Bone health and autism continued

It's been a while since I last wrote about the topic of bone health and autism (see here). On that particular occasion, it was the work by Ann Neumeyer and colleagues [1] that provided the blogging fodder and the observation that: "BMD [bone mineral density] is lower in peripubertal boys with ASD [autism spectrum disorder]." BMD is important because of a possible association between lower BMD and risk of fracture or indeed, something more pathological.

Today I continue with this topic as per further work from Neumeyer and colleagues [2] looking to "examine macro- and micronutrient intakes and self-reported physical activity in boys with ASD compared to TDC [typically developing controls] and the relationship of these variables with BMD."

Based on data from nearly 50 boys aged 8-17 years of age (25 diagnosed with ASD and 24 not-autism controls), researchers once again relied on the technique known as dual-energy x-ray absorptiometry (DXA) for the measurement of bone mineral density. Various measures were taken from various parts of the body -"whole body less head, hip, and spine." Alongside, food diaries provided a rough-and-ready measure of food intake, self-reported physical activity (that's self-reported) did what it said on the tin, and fasting levels of 25(OH) vitamin D and calcium were garnered. I'll come back to some of the pros-and-cons of some of these measures shortly.

Results: consistent with the peer-reviewed data that has come before, BMD z scores at the lumbar spine, femoral neck, total hip, and whole body less head were lower in those with autism compared with control participants. A BMD z score by the way, is basically a comparison of BMD with that of standardised data (i.e. an average person of the same sex and age). Added to such results, authors also observed that less calorie intake was present in the ASD group (again compared with controls) and a "lower proportion of ASD participants were categorized as "very physically active" (27% vs 79%; P<0.001)." Interestingly however: "Body mass index and serum vitamin D and calcium levels were similar."

I was rather intrigued by the Neumeyer results. Not least that vitamin D and calcium levels were 'similar' in the autism and control groups. As I've discussed before on this blog, there have been calls for preferential screening for these biological parameters as and when an autism diagnosis is received (see here) in light of other findings (see here). The Neumeyer observations perhaps reflect a wider need for such screening.

The use of self-report as a measure for physical activity, whilst useful, is slightly outdated in these times of actigraphy. Wearable technology to measure activity and rest cycles is cheap and abundant these days and, as I've mentioned on other occasions, really should be the research industry standard. I'm not saying people might not be accurate in reporting their short-term physical activity but...

I do think there are some additional 'where next?' things to consider when it comes to future work looking at BMD and autism. Noting for example, that both dietary and malabsorptive issues seem to be able to influence BMD [3] there are additional parameters to be looked at. Given previous peer-reviewed reports on lactose issues being present in relation to autism (see here), this could feature in future work. Although still possessing the ability to furrow brows in certain quarters, the observation of issues with intestinal permeability ('leaky gut') in relation to some autism (see here) also could be an additional parameter to examine. I daresay also that some initial chatter about a compound called zonulin potentially serving as a 'biomarker of impaired gut barrier function' in relation to some autism (see here) might also be revealing. And then there is the important issue of epilepsy / seizure disorder often being comorbid with autism (see here), and how certain [important] intervention measures for said issues might affect parameters such as vitamin D (see here) and what that might mean for long-term bone health...

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[1] Neumeyer AM. et al. Bone density in peripubertal boys with autism spectrum disorders. J Autism Dev Disord. 2013 Jul;43(7):1623-9.

[2] Neumeyer AM. et al. Nutrition and Bone Density in Boys with Autism Spectrum Disorder. J Acad Nutr Diet. 2018 Feb 3. pii: S2212-2672(17)31749-5.

[3] Di Stefano M. et al. Lactose malabsorption and intolerance and peak bone mass. Gastroenterology. 2002 Jun;122(7):1793-9.

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On biotin and 'some autism'

Although I've mentioned biotin (vitamin B7) in the context of autism before on this blog (see here), due credit needs to be given to Peter over at the Epiphany blog for more extensive coverage (peer-reviewed based) of this nutrient (see here). Discussing how, within the increasingly large range of conditions that manifest autism or autistic behaviour(s), there may be one or two 'types' of autism that manifest biotin deficiency, there is a pretty obvious course of intervention as and when deficiency is found: supplementation.

And supplementation is exactly what was discussed in the paper by Paul Benke and colleagues [1] reporting on a case report of a young female who presented with "features of autism spectrum disorder, isolated headaches, and episodes of headaches and limb shaking." Alongside those symptoms, authors also discussed a fairly unusual part of her clinical history where "hair and nails did not grow."

Although there are various reasons why hair and nails might not grow - indeed, just about every nutritional deficiency seems to affect something like nail health and growth - biotin was noted as a point of concern in this young lady's clinical picture. Indeed authors noted that: "Administration of biotin restored her nail and hair growth and improved intellectual ability and school performance." They added that use of acetazolamide, more typically indicated for glaucoma and/or epilepsy, seemed to provide some relief from other symptoms: "episodes of headaches, single limb shaking, and loss of consciousness." And before you say it, yes, autism is no protection against the development of headaches (see here).

Bearing in mind this was a single case report yet also acknowledging the tenet: 'if you've met one person, you've met one autistic person', I find descriptions such as this to often be revealing. Other case reports talking about biotinidase deficiency associated with autism [2], where biotinidase is the enzyme responsible for freeing up biotin bound to food (see here), add to the interest in this area. Specifically how some other symptoms - "seizures, weak muscle tone (hypotonia), breathing problems, hearing and vision loss, problems with movement and balance (ataxia), skin rashes, hair loss (alopecia), and a fungal infection called candidiasis" - associated with biotinidase deficiency are not a million miles away from what has been talked about in some autism literature too (see also the comments section of another post here).

As per my discussions on various other nutrients that seem to be 'deficient' in at least some people on the autism spectrum (see here and see here), the defining message seems to be that post-diagnosis of autism, a screening program needs to be put into place looking at various nutrients in the context of something like eating patterns and behaviours. This could be part of a broader range of screening for something like inborn errors of metabolism that can and do show a connection to some autism (see here) and often (always?) involve nutrients (see here for example). Or could just mirror what is happening in other parts of psychiatry, where physiological parameters are starting to gain some parity with behavioural/developmental/psychiatric ones (see here) mindful of what correcting any deficiency might bring to various aspects of health (see here)...

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[1] Benke PJ. et al. Biotin and Acetazolamide for Treatment of an Unusual Child With Autism Plus Lack of Nail and Hair Growth. Pediatr Neurol. 2018 Feb;79:61-64.

[2] Zaffanello M. et al. A case of partial biotinidase deficiency associated with autism. Child Neuropsychol. 2003 Sep;9(3):184-8.

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"Autologous Umbilical Cord Blood Stem Cells to Improve Symptoms in Children with Autism" safe but...

On a recent visit to the local aquarium with some of my brood, I listened to an interesting talk given by one of the staff. It concerned starfish and, among other things, how these creatures possess the fantastic ability to grow new limbs as and when one or more are 'given' to predators. The mechanism behind such fabulous regenerative power is down to stem cells I was told; those marvels of biological engineering that have the potential to "develop into many different cell types in the body during early life and growth." From what I understand, most, if not all animals have stem cells, although us human folk aren't quite Curt Connors just yet...

Anyhow, stem cells as well as allowing some animals to regrow limbs, have been touted as being potentially *useful* for all manner of other conditions/diseases/ailments (see here). You probably won't be surprised to hear that autism has been mentioned with stem cells in mind (see here for example), with various potential modes of action being discussed. Some of the peer-reviewed research talking about various types of stem cell use in the context of some autism has been quite *hopeful* in terms of observed effects (see here and see here) but not all...

The findings reported by Michael Chez and colleagues [1] (open-access available here) probably fall into that 'but not all' category. Reporting results based on a clinical trial listing (see here), authors concluded that: "autologous umbilical cord infusions are safe for children with ASD [autism spectrum disorder]" but "no statistically significant differences for any endpoints" were detected in their "randomized, blinded, placebo-controlled, crossover trial." I'm not entirely sure therefore as to how at least one press release on the Chez study was able to arrive at some of the text that they did (see here)...

OK, a few descriptions might be useful. Autologous basically means 'obtained from the same individual'. Indeed this was one of the inclusion criteria for the study: "Participants were required to have AUCB [autologous umbilical cord blood] cryopreserved at Cord Blood Registry (CBR, South San Francisco, CA) processed on the AutoXpress (AXP) Platform (Cesca Therapeutics, Rancho Cordova, CA)." That means that stem cell rich blood taken from the umbilical cord that united infant with their placenta had to be available for this study use. The "randomized, blinded, placebo-controlled, crossover trial" bit basically means that this study followed a gold-standard scientific methodology; participants were randomly allocated to receive a cord blood infusion or a placebo, none of the investigators who administered the various tests knew who was receiving which (cord blood or placebo), and at some point in the study, participants switched from cord blood to placebo or vice-versa continuing with the not-knowing status. As for those 'various tests', the primary outcome was scores on the "Expressive One Word Picture Vocabulary Test, 4th edition (EOWPVT-4) and Receptive One Word Picture Vocabulary Test, 4th edition (ROWPVT-4)" alongside some other secondary outcomes looking at behaviour "at baseline 12, and 24 weeks after infusion of each product." Safety of the product was also a key part of this study.

Results: bearing in mind the loss of one participant (to the study results, not anything else!), there are a few noteworthy findings. First, it looks like over the course of the study period at least, this was a fairly safe intervention. Out of a total of 86 adverse events reported, only 3 were eventually thought to be 'probably' related to the autologous umbilical cord blood infusion. Importantly: "No adverse events required treatment" so there is a potential tick for the tenet 'first, do no harm' at least in the short-term. When however it came to looking at those language and behaviour outcomes, the authors note that: "There were also no statistically significant differences between scores on the two primary or secondary endpoints after infusion with AUCB versus infusion of placebo." The authors do talk about "trends in improvement on the Socialization Subscale of the Vineland" but a trend is not the same as a statistically significant result...

The authors opine as to the possible reasons for the lack of statistically significant changes following the use of the cord blood infusion. Dose is mentioned as one possibility, and specifically: "participants varied widely in percentage and number of CD34+ cells in samples infused." Although no expert on CD34+ cells, from what I gather the numbers of these cells present in cord blood samples provides some potential important information on the 'quality' of the infusion as a function of their connection to hematopoietic progenitor cells. The authors also talk about the 'reticence' of parents of participants to "use the entire banked sample on an investigational treatment" given the finite material available.

So, where next for stem cells 'for autism'? Well, given the data showing such an intervention to be safe at least in the short-term, this research area is still ripe for further study alongside chatter about modelling autism via stem cells [2] and beyond [3]. I know there are varied opinions out there about the 'usefulness', long-term safety and acceptability of this class of intervention [4], but like any other area of the autism research landscape, issues such as potential best and non-responders need to be considered before baby and bathwater are thrown out completely...

To close, that (recent) feeling when, at the birthday party of one of your brood, a song by Loded Diper is introduced as the song of the day for the birthday child. Cue the curious looks from other mums and dads and the embarrassed smiles from yours truly...

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[1] Chez M. et al. Safety and Observations from a Placebo-Controlled, Crossover Study to Assess Use of Autologous Umbilical Cord Blood Stem Cells to Improve Symptoms in Children with Autism. Stem Cells Transl Med. 2018 Feb 6.

[2] Ilieva M. et al. Psychiatry in a Dish: Stem Cells and Brain Organoids Modeling Autism Spectrum Disorders. Biol Psychiatry. 2017 Nov 16. pii: S0006-3223(17)32197-2.

[3] Donegan JJ. et al. Embryonic stem cell transplants as a therapeutic strategy in a rodent model of autism. Neuropsychopharmacology. 2018. Feb 7.

[4] Simberlund J. et al. Mesenchymal stem cells in autism spectrum and neurodevelopmental disorders: pitfalls and potential promises. World J Biol Psychiatry. 2015 Jul 31:1-8.

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ADHD and non-suicidal self-injury (NSSI)

I've covered the growing literature observing a link between a diagnosis of attention-deficit hyperactivity disorder (ADHD) and risk of unintentional injury a few times on this blog (see here and see here). The quite consistent picture emerging from that body of peer-reviewed research is that yes, a diagnosis of ADHD does seem to increase the risk of injury for whatever reason(s). Further, that pharmacotherapy utilising some of the various medicines indicated for ADHD, seems to have something of a 'reducing' effect on that elevated injury risk (see here).

Today I'm extending that ADHD-injury risk work to include the findings reported by Judit Balázs and colleagues [1] who concluded that: "ADHD symptoms are associated with an increased risk of NSSI [non-suicidal self-injury] in adolescents." Further that: "the symptoms of affective disorders and alcohol abuse/dependence psychotic symptoms" seem to be important 'mediators' of that risk of NSSI in the context of ADHD symptoms.

Based on the examination of adolescents who "were inpatients in the Vadaskert Child and Adolescent Psychiatric Hospital and Outpatient Clinic, Budapest, Hungary between 25.02.2015 and 09.05.2016", researchers reported that some 50 adolescents met the full criteria for ADHD and a further 70-odd "showed symptoms of ADHD at the subthreshold level." They employed the "Hungarian version of the modified Mini International Neuropsychiatric Interview Kid" to assess for various psychiatric symptoms, alongside the Deliberate Self-Harm Inventory (DSHI) to provide details on self-injury and some further questioning on suicidality. The aim was to investigate rates of NSSI in their cohort but also "how the symptoms of comorbid psychiatric conditions influence this [relationship], and whether there is a difference between girls and boys at this age."

Results: alongside the finding that at the very least, ADHD or ADHD symptoms are not protective against non-suicidal self-injury (NSSI), authors also observed that "people with ADHD have a higher risk than those without of developing comorbid psychiatric problems, both externalizing and internalizing ones" and "there is no direct association between the symptoms of ADHD and the prevalence of NSSI in a clinical sample of adolescents in any sex." On that last point, authors further opine that: "Comorbidities fully mediate the association between these conditions." In other words, clinicians should be screening for various psychiatric comorbidities - major depressive episode, dysthymic disorder, hypo/manic episode, psychotic disorders, substance-related dependence/abuse - and treating said comorbidities to potentially offset the risk of NSSI appearing alongside ADHD or subclinical ADHD.

In these days of ESSENCE - Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations - where the rule seems to be that various labels do not appear in some sort of diagnostic vacuum (see here for example), the Balázs findings fit well. The implication being that before grand associations are made on the basis of one variable = one condition/label/diagnosis (see here for example), one should perhaps consider a wider clinical picture. Indeed, to further extend the Balázs findings talking about NSSI, and based on the idea that autism and ADHD seem to be an important clinical combination (see here), I would perhaps encourage a greater depth of screening in future research (see here). That also might apply to the delicate issue of suicidality too (see here)...

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[1] Balázs J. et al. Attention-deficit hyperactivity disorder and nonsuicidal self-injury in a clinical sample of adolescents: the role of comorbidities and gender. BMC Psychiatry. 2018; 18:34.

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Folate receptor autoantibodies and autism... replicated

I should warn you that this is another of my long posts, so make yourself a cup of tea/coffee/other, get comfy and read on...

"Overall, 76% of the affected children, 75% of the unaffected siblings, 69% of fathers and 59% of mothers were positive for either blocking or binding Ab, whereas the prevalence of this Ab in the normal controls was 29%."

'Normal controls' is not a term that I would use in the context of autism research, but the findings reported by Edward Quadros and colleagues [1] are a cause for some excitement as the topic of folate receptor alpha (FRα) autoantibodies (Abs) and autism receives some welcome interest and importantly, scientific replication (see here).

Just in case you're new to the concept of folate receptor autoantibodies, it all starts with folate (folic acid). Folates are a pretty important range of nutrient for lots of different reasons, not least the role they play in various brain functions. There are however, a variety of conditions where folate and its various metabolites are 'atypical', one of which is called cerebral folate deficiency (CFD). CFD is characterised by low levels of 5-methyltetrahydrofolate (5-MTHF) in cerebrospinal fluid (CSF) despite fairly typical levels of circulating folates in blood. One of the ways that 5-MTHF gets to the brain is via something called the folate receptor protein alpha. It is this pathway that appears to be 'aberrant' in cases of CFD, and hence use of a compound called folinic acid (leucovorin) (also called 5-formyltetrahydrofolic acid), another 'type' of folate', is used as a result of it utilising an alternative system for getting to the brain (the reduced folate carrier, RFC).

Still here? Good. The hows-and-whys of the folate receptor protein alpha being 'dysfunctional' in relation to CFD has focused on particular autoantibodies (where the immune system starts to mount a response against 'self' tissues) called folate receptor autoantibodies. There are two types of autoantibody: blocking and binding antibodies [2]. These autoantibodies block the transport of folate metabolites to places like the CFS and brain. Finally, there are ways and means that these autoantibodies can be detected in serum samples and, outside of CFD, autism has been a focus for such analyses [3] alongside other, potentially related, diagnoses (see here).

Clear as mud right?

So: "families of 82 children with ASD [autism spectrum disorder], 53 unaffected siblings, 65 fathers, and 70 mothers, along with 52 unrelated... controls" were tested for folate receptor alpha (FRα) autoantibodies in the current Quadros study. I should also mention that Quadros is a name that comes up quite a bit with folate receptor alpha (FRα) autoantibodies in mind. As per the opening line of this post, those autoantibodies were detected in a fairly high frequency in families where autism has been diagnosed. The authors note that the presence of such antibodies "may have a familial origin but the risk of developing ASD is likely influenced by other mitigating factors since some siblings who had the antibodies were not affected." True, absolutely true bearing in mind other work on things like the broader autism phenotype for example (see here).

But there's another strand to this work worthwhile talking about... milk. Milk and autism has been something of real interest to my autism research career down the years (see here) and continues to be. Use of a milk-free - casein-free - diet has filled quite a few peer-reviewed science column inches in relation to both behaviour (see here for example) and physiology (see here) for some on the autism spectrum. In relation to those folate receptor alpha (FRα) autoantibodies, consumption of milk seems to have some rather interesting effects on their presence [4]. The suggestion is that there may be some kind of 'cross-reactivity' going on given the 'homology' between human folate receptor alpha (FRα) and bovine (from cows) folate receptor alpha (FRα). This biological mix-up means that "repeated exposure to milk FR in the digestive tract is the likely mechanism for autoantibody generation" [5]. I'm left wondering a few things: (a) did Quadros and colleagues ask about milk consumption and/or was it recorded? and (b) regarding the 'heritability' issue, could this be part of a wider 'autoantibody heritability' issue among families where autism is present? Y'know, based on the idea that autoantibodies and autoimmunity seems to be a recurring theme for at least some people diagnosed with autism (see here) and in their families (see here)?

And finally, a few research direction suggestions to perhaps take this area forward: (a) wide-scale screening for those for those folate receptor autoantibodies when autism is diagnosed to see if the pretty high 'positives' numbers continue, (b) the requirement for a large (LARGE) study looking at both supplementation with folinic acid and use of a milk-free diet to ascertain exactly what symptoms/traits can potentially be impacted, and finally (c) the inclusion of other parameters when looking at the familial element to folate receptor autoantibodies, such as everyone's favourite 'leaky gut' (also reported in other family members [6]) as a 'vehicle' for possible antibody production. Speculative, yes. Testable, also yes.

Oh, and perhaps a little more inquiry into the thyroid connection (see here) too (with links to yet another autoimmune condition mentioned with autism in mind)...

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[1] Quadros EV. et al. Folate receptor autoantibodies are prevalent in children diagnosed with autism spectrum disorder, their normal siblings and parents. Autism Res. 2018 Feb 2.

[2] Frye RE. et al. Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups. Frontiers in Neuroscience. 2016;10:80.

[3] Ramaekers V. et al. Clinical recognition and aspects of the cerebral folate deficiency syndromes. Clin Chem Lab Med. 2013 Mar 1;51(3):497-511.

[4] Berrocal-Zaragoza MI. et al. High milk consumers have an increased risk of folate receptor blocking autoantibody production but this does not affect folate status in Spanish men and women. J Nutr. 2009 May;139(5):1037-41.

[5] Ramaekers VT. et al. A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Developmental medicine and child neurology. 2008;50(5):346-352.

[6] de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24.

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On treating psychosis in the context of autism

"This report describes the successful improvement in symptoms and quality of life in a young man with psychosis and ASD [autism spectrum disorder], who had previously tried numerous medical interventions."

So said the findings published by Victoria Bell and colleagues [1] (open-access available here) providing some discussion not only about how a diagnosis of autism is seemingly not protective against the development of something like psychosis (see here) but also how psychosis in this context can be successfully managed with a little bit of [clinical] thought. I'll also draw your attention to some other quite recent research that has conversely talked about how difficult it can be to treat psychosis when an autism diagnosis is also in the frame (see here).

Bell et al discuss a case report of a young man (HP) who came to clinical attention in his mid-teens. School examinations seemed to be a possible trigger for episodes of vomiting after eating, leading to hospitalisation. Other symptoms also appeared - "a lowering of mood and poor sleep, and weight loss" - leading to more clinical contact. Bullying was also a feature; as we are told that: "a group of boys had made videos of him, including him being flash mobbed, which had been placed on YouTube; they had also made a persecutory Facebook page." I can think of a few choice words to describe such boys and their antics but won't.

As time progressed, he had "an in-patient admission to a Child and Adolescent Mental Health Services ward, for over a year" where a diagnosis of Asperger syndrome was made alongside "dissociative disorder, and a severe depressive episode with psychotic features." Lots more followed including him becoming "increasingly non-communicative and episodically aggressive toward his parents" culminating in him returning to an in-patient setting.

What is rather refreshing to see is the clinical work-up that this young man received. So: "magnetic resonance imaging (MRI) scans, electroencephalograms (EEGs), anti-NMDA antibodies, as well as B12, folate and thyroid function tests were repeatedly normal." Some critical thinking eventually led clinicians to discount the idea that his symptoms 'were just part of his autism' - "differentiating between psychotic catatonia and autism-related catatonia" - and instead look to a comorbid diagnosis of psychosis. Further: "this was adopted as our working diagnosis for treatment."

Treatment came in the form of various pharmacotherapy and some 'psychological input' bearing in mind "HP remained selectively mute throughout his admission." His clinical management wasn't exactly helped by the fact that another 'very disruptive patient' was admitted at the same time as HP and, on more than one occasion, physically attacked him. But eventually the 'number of days out' increased and symptoms such as vomiting, incontinence and aggression decreased as the "symptom-based approach" adopted seemed to work.

What lessons can be learned from this case report? Well, several. Not least that as well as not existing in some sort of diagnostic vacuum (see here), a diagnosis of autism can and does raise the risk of various psychiatric comorbidity potentially appearing. And sometimes it's hard to see where autism ends and said comorbidity starts (see here for example); assuming that is, that you see comorbidity as comorbidity and not something rather more core.

There is also a positive message from the Bell findings in relation to the 'treatability' of various comorbidity over-represented alongside autism. Yes, it takes time and resources to diagnose and rule things in or out, but quality of life can be improved for the person and those around them. Indeed the authors add: "The level of violence upon admission concerned our team and his parents... if psychotic symptoms were ignored, violence may have continued and led to long-term placements in a more secure environment." Indeed.

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[1] Bell V. et al. A symptom-based approach to treatment of psychosis in autism spectrum disorder in October 2017. BJPsych Open. 2018 Jan;4(1):1-4.

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