AAP policy statement on iodine deficiency and pollutants

The quite recent policy statement from the American Academy of Pediatrics (AAP) drafted by Rogan and colleagues [1] is the source for today's short(ish) post. Highlighting a growing concern on the issue of iodine deficiency in women of reproductive age, the policy document also raises awareness of "commonly encountered environmental chemicals" potentially exacerbating such deficiency, and in particular "thiocyanate, nitrate and perchlorate". These chemicals are specifically mentioned because of their competition "for transport by the sodium iodide symporter (NIS)" involved in thyroid hormone biosynthesis. The paper by De Groef and colleagues [2] (open-access here) provides quite a good overview of the hows and whys of this chemical inhibition.

With my autism research hat on and hopefully without trying to make mountains out of molehills, I was interested in this latest policy statement in light of some interesting work talked about on this blog before. The Stine Andersen paper [3] covered in a previous post (see here) kinda sums up where we seem to be with regards to the 'association' between maternal hypothyroidism and subsequent heightened offspring risk of autism or an autism spectrum disorder (ASD). I did, on that post, also talk about iodine and the importance of iodine when it comes to making thyroid hormones. That iodine deficiency has also itself been linked to risk of offspring autism (see here) is another potentially important point to make.

The slightly more contentious area of 'chemical' (yes, that word again) involvement affecting iodine transport also seems to overlap with at least some work/speculation in the autism research arena. The paper by Gustavo Román [4] talking about environmental antithyroid agents and "transient in utero hypothyroxinemia" with autism in mind might be relevant. Román has already done some work in the area of thyroid hormones and offspring autism risk (see here) based on analyses from the Generation R cohort [5] (open-access). In that review article [4] there is talk about thiocyanate for example, and it being found in both food and other environmental sources as well as quite a few more other agents which have the ability to interfere with thyroid manufacture or function.

Perchlorate and autism is a slightly less well researched area. The paper by Chang and colleagues [6] is a good first effort when it came to assessing whether perchlorate-contaminated water might have any population-wide connection to rates of autism based on an ecological study design. On that occasion, no link was reported. That being said, measuring autism rates from a social healthcare program and perchlorate levels in drinking water from local water authority data might not necessarily provide the most accurate data as per the implications from the data from Mandell and colleagues [7] for example and the question of individual exposure patterns (something which might also be relevant to the recent pesticide-autism work too).

Given what is already known about maternal iodine deficiency and offspring outcome [8] the AAP policy document should be a welcome addition to the recommendations to US healthcare professionals in terms of ensuring iodine sufficiency particularly during pregnancy and early nursing periods. The addition of environmental variables also potentially affecting iodine levels whilst not shared by everyone [9] is something which requires further investigation. The more specific discussion about thiocyanate exposure from tobacco smoke in particular, taps into more generalised guidance for women to avoid smoking and second-hand smoke during pregnancy.

Music to close, and a bit of a favourite of mine... Fireflies (best listened to loud).

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[1] Iodine Deficiency, Pollutant Chemicals, and the Thyroid: New Information on an Old Problem. Council on Environmental Health. Pediatrics. 2014. 26 May.

[2] De Groef B. et al. Perchlorate versus other environmental sodium/iodide symporter inhibitors: potential thyroid-related health effects. Eur J Endocrinol. 2006 Jul;155(1):17-25.

[3] Andersen S. et al. Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study. BJOG. 2014 Mar 10.

[4] Román GC. Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents. J Neurol Sci. 2007 Nov 15;262(1-2):15-26.

[5] Román GC. et al. Association of gestational maternal hypothyroxinemia and increased autism risk. Ann Neurol. 2013 Nov;74(5):733-42.

[6] Chang S. et al. Pediatric neurobehavioral diseases in Nevada counties with respect to perchlorate in drinking water: an ecological inquiry. Birth Defects Res A Clin Mol Teratol. 2003 Oct;67(10):886-92.

[7] Mandell DS. et al. Age of diagnosis among Medicaid-enrolled children with autism, 2001-2004. Psychiatr Serv. 2010 Aug;61(8):822-9.

[8] Zimmerman MB. The effects of iodine deficiency in pregnancy and infancy. Paediatr Perinat Epidemiol. 2012 Jul;26 Suppl 1:108-17.

[9] Leung AM. et al. Environmental perchlorate and thiocyanate exposures and infant serum thyroid function. Thyroid. 2012 Sep;22(9):938-43.

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(2014). Iodine Deficiency, Pollutant Chemicals, and the Thyroid: New Information on an Old Problem PEDIATRICS, 133 (6), 1163-1166 DOI: 10.1542/peds.2014-0900

A gluten-free diet for asymptomatic patients with coeliac disease

The tip of the iceberg? @ Wikipedia 

Today I'd like to focus on the paper by Kalle Kurppa and colleagues [1] and their suggestion that: "GFDs [gluten-free diets] benefit asymptomatic EMA-positive [endomysial antibody] patients" with coeliac (celiac) disease in mind.

Asymptomatic, when it comes to a condition like coeliac disease (CD) - an autoimmune condition linked to the consumption of gluten - is not necessarily all that surprising given the numbers of cases where the words 'clinically silent' are used [2]. Indeed, the term 'coeliac iceberg' [3] is something I remember from my very earliest reading about CD reflective of the quite large numbers of people walking around with the serological and/or histopathological markers of the condition yet not seemingly experiencing the more classical signs of the disease or at least not severe enough to seek medical advice.

The Kurppa paper concluded that even in those cases where clinically silent is a feature of someones CD, the adoption of a gluten-free diet should still be considered. If anything because outside of changes (improvements) to the serological marker measures and any gastrointestinal (GI) symptoms: "The GFD group also had reduced indigestion (P=.006), reflux (P=.05), and anxiety (P=.025), and better health, based on the visual analog scale (P=.017), than the gluten-containing diet group".

Reduced anxiety eh? Well, obviously I don't want to make too much of a meal of this one even though that previous Catassi 'iceberg' study [3] talked about "decreased psychophysical well-being" as being part and parcel of "low-grade intensity illness". What I will however draw to your attention are two potentially important things:

The possible 'autism' connection. 
I doubt that readers will remember my post a while back on the paper by Jonas Ludvigsson and colleagues [4] talking about a sort of not-quite-coeliac-disease condition seemingly present in some children diagnosed with an autism spectrum disorder (ASD). Ludvigsson et al concluded that: "there was a markedly increased risk of ASDs in individuals with normal mucosa but a positive CD serologic test result". Ergo, not coeliac disease (CD) but something perhaps along the lines of a non-coeliac gluten sensitivity (NCGS). Tagged on to the the paper by Giacomo Caio [5] (open-access here), I'm wondering whether the Kurppa results might indeed hold some research promise when applied to at least some diagnosed as being on the autism spectrum perhaps with those CD serological markers? Particularly given that something like anxiety, when it occurs comorbid, can be absolutely disabling for some on the autism spectrum (see here) alongside other mention of a possible link between things like anxiety and GI issues with autism in mind (see here). Just thinkin' out loud.

Gluten exposure and feelings of depression?
The paper by Simone Peters and colleagues [6] talked about in another post (see here) might also fit with some of the Kurppa findings. I know I'm probably stretching things a little bit here but the Peters finding of that gluten ingestion "induced current feelings of depression" specifically in cases of "self-reported non-coeliac gluten sensitivity (NCGS)" may be related. Again with the speculating machine in full operation, I do wonder if the relationship between psychological health and wellbeing seemingly linked to CD or NCGS might hint at some shared mechanisms between the two states?

As per my blogging caveats - no medical or clinical advice given or intended - I'm not suggesting anything above and beyond what the Kurppa findings reported. There are also quite a few other potential explanations for the results they got insofar as not just what was excluded from the diet (gluten) but what might have also been added to the diet too also affecting health and wellbeing [7]. What I would perhaps champion however is a research agenda further tuned to the potential role that gluten may have on psychological health and wellbeing bearing in mind what gluten-free might have to cover [8]. As per the review paper by Genuis & Lobo [9] talked about in a previous post (see here), whether this important foodstuff might have much more to answer for than just CD. Oh, and then there are the results from Volta and colleagues [10] to also consider...

Music to close. Don't you worry child...

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[1] Kurppa K. et al. Benefits of a Gluten-free diet for Asymptomatic Patients with Serologic Markers of Celiac Disease. Gastroenterology. 2014 May 13. pii: S0016-5085(14)00609-X.

[2] Tursi A. et al. Prevalence and clinical presentation of subclinical/silent celiac disease in adults: an analysis on a 12-year observation. Hepatogastroenterology. 2001 Mar-Apr;48(38):462-4.

[3] Catassi C. et al. The coeliac iceberg in Italy. A multicentre antigliadin antibodies screening for coeliac disease in school-age subjects. Acta Paediatr Suppl. 1996 May;412:29-35.

[4] Ludvigsson JF. et al. A nationwide study of the association between celiac disease and the risk of autistic spectrum disorders. JAMA Psychiatry. 2013 Nov;70(11):1224-30.

[5] Caio G. et al. Effect of gluten free diet on immune response to gliadin in patients with non-celiac gluten sensitivity. BMC Gastroenterol. 2014 Feb 13;14:26.

[6] Peters SL. et al. Randomised clinical trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity - an exploratory clinical study. Aliment Pharmacol Ther. 2014 May;39(10):1104-12.

[7] Gautam M. et al. Role of antioxidants in generalised anxiety disorder and depression. Indian J Psychiatry. 2012 Jul;54(3):244-7.

[8] Sjöberg V. et al. Noncontaminated dietary oats may hamper normalization of the intestinal immune status in childhood celiac disease. Clin Transl Gastroenterol. 2014 Jun 26;5:e58.

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

[10] Volta U. et al. An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity. BMC Medicine 2014, 12:85

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Kurppa K, Paavola A, Collin P, Sievänen H, Laurila K, Huhtala H, Päivi Saavalainen, Mäki M, & Kaukinen K (2014). Benefits of a Gluten-free diet for Asymptomatic Patients with Serologic Markers of Celiac Disease. Gastroenterology PMID: 24837306

On parental inflammatory bowel disease and offspring autism risk

The paper by Ane Birgitte Telén Andersen and colleagues [1] (open-access here) concluding "no evidence of an increased risk of ASD [autism spectrum disorders] among children born to parents with IBD [inflammatory bowel disease]" caught my eye recently.

Qays and Layla @ Wikipedia 

Based on an analysis of one of those Danish Registries which seem to be providing all-manner of important correlations and non-correlations, the authors looked for the presence of parental IBDs such as ulcerative colitis (UC) or Crohn's disease (CD) in the files of over a million children, including some who went on to receive a diagnosis of autism or ASD. They reported that: "The 10-year risks of ASD were 0.7% among children of parents with IBD and 0.9% among children of parents without IBD". Indeed, judging by other figures presented one might even assume that a parental diagnosis of IBD might actually be somewhat protective against offspring autism...

This is interesting data. I've talked before about the strength of these types of large datasets; big data in action you might say. This authorship team are also no strangers to looking at the offspring risks or not following a parental diagnosis of an IBD. Take for example their results on paediatric asthma [2] (open-access here) similarly concluding no evidence for "an increased risk of asthma in offspring with a parental history of IBD".

Certainly the numbers being talked about by Andersen et al mean their results have to be taken seriously and as the authors note "reassuringly suggest that neither maternal or paternal IBD increases the overall risk of ASD in a child". That being said, I was also intrigued by how the Andersen findings contrasted with other studies in this area. Take for example the results of the much smaller study by Mouridesen and colleagues [3] covered in a previous post (see here) which hinted at some increased frequency of autoimmune related conditions in parents of children with autism. Maternal UC was noted as a potentially important variable in that study. Obviously there is quite a difference in the participant numbers between the two studies but still it's a contrast.

It is important to note that Andersen et al are only commenting on how parental IBD diagnosis seems not to be related to offspring autism risk. They are not saying that the known IBDs or even some prodromal / new-variant IBD (see here) are not related to at least some cases of autism. I'm also minded to suggest that the Andersen results might even offer some support to the idea that IBDs, when established in cases of autism, might have more of an 'acquired' element to them over and above a genetic link. I say this if one (a) assumes that some cases of autism have an autoimmune element to them, and (b) that certain factors listed in relation to autism such as early antibiotic use [4] might also might have some bearing on the 'acquisition' of the IBDs (see here).

Music to close... Before Candy Crush there was Orange Crush by REM.

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[1] Andersen AB. et al. Autism spectrum disorders in children of parents with inflammatory bowel disease - a nationwide cohort study in Denmark. Clin Exp Gastroenterol. 2014 May 7;7:105-10.

[2] Andersen AB. et al. Parental inflammatory bowel disease and risk of asthma in offspring: a nationwide cohort study in Denmark. Clin Transl Gastroenterol. 2013 Aug 22;4:e41.

[3] Mouridsen SE. et al. Autoimmune diseases in parents of children with infantile autism: a case-control study. Dev Med Child Neurol. 2007 Jun;49(6):429-32.

[4] Niehus R. & Lord C. Early medical history of children with autism spectrum disorders. J Dev Behav Pediatr. 2006 Apr;27(2 Suppl):S120-7.

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Andersen AB, Ehrenstein V, Erichsen R, Frøslev T, & Sørensen HT (2014). Autism spectrum disorders in children of parents with inflammatory bowel disease - a nationwide cohort study in Denmark. Clinical and experimental gastroenterology, 7, 105-10 PMID: 24855384

Scurvy, vitamin C and autism

I'd been thinking about writing this post on scurvy, vitamin C and autism for quite a while. The paper by Kitcharoensakkul and colleagues [1] really made the decision for me, following their discussions on three young children with walking difficulties who were eventually diagnosed with scurvy, one of whom was diagnosed with autism. The authors concluded: "These clinical manifestations and radiologic findings highlight the importance for rheumatologists to have a higher index of suspicion for scurvy in nonambulatory children". Nonambulatory by the way, means not able to walk about (independently). "Interestingly, all patients had concomitant vitamin D deficiency" was another important point made in the Kitcharoensakkul study which is something I'm always a little interested in on this blog (see here).

Limes... @ Fludkov @ Wikipedia 

Scurvy, as some people might already know, is a condition characterised by a lack of sufficient vitamin C (ascorbic acid). It can manifest in a variety of ways including fatigue, lack of appetite, irritability alongside various functional gastrointestinal (GI) symptoms. Gingival swelling or bleeding (the gums) is perhaps one of the best known [oral] signs of the disease. Nowadays it is quite a rare condition.

In other blog entries I've referred to myself as a Limey reflective of a slang phrase for someone from these hallowed Isles called Great Britain (Britain, Britain, Britain..), which seems to derive from the practice of giving lime juice to British sailors way back when, to prevent scurvy.

Suffice to say however that the Kitcharoensakkul paper is not the first time that scurvy has appeared alongside the word autism or words autism spectrum disorder (ASD) as I'll attempt to show you...

• Case studies describing scurvy concurrent to a diagnosis of autism can be found in the peer-reviewed research literature [2]. The description by Mawson [3] is typical although some symptoms reported in that particular case as being perhaps complicated by "treatment with indomethacin, which lowers vitamin C levels" is an important addition. I do think it is important to raise the point that some medicines can interfere with the availability of things like vitamins and minerals similar to such nutraceuticals affecting some medicines.
• Cole and colleagues [4] talked about the continued presence of scurvy "among susceptible populations" which includes "certain unique populations-particularly the elderly subjects, patients with neurodevelopmental disabilities or psychiatric illnesses, or others with unusual dietary habits" in their report on a "10-year-old autistic child". 'Unusual' dietary patterns are no stranger to autism [5] (open-access here) over and above any special dietary regimes being implemented (see here).
• Congidi and colleagues [6] described another case of scurvy in "an autistic child with food-avoidant behavior". They also described MRI findings for their patient. Indeed, this is something also described in the report by Tetsu and colleagues [7] who reported that the: "imaging findings of the thigh showed diffuse signal abnormality in the bone marrow, periosteum, and the femoral muscle". Further: "A biopsy specimen of the femur showed hematoma, proliferative fibroblasts, and few collagen fibers, which suggested a deficiency of vitamin C".
• Slightly outside of the issue of scurvy is the study presented by Dolske and colleagues [8] "exploring the effectiveness of ascorbic acid (8g/70kg/day) as a supplemental pharmacological treatment for autistic children in residential treatment". Although this was a small trial in terms of participant numbers, it was a "double-blind, placebo-controlled trial" lasting 30 weeks. The authors reported "a reduction in symptom severity associated with the ascorbic acid treatment" making specific mention of "sensory motor scores". Obviously I'm not making any recommendations about these findings (no medical or clinical advice given or intended) but do find them to be interesting and perhaps overlapping with other research where vitamin C supplementation has been included. So, think back to the Jim Adams trial data (see here) based on some older research [9]. As to the hows and whys, well, unlike the chatter about vitamin C therapy potentially impacting on Epstein-Barr antibodies no biological measure was used in the Dolske study so we are left speculating...

As you've probably realised, most of the research evidence surrounding the presence of scurvy in cases of autism is based on individual case reports. I can't for example, provide you with any population estimates of how prevalent scurvy might be in cases of autism because no-one has really looked at this issue with any great assiduity. I can point you in the direction of other work talking again about cases of scurvy appearing alongside schizophrenia for example [10] but will only say that a poor diet lacking in sources of vitamin C is as much to blame in those examples as it probably is where cases of autism are discussed.

Just before I go, there are a few other things to note about vitamin C and autism which may also be pertinent to other issues. I've talked about iron before on this blog and how there is some data suggesting issues with iron for some on the autism spectrum (although certainly not all). It's quite long been recognised that vitamin C also plays a role in the absorption of iron [11] particularly non-heme iron sources and a deficiency in vitamin C is probably not going to be conducive to 'optimal' function. Quite a while back I also talked about autism and oxalates (see here) but will say no more than re-iterating the study by Chai and colleagues [12] with the requirement for lots more investigation in this area.

To close, I was saddened to hear of the death of Prof. Paul Patterson this week, a real research pioneer who's studies on autism and schizophrenia were frequently discussed on this blog (see here and see here). One of his final research contributions was the very important study fronted by Elaine Hsiao supporting a "gut-microbiome-brain connection in a mouse model of ASD". My condolences go to his family and those who knew him.

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[1] Kitcharoensakkul M. et al. Scurvy revealed by difficulty walking: three cases in young children. J Clin Rheumatol. 2014 Jun;20(4):224-8.

[2] Monks G. et al. A case of scurvy in an autistic boy. J Drugs Dermatol. 2002 Jul;1(1):67-9.

[3] Mawson AR. Bone pain, growth failure, and skin rash after an upper respiratory illness in a boy with autism: possible association with altered retinoid metabolism. Clin Pediatr (Phila). 2009 Jan;48(1):21-5.

[4] Cole JA. et al. Scurvy in a 10-year-old boy. Pediatr Dermatol. 2011 Jul-Aug;28(4):444-6

[5] Bandini LG. et al. Food selectivity in children with autism spectrum disorders and typically developing children. J Pediatr. 2010 Aug;157(2):259-64.

[6] Gongidi P. et al. Scurvy in an autistic child: MRI findings. Pediatr Radiol. 2013 Oct;43(10):1396-9.

[7] Tetsu N. et al. curvy in a Child With Autism: Magnetic Resonance Imaging and Pathological Findings. Journal of Pediatric Hematology/Oncology. 2012; 34: 484-487.

[8] Dolske MC. et al. A preliminary trial of ascorbic acid as supplemental therapy for autism. Prog Neuropsychopharmacol Biol Psychiatry. 1993 Sep;17(5):765-74.

[9] Adams JB. & Holloway C. Pilot study of a moderate dose multivitamin/mineral supplement for children with autistic spectrum disorder. J Altern Complement Med. 2004 Dec;10(6):1033-9.

[10] Dubé M. Scurvy in a man with schizophrenia. CMAJ. Aug 9, 2011; 183(11): E760.

[11] Hallberg L. et al. The role of vitamin C in iron absorption. Int J Vitam Nutr Res Suppl. 1989;30:103-8.

[12] Chai W. et al. Oxalate absorption and endogenous oxalate synthesis from ascorbate in calcium oxalate stone formers and non-stone formers. AJKD. 2004; 44: 1060-1069.

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Kitcharoensakkul M, Schulz CG, Kassel R, Khanna G, Liang S, Ngwube A, Baszis KW, Hunstad DA, & White AJ (2014). Scurvy revealed by difficulty walking: three cases in young children. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases, 20 (4), 224-8 PMID: 24847751

Increased rates of suicidal ideation in adults with Asperger syndrome

"Our findings lend support to anecdotal reports of increased rates of suicidal ideation in adults with Asperger's syndrome, and depression as an important potential risk factor for suicidality in adults with this condition".

Sunrise @ Wikipedia 

That was the very stark conclusion reached by the study by Sarah Cassidy and colleagues [1] (open-access) looking at self-reported rates of suicide ideation and suicide plans/attempts in a sample of adults newly diagnosed with Asperger syndrome attending a "specialist diagnostic clinic" between 2004 and 2013. That depression seemed to play an important role in the engagement of such extreme thoughts or behaviour was also important. The press release accompanying the research can be read here.

As per some previous discussion on this topic (see here), suicide, whether attempted or completed, is a difficult topic to talk about. Not only because of the emotions which it invariably stirs up but also because the various paths towards someone reaching such an extreme point are complex, often very individual and still not well understood. Among the various risk factors suggested to be linked to [completed] suicide [2] some key points quite consistently come out including (a) a previous history of suicide ideation or suicide attempts, (b) the presence of psychiatric comorbidity such as depression or psychotic illness, and (c) some degree of social exclusion or alienation. I should mention that this is not an extensive list of risk factors, merely those which seem to appear with greatest frequency in the various research literature in this area.

The Cassidy paper is open-access but a few points are pertinent:

• As part of their attendance at clinic, nearly 400 adults ranging in ages from 17 - 67 years old at time of diagnosis, completed a self-report "patient screening questionnaire" containing items of about suicide and mood. The paper states the relevant questions: "have you ever been diagnosed with depression?", "have you ever felt suicidal?" and "if yes, have you ever planned or attempted suicide?".
• Participant were also asked to complete the Empathy Quotient (EQ) and the Autism Spectrum Quotient (AQ) questionnaires, both self-report measures which provide information about empathy and some of the "cognitive-behavioural traits associated with autism". Data derived from the suicide questioning items were compared with "published rates of suicidal ideation in the general population and other clinical groups".
• Results: "a 66% lifetime experience of suicidal ideation and a 35% lifetime experience of planned or attempted suicide supports the assertion that these occurrences are common in people with Asperger's syndrome". Compared with the population control data on these issues, the authors report that their sample were "more likely to report lifetime experience of suicidal ideation than were individuals from a general UK population sample". This included those with medical illnesses or psychotic illness. But... those with drug dependency and ADHD were still marginally more likely to report suicide ideation.
• Depression also seemed to play it's part in the reports. "Individuals with a history of depression ... were more likely to report suicide ideation ... and more likely to report suicide plans or attempts" compared with those without depression. And as for the EQ and AQ data, well higher scores on the AQ seemed to link with those reporting suicide plans or attempts but that was about it.

There are limitations to this study based on issues like the use of self-report questionnaire items asking about things like planned or attempted suicide or depression diagnosis without other evidence sources. Also as the authors note, their focus on "the population of people who reach adulthood without a diagnosis of Asperger's syndrome" is relevant. But the results are pretty stark particularly in respect to the numbers who have actually planned or attempted suicide. 

Going back to those more generalised population risk factors linked to suicide ideation or completion, it's not difficult to see how many of those might especially apply to some diagnosed with Asperger syndrome. Comorbidity such as depression is quite a well-known issue in relation to the autism spectrum [3]. Indeed, not so long ago I was interested to read the paper by Gotham and colleagues [4] on how rumination - "compulsively focused attention on the symptoms of one's distress" - might play a role in depression in some cases of autism and where this could lead from a therapeutic standpoint. I'll also direct you to the paper by Ljung and colleagues [5] concluding that: "Attention-deficit/hyperactivity disorder [ADHD] is associated with an increased risk of both attempted and completed suicide" which might tie into the links being made between autism and ADHD (see here).

Insofar as other conditions more generally linked to suicide such as psychosis [6] there is also perhaps something to do with the Cassidy results in mind, as a consequence of Asperger syndrome not being protective against the development of psychosis (see here). Social exclusion or alienation is also something reported with regards to the autism spectrum. I'm due to publish a mega-post quite soon on some of the research literature looking at quality of life (QoL) with autism in mind. Certainly in amongst that collected work, there are multiple examples of how loneliness and social isolation can be very detrimental factors to QoL.

At this point I'm also minded to bring in the possibility that suicide ideation or planning might not be just solely due to psychological or societal factors but rather may be influenced by something like biology too. Regular readers of this blog probably already know about my fascination with all-things vitamin D. It's timely that I talked about some of the collected literature looking at vitamin D deficiency in relation to something like depression recently (see here). Even perhaps more timely that said deficiency of the sunshine vitamin/hormone might also be something to look at with [adult] autism in mind (see here). I'm not necessarily suggesting a cause-and-effect scenario linking these elements, merely that this could be something to look at in future. Perhaps also in the same light as looking at another interest of mine: gluten and "feelings of depression"? How about other trace minerals and suicide too?

Whatever the reasons for thoughts of suicide to be linked to the autism spectrum, there is an important message to come from the Cassidy results and other papers on this topic: "inform appropriate service planning and support to reduce risk in this clinical group". Or I could just say make greater efforts to ensure that everyone knows how valuable their lives are, how valued they are as individuals and that there are people to talk to...

Everybody Hurts... so hold on.

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[1] Cassidy S. et al. Suicidal ideation and suicide plans or attempts in adults with Asperger's syndrome attending a specialist diagnostic clinic: a clinical cohort study. Lancet Psychiatry. 2014. June 25.

[2] Pelkonen M. & Marttunen M. Child and adolescent suicide: epidemiology, risk factors, and approaches to prevention. Paediatr Drugs. 2003;5(4):243-65.

[3] Matson JL. & Williams LW. Depression and mood disorders among persons with Autism Spectrum Disorders. Res Dev Disabil. 2014 Sep;35(9):2003-2007.

[4] Gotham K. et al. Rumination and Perceived Impairment Associated With Depressive Symptoms in a Verbal Adolescent-Adult ASD Sample. Autism Res. 2014 Jun;7(3):381-91.

[5] Ljung T. et al. Common Etiological Factors of Attention-Deficit/Hyperactivity Disorder and Suicidal Behavior. JAMA Psychiatry. 2014. June 25.

[6] Björkenstam C. et al. Suicide in first episode psychosis: A nationwide cohort study. Schizophr Res. 2014 May 31. pii: S0920-9964(14)00240-0.

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Sarah Cassidy, Paul Bradley, Janine Robinson, Carrie Allison, Meghan McHugh, & Simon Baron-Cohen (2014). Suicidal ideation and suicide plans or attempts in adults with Asperger's syndrome attending a specialist diagnostic clinic: a clinical cohort study Lancet Psychiatry : doi:10.1016/S0140-6736(08)61345-8

Silence ENO2! More epigenetics and autism

The paper by Yu Wang and colleagues [1] (open-access here) concluded that: "reduced ENO2 expression may be a biomarker for a subset of autistic children" following their genome-wide methylation study of autism. For those who've picked up the word 'methylation' in that first sentence, this is yet another sign that epigenetics - the science of changes to gene function not entailing structural genomic changes - is starting to impact on autism research.

Silentio! @ Wikipedia 

Based on an initial analysis of 5 pairs of participants - five diagnosed with autism, the other five being asymptomatic controls - drawn from a larger study population (n=131 pairs), researchers conducted a genome-wide study of venous blood samples for methylation variations in gene promoter regions and CpG islands using a method called MeDIP. Candidate genes (LASS3, PANX2, SLC15A4 and ENO2) which showed differential methylation patterns between the autism vs. control samples were selected for further investigation, after which ENO2 became the target gene for the study. It was then a case of verifying the methylation status of ENO2 (via BSP sequencing) in cases and controls of the larger participant groups followed by some analysis of the expression of ENO2 with regards to RNA levels and protein expression.

The results: "hypermethylation of a single gene, ENO2, may be associated with about 15 % of
autistic cases". All of the children with ENO2 hypermethylation had "significant language development disorder" which contrasted with the other children in the autism group who "had more or less spoken language" although I didn't note any specific language measure to be used in this trial. ENO2 RNA levels were "reduced by about 70% relative to that in controls" and ENO2 protein expression in the hypermethylated group "was about half of that of controls".

Ergo, "ENO2 expression may be a biomarker for a subset of autistic children".

OK first things first, CpG sites and DNA. Imagine if you will, that in amongst the very complicated genetic blueprint which guides things like eye colour or whether you've inherited that magnificent nose from dad or mum, there are islands of DNA which contain a particular sequence separated by phosphate: cytosine - phosphate - guanine (CpG). The cytsosine part of the CpG site can be methylated - the addition of a methyl group - to form 5-methylcytosine; methylation in this respect generally taken to mean gene silencing or at least a reduction in gene function which can then lead to decreased gene transcription and onwards less protein expression.

The Wang results basically plotted how from looking at the methylation status of the genome, a specific candidate gene showing something like a distinct methylation pattern in some cases of autism was followed through to see how said methylation affects gene function. It goes without saying that this was a very preliminary study and judging by the participant numbers needed in more traditional studies looking at structural changes to the genome (SNPs, CNVs et al) replication on a much grander scale (and looking at specific tissues) is absolutely implied before anyone gets too carried away. That also it's most probably autisms over autism together with the the principles of RDoC are other issues to be kept in mind.

Still, I don't want to take anything away from the Wang results and what they 'could' potentially mean in light of other research in this area. Whether or not ENO2 survives future replicative studies is to some extent secondary to the question of why this gene was hypermethylated in the first place? Does this suggest a role for some of the DNA methyltransferases in relation to autism? What about the mechanisms of methyl donation and the functions of things like S-Adenosyl methionine (SAMe) in that process? Lots of different layers of complexity to be added to our knowledge of the genome.

Music to close. Coldplay and Magic...

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[1] Wang Y. et al. Hypermethylation of the enolase gene (ENO2) in autism. Eur J Pediatr. 2014 Apr 17.

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Wang Y, Fang Y, Zhang F, Xu M, Zhang J, Yan J, Ju W, Brown WT, & Zhong N (2014). Hypermethylation of the enolase gene (ENO2) in autism. European journal of pediatrics PMID: 24737292

Pesticides and autism: chapter II

I've labelled this entry a chapter II post reflecting some continued interest in how agricultural pesticide exposure might fit into autism research (see here for the chapter I post). In that previous post, I talked about various issues such as the old correlation-is-not-necessarily-causation mantra and indeed, how use of something like galantamine for cases of autism spectrum disorder (ASD) [1] might present something of a paradox for certain types of pesticides being involved in the condition, as a function of its similar acetylcholinesterase inhibitor activity (albeit reversible).

Altogether Now? @ Wikipedia 

Continuing the pesticide theme, I'm talking today about the paper by Janie Shelton and colleagues [2] (open-access) and their results strengthening "the evidence linking neurodevelopmental disorders with gestational pesticide exposures, and particularly, organophosphates". Some of the press on this study be seen here.

Based on data derived from the CHARGE study (beincharge!) authors reported that maternal residence during pregnancy close to locations undertaking "agricultural pesticide application" might elevate the risk of offspring autism; something previously discussed by some of the authors [3]. Results from CHARGE by the way, have already talked about other environmental associations with autism risk such as air pollution (see here). This initiative also recently confirmed what many people already knew in saying the gastrointestinal (GI) symptoms seem to be over-represented in cases of autism (see here).

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

• With an authorship list of the great and the good associated with CHARGE, commercial pesticide use data was linked to the addresses of mothers when pregnant for groups diagnosed with autism (n=486) or developmental delay (DD) (n=168) compared with asymptomatic controls (n=316) living in California, USA. As alluded to in a post on that most undesirable of jobs - the commercial pesticide applicator - commercial pesticide use tends to be quite tightly regulated as a result of the potential for health effects when mis-used.
• Various models and algorithms built up a statistical picture of different classes of pesticides, their use and when and where they sprayed. The authors aimed to ascertain whether gestational exposure was linked to autism risk and whether there were "specific windows of vulnerability during gestation". 
• Results: bearing in mind there were quite a few estimates built into this study, a few points are worth mentioning. "Proximity to organophosphates at some time during gestation was associated with a 60% increased risk for ASD". Organophosphate (OP) pesticides were also "the most commonly applied agricultural pesticide near the home during pregnancy" and chlorpyrifos exposure in particular, during the 2nd trimester, seemed to show some association with offspring ASD risk.
• "Children of mothers residing near pyrethroid insecticide applications, just prior to conception or during 3rd trimester were at greater risk for both ASD and DD". Pyrethroids were the "second most commonly applied class of pesticides".
• A few additional points: males were slightly more likely than females to be exposed to pesticides during gestation, and the effects of multiple exposures (various different classes of pesticides) was generally "not found to be higher that the observations of the individual classes of pesticides".

Reiterating that this was a study based on estimation rather than looking at actual individual pesticide exposure during pregnancy or any biological testing for said exposure, this is an interesting study. I say that not to further condemn pesticides, which actually do quite a good job at helping to maintain our food supply and reduce our exposure to various pests. But rather that further study is indicated in this area as a result. The authors note the various strengths of their study based to a large extent on the fairly extensive data held on CHARGE participants. Likewise they note that their study did not for example, take into account "external non-agricultural sources" of pesticides such as those which many of us see sprayed around our homes, gardens and other areas of residence/work which could have affected their data. An 'underestimate' in actual exposure according to some external commentary on the study.

The question of pesticide exposure being potentially linked to autism risk carries quite a bit of the same baggage as the air pollution correlation. Yes, to some degree, we're all pretty unfit for consumption (see here) as a function of our 'chemical load' - bearing in mind the mis-representation of that word. Some people use this generality as a stick to beat such hypotheses on environment being potentially linked to conditions like autism (yes, we know the autisms are a complicated set of conditions). But as we've seen with the air pollution work, it may be the sum of the environmental risks combined with some genetic fragility which eventually provides the more important answers (see here); something which Shelton et al conclude: "Further research on gene-by-environment interactions may reveal vulnerable sub-populations". I might at this point also throw in a related post on Reelin and OPs as one area where we might begin searching.

In terms of the mechanism of effect, well if other autism research is anything to go by, it's gonna be complicated and probably not just confined to old the grey-pink matter. The obvious place to start looking would be the biological mechanisms which we rely on to metabolise things like OPs. PON1 is a good example, and as I've mentioned in other posts (see here) how PON1 has already seen some autism research action [4]. Indeed the paper by Gaita and colleagues [5] adds to the interest here and their findings of decreased serum arylesterase activity in case of autism. Paşca and colleagues [6] further suggested that a correlation (that word again) between high levels of homocysteine and low serum paraoxonase 1 arylesterase activity in cases of autism might be important. Certainly, when it comes to the 'big H' there is quite a bit of data with autism in mind (see here) but I'm not going to get ahead of myself here. I'll also direct your attention to other research talking about in-utero OP exposure being linked to shortened gestational duration [7] as an example of how effects may be peripheral as well as central. Oh and how PON1 enzyme levels might also tie into birth measurements [8].

If there is a take-home point to this post it is that the Shelton results suggestive of a link between gestational pesticide exposure and autism risk invite quite a bit more further scientific inspection of this area. I don't give clincial or medical advice on this blog but certainly the idea that pregnant women should perhaps "take special care to avoid contact with agricultural chemicals whenever possible" seems like a sensible statement to make (see here).

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[1] Ghaleiha A. et al. Galantamine efficacy and tolerability as an augmentative therapy in autistic children: A randomized, double-blind, placebo-controlled trial. J Psychopharmacol. 2013 Oct 15;28(7):677-685.

[2] Shelton JF. et al. Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: The CHARGE study. Environ Health Perspect. 2014: June 23.

[3] Shelton JF. et al. Tipping the balance of autism risk: potential mechanisms linking pesticides and autism. Environ Health Perspect. 2012 Jul;120(7):944-51.

[4] D'Amelio M. et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Mol Psychiatry. 2005 Nov;10(11):1006-16.

[5] Gaita L. et al. Decreased serum arylesterase activity in autism spectrum disorders. Psychiatry Res. 2010 Dec 30;180(2-3):105-13.

[6] Paşca SP. et al. High levels of homocysteine and low serum paraoxonase 1 arylesterase activity in children with autism. Life Sci. 2006 Apr 4;78(19):2244-8.

[7] Eskenazi B. et al. Association of in Utero Organophosphate Pesticide Exposure and Fetal Growth and Length of Gestation in an Agricultural Population. Environ Health Perspect. 2004; 112(10): 1116–1124.

[8] Harley KG. et al. Association of organophosphate pesticide exposure and paraoxonase with birth outcome in Mexican-American women. PLoS One. 2011;6(8):e23923.

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Janie F. Shelton, Estella M. Geraghty, Daniel J. Tancredi, Lora D. Delwiche, Rebecca J. Schmidt, Beate Ritz, Robin L. Hansen, & Irva Hertz-Picciotto (2014). Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: The CHARGE study Environmental Health Perspectives : 10.1289/ehp.1307044

Kata training and autism

The actor and musician Steven Seagal is probably not natural fodder for this blog about autism research but he does nevertheless make an appearance today. More readily known for his action films - my favourite was always 'Under Siege' - one of the appeals of Mr Seagal was his knowledge and use of martial arts in his various roles, as a function of his quite impressive real-life black belt in Aikido.

Obi Wan... no Obi knot @ Wikipedia 

It is with martial arts in mind that today I'm talking about an interesting paper by Ahmadreza Movahedi and colleagues [1] and some observations on the use of kata techniques on social interactive abilities in a small group of children diagnosed with an autism spectrum disorder (ASD). Kata by the way, refer to the various structured patterns of movements practised as part of martial arts like karate. Normally incorporating various blocks and offensive (attacking) movements, kata are an integral part of martial arts training and vary in their complexity and number of moves (see here). Practice makes perfect is the primary tenet of kata training.

A few details about the Movahedi paper might be useful:

• Thirty children diagnosed with ASD formed the participant group. None had any experience or training in kata techniques. They were randomly assigned to an exercise group (n=15) or a control group (n=15). Heian Shodan (see this video for what this encompasses) kata was the chosen "experimental task" (one of the first kata taught in Shotokan karate). Training was delivered to the exercise group as part of a structured schedule; all sessions were videotaped to "control the trainers' teaching method as precisely as possible".
• Exercise group participants received kata instruction "1 session/day. 4 days/week for 14 weeks (56 sessions)". Sessions involved initially watching a video of someone performing the kata and then receiving personal instruction from trainers onwards to performing the kata. Warm-up and cool-down exercise started and finished each session whilst "Persian music" was playing (this study was completed in Iran).
• Social interaction was measured at baseline before intervention and post-intervention at 14 weeks based on the use of the Gilliam Autism Rating Scale (GARS-2). Observations were carried out by "caregivers, parents and teachers" and based on the "frequency of occurrence of each social behaviour under ordinary circumstances in a 6-h period".
• Results: there was no significant differences on the social interaction subscale of the GARS at baseline (before intervention) between the groups. After intervention however "the participants of the exercise group demonstrated a substantial improvement in social interaction" compared to the control participants. This improvement also seemed to last even after 30 days of no training at the conclusion of the kata training for the exercise group. 
• The authors concluded that kata training is an effective avenue for improving social interaction for children with ASD. Perhaps wider that their results may help providers to "decide to establish strategic plans under which martial arts techniques will best be instructed to children with ASD".

Bearing in mind the small numbers of participants included in this study, I was impressed by these findings. I'm quite a fan of the martial arts and some of the philosophy behind them and how they might relate to various facets of autism, be it stress (see here and see here), self-confidence (see here) or just getting someone more active (see here). Most people who take part in and/or watch loved ones take part in activities such as karate, whether diagnosed with autism or not, see very quickly how such training offers a multitude of benefits outside of just increased physical activity (and onwards academic performance?). Self-confidence and self-regulation (difficult concepts to measure) tend to be some of the primary psychological benefits of the martial arts. Whether this comes from the actual training or as a result of the knowledge that the training brings is still a question open to some debate. Anger and aggression can also be 'channelled' as a function of certain martial arts training [2]. Given the principles on which something like karate is based, this is perhaps not all that surprising. The social interactive aspect included in martial arts reflects interaction with both Sensei (teacher) and other students, who, in a real-life setting, will generally include various ages and various different grades (see here) and hence incorporates a spirit of partner practising and helping out those less experienced. All these elements can positively combine together to promote a sense of belonging.

Other research has also looked at the effects of kata training on other aspects of autism. The paper by Bahrami and colleagues [3] (yes, the same authorship group) talked (I think) about the same participant group also showing "significantly reduced stereotypy" following training. Again, the benefits were seen even after the training period had been completed. A further case study paper by the same authors showed similar things [4].

The paper by Torres [5] using martial arts training as a means to assess movement in relation to autism hints at another interesting area of potential study. It's long been discussed in autism research circles that movement and gait seem to be 'affected' in quite a few instances of autism [6]. I've covered some of the peripheral issues on this blog including toe walking (see here) and that curious issue of joint hypermobility (see here) talked about further in a paper by Shetreat-Klein and colleagues [7]. The intriguing question is whether the often very intricate and certainly 'balance-orientated' movements included in kata training might likewise have some positive effects on autism. Indeed if, as is starting to be discussed, motor skills do show a connection with autism characteristics [8], whether the effects of kata training on motor skills may be a route to affecting other core issues associated with autism?

So, music to close. I'll forgo the obvious music with a martial arts slant (no, not Kung-Fu fighting) and instead go for some Arctic Monkeys.... I bet that you look good on the dance floor (well, do yer?)

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[1] Movahedi A. et al. Improvement in social dysfunction of children with autism spectrum disorder following long term Kata techniques training. Research in Autism Spectrum Disorders. 2013; 7: 1054-1061.

[2] Lotfian S. et al. An analysis of anger in adolescent girls who practice the martial arts. Int J Pediatr. 2011;2011:630604.

[3] Bahrami F. et al. Kata techniques training consistently decreases stereotypy in children with autism spectrum disorder. Research in Developmental Disabilities. 2012; 3: 1183-1193.

[4] Bahrami F. et al. Effect of Kata Training on Stereotypic Behaviors in Three Boys with Asperger Syndrome. Iranian Journal of Psychiatry & Clinical Psychology. 2013; 19: 54-64.

[5] Torres EB. Atypical signatures of motor variability found in an individual with ASD. Neurocase. 2013 Apr;19(2):150-65.

[6] Calhoun M. et al. Gait patterns in children with autism. Clin Biomech (Bristol, Avon). 2011 Feb;26(2):200-6.

[7] Shetreat-Klein M. et al. Abnormalities of joint mobility and gait in children with autism spectrum disorders. Brain & Development. 2014; 36: 91-96.

[8] MacDonald M. et al. Motor skills and calibrated autism severity in young children with autism spectrum disorder. Adapt Phys Activ Q. 2014 Apr;31(2):95-105.

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Movahedi, A., Bahrami, F., Marandi, S., & Abedi, A. (2013). Improvement in social dysfunction of children with autism spectrum disorder following long term Kata techniques training Research in Autism Spectrum Disorders, 7 (9), 1054-1061 DOI: 10.1016/j.rasd.2013.04.012

Meta-analysing cytokine involvement in autism

A fairly brief post today to draw your attention to the "systematic review and meta-analysis" paper by Masi and colleagues [1] on all-things cytokine in relation to autism. They concluded that there was "strengthening evidence of an abnormal cytokine profile in ASD [autism spectrum disorder] where inflammatory signals dominate". I should point out that other authors have reached similar conclusions in previous reviews [2] and here also [3].

"The herring does not fry here" @ Wikipedia 

In case you didn't know, cytokines are the chemical messengers of the immune system (see here) and perform various important tasks in relation to processes such as inflammation (see here). Autism research has a growing respect for the role of cytokines in quite a few cases of autism as per the growth in the amount of research literature available in this area (see here). I've covered quite a few papers focused on cytokines and autism on this blog (see here and see here for example) down the years.

The Masi paper is an important one because it gathered quite a bit of the peer-reviewed research literature mentioning cytokines and autism together and for want of better words, 'statistically spat' out the sum total of the findings from the various studies. A couple of old friends "were significantly higher in the participants with ASD" compared with control populations including interleukin 1-beta (IL-1β), IL-6, interferon-gamma (IFNγ) and monocyte chemotactic protein-1 (MCP-1) potentially indicative of a more pro-inflammatory state. A general reduction in the levels of more 'anti-inflammatory' molecules such as transforming growth factor-beta 1 (TGF-β1) [4] added to proceedings.

It's perhaps slightly unfair to say that these and other cytokines noted to be generally elevated in relation to autism are solely pro-inflammatory cytokines (i.e. inducing or maintaining inflammation) because that's not necessarily the way they always work. IL-6 for example, is now realised as being both a pro-inflammatory and anti-inflammatory molecule [5]. That being said, the growing recognition that inflammation and inflammatory processes may have some bearing on brain and behaviour (see here) ties in well with the Masi findings and where science perhaps needs to start looking with greater vigour if one is going to understand the interplay between immune function and psychiatry. As the authors note: "A better understanding of the inflammatory biology of ASD and possible associations with behavioral impairments and non-diagnostic features warrants further investigation and may have significant therapeutic implications". I can't argue with those sentiments, although as per the recent paper by Careaga and colleagues [6] how science goes about looking at that relationship is going to be important.

Oh, and on the topic of MCP-1, the paper by Zerbo and colleagues [7] observing elevations in the levels of this cytokine in newborn blood spots from those subsequently diagnosed with autism is indeed timely... (and again reiterates the potentially usefulness of those drops of blood which many children give in their earliest days welcomed into the big, wide world).

Music now. Daft Punk, and before Get Lucky, they were already Around the World.

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[1] Masi A. et al. Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis. Molecular Psychiatry. 2014. June 17.

[2] Goines PE. & Ashwood P. Cytokine dysregulation in autism spectrum disorders (ASD): possible role of the environment. Neurotoxicol Teratol. 2013 Mar-Apr;36:67-81.

[3] Onore C. et al. The role of immune dysfunction in the pathophysiology of autism. Brain Behav Immun. 2012 Mar;26(3):383-92.

[4] Qian L. et al. Potent anti-inflammatory and neuroprotective effects of TGF-beta1 are mediated through the inhibition of ERK and p47phox-Ser345 phosphorylation and translocation in microglia. J Immunol. 2008 Jul 1;181(1):660-8.

[5] Scheller J. et al. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2011; 1813: 878-888.

[6] Careaga M. et al. Inflammatory profiles in the BTBR mouse: How relevant are they to Autism Spectrum Disorders? Brain Behav Immun. 2014 Jun 14. pii: S0889-1591(14)00171-8.

[7] Zerbo O. et al. Neonatal cytokines and chemokines and risk of Autism Spectrum Disorder: the Early Markers for Autism (EMA) study: a case-control study. Journal of Neuroinflammation 2014, 11:113

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Masi, A., Quintana, D., Glozier, N., Lloyd, A., Hickie, I., & Guastella, A. (2014). Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis Molecular Psychiatry DOI: 10.1038/mp.2014.59