

I've probably mentioned it before but outside of some light reading around the topic, mitochondria (plural) and mitochondrial dysfunction still remains a source of bafflement to me. Yes, I think I know the basics as per my learner post (see here) but it's the kinda of topic where I need to keep reading and re-reading sentences before any sense comes of it.

Bord de mer II @ Wikipedia 

It is therefore with a degree of trepidation that I approach the paper by Shannon Rose and colleagues [1] (open-access here) and their conclusion: "a significant subgroup of AD [autistic disorder] children may have alterations in mitochondrial function, which could render them more vulnerable to a pro-oxidant microenvironment as well as intrinsic and extrinsic sources of ROS [reactive oxygen species] such as immune activation and pro-oxidant environmental toxins". I might add that reports of mitochondrial dysfunction in cases of autism are seemingly increasing in the peer-reviewed literature [2].

OK, in very small steps, a few things to talk about here outside of my previous links to describing mitochondria shown above. ROS - reactive oxygen species - describes as the name suggests, molecules which contain oxygen (the important stuff that most creatures including us humans rely on for living). ROS are both a by-product of living (endogenous production) and can produced via other external sources (exogenous ROS). Endogenous production of ROS involves mitochondria, the so-called power plants in cells. Oxygen and various simple sugars are used to create ATP (adenosine triphosphate) as part of the process of oxidative phosphorylation. ROS are a by-product of this reaction which under certain circumstances can result in cell damage.

I'll also draw your attention to the concept of oxidative stress and it's relevance to this story. Basically, the body has ways to ensure that ROS production doesn't get out of hand via various cellular antioxidants. Regular readers of this blog might have already comes across some discussions on one of those antioxidants - glutathione - and the various findings in relation to autism (see here). As long as a happy balance is struck between appropriate levels of ROS and the scavenging availability of antioxidants, everything should tick along just fine. If however, ROS start to get the upper hand as described by the term oxidative stress, all sorts of effects can occur such as lipid peroxidation and oxidative damage to DNA. Ergo, balance is an important concept.

Back to the Rose paper then, which relied on something called lymphoblastoid cell lines (LCLs) as a means of measuring something called reserve capacity: "a measure of the ability of the mitochondria to respond to physiological stress" in cases of autism. LCLs came from the AGRE or the NIMH and researchers looked at mitochondrial reserve capacity "before and after exposure to reactive oxygen species (ROS)". Actually that wasn't the only research done on these LCLs, as the effect of N-acetylcysteine (NAC), "a glutathione precursor", pretreatment was also reported in the paper. The agent of choice for representing ROS in the study was something called DMNQ by the way.

Results, bearing in that I'm not going to go into the details of all the results because it's all there in open-access form for your interpretation:

• First and foremost: "LCLs derived from children with AD exhibit significant abnormalities in mitochondrial respiration after exposure to increasing levels of ROS". I temper those words with the authors suggestion that getting on for about half of the LCLs looked at (44%) seemed to drive the results obtained for the autism group. This might imply that in amongst all the talk about plural autisms, a sizeable subgroup of people on the autism spectrum may demonstrate such issues.
• "NAC rescues the atypical mitochondrial respiratory response". So, that pretreatment of the LCLs with NAC, specifically those 44% (10/22) who showed an abnormal adaptive response to ROS, seemed to improve mitochondrial respiration. This effect was not significantly present in the remaining LCLs from participants with autism.
• Glutathione (GSH) levels were also checked in cells (intracellular free GSH and also reduced glutathione - GSSG). As probably would be expected based on the other research literature in this area [3] lower glutathione levels were reported in the LCLs from participants with autism and a higher GSSG compared with controls. Perhaps not unexpectedly: "Pretreatment with NAC increased intracellular GSH and the GSH/GSSG ratio and reduced GSSG" in the LCLs from participants with autism.
• There are various other findings reported but the authors summarise by saying: "we demonstrate a new type of mitochondrial disorder that may affect a significant subgroup of AD children and provide insight into the interactions between systems that have been independently demonstrated to be abnormal in ASD [autism spectrum disorder]".

I know that I have gone on a little bit in this post because of the often quite technical jargon which is included in a study like this, so for that I apologise. My amateur status when it comes to talking about mitochondria and autism has probably not helped matters but I hope you can seem some glimmers of what the important results were derived from this relatively small-scale study. And yes, replication - independent replication - is an absolute must for this area of research bearing in mind facets of these results overlap with previous research by some of the same authors [4] and also here [5]. I might also add that other groups have started to talk about similar processes being involved in some autism too [6].

That all being said, I think you can see how important this work might eventually turn out to be when it comes to the area of mitochondrial dysfunction and autism, and indeed the possibility of links with other important areas of work such as the glutathione and NAC stories. Once again, I'm waiting attentively to see other published results in this area... including further replication of even more results from Napoli and colleagues [7] further discussed here.

And just in case my explanation of this area of work still leaves you baffled, I'll hand over to the experts and their recent review paper [8] ...

[Update: 16 March 2015: a clarification has been published over the paper from Rose and colleagues. Overlapping results had been mentioned...]

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[1] Rose S. et al. Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines. Transl Psychiatry. 2014 Apr 1;4:e377.

[2] Giulivi C. et al. Mitochondrial Dysfunction in Autism. JAMA. 2010; 304(21): 2389–2396.

[3] Main PAE. et al. The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis. Nutr Metab (Lond). 2012; 9: 35.

[4] James SJ. et al. Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism. FASEB J. 2009 Aug;23(8):2374-83.

[5] Rose S. et al. Oxidative stress induces mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines in a well-matched case control cohort. PLoS One. 2014 Jan 8;9(1):e85436.

[6] Napoli E. et al. Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism. Mol Autism. 2013 Jan 25;4(1):2.

[7] Napoli E. et al. Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism. Pediatrics. 2014. April 21.

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

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Rose, S., Frye, R., Slattery, J., Wynne, R., Tippett, M., Melnyk, S., & James, S. (2014). Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines Translational Psychiatry, 4 (4) DOI: 10.1038/tp.2014.15