Autism in phenylketonuria (PKU)

"Autism has been reported in untreated patients with phenylketonuria."

Indeed it has, as the paper by Sameh Khemir and colleagues [1] revisits something of a long known about association whereby the archetypal inborn error of metabolism that is phenylketonuria (PKU) has been linked to the presentation of autism or autistic traits [2].

Looking at 18 participants diagnosed with PKU, Khemir et al "report their clinical, biochemical and molecular peculiarities" (authors words not mine) and how 15 of the 18 presented with autism as per assessment with "The Childhood Autism Rating Scale and the Autism Diagnostic Interview-Revised." Following some molecular biological analysis specifically with the "phenylalanine hydroxylase gene" in mind (a key player in PKU), the authors reported on various potentially important issues but "no correlation between autism and mutations affecting the phenylalanine hydroxylase gene."

I have a lot of time for PKU on this blog. Not only because PKU represents one of the best examples of how certain foods for some can affect development and onwards mental health (see here) but also because some of the other intervention options for PKU (outside of low phenyalanine diet) might hold some promise for some autism too (see here). Indeed, the idea that tetrahydrobiopterin (BH4) - an important cofactor for phenyalanine hydroxylase and related aromatic amino acid hydroxylase enzymes - might be quite good at helping to mop up excess phenylalanine and other compounds continues to find favour in some autism research circles. Dare I also mention the effects of BH4 on tryptophan and 5-HTP as potentially being relevant to some autism too? (see here)

In many parts of the world, the advent of the newborn screening program (built on the genius of people like Robert Guthrie and others) has all but eradicated untreated PKU and perhaps impacted on the number of people presenting with autism too. There remain however, challenges in certain areas of the globe, where people are not so fortunate to have such screening measures in place. Indeed, Khemir and colleagues report their results based in Tunisia and Algeria; other geographically related areas might also benefit from the implementation of such screening practices [3].    

Just before I go, there is one last comment to make on something discussed by Khemir and colleagues: "age of diet onset was the determining factor in autistic symptoms' evolution." Diet, as I've mentioned, refers to the low phenylalanine (low protein) diet commonly used to manage PKU. It appears that there might be more to see in terms of how long PKU goes untreated and the progression of autistic traits similar to other descriptions, particularly the findings reported by Baieli and colleagues [4]: "None out of 62 patients with classic PKU diagnosed early met criteria for autism. In the group of 35 patients diagnosed late, two boys (5.71%) ages 16 and 13 years fulfilled the diagnostic criteria for autism."

Diet potentially affecting the presentation of autism eh? I'll be coming to the paper by Oyarzabal and colleagues [5] soon enough built on some related research...

Music: Led Zeppelin - Rock And Roll.

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[1] Khemir S. et al. Autism in Phenylketonuria Patients: From Clinical Presentation to Molecular Defects. J Child Neurol. 2016 Jan 12. pii: 0883073815623636.

[2] Miladi N. et al. Phenylketonuria: an underlying etiology of autistic syndrome. A case report. J Child Neurol. 1992 Jan;7(1):22-3.

[3] Saad K. et al. ADHD, autism and neuroradiological complications among phenylketonuric children in Upper Egypt. Acta Neurol Belg. 2015 Dec;115(4):657-63.

[4] Baieli S. et al. Autism and phenylketonuria. J Autism Dev Disord. 2003 Apr;33(2):201-4.

[5] Oyarzabal A. et al. Mitochondrial response to the BCKDK-deficiency: Some clues to understand the positive dietary response in this form of autism. Biochim Biophys Acta. 2016 Jan 22. pii: S0925-4439(16)30003-5.

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Khemir S, Halayem S, Azzouz H, Siala H, Ferchichi M, Guedria A, Bedoui A, Abdelhak S, Messaoud T, Tebib N, Belhaj A, & Kaabachi N (2016). Autism in Phenylketonuria Patients: From Clinical Presentation to Molecular Defects. Journal of child neurology PMID: 26759449

Mortality and autism: comorbidity counts

I don't enjoy talking about mortality and autism on this blog but once again I'm drawn to discuss this important topic based on some recent findings published by Diana Schendel and colleagues [1]. I say these are important findings on the basis of how researchers took into account the possible role played by psychiatric and neurological comorbidity occurring alongside autism when it comes to the quite alarming mortality statistics.

Drawing on the findings reported in their paper and an interview discussing the study (see here), the Schendel results are again based on the examination of one of those very useful Scandinavian registries (several in fact) based in Denmark. Following the "unique 10-digit identifier assigned to all live births and new residents in Denmark" researchers were able to track down the records of over 20,000 children and young adults diagnosed with an autism spectrum disorder (ASD) from a total population of some 1.9 million people "born in Denmark during the period from 1980 to 2010 who were alive at 1.5 years of age and followed up through 2013." The presence of "comorbid mental, behavioral, and neurologic disorders" was also deciphered from records and the rather grim process of determining death and causes of death among any cohort members was carried out.

Results: perhaps unsurprisingly there was a difference in mortality risk between those with ASD compared with those without. Those with autism had a 2-fold higher mortality risk, bearing in mind that older children and young adults were the focus of this study - "Of the 20 492 persons with ASD, 68 died (0.3%)." Most of those who had passed away also had additional comorbidity (83%). Worryingly, in about a quarter of deaths, suicide was listed as the cause; a further quarter died in accidents. Also: "The co-occurrence of ASD added no additional mortality risk for persons with neurologic... or mental/behavioral disorders...  compared with persons with these disorders and no ASD."

There is quite a bit to take from these results. First and foremost is that they provide further evidence that the risk of [early] mortality is seemingly heightened when a diagnosis of autism is received. Sixty-eight deaths out of over 20,000 might not sound a lot in cold statistical terms, but those were 68 people with 68 families and loved ones.

Next is the idea that comorbidity often plays a big role in relation to autism. I've lost count of the number of times that both medical and psychiatric comorbidity attached to autism have been discussed on this blog. Suffice to say that the label of autism is seemingly protective of nothing when it comes to other diagnoses/labels appearing (see here for example) and certain types of comorbidity carry their own early mortality risks (see here). I might also add that, on occasion, the diagnosis of autism may also represent an obstacle to receiving another appropriate medical diagnosis and where possible, intervention (see here).

The suggestion that suicide was represented in the mortality figures detailed by Schendel et al is a real worry although not entirely a new finding. Previous research has talked about levels of suicide ideation when it comes to the autism spectrum (see here) and even some extreme examples of euthanasia requests from individuals on the autism spectrum (see here). A lot more needs to be done to find out why suicide is over-represented and what we can do about it. I might suggest that preferential screening and monitoring for potential correlates of suicide (ideation or attempted) might be a good starting point (see here).

Finally, the idea that accidental death featured in the statistics is also concerning. I can't comment on the specific types of accident that may more readily feature when it comes to early mortality and autism but one only needs to look at the literature and very sad reports on the issue of wandering and autism to see what might potentially figure (see here). With this issue in mind, I'll draw your attention to some positive activities designed to counteract or mitigate such risk (see here).

And just before I leave you, I might also draw your attention to some other research from some of the authors on the Schendel paper talking about an increased mortality risk in cases of obsessive-compulsive disorder (OCD) [2] potentially also relevant in light of the topic of comorbidity and autism (see here)...

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[1] Schendel DE. et al. Association of Psychiatric and Neurologic Comorbidity With Mortality Among Persons With Autism Spectrum Disorder in a Danish Population. JAMA Pediatr. 2016 Jan 11:1-8.

[2] Meier SM. et al. Mortality Among Persons With Obsessive-Compulsive Disorder in Denmark. JAMA Psychiatry. 2016. 27 Jan.

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Schendel, D., Overgaard, M., Christensen, J., Hjort, L., Jørgensen, M., Vestergaard, M., & Parner, E. (2016). Association of Psychiatric and Neurologic Comorbidity With Mortality Among Persons With Autism Spectrum Disorder in a Danish Population JAMA Pediatrics DOI: 10.1001/jamapediatrics.2015.3935

ICF core sets for autism continued: what do experts think about autism?

Consider this post an extension of a previous discussion thread (see here) continuing the voyage of developing "International Classification of Functioning, Disability and Health (ICF; and Children and Youth version, ICF(-CY)) Core Sets for Autism Spectrum Disorder (ASD)."

This time around it is another paper by Elles de Schipper and colleagues [1] (open-access available here) providing the blogging fodder and specifically the stage two of their four stage project building up those core sets for how we might conceptualise functioning and health when it comes to the autism spectrum. So: "The objective of this study was to survey the opinions and experiences of international experts on functioning and disability in ASD."

Those experts included responses from over 200 professionals ranging from physicians (22%) to nurses (3%) and everyone in-between including some really worthwhile representation from the all-rounder that is the occupational therapist (OT) (20%). They were asked various questions pertinent to the development of the core sets for autism including aspects designed to cover the "bio-psycho-social of the ICF(-CY)" and questions around "the possible functional strengths in ASD and the... possible gender differences in functioning and disability."

The data presented provides a fascinating insight into what experts think about [childhood] autism derived from the extracted "8792 meaningful concepts." I don't want to plagiarise the whole document but some key points emerge:

• As perhaps expected, social interaction issues feature heavily when it comes to defining important items for the ICF; "complex interpersonal interactions" comes top in one category of definable codes followed not so far behind by "basic interpersonal interactions." Communication issues are also mentioned as, importantly, are motor issues e.g. "fine hand use." I've talked about motor issues and autism before (see here).
• When asked about "ASD-related skills and functional strengths", the notion of "attention to detail" was prominent as was: "A preference to work on repeated or monotonous tasks." Experts also recognised that a "Strong sense of morality (e.g., honesty, lack of judgmental attitude, etc.)" was also a functional strength with other keywords such as "Trustworthiness" and "Loyalty" following suit. I was also interested to see that "Mathematical abilities" and "Technical abilities (computer skills, engineering)" were also reported in this section (see Table 6). Personally I think we have to be quite careful about sweeping generalisations of people on the autism all being 'maths geniuses' given data suggesting the contrary (see here) even when information might "mainly [be] associated with higher functioning individuals." Likewise, technical abilities in computing or engineering although important for quite a few people on the autism spectrum should not necessarily define all autism or all future job prospects (see here).
• When it came to opinions about 'body structures' potentially pertinent to autism, it is interesting that although most experts heavily endorsed involvement of the brain - "structures of the nervous system" - quite a few also saw other body structures as being important. So: "structure of intestine" was mentioned by about 15% of experts and "structure of stomach" by a smaller percentage. Bearing in mind the array of experts quizzed about these core sets and their varied areas of work and expertise, the inclusion of the gastrointestinal (GI) tract will be a welcome one for quite a few people (see here).
• Gender differences in the presentation of autism also created some discussion. Of the 60% or so of experts who "reported gender-related differences in ASD" quite a few focused on the idea that "more externalizing behaviors among males and more internalizing behaviors in females" were notable. Indeed, that females may be more likely to be 'overlooked' as being on the autism spectrum as a function of being "better socially adjusted, showing more prosocial behaviors, communication skills and friendships than males." This perhaps accords with other findings in the research literature (see here) onwards to the idea of a female phenotype or more.

I would encourage readers to take some time to read through the latest article from de Schipper et al for the important information that it holds. As and when the development of the core sets is eventually finished, autism research and practice will probably be hearing a lot about them. I dare say that one day they may become fundamental to autism research and practice. In the meantime, I'll be keeping my eyes open for further peer-reviewed publications from this group on this topic; the expected next stage I think being 'a patient and caregiver qualitative study' and thereafter a 'clinical cross-sectional study'. Interesting times lie ahead for the core sets for autism as indeed applied to other labels too [2].

Music and something from arguably one of the most well-educated singers/bands ever... Stranger Than Fiction.

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[1] de Schipper E. et al. Functioning and disability in autism spectrum disorder: A worldwide survey of experts. Autism Res. 2016 Jan 8.

[2] de Schipper E. et al. Towards an ICF core set for ADHD: a worldwide expert survey on ability and disability. Eur Child Adolesc Psychiatry. 2015 Dec;24(12):1509-21.

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de Schipper E, Mahdi S, de Vries P, Granlund M, Holtmann M, Karande S, Almodayfer O, Shulman C, Tonge B, Wong VV, Zwaigenbaum L, & Bölte S (2016). Functioning and disability in autism spectrum disorder: A worldwide survey of experts. Autism research : official journal of the International Society for Autism Research PMID: 26749373

Feigning ADHD?

Feign: "to pretend to feel or be affected by (something)."

I tread very carefully today with this post based on the findings reported by Paul Marshall and colleagues [1] who concluded that: "a significant percentage of those making a suspect effort will be diagnosed with ADHD [attention-deficit hyperactivity disorder] using the most commonly employed assessment methods."

Their findings, based on the examination of "how many adult patients would plausibly receive a diagnosis of attention-deficit/hyperactivity disorder (ADHD) if performance and symptom validity measures were not administered during neuropsychological evaluations" highlights something of a worrying situation involving the 'faking' or 'feigning' of the symptoms of ADHD.

Why would anyone want to do such a thing, you might ask? Well, accessing some of the treatments of choice (stimulants) is one possibility entertained in other peer-reviewed literature [2] in light of their potential nootropic effects but doubtless there are probably other reasons too including the possibility of receiving various academic accommodations as a result of diagnosis.

Marshall et al describe results based on the comparison of data between 102 participants quite comprehensively diagnosed with ADHD and 115 who "were identified as putting forth suspect effort in accordance with the Slick, Sherman, and Iverson (1999) criteria." The criteria by Slick et al by the way, represents an attempt to "define psychometric, behavioral, and collateral data indicative of possible, probable, and definite malingering of cognitive dysfunction." Marshall and colleagues reported that it was pretty difficult to distinguish between "suspect effort and ADHD groups" and that quite a bit more needs to be done to separate feigned and real symptoms/participants.

As other commentators have noted (see here) the relative ease that the symptoms of ADHD can be 'faked' during assessment is a worry particularly in light of the ballooning prevalence figures for the condition (see here). The prospect of diagnosing conditions such as ADHD on the basis of current behaviour, neuropsychological test functioning and/or developmental history without any objective biological or genetic test is an important reason why the label is potentially open to mis-use and abuse. One might even argue that the changes to the diagnostic criteria for ADHD in DSM-5 for example (see here) are only likely to make matters worse.

As with other instances where symptoms or illness is feigned or faked, it is the people who genuinely present with ADHD or related hyperkinetic disorders who ultimately suffer as a result of such actions. Not only because their diagnosis and symptoms may be spuriously called into question (people so love to generalise) but also because research looking to discover the cause(s) or ways to intervene in ADHD may also be potentially tarnished as a result of the inclusion of such fakers and their data in the science. Indeed, one could argue that where instances of feigning illness are detected, and relevant reasons for such faking are excluded, one might consider this type of fraud the same as any other type of fraud...

Music: Faith No More - Epic. More bands should dance with boxing gloves don't you think?

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[1] Marshall PS. et al. The Impact of Failing to Identify Suspect Effort in Patients Undergoing Adult Attention-Deficit/Hyperactivity Disorder (ADHD) Assessment. Psychol Assess. 2016 Jan 11.

[2] Sansone RA. & Sansone LA. Faking Attention Deficit Hyperactivity Disorder. Innovations in Clinical Neuroscience. 2011;8(8):10-13.

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Marshall PS, Hoelzle JB, Heyerdahl D, & Nelson NW (2016). The Impact of Failing to Identify Suspect Effort in Patients Undergoing Adult Attention-Deficit/Hyperactivity Disorder (ADHD) Assessment. Psychological assessment PMID: 26751085

Quality of life of parents of children with autism systematically reviewed

"This review verified previous reports on lower QoL [quality of life] among parents of children with ASD [autism spectrum disorder] and highlighted potential areas of support."

So said the findings reported by Eleni Vasilopoulou & Joy Nisbet [1] who surveyed the available peer-reviewed literature looking at "QoL among parents of children with ASD (<18 years)". They also reported on various factors potentially contributory to the reported lower QoL including "child behavioural difficulties, unemployment, being a mother and lack of social support."

Being careful not to generalise nor stigmatise, these are important results. On a previous blogging occasion I talked about the issue of parental stress in relation to raising a child with additional needs (see here) and how there may be evidence-based ways and means of reducing stress so helping allow parents to focus on being parents. Certainly the potentially contributory factors cited by Vasilopolou & Nisbet accord with some of tenets in that post (i.e. the positive impact of social support including respite and the need to tackle the more disruptive aspects of behaviour more likely to lead to greater stress for person and parent).

As per my recent ramblings on supporting other family members when a diagnosis of autism is received (see here), there are additional lessons to be learned. By all means focus attention and services on the person diagnosed in order to improve their quality of life (see here). Try and ensure that their personal, social and medical needs are met (see here) and that meaningful opportunities are offered, mindful that sweeping generalisations don't tend to work too good when it comes to the autism spectrum (see here). Snowflakes, people, snowflakes.

But also don't forget about families and other significant others. Don't forget about the mothers, fathers and other caregivers and their day-to-day and longer term needs and concerns (see here). Parents are the foundations of families. Those foundations need to be tended every once in a while in order to ensure the family home stays strong and upright.

Music: Red Hot Chili Peppers - Higher Ground.

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[1] Vasilopoulou E. & Nisbet J. The quality of life of parents of children with autism spectrum disorder: A systematic review. Research in Autism Spectrum Disorders. 2016; 23: 36-49.

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Vasilopoulou, E., & Nisbet, J. (2016). The quality of life of parents of children with autism spectrum disorder: A systematic review Research in Autism Spectrum Disorders, 23, 36-49 DOI: 10.1016/j.rasd.2015.11.008

Gastrointestinal symptoms and autism yet again

It's been a few weeks since I last posted on the quite well-known [evidence-based] overlap that is autism and gastrointestinal (GI) symptoms. Today I'm remedying the situation by briefly discussing the findings reported by Francesca Fulceri and colleagues [1].

Drawing on data from 230 preschoolers including "four groups of children... ASD individuals suffering from GI symptoms (ASD/GI+), ASD subjects without GI symptoms (ASD/GI-), TD peers with (TD/GI+) and without (TD/GI-) GI symptoms" researchers reported that functional GI symptoms as reported by parents, were more frequent in the autism vs. not-autism group (37% vs 15% respectively). Not only that, but: "ASD/GI+ children had more anxiety problems, somatic complaints, externalizing and total problems than ASD/GI- individuals" leading the authors to conclude that we need to be looking for GI symptoms when autism is diagnosed and particularly where "anxiety and/or externalizing behavioral problems" are present. I might remind you that we already have quite a few recommendations on how best to do this (see here and see here).

Although important, these results are not necessarily new news. That functional bowel issues are over-represented when it comes to autism is not generally disputed any more; allowing for the fact that for example: "Parents were sensitive to the existence, although not necessarily the nature, of GID [gastrointestinal dysfunction]" [2] when it comes to parent-report of such issues in the context of autism. That also, certain behaviours may show a 'connection' to the presence of GI issues in cases of autism has also been previously discussed in the peer-reviewed arena (see here).

Mention of the possibility of a 'gut-brain axis' in relation to [some] autism by Fulceri et al is also deserving of comment to indicate how physiology/biochemistry and psychology/behaviour may indeed be closely related. I know this takes us into some rather uncomfortable territory insofar as concepts such as intestinal hyperpermeability (see here) - the so-called 'leaky gut' - and autism but one can only go where the data leads. Leaky gut, I might add, is starting to move out of the realms of 'woo' and further into the scientific consciousness (see here). That modification or treatment of bowel issues (whether functional or pathological) may also have important knock-on effects for the behavioural presentation of some autism (see here) is also an area ripe for further scientific investigation.

Music: Razorlight - In The Morning.

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[1] Fulceri F. et al. Gastrointestinal symptoms and behavioral problems in preschoolers with Autism Spectrum Disorder. Dig Liver Dis. 2015 Dec 11. pii: S1590-8658(15)30030-X.

[2] Gorrindo P. et al. Gastrointestinal Dysfunction in Autism: Parental Report, Clinical Evaluation, & Associated Factors. Autism Research. 2012;5(2):101-108.

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Fulceri F, Morelli M, Santocchi E, Cena H, Del Bianco T, Narzisi A, Calderoni S, & Muratori F (2015). Gastrointestinal symptoms and behavioral problems in preschoolers with Autism Spectrum Disorder. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver PMID: 26748423

22q11.2 Deletion Syndrome and 'a highly increased risk of schizophrenia spectrum disorders'

22q11.2 deletion syndrome has turned out to be something of real interest to this blog. Not only because of the reported connection to the presentation of autism (see here) including some suggestion of a role for the immune system (see here) but also because of the idea that certain somatic comorbidity linked to the gastrointestinal (GI) tract might also figure as part of the presentation of at least some cases of Del22 (see here). Said GI issues have also cropped up across quite a few other labels including cases of autism.

One of the other important psychiatric comorbidities suggested to be over-represented where Del22 is present is that of schizophrenia and related conditions. Indeed, a recent paper by Anders Vangkilde and colleagues [1] confirms that: "Carriers of a 22q11.2 deletion who had been clinically identified had a highly increased risk of schizophrenia spectrum disorders."

Based on the analysis of data from one of those oh-so-grand Scandinavian nationwide registers (in this case based in Denmark), researchers identified just over 150 people diagnosed with 22q11.2 deletion syndrome. Further inspection of those carrying the 22q11.2 deletion revealed that "6 individuals were diagnosed with schizophrenia spectrum disorders." Although seemingly only a small number, the calculated risk of schizophrenia spectrum disorder (SSD) occurring alongside Del22 was judged to be quite a bit higher than when Del22 is not present: "an 8.13(95% CI: 3.65-18.09) fold increased risk."

Schizophrenia and related conditions appearing alongside Del22 is not new news. Quite a bit of peer-reviewed literature has been generated on this topic including the idea that there may be changes to cognitive skills preceding the development of a psychotic illness [2]. Such evidence has obvious repercussions for issues such as preferential screening and the like, but perhaps just as importantly is the idea that such an association might carry important information on the mechanism pertinent to at least some types of SSD. Take for example the findings reported by Monks et al [3] who, alongside reporting that psychotic illness was present in approaching a third of their cohort with Del22 also suggested that: "Psychosis proneness seems to be of genetic origin in 22q11.2DS" on the basis of their comparing features with "non-deleted individuals with schizophrenia." I say all this bearing in mind that plurality might be as much of a feature of schizophrenia (see here) as it is with autism (see here).

Although perhaps stretching the association a little, I am minded to bring in a few blog entries I've previously made about how the reported genetics and biology of schizophrenia might yield some more information about this Del22-SSD tie-up. Y'know, things like the much-discussed schizophrenia and microglia connection (see here) or the idea that markers of gluten sensitivity might show more than a passing connection to schizophrenia (see here). Continuing the theme of immune function being potentially linked to Del22, how about looking at various inflammatory markers in cases of Del22-SSD (see here) on the basis also that inflammation might have social cognition effects too (see here)? And finally, what about the suggestion that the use of fish oil supplementation might help prevent psychosis in 'at-risk' groups (see here)? The research list is potentially endless.

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[1] Vangkilde A. et al. Schizophrenia Spectrum Disorders in a Danish 22q11.2 Deletion Syndrome Cohort Compared to the Total Danish Population-A Nationwide Register Study. Schizophr Bull. 2016 Jan 5. pii: sbv195.

[2] Vorstman JA. et al. Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome. JAMA Psychiatry. 2015 Apr;72(4):377-85.

[3] Monks S. et al. Further evidence for high rates of schizophrenia in 22q11.2 deletion syndrome. Schizophr Res. 2014 Mar;153(1-3):231-6.

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Vangkilde, A., Olsen, L., Hoeffding, L., Pedersen, C., Mortensen, P., Werge, T., & Trabjerg, B. (2016). Schizophrenia Spectrum Disorders in a Danish 22q11.2 Deletion Syndrome Cohort Compared to the Total Danish Population—A Nationwide Register Study Schizophrenia Bulletin DOI: 10.1093/schbul/sbv195

Fatigue and severe behaviour problems associated with autism

Challenging behaviours or behavioural crisis in relation to autism is a topic that has graced this blog before (see here). Covering a whole spectrum of issues ranging from aggression (self and/or directed against others) to various other quite undesirable presentations (such as smearing) quite a lot of behaviour can potentially fall into this description.

Without heading too far into the possible [often very individual] reasons as to why challenging behaviours occur and their meaning (see here for more information), I think most people would be satisfied by the idea that such behaviours are not normally random or without purpose. Whether communicative or as a response to external stimuli, behaviour - even challenging behaviour - normally serves some kind of function. The trick is finding out what function.

So it was that the paper from Christopher Smith and colleagues [1] explored this issue and concluded that: "problem behavior was most likely to occur when both task demands (discriminative stimuli) were presented and when the setting event (fatigue) was operative." Smith et al report results for 3 individuals, all males, all diagnosed with autism and accompanying learning disability and all with "a history of behavior problems that became more frequent when they were fatigued and when task demands were given." Various steps of investigation were included covering a functional assessment of each participant, a functional analysis of behaviour based on times of fatigue or not and using demands or not and also: "a multicomponent intervention package developed for each individual based on the assessment information derived from Steps 1 and 2." As previously indicated, in times of fatigue + demands, problem behaviour predominated more than on other occasions.

I don't want to get to heavily into any psycho-babble explanations when it comes to the Smith findings based on the results of just 3 participants and other methodological factors. The main point that: fatigue + setting event, specifically the requirement to complete a task = an important combination when it comes to the presentation of challenging behaviours in the context of autism is however potentially important. More so when one considers that issues pertinent to the presentation of fatigue such as sleep quantity and quality have already found a place in autism research history (see here). Indeed, the recent results from Andréane Lambert and colleagues [2] are testament to that.

Although the concept of fatigue is quite a nebulous term, I'd like to think that there is more research to do in this area specifically with autism in mind. Take for example the results reported by Claro and colleagues [3] who "examined whether the fatigue level of children diagnosed with cri du chat syndrome was associated with the expression of autistic symptoms." They concluded that yes, "children who exhibited high levels of fatigue were more likely to express high levels of autistic symptoms." Whether those 'autistic symptoms' translate into severe behavioural problems is still to be determined with the wider autism spectrum in mind.

Without also wishing to make connections where none might exist, I'd put forward the idea that beyond just instances of fatigue, the concept of chronic fatigue might also be something to investigate, at least with some autism in mind. I've previously introduced the idea that a diagnosis of autism is seemingly protective of nothing when it comes to comorbidity (see here) and allied to some very preliminary reports of chronic fatigue syndrome(s) (probably plural) appearing alongside autism (see here) I'd be interested to see if this was generalisable to many more cases or not and what this might say for challenging behaviours in specific individuals.

Music: Blondie - The Tide Is High.

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[1] Smith CE. et al. Fatigue as a biological setting event for severe problem behavior in autism spectrum disorder. Research in Autism Spectrum Disorders. 2016; 23: 131-144.

[2] Lambert A. et al. Poor sleep affects daytime functioning in typically developing and autistic children not complaining of sleep problems: A questionnaire-based and polysomnographic study. Research in Autism Spectrum Disorders. 2016; 23: 94-106.

[3] Claro A. et al. Association between fatigue and autistic symptoms in children with cri du chat syndrome. Am J Intellect Dev Disabil. 2011 Jul;116(4):278-89.

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Smith, C., Carr, E., & Moskowitz, L. (2016). Fatigue as a biological setting event for severe problem behavior in autism spectrum disorder Research in Autism Spectrum Disorders, 23, 131-144 DOI: 10.1016/j.rasd.2015.12.003

Pendulum swings... prenatal antidepressant exposure not linked to autism or ADHD

"Multiple studies have examined the risk of prenatal antidepressant exposure and risk for autism spectrum disorder (ASD) or attention-deficit hyperactivity disorder (ADHD), with inconsistent results."

And...

"These results suggest that prior reports of association between prenatal antidepressant exposure and neurodevelopmental disease are likely to represent a false-positive finding, which may arise in part through confounding by indication."

'These results' refers to the findings reported by Castro and colleagues [1] (open-access available here) who looked at the records of over 1200 children diagnosed with ASD and ~1700 children diagnosed with ADHD compared with over 3400 and 3700 controls respectively with regards to antidepressant exposure during pregnancy and maternal antidepressant use before pregnancy. Based on exposures identified "using e-prescribing data in the EHR [electronic health records], both inpatient and outpatient, which record number of pills, frequency and refill number, allowing calculation of exposure period" researchers were, with reasonable confidence, able to test the idea that a diagnosis of ASD or ADHD might be elevated following prenatal exposure to said pharmaceutics.

The headline that most media discussing this study picked up on was the lack of any significant association between antidepressant use during pregnancy and risk of offspring autism or ADHD. This finding kinda contrasts with other recent independent reports that have been covered on this blog (see here). Indeed the authors - including one Isaac Kohane (see here) - suggest that their results, bearing in mind certain limitations, highlight how 'false-positive' might indeed be a good description of some of the previous data in this area.

But just before any sweeping generalisations are made about this class of pharmaceutic being 'off the hook' there were some other potentially important findings also reported by Castro et al. To quote once again: "For both ASD and ADHD, pre-pregnancy antidepressant use was associated with greater risk, even after adjustment for maternal major depression." The risk reported was significant insofar as what it might mean for offspring autism and/or ADHD and also how "the requirement for maternal antidepressant treatment, rather than the medication itself, may be associated with risk for neurodevelopmental disorders in offspring".

As I've discussed before, the idea that antidepressant use during pregnancy might be linked to offspring developmental outcomes is a complicated area. That such medicines use is not generally entered into lightly is something to bear in mind given what depression can do to a person and those around them. I cannot readily account for the discrepancy between these and other reports on this topic outside of the idea that the question of a connection or not may not be as simple as 'yes' or 'no' but rather a slightly more convoluted story where genetics and other more 'environmental' factors might play some role. The idea that there may be specific phenotypes of autism associated with such medication use has received a boost in other independent studies [2] looking at other medicines. I suppose such confusion kinda sums up autism research when it comes to questions of such exposure and the range of pharmaceutics that have been correlated with offspring risk (see here and see here).

Music: Björk - It's Oh So Quiet. Shhh.

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[1] Castro VM. et al. Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study. Transl Psychiatry. 2016 Jan 5;6:e708.

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Castro VM, Kong SW, Clements CC, Brady R, Kaimal AJ, Doyle AE, Robinson EB, Churchill SE, Kohane IS, & Perlis RH (2016). Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study. Translational psychiatry, 6 PMID: 26731445

Middle ear infections and autism

I'm gonna be fairly brief today in drawing your attention to the paper published by Daniel Adams and colleagues [1] reporting that: "Children with ASD [autism spectrum disorders] are more likely to have middle ear infections and otitis-related complications."

The results, which we've known were coming (see here), detail findings based on a retrospective case-cohort study where the health insurance records of children of US military families were initially screened for the presence of autism or an ASD and then further screened for ICD-9-CM diagnostic codes relevant to acute otitis media and related diagnoses. The supplementary material provided alongside the article gives further details (see here).

Alongside the findings of an elevated rate of acute otitis media (AOM) among children diagnosed with autism were various other details including a higher rate of complications following AOM such as mastoiditis - affecting the mastoid bone behind the ear - and the requirement for a mastoidectomy. The surgical reconstruction of the eardrum (tympanoplasty) was also more frequently noted for the autism group versus the non-autism controls. The authors conclude that quite a bit more research is required in this area alongside "highlighting the importance of routine middle ear examinations and close attention to hearing impairment in this population."

This is interesting work. For many years I've heard about how quite a few children on the autism spectrum had a history of early ear infections that were typically followed by quite an aggressive schedule of antibiotic use. Indeed, on one of the previous blogging occasions when I've mentioned ear infections and autism it was to speculate on the double-edged sword that might be the [early repeated] use of antibiotics with [some] autism in mind (see here). That 'association' remains as relevant today as it did during earlier descriptions [2] playing into the various emerging gut bacteria studies of autism.

I have only a few more things to add. First is the idea that screening for middle ear infections might be an important issue for children on the autism spectrum. I can't argue with that; and indeed added to the requirement for screening other sensory gateways such as the eyes (see here), the evidence is accumulating for preferential services to be offered. Second is the idea that recurrent otitis media might show some connection with aspects of sleep too [3] such that issues such as sleep apnoea occurring alongside autism (see here) might also be something to look out for. Finally is the need for quite a bit more research on what happens to autistic symptoms when ear infections are finally diagnosed and treated. Take for example the case report detailed by Kazuhiro Tajima-Pozo and colleagues [4] and the suggestion that surgical correction of the "middle ear for repetitive otitis" correlated with "an improvement in autistic behaviours". One wonders how many other children have shown or might show similar effects and what the possible mechanism(s) could be...

Music: Alanis Morissette - Ironic.

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[1] Adams DJ. et al. Otitis Media and Related Complications Among Children with Autism Spectrum Disorders. J Autism Dev Disorders. 2016. Jan 6.

[2] Bolte ER. Autism and Clostridium tetani. Med Hypotheses. 1998 Aug;51(2):133-44.

[3] Gozal D. et al. Prevalence of Recurrent Otitis Media in Habitually Snoring School-Aged Children. Sleep medicine. 2008;9(5):549-554.

[4] Tajima-Pozo K. et al. Otitis and autism spectrum disorders. BMJ Case Rep. 2010 May 6;2010. pii: bcr1020092351.

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Adams, D., Susi, A., Erdie-Lalena, C., Gorman, G., Hisle-Gorman, E., Rajnik, M., Elrod, M., & Nylund, C. (2016). Otitis Media and Related Complications Among Children with Autism Spectrum Disorders Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-015-2689-x

Get your (autism genetics) kicks on root 66?

With the ever-increasing volumes of research being published in the peer-reviewed domain these days, one sometimes has to be a little creative to ensure that your research paper stands out and is not lost in the scientific noise. Quite a good way of getting noticed is to make sure that your paper catches the attention of your reader base. Y'know, give it a snappy title; something that social media might pick up on...

So it was that my attention was taken when coming across the paper by Diaz-Beltran and colleagues [1] (open-access) titled: 'A common molecular signature in ASD gene expression: following Root 66 to autism'. Root 66 and Route 66 eh?

The 'root 66' appearing in the title of the Diaz-Beltran paper actually refers to the results of an "integrated systems biology analysis of 9 independent gene expression experiments covering 657 autism, 9 mental retardation and developmental delay and 566 control samples to determine if a common signature exists and to test whether regulatory patterns in the brain relevant to autism can also be detected in blood." I might add that those are the authors words and not my own.

Including a familiar name on the authorship list - one Dennis Wall, he of 'boiling down ADOS' and 'screening triage by YouTube' fame - researchers used various automated statistical methods to see whether "a signature of autism can be found in the blood that might be a molecular echo of autism-related regulatory impairment in the brain." The identified signature included a collection of 66 genes based on their examination of "27 case–control biosets of 9 independent experiments" - the root 66 cluster.

That root 66 cluster was subsequently tested to see what genes might be connected and some data about "related biological functions" across various conditions including autism. I really can't provide anything more detailed about the hows and whys of this process as I am fast approaching the limits of my knowledge in this area. Suffice to say that there was some previous work on some of the root 66 genes with autism in mind (4 genes) and quite a few others "have been shown to interact directly with known autism candidates or have been implicated in other autism-related neurological disorders."

When it came to looking at what those root 66 genes might be doing (functionally), the authors reported that quite a few of the genes were involved in one of three processes: (1) brain growth and development with a side-order of "neuroendocrine activity", (2) nervous system inflammation and loss of neurological functions, and (3) neurodegeneration "and damage of the nervous system." In that last category the authors made an important point that genes thought to be connected with cases of autism are generally not 'autism-specific' in terms of their possible connections with other conditions and labels. Without scaremongering or wishing to equate autism with cancer, some of the root 66 genes have been mentioned with various cancers in mind; something that might be important for at least some people on the autism spectrum (see here). On the basis of their collected studies, they concluded that: "the Root 66 cluster is non-random and likely plays a role unique to autism."

It is important to understand that whilst this is an important piece of research, further independent validation of the root 66 cluster is required before anyone gets ahead of themselves. As per other examples where genetic 'markers' have been talked about (see here), replication is the name of the scientific game bearing in mind how wide the autism spectrum is (the autisms) and the important idea that the label rarely appears in some sort of diagnostic vacuum (see here). I don't believe that we are witnessing a genetic profile for [all] autism just yet...

Before I go, I do also want to comment on at least one area where the genetics of autism seems to be heading: inflammation. As per other research occasions, inflammation and immune function seem to be quite a regular feature of autism genetics studies (see here and see here) and the analysis of more functional biological processes (see here for example). Added to some interesting data on a possible role for those chemical messengers called cytokines with autism in mind (see here) and it looks to me like we have further evidence for how immune function and behaviour might have some interesting connections pertinent to at least some autism (see here).

Music: Amy Winehouse - Back To Black.

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[1] Diaz-Beltran L. et al. A common molecular signature in ASD gene expression: following Root 66 to autism. Translational Psychiatry. 2016. 6, e705.

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Diaz-Beltran L, Esteban FJ, & Wall DP (2016). A common molecular signature in ASD gene expression: following Root 66 to autism. Translational psychiatry, 6 PMID: 26731442

Supporting siblings of children with autism too

A weekend not wasted...

The idea that a diagnosis/label of autism may have repercussions for quite a few more people than just the person diagnosed is not a new one.

Without trying to generalise nor stigmatise, the process of working up to and receiving a diagnosis on the autism spectrum can often have profound consequences for family life. Parents typically shoulder quite a lot of the additional duties that follow from a diagnosis (and indeed before diagnosis) but other family members also have to play their part. When it comes to the possible 'impact' of receipt of an autism diagnosis on some of those other family member, science is starting to come around to the idea that siblings in particular, might need a little more support.

So it was found in the paper by Brian Lovell & Mark Wetherell [1] who reported findings based on the examination of "the psychophysiological impact of childhood ASD [autism spectrum disorder] on siblings." Looking at a variety of measures including those measuring depressive symptoms and cortisol levels, researchers compared values for "25 siblings of children with ASD (and their mothers) and a control group of 20 siblings of neuro-typical children (and their mothers)." They found that depressive symptoms were elevated for the ASD sibling group but when it came to cortisol measurements "groups were comparable on all cortisol indices." They concluded by suggesting that more needs to be done to tackle the "greater emotional problems and overall depressive symptoms" noted in the ASD sibling group. Cortisol, I might add, has been talked about with autism in mind before (see here) bearing in mind 'issues' emerging as to when the best time for collection should be with autism in mind [2].

There are a couple of ways that such results can be interpreted. One could argue that the increased frequency of 'emotional issues' and depressive symptoms noted in the ASD sibling group might well be associated with their sibling ASD label and much of what comes with it. Again avoiding any sweeping stigmatisation of autism, this is a serious matter and reiterates how the impact of autism goes well beyond that of personal experience when it comes to affecting family and other loved ones.

The other way one could interpret this data is by suggesting that within the scope of the broader autism phenotype (BAP) - that is, the idea that around the diagnostic edges of autism there may be a spectrum of more subtle presentations (see here) - [some] siblings may already be more prone to emotional and/or depressive issues on the basis of how depression for example, shows some pretty strong links to autism (see here for example). Without any psycho-babble explanations, one could foresee how an increased tendency towards depressive symptoms or depression might be to some degree compounded by the lived experience of having a sibling diagnosed with ASD; particularly if and when there is significant disruption to typical family life. I might also acknowledge that autism does not normally reside in some sort of diagnostic vacuum (see here) so one has to be mindful that other behaviours outside of autism might also be contributory to any additional family stress.

Irrespective of the whys and wherefores, the idea that other family members may require additional support as well as children/adults diagnosed with an ASD is paramount. As I've previously discussed on this blog, support can take many guises (see here) as this authorship team have previously discussed [3]; some of which could be transferable to siblings too. Other research has looked at issues such as family adaptation [4] and I'm minded to bring in the concept of resilience too. That also having a sibling diagnosed with ASD may be a significant influence on career choices of unaffected siblings (unaffected in terms of symptom presentation) is an additional variable to take into account, save any charges of me painting a too one-sided, negative picture of the possible familial effects of autism.

The picture included in this post by the way, represents a nearly full weekend attempt by some of my brood to muster enough 'snow' to put together this marvellous fellow. Don't you just love winter?

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[1] Lovell B. & Wetherell MA. The psychophysiological impact of childhood autism spectrum disorder on siblings. Res Dev Disabil. 2015 Dec 22;49-50:226-234.

[2] Sharpley CF. et al. Is afternoon cortisol more reliable than waking cortisol in association studies of children with an ASD? Physiol Behav. 2015 Dec 21. pii: S0031-9384(15)30217-1.

[3] Lovell B. et al. With a little help from my friends: psychological, endocrine and health corollaries of social support in parental caregivers of children with autism or ADHD. Res Dev Disabil. 2012 Mar-Apr;33(2):682-7.

[4] O'Brien S. Families of Adolescents with Autism: Facing the Future. J Pediatr Nurs. 2015 Dec 19. pii: S0882-5963(15)00352-8.

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Lovell B, & Wetherell MA (2015). The psychophysiological impact of childhood autism spectrum disorder on siblings. Research in developmental disabilities, 49-50, 226-234 PMID: 26720849

Vitamin D and cognitive function (again)

Today I'd like to draw your attention to the paper by Natasja van Schoor and colleagues [1] and some further potential support for the idea that vitamin D levels might have some important connections to cognitive functioning.

I've tackled this subject before on this blog (see here) and specifically the idea that functional vitamin D levels below a certain point might 'correlate' with poorer cognitive functioning. This time around van Schoor et al report findings based on data collected from the "Longitudinal Aging Study Amsterdam (LASA)", an initiative that aimed to specifically look at 'the predictors and consequences of aging'.

Based on various measures of cognitive functioning and serum levels of 25-hydroxyvitamin D (25(OH)D) "determined using a competitive protein binding assay", researchers concluded that lower levels of vitamin D - "below 30 nmol/L" - seemed to be linked to poorer cognitive functioning and slower information processing speeds. Further, the authors suggest that serum levels of vitamin D in the range of "about 60 nmol/L" might be something to aim for when it comes to optimal functioning on tests of cognitive ability. I might add that these days we have much more accurate methods for assaying for vitamin D levels than were used in the van Schoor study.

I don't want this post to turn into some advert for vitamin D as being a nootropic of choice on the basis of these and other research results. Cognitive tests might be a good indicator for cognitive ability but that does not mean that everyone who is vitamin D insufficient or deficient is somehow less cognitively 'able' than those with higher levels. I doubt very much that nature designed things so simple.

That all being said, it is getting difficult to ignore the accumulating evidence suggesting that vitamin D levels may indeed confer something of an effect on cognitive ability even if with specific groups in mind (based on age for example). The idea of a 'connection' opens up some intriguing possibilities on how vitamin D may have quite a few more extra-skeletal effects than we've all perhaps appreciated. Indeed, perhaps the most intriguing prospect is that of another association - between vitamin D and frailty [2] - and how it might bridge the proposed association between frailty and cognitive impairment [3] for example.

As if to prove a point, yet more research has been published at the time of writing this post with vitamin D status and cognitive functions in mind [4] focussed on mild cognitive impairment and Alzheimer's disease. Add it to the list by all means; indeed without wishing to make connection where none may exist, I'd be minded to suggest that talk of microglia being linked to [some] cases of Alzheimer's disease (see here) may well benefit from future study of a possible vitamin D - microglia connection too [5].

Music: Shakira - Can't Remember to Forget You.

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[1] van Schoor NM. et al. Cross-sectional and longitudinal associations between serum 25-hydroxyvitamin D and cognitive functioning. Int Psychogeriatr. 2015 Dec 22:1-10.

[2] Wong YY. et al. Low vitamin D status is an independent predictor of increased frailty and all-cause mortality in older men: the Health in Men Study. J Clin Endocrinol Metab. 2013 Sep;98(9):3821-8.

[3] Robertson DA. et al. Frailty and cognitive impairment--a review of the evidence and causal mechanisms. Ageing Res Rev. 2013 Sep;12(4):840-51.

[4] Yeşil Y. et al. Vitamin D status and its association with gradual decline in cognitive function. Turk J Med Sci. 2015;45(5):1051-7.

[5] Hur J. et al. Regulatory Effect of 25-hydroxyvitamin D3 on Nitric Oxide Production in Activated Microglia. Korean J Physiol Pharmacol. 2014 Oct;18(5):397-402.

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van Schoor NM, Comijs HC, Llewellyn DJ, & Lips P (2015). Cross-sectional and longitudinal associations between serum 25-hydroxyvitamin D and cognitive functioning. International psychogeriatrics / IPA, 1-10 PMID: 26691864

What exercise might do to the gut microbiome and gut permeability in CFS/ME

"These findings suggest a role for an altered gut microbiome and increased bacterial translocation following exercise in ME/CFS [myalgic encephalomyelitis/chronic fatigue syndrome] patients that may account for the profound post-exertional malaise experienced by ME/CFS patients."

That was the conclusion reached by Sanjay Shukla and colleagues [1] (open-access available here) who analysed the "microbiomes of blood and stool samples" for a small group of "clinically characterized ME/CFS patients" (n=10) and ten matched asymptomatic controls undertaking an exercise test ("a maximal exercise test on an electronically braked cycle ergometer"). Clinically characterised by the way, refers to a diagnosis of CFS using the 1994 CDC case definition.

Blood and stool samples were provided by participants at various time points including baseline, 15 minutes and some days following the exercise test. Indeed we are told that: "Stool samples were collected at baseline (pre-exercise) and 48 and 72 hours post-exercise" which is certainly quite a feat getting 20 people to er, poo(p) on demand on such a timescale.

Analyses of samples and importantly, the state of participants following the exercise test, yielded some potentially interesting results. So: "Following maximal exercise challenge, there was an increase in relative abundance of 6 of the 9 major bacterial phyla/genera in ME/CFS patients from baseline to 72 hours post-exercise compared to only 2 of the 9 phyla/genera in controls." The authors interpret this as meaning that bacterial load in those with ME/CFS may be "preferentially enhanced during post-exertional malaise." This was to some degree complemented by blood results "with high levels of bacterial sequences maintained at 72 hours post-exercise in ME/CFS patients versus clearance in the controls." Again the authors tentatively interpret this as meaning that "bacteria may have translocated into the blood stream from the gut after the maximal exercise challenge" and hence there may be a preferential role for intestinal dysbiosis and altered intestinal permeability in relation to at least some cases of CFS/ME.

These are interesting if preliminary findings. I've previously touched upon the idea that the gut microbiome might be a research target for CFS/ME before on this blog (see here). Allied to the idea that altered intestinal permeability (a.k.a the leaky gut - yes it is a real thing) might also be a feature of 'some' CFS/ME (see here) and one has some intriguing potential investigations to be done alongside the notion that new therapeutic targets could be on the horizon. I say this acknowledging again the small participant group included for study in the Shukla study.

I must also pay further attention to the exercise element of the Shukla paper. Exercise and post-extertional fatigue/malaise is a core feature of CFS/ME (even SEID) and has been the topic of quite a lot of discussion and even arguments when it comes to certain 'therapeutic' options put forward in recent years. Other studies looking more generally at the effects of vigorous exercise on measures of intestinal permeability have suggested that there may be some important physiological changes associated with undertaking a strenuous workout [2]. A specific measure of intestinal permeability is not reported by Shukla and colleagues on this occasion but one wonders whether there may be some important further research to do in this area particularly when one notices the lack of statistical difference in various physiological measures between the ME/CFS participants and controls on this [preliminary] research occasion (see here)?

To close, remembering Alan Rickman...

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[1] Shukla SK. et al. Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). PLoS One. 2015 Dec 18;10(12):e0145453.

[2] Pals KL. et al. Effect of running intensity on intestinal permeability. J Appl Physiol (1985). 1997 Feb;82(2):571-6.

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Shukla SK, Cook D, Meyer J, Vernon SD, Le T, Clevidence D, Robertson CE, Schrodi SJ, Yale S, & Frank DN (2015). Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). PloS one, 10 (12) PMID: 26683192