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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"Mitochondrial Modifying Nutrients" and chronic fatigue syndrome: a pilot study

"Recent evidence suggests that mitochondrial dysfunction may play a role in the pathophysiology of chronic fatigue syndrome (CFS)" was the starting point for the study results reported by Ranjit Menon and colleagues [1].

Detailing findings -  "open-label trial" findings - following use of a 'nutraceutical combination' in a small number of participants with CFS, researchers produced evidence that further investigations might be needed. The trial protocol for their investigation can be viewed here. The 'combination' under inspection included "primary nutrients: Coenzyme Q10, Alpha lipoic acid, Acetyl-l-carnitine, N-acetyl cysteine, B Vitamins"; many of which have been shown to act on various "mitochondrial targets" in the context that mitochondria might play a role in at least some cases of CFS (see here for example), but not necessarily all (see here). Indeed, I'll draw your attention when other groups have talked about nutraceutical 'intervention' (see here) in the context of mitochondria and CFS previously (see here and see here).

Over the 16 weeks of the trial period, researchers quite regularly assessed various parameters relating to the core feature of fatigue (based on use of the Chalder Fatigue Scale) and various mood, sleep and general health variables. They observed that alongside "a significant improvement in fatigue symptoms across [the] treatment period on the Chalder Fatigue Scale" there were also some potentially important differences noted in other measures too. Not least with "clinician-reported symptom-improvement" in mind.

Obviously the emphasis on the Menon results being an open trial (i.e. not blinded/masked, not randomised, with no control group), and very much, a small open trial, mean that these are preliminary findings and shouldn't yet be informing any research or clinical opinions. The additional fact that no objective 'actigraphic' measure of physical functioning was included for study is something else to bear in mind. Such results *should* support further research; indeed, one would hope that in this new era of interest and 'changing perspectives' with CFS in mind (see here), many more investigations in this thread would be forthcoming.

And whilst on the topic of clinical trials for CFS, the news out of Norway when it comes to the use of Rituximab is not looking too good despite a previously promising start [2]. No-one said it was going to be easy...

To close, I've nabbed a screenshot of a picture from the film Unrest that I think is starting to take on an almost iconic status...

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[1] Menon R. et al. Mitochondrial Modifying Nutrients in Treating Chronic Fatigue Syndrome: A 16-week Open-Label Pilot Study. Advances in Integrative Medicine. 2017. Nov 15.

[2] Fluge Ø. et al. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS One. 2011;6(10):e26358.

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The inter-pregnancy interval and risk of offspring autism yet again

I'm gonna try and keep this post quite brief starting with the observation that: "ASD [autism spectrum disorder] was increased in second and later-born children who were conceived less than 18 months or 60 or more months after the mother's previous birth."

So said the findings reported by Laura Schieve and colleagues [1] adding to quite a consistent research theme (see here and see here and see here). Based on "data from the Study to Explore Early Development [SEED]" initiative, with "rigorous case-finding and case-classification methods and detailed data collection on maternal reproductive history" researchers were quite confident in their observations. SEED, I might add, is developing quite a good peer-reviewed autism research reputation (see here).

Implications? Well, based on the current collected peer-reviewed research literature in this area it appears that there may be a specific time frame when it comes to potentially modifying the risk of offspring autism. Please don't take this as gospel but an interpregnancy interval (IPI) of somewhere between 12-18 and 60-72 months 'seems' to be emerging as an 'optimal' period based on the collected data currently to hand. I say this bearing in mind that multiple factors associated with pregnancy and birth *seem* to be associated with offspring outcomes (indeed, Schieve and colleagues have examined others too). This probably also includes what happens after birth (see here for example) and factors like parental age at conception/birth too (see here).

Possible mechanisms of effect? Yet again, it is more than likely that multiple factors are going to be influencing risk (or not) of offspring autism. I am drawn to the idea that a depletion of micronutrients associated with pregnancy might be an area for further investigation in relation to the IPI effect on offspring autism risk. This set in the context that pregnancy places some significant physical and biological demands on a mother's body; demands probably not immediately resolved as soon as baby enters the big, wide world. As to which micronutrients might be the more important to replenish, well, take yer pick (see here and see here for examples). Bearing, that is, in mind that no medical or clinical advice is given or intended...

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[1] Schieve LA. et al. Autism spectrum disorder and birth spacing: Findings from the study to explore early development (SEED). Autism Research. 2017. Nov 22.

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Vitamin-mineral mix for ADHD part 2

"Although direct benefit for core ADHD [attention-deficit hyperactivity disorder] symptoms was modest, with mixed findings across raters, the low rate of adverse effects and the benefits reported across multiple areas of functioning indicate micronutrients may be a favourable option for some children, particularly those with both ADHD and emotional dysregulation."

So said the findings reported by Julia Rucklidge and colleagues [1] posting results from their "fully blinded randomized controlled trial" of micronutrients in the context of childhood ADHD. Said study is similar to other research from this authorship group that has been previously covered on this blog (see here). The trial protocol (prospectively registered!) can be seen here and provides further details of the micronutrients in question, study design and various outcome measures employed.

Medication-free children diagnosed with ADHD were assigned to either the micronutrient formulation or placebo for 10 weeks. This was not a study for faint-hearted when it came to pill swallowing as up to 12 capsules a day were required to taken over the course of the study period. Then: "Data were collected from clinicians, parents, participants and teachers across a range of measures assessing ADHD symptoms, general functioning and impairment, mood, aggression and emotional regulation."

Results: well as per the opening sentence to this post, there were some important differences noted across the vitamin-mineral supplement group compared with the placebo arm of the trial. But: "No group differences were identified on clinician, parent and teacher ratings of overall ADHD symptoms." It appeared instead that specific aspects of ADHD presentation and more general issues such as aggression were seemingly affected by the micronutrient supplementation but effects were not necessarily just in universal terms of ADHD.

There are a few other important details to add to this post. First: "no group differences in adverse events and no serious adverse events identified" so taking a vitamin-mineral supplement in the context of paediatric ADHD over 10 weeks is a relatively safe affair we are told. I wouldn't have thought anything different to be honest. Bear also in mind that those diagnosed with ADHD may be at greater risk of vitamin deficiencies according to other research (see here) so there may have been a clinical need here also. Second, vitamin and mineral supplements are pretty widely available for many different age groups so getting hold of them is not likely to be a problem. Looking at the specific formulation used, it appears however that an important class of nutrient(s) are missing: essential fatty acids. I could be wrong, but given the quite large body of peer-reviewed research talking about specific fatty acid supplementation in the context of ADHD (see here) one might have expected to have seen this in the formulation used?

There is apparently more to come from this research initiative so I'll probably be posting a part 3 to complement this and the previous post on this topic. As part of the whole 'nutritional medicine as mainstream in psychiatry' ethos (see here) and bearing in mind the range of adverse outcomes over-represented when it comes to a diagnosis of ADHD (see here for example) I'd like to think that relatively simple and affordable moves to manage [some aspects of some] ADHD involving nutritional tools (see here also) are going to continue to be on the research agenda for some time yet.

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[1] Rucklidge JJ. et al. Vitamin-mineral treatment improves aggression and emotional regulation in children with ADHD: a fully blinded, randomized, placebo-controlled trial. J Child Psychol Psychiatry. 2017 Oct 2.

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The inter-pregnancy interval and risk of autism reviewed

"Short IPIs [interpregnancy intervals] are associated with a significantly increased risk of ASD [autism spectrum disorder]. Long IPIs also appear to increase the risk of ASD.

So said the results of the systematic review undertaken by Agustín Conde-Agudelo and colleagues [1] into how birth spacing might impact on the risk of a child developing an ASD. Drawing on data from 7 studies that "reported an association between short IPIs and increased risk of ASD" including over 1.1 million children, the authors confirmed what quite a few people already suspected: "children born to women with IPIs of <12 months had a significantly increased risk of any ASD." 'Autistic disorder' a.k.a autism (over other ASDs such as Asperger syndrome) seemed to shoulder the largest risk following a short IPI.

Of course we've been here before on the topic of IPI and autism risk (see here and see here) and as such the latest review results are not a complete surprise. What perhaps science does have to start thinking about are the various ways and means that a short IPI might confer additional risk of offspring autism. Personally, I'd initially go with the issue of a 'depletion of micronutrients' as being a prominent possible factor, as per what other research in this area has speculated on (see here). Combined with the so-called 'foetal programming hypothesis' (see here) drawing on the work of the late David Barker and others, the 'nine months that made us' is indeed an extremely important time from a nutritional point of view and potentially very relevant to at least some autism.

To close: Victoria Wood - Brief Encounter. RIP mince pie in the eye...

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[1] Conde-Agudelo A. et al. Birth Spacing and Risk of Autism and Other Neurodevelopmental Disabilities: A Systematic Review. Pediatrics. 2016. April 7.

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Conde-Agudelo, A., Rosas-Bermudez, A., & Norton, M. (2016). Birth Spacing and Risk of Autism and Other Neurodevelopmental Disabilities: A Systematic Review PEDIATRICS DOI: 10.1542/peds.2015-3482

Camel milk and autism: two humps or three?

In a previous post with the cringe-worthy title: 'Camel milk for autism: one hump or two?' (you can see why I could never be a comedian) I talked about some rather intriguing research [1] asking whether, under double-blind, placebo-controlled conditions, camel milk could affect various clinical measures of severity when it comes to the label of autism, some autism. The answer was very possibly, yes; with the strong requirement for quite a bit more follow-up research in this area.

Lo and behold, yet more data has emerged from the research pen of one Laila Al-Ayadhi and colleagues [2] (open-access available here) on the topic of camel milk and autism and specifically the idea that: "camel milk could be [a] very promising therapeutic intervention in ASD [autism spectrum disorder]." Again, under double-blind, placebo-controlled conditions, Al-Ayadhi et al describe how 2 weeks of camel milk (raw or boiled) seemed to show some 'significant differences' on schedules such as the CARS (Childhood Autism Rating Scale), SRS (Social Responsiveness Scale) and the ATEC (Autism Treatment Evaluation Checklist). The placebo (cow milk) group by contrast, didn't show anything at all in terms of significant changes between baseline and post-intervention testing occasions.  The ATEC in particular, is something I'm quite keen to see more autism investigations using (see here).

I have some time for Dr/Prof. Al-Ayadhi and colleagues given some previous musings on their wide and varied research with autism in mind (see here). This recent work continues one of their important themes based on the idea that not all mammalian milk forms are alike (see here) and hence, following a tradition potentially implicating milk and dairy products in some autism (see here), a switch to other varieties of milk outside of those normally populating our diet might be beneficial for at least some. Other more 'N=1' reports [3] have offered similar discussions on this topic.

As per my previous musings on this topic, I can't readily offer a substantial and/or universal reason for what it is about camel milk that may be important to some people on the autism spectrum. Lactose content, milk protein structure or nutritional content are perhaps some of the most pertinent variables to consider given that all have some research 'history' when it comes to at least some autism (see here for some discussion on the seemingly forgotten work by Tim Buie et al on lactose issues and autism for example). In other peer-reviewed publications, Dr/Prof. Al-Ayadhi has talked about the antioxidant properties of camel milk as being key [4]. I'm hoping that in future times I might be able to discuss further this area of investigation as and when some research ideas in my own day job reach fruition.

And just in case you think I'm advocating camel milk for all autism, no I'm not. As we've seen from other research outside of autism recently, personalised nutrition is the way forward [5] not sweeping generalisations...

Music to close and a song that's growing on me (I think I need some earworm therapy).
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[1] Al-Ayadhi LY. et al. Behavioral Benefits of Camel Milk in Subjects with Autism Spectrum Disorder. J Coll Physicians Surg Pak. 2015 Nov;25(11):819-823.

[2] Bashir S. & Al-Ayadhi LY. Effect of camel milk on thymus and activation-regulated chemokine in autistic children: double-blind study. Pediatr Res. 2014 Apr;75(4):559-63.

[3] Adams CM. Patient report: autism spectrum disorder treated with camel milk. Glob Adv Health Med. 2013 Nov;2(6):78-80.

[4] Al-Ayadhi LY. & Elamin NE. Camel Milk as a Potential Therapy as an Antioxidant in Autism Spectrum Disorder (ASD). Evid Based Complement Alternat Med. 2013;2013:602834.

[5] Zeevi D. et al. Personalized Nutrition by Prediction of Glycemic Responses. Cell. 2015 Nov 19;163(5):1079-1094.

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Al-Ayadhi LY, Halepoto DM, Al-Dress AM, Mitwali Y, & Zainah R (2015). Behavioral Benefits of Camel Milk in Subjects with Autism Spectrum Disorder. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP, 25 (11), 819-823 PMID: 26577969

Is a GFCF diet for autism inherently unhealthy? (part 2)

Consider today's entry as a sort of continuation of a previous post looking at the 'horror' that is a gluten-free, casein-free (GFCF) diet for autism (see here).

This time around I'm bringing the paper by Salvador Marí-Bauset and colleagues [1] to your attention and the idea that things might not necessarily be all bad when it comes to the use of a GFCF diet in terms of nutritional quality nor anthropometric values. Indeed, subject to the correct dietetic input, that there may be some important food exchanges going on when a diet devoid of gluten and casein is instigated specifically where an autism diagnosis is mentioned.

I realise that not everyone is as enthusiastic about how food might impact on behaviour and development with at least some autism in mind as I am, but science is coming around to the idea that what we eat (or not) might have some important influences on our being (see here). Appreciating that the GFCF diet is also probably not for everyone [2] (see here also), there continues to be some 'appetite' for such an approach for at least some autism [3]. It is therefore important to understand a little more about what might be the positives and negatives to following such a restrictive dietary regime.

Marí-Bauset et al report results for some 20 children with autism following a GFCF diet compared with 85 "on a regular diet in Valencia (Spain)." This follows a scheme of work from this authorship group looking at various aspects of nutrition when applied to autism [4]. Upon analysing 3-day food diaries, researchers concluded that: "Those on the GFCF diet had a lower weight, body mass index, and total energy, pantothenic acid, calcium, phosphorus and sodium intake." Further however, the GFCF group had: "a higher intake of fiber, legumes, and vegetables" and something of a more favourable fat intake profile that non-GFCF dieters. That last point also ties into other work from the authors [5].

As per the part 1 entry on the nutritional and health related aspects to a GFCF diet for autism (here it is again) there are some details in the Marí-Bauset data that perhaps require some clinical input. I'm thinking specifically about the lower calcium intake in this case, bearing in mind calcium and autism is a very complicated issue (see here) and some continued questioning about the more general link between calcium intake and bone health. The idea that those following a GFCF diet might also present with a lower weight and body mass index (BMI) is also interesting; particularly in light of quite a lot of the chatter in this area focusing on elevated weight and the health effects that can have with autism in mind (see here). I might add that I am in no way endorsing a GFCF diet (or any other diet) for weight loss or management; that's not my job.

The slightly more positive idea that those following a GFCF diet might have a better intake of vegetables and legumes probably also tied into a higher intake of fibre is important. I've previously talked about where the extremes of a limited diet can lead when it comes to [some] autism (see here). Although supplementation has its place in terms of as and when specific deficiencies are present and identified (see here) I think most people would agree that consumption of foodstuffs like fruit and vegetables probably do a better job of supplying nutritional needs than a pill (most of the time). In that respect, one might assume that those on a GFCF diet with more favourable vegetable consumption profile, might be slightly less prone to certain deficiencies. As per other research in this area, we would need a little more biological testing to be sure (see here). The specific idea that fibre intake was higher for the GFCF group is also an important point if one considers fibre to be an essential component when it comes to gastrointestinal (GI) motility, again, as has been specifically mentioned with autism in mind (see here).

In short, and with more research required, the horror that is a GFCF diet for autism might actually with the right clinical input, not be so horrible...

Music: Lily Allen - The Fear.

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[1] Marí-Bauset S. et al. Nutritional Impact of a Gluten-Free Casein-Free Diet in Children with Autism Spectrum Disorder. J Autism Dev Disord. 2015 Oct 1.

[2] Buie T. The relationship of autism and gluten. Clin Ther. 2013 May;35(5):578-83.

[3] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2015 Aug;74(3):202-7.

[4] Marí-Bauset S. et al. Nutritional status of children with autism spectrum disorders (ASDs): a case-control study. J Autism Dev Disord. 2015 Jan;45(1):203-12.

[5] Marí-Bauset S. et al. Fat intake in children with autism spectrum disorder in the Mediterranean region (Valencia, Spain). Nutr Neurosci. 2015 May 28.

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Marí-Bauset S, Llopis-González A, Zazpe I, Marí-Sanchis A, & Suárez-Varela MM (2015). Nutritional Impact of a Gluten-Free Casein-Free Diet in Children with Autism Spectrum Disorder. Journal of autism and developmental disorders PMID: 26428353