Maternal prenatal vitamin use and reduced risk of offspring autism recurrence

Question: "Is maternal use of prenatal vitamins associated with decreased risk for autism recurrence in siblings of children with autism spectrum disorder?" Answer: "Maternal prenatal vitamin intake during the first month of pregnancy may reduce ASD [autism spectrum disorder] recurrence in siblings of children with ASD in high-risk families." So that looks like a 'very possibly' then.

That was the long-and-short of the findings reported by Rebecca Schmidt and colleagues [1]. Some notable names are included on the authorship list of the Schmidt paper who are no strangers to the idea that maternal prenatal vitamin use may very well impact on offspring risk of autism or ASD (see here and see here for examples).

The Schmidt study on this occasion relied on data from the MARBLES (Markers of Autism Risk in Babies: Learning Early Signs) study, an important longitudinal initiative originally designed to investigate "possible pre-natal and post-partum biological and environmental exposures and risk factors that may contribute to the development of autism." Yes, you read that right, that's 'biological and environmental' exposures and risk factors (see here)...

In this "prospective cohort study" younger brothers and sisters deemed to be at high-risk of autism (N=241) by virtue of their older sibling having been diagnosed with autism were the target participant group. Said group were followed from 6 months to around about their third birthday and developmentally assessed. Mums of the children were also asked about their vitamin use during pregnancy via interview. All the collected data was crunched and results presented.

"The prevalence of ASD was 14.1% (18) in children whose mothers took prenatal vitamins in the first month of pregnancy compared with 32.7% (37) in children whose mothers did not take prenatal vitamins during that time." As you can see, that is quite a stark [statistically significant] difference between the groups bearing in mind that around 25% of the total cohort were eventually diagnosed with autism (or at least met thresholds for a diagnosis based on the use of a gold-standard instrument). Authors also add that prenatal vitamin use did not seemingly impact on "other nontypical development" which included various other developmental 'outcomes'. They also reported that: "Children in the former maternal prenatal vitamin group also had statistically significantly lower autism symptom severity... and higher cognitive scores." This implies that even if such vitamin use did not 'halt' a/the pathway to an autism diagnosis in some, it might well have affected the presentation of their autism in terms of symptoms and intellectual functions (see here).

So an important question: what were the nutrients being supplemented that seemed to show such an effect? Well, as per that other previous research from Schmidt et al folic acid popped up again, as well as another important nutrient, iron (Fe) which she's also been previously interested in (see here).

As per some 'expert reaction' to the study (see here) there is a need for further research in this area before any sweeping generalisations are made. Ideally, I'd like to see Schmidt or others go further into the whole folate metabolism bit applied to autism (see here and see here) and what that means for supplementation levels in mums-to-be where offspring autism recurrence risk is potentially high. Indeed, whether folic acid is actually the ideal supplement for some pregnant mums (see here) is another potential route of investigation on the basis of what has previously turned up in 'some autism' (see here). By saying all that, I want to make it clear that I'm not giving anything that looks, sounds or smells like medical or clinical advice on this or any topic. The Schmidt findings also potentially tie into another area of autism research looking at the inter-pregnancy interval (IPI) with autism in mind (see here and see here). This, on the basis that words like 'depletion of micronutrients' have been banded around as being one possible explanation for the elevated risk of offspring autism correlating with a short IPI. Again, more study is indicated.

I try not to get too excited about new findings when it comes to autism because, inevitably, many end up falling by the wayside or being over-hyped. Given however the history of peer-reviewed science on the topic of pregnancy nutrition and risk of offspring autism, I'm inclined to think that there may be something quite special in the Schmidt findings and what directions they could eventually take with regards to both research and policy. Certainly when I read another study talking about siblings at 'high-risk' for autism, I'll be looking to see whether pregnancy nutrition has been considered as a potentially modifying variable...

28 February 2019: An addition. So, here I am talking about prenatal vitamin use and offspring autism risk and lo-and-behold, someone has just published a meta-analysis and systematic review of this topic [2]. The conclusion: "the likelihood of ASD in offspring whose mothers used multivitamin supplements during the prenatal period was significantly reduced compared with that in offspring of mothers without such supplementation."

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[1] Schmidt RJ. et al. Association of Maternal Prenatal Vitamin Use With Risk for Autism Spectrum Disorder Recurrence in Young Siblings. JAMA Psychiatry. 2019. Feb 27.

[2] Guo B-Q. et al. Maternal multivitamin supplementation is associated with a reduced risk of autism spectrum disorder in children: A systematic review and meta-analysis. Nutrition Research. 2019. Feb 24.

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Autism research really needs to study the prevalence and treatment of scurvy in autism

The results published by Melinda Saavedra and colleagues [1] describing another case report where scurvy was [eventually] diagnosed as appearing alongside autism represents yet another 'call to action' on this topic.

I've covered this issue quite a few times before on this blog (see here and see here and see here), and quite frankly it's reached the point where autism research really needs to step up and formally study the prevalence of scurvy in relation to autism. Indeed given the almost universal reports of medical science not initially recognising that scurvy can be no stranger to autism, the time has also come to "announce [to] the pediatrician and other professionals dedicated to primary health care about scurvy as a potential consequence of restrictive diets in children with autism spectrum disorders."

This time around the clinical focus was on a 4 year old boy who was brought to clinical attention as a result of "hip pain and refusal to walk, associated with petechiae and bruising of the lower limbs." The clues were all there that scurvy could be a cause of such symptoms, but it was only when it was revealed that the child had "selective feeding habit" that the penny seemed to finally drop. Indeed: "Levels of Vitamin C in blood were measured and without waiting for results he started treatment with 300 mg per day of ascorbic acid." Lo and behold, his vitamin C results were found to be low, and vitamin C supplementation eventually did the trick. Of vital importance, the pain associated with scurvy also showed improvement and he was discharged from clinical care with a maintenance dose of vitamin C and some nutritional advice.

'Selective feeding patterns', 'picky eating' or whatever you want to call it, is an issue that is not stranger to autism (see here). It's reasonable to assume that where such feeding issues continue into the longer-term, and dependent on what foods are consumed as part of such a restrictive pattern, there are likely to be biological consequences for the person concerned as a function of what nutritional inadequacies follow. Indeed, I daresay that such a pattern follows what is being noticed in connection with other food-related conditions in the longer term (see here). Set in this context, a lot more research and importantly, clinical practice, needs to focus on the hows-and-whys of such behaviours and their remediation. There is no longer any excuse for allowing diseases of the past such as scurvy and also others like rickets, to plague the children of today, vulnerable children of today, where healthy food in most parts of the world, is not in short supply.

Oh, and bear in mind that 'picky eating' might not be the only reason why scurvy might appear alongside autism [2]. We need lots more data.

And also, as I write this [3]...

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[1] Saavedra MJ. et al. Scurvy due to restrictive diet in a child with autism spectrum disorder: case report. Arch Argent Pediatr. 2018 Oct 1;116(5):e684-e687

[2] Hasan Al-Breiki S. et al. Scurvy as the tip of the iceberg. Journal of Dermatology & Dermatologic Surgery. 2014; 18: 46-48.

[3] Caldwell KJ. et al. Child With Autism and a Limp. Ann Emerg Med. 2018 Oct;72(4):493-495.

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KPAX002 for Chronic Fatigue Syndrome part 2: controlled study says no

KPAX002 mentioned in the title of this post refers to "a mitochondrial modulator technology platform" according to the manufacturer that includes a low dose of methylphenidate combined with various nutrients designed to impact on mitochondrial function. Within the context of chronic fatigue syndrome (CFS) also known as myalgic encephalomyelitis (ME) (but not necessarily accurately so!), there is some preliminary research history suggesting that KPAX002 might be something to look at for intervening in some of the disabling characteristics of CFS/ME (see here). This, on the basis that mitochondria in particular, might be something quite important to at least some cases (see here and see here).

The fly in the scientific ointment?

Well the results of the "phase 2 randomized, double-blinded, placebo-controlled trial" on KPAX002 published by Jose Montoya and colleagues [1] that, from an intention-to-treat point of view, reported no significant statistical difference in self-reported group scores of fatigue and other measures between active treatment and a placebo. In keeping with the phase 2 label attached to the trial - looking at both initial clinical results and also any side- or adverse effects - authors reported no statistically significant difference in the frequency of reported adverse effects between KPAX002 and a placebo over the 12 weeks of study. First, do no harm and all that.

The Montoya paper is open-access so readers can see for themselves how things were done and the details of the results. I however, want to highlight a few points that I thought were important:

First, the authors acknowledge the "unexpectedly positive results" observed the last time around [2] that led to this more rigorous trial. Personally, I don't think there was anything too unexpected about those pilot study results, given the methodological issues typically associated with a pilot study. Y'know, a small un-blinded participant group taking part in a trial using a preparation that they probably will have been told *might* affect various symptoms they experience or themselves possibly 'exposed' to other anecdotal reports of good effects. That and no control group, no placebo included and importantly, no objective measure of fatigue (a real issue when it comes to quite a bit ME/CFS research) and well, I'd be surprised if something significant didn't come up during the initial findings. And just in case you think I'm being all 'high-and-mighty' about this, I've published using the same type of pilot study methodology before, including some of the same inherent issues (see here).

Second, I'm a little bit disappointed that the authors weren't more forthright in how the results weren't statistically significant on any and all measures included for study. I say this on the basis of both the commercial take on the results (see here) and also sentences like: "The two groups demonstrating the most robust response to KPAX002 were subjects with more severe ME/CFS symptoms at baseline (P=0.086) and subjects suffering from both fatigue and pain (P=0.057)." Both those p-values (p being a measure of statistical significance) are above the [currently] recognised threshold for p equal to or less than 0.05, yet are listed as a 'robust response'. Even more, throughout the paper I note the words 'trend in favor of' being used, which some people might translate as being 'well, they were nearly statistically significant results'. I say this also bearing in mind that the final participant numbers - KPAX002 use = 48 and placebo = 57 - are not exactly facets of what one would call an under-powered study. I'm probably being a nit-picker here but like it or not, the [current] rules of science are the [current] rules of science.

Finally, once again, I note that under the heading 'Disclosure of conflict of interest', the word 'none' appears as per the last research occasion [2]. Personally, and with no malice intended, I would have listed the detail that at least one of the authors is an employee of the manufacturer of KPXA002 given the affiliation details and email address for further correspondence provided on the paper. Again, it's a small detail but one that should nevertheless be acknowledged. I would have also like to have seen a little more on who funded the trial too and especially who funded the provision of the KPAX002 supplement for trial purposes. I reiterate that there is no malice is intended in saying that, but readers require such details.

I don't want to come down too hard on these results because it's obvious that quite a bit of work has gone into their production. I'm also not closing the door on the idea that future research with a more targeted group with ME/CFS might not produce something a little more statistically significant with regards to KPAX002. But for now, the answer must be that controlled study of the formulation did not meet clinical endpoints in a statistical sense, and hence KPAX002 cannot be said to be superior to placebo for CFS/ME. With all the setbacks that the label(s) ME/CFS has had to endure down the years with regards to the 'psychobabble' explanations (see here) and other 'eureka' moments (see here), the Montoya findings are bad news for patients yet again. But, they also should represent a further call to re-double research efforts; particularly when it comes to the biology of the condition(s) and onward the acceleration of research for interventions for this quality of life draining condition (see here).

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[1] Montoya JG. et al. KPAX002 as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a prospective, randomized trial. Int J Clin Exp Med 2018;11(3):2890-2900

[2] Kaiser JD. A prospective, proof-of-concept investigation of KPAX002 in chronic fatigue syndrome. Int J Clin Exp Med. 2015 Jul 15;8(7):11064-74.

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"Comprehensive Nutritional and Dietary Intervention for Autism Spectrum Disorder"

It's been a while coming but the paper by Jim Adams and colleagues [1] detailing the effects of a "comprehensive nutritional and dietary intervention for autism spectrum disorder" has finally seen the peer-reviewed light of day. I say 'a while coming' because as per the ClinicalTrials.gov entry for this research (see here), it was seemingly scheduled to start back in 2011 and be completed by 2013, I assume, without taking 5 years to write up and be published. But better late than never I suppose.

Anyhow, the nutritional and dietary intervention scheduled adopted by Adams et al was rather a complicated affair as per the study description. So: "Day 0: Vitamin/Mineral supplementation begins. Day 30: Essential Fatty Acid supplementation begins. Day 60: Epsom salt baths begin. Day 90: Carnitine Supplementation begins. Day 180: Digestive Enzyme supplementation begins. Day 210: Healthy, casein-free, gluten-free diet [HGCSF] begins." Quite a few of those individual intervention elements have been fodder for this blog before (see here and see here for examples); also reflecting other research interests from Adams and colleagues (see here). Talk about a gluten- and casein-free diet is also music to my [research] ears (see here), as is the welcome inclusion of sulfate / sulphate back into autism research proceedings (see here).

Results of that nutritional and dietary schedule are reported for a starting pool of 67 children diagnosed with an autism spectrum disorder (ASD), where 28 participants completed the 'treatment' arm and some 27 participants completed a non-treatment arm (where no new intervention(s) were reported for the 12 months of the study). Additional findings for 50 not-autism controls (I don't like the word 'neurotypical' and its rather sweeping connotations) are also reported. The study duration was a year, and the sorts of measures examined over the course of the intervention were quite comprehensive, covering both behaviour and cognition and also physiological parameters.

Results: it's always refreshing to see a study first and foremost reports any adverse effects based on the tenet 'first, do no harm'. Authors note that: "A few adverse effects were reported for some treatments" and go on to list what happened over the course of each element of the intervention. They talk for example, how: "One parent reported that implementation of the diet [healthy, gluten- and casein-free diet] in a strict manner resulted in increased aggression towards peers, inability to problem solve, and increased spinning behavior, probably due to frustration in regards to removal of favorite foods." Thankfully, most of the adverse effects noted over the study period were relatively minor and certainly not life threatening. Once again, first, do no harm.

With levels of compliance regarding the various study elements also reported as being quite high, the authors report that across the various behavioural assessments - including the CARS, SRS, VABS, and ATEC - significant effects in favour of intervention were found. Based on blinded evaluations using something called the Reynolds Intellectual Assessment Scales (RIAS), authors reported "a significant improvement in nonverbal intellectual ability in the treatment group compared to the non-treatment group." By contrast, blinded use of the gold-standard assessment instrument known as ADOS revealed "no significant change on the ADOS scores for either treatment or non-treatment group." Interestingly, when parents were asked to rate the effectiveness of each part of the intervention, results revealed that: "The highest rated treatments were the vitamin/mineral supplement and the essential fatty acids, followed by the Healthy HGCSF diets, followed by the carnitine, digestive enzymes, and Epsom salt baths."

Adams and colleagues also provide further details on "3 exceptional cases of improvement during the study, all of which occurred in the treatment group." For one participant it appears that the introduction of a carnitine supplement was associated with some quite remarkable improvements in relation to strength and energy levels in particular. The authors note that: "low carnitine seems likely to have contributed to her challenges, and carnitine supplementation seems to have helped." There could be some interesting tie-ups there with regards to previous peer-reviewed results too (see here for example). For another participant it seemed that the introduction of a HGCSF diet *correlated* with the resolution of urination problems, where a dairy-free diet removed the need for "intermittent catheterization" and resolution of associated problems. OK, these examples don't so much focus on the core issues associated with autism, but I'm pretty sure that they were factors that would have influenced quality of life.

There is quite a bit more to see in the Adams paper and I would encourage readers to take the time to read it in its entirety. Despite the fact that not every measure showed significant effects from such an intervention regime, I like the idea that authors didn't just focus on one intervention but rather, in a systematic way, looked at a whole suite of interventions focused on nutritional and dietary factors. I believe this is more 'naturalistic' in terms of what parents/caregivers tend to report. Indeed the authors themselves discuss how: "A limitation of this study is that all participants received all treatments, whereas probably only a subset are likely to benefit from any single intervention (for example, only participants with low carnitine are likely to benefit from carnitine supplementation)." Yup.

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[1] Adams JB. et al. Comprehensive Nutritional and Dietary Intervention for Autism Spectrum Disorder—A Randomized, Controlled 12-Month Trial. Nutrients. 2018; 10(3): 369.

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Pre- and peri-pregnancy use of folic acid and multivitamins and risk of offspring autism

The findings reported by Stephen Levine and colleagues [1] observing that: "Maternal exposure to folic acid and multivitamin supplements before and during pregnancy is associated with a reduced risk of ASD [autism spectrum disorder] in the offspring compared with the offspring of mothers without such exposure" provides the blogging fodder today.

Accompanied by media headlines such as 'Taking vitamins before and during pregnancy slashes autism risk by 75%, new study shows' the Levine paper adds to the growing research literature suggesting that certain nutrients taken during critical periods of pregnancy *might* be important when it comes to offspring development (see here).

"Epidemiologic studies report inconsistent associations between maternal supplementation with multivitamins or FA [folic acid] before and during pregnancy and the risk of ASD in offspring." I'm glad the authors have mentioned that the peer-reviewed literature on folic acid in relation to offspring autism risk is not all one-way. It's something that I've been particularly interested in on this blog for some time (see here and see here for examples) in terms of countering the often simplistic view that mothers-to-be should all be loading up on folic acid for example, to offset any enhanced risk of offspring autism. Yes, folic acid is a required supplement during pregnancy when it comes to something like reducing the risk of  neural tube defects (NTDs) in offspring, but with autism in mind, the evidence is not yet so clear-cut.

Levine et al report results based on Israeli children born between 2003 and 2007 and followed-up until early 2015. Their cohort included "all children with ASD and a randomly selected one-third of all children" born during their index dates including some 45,000 participants in total. When it came to exposure patterns (exposure to folic acid and/or multi-vitamins during pregnancy), the authors relied on a prescription register that included "drug names, prescription and dispensation dates, number of pills dispensed, and ATC codes." Importantly, this meant that researchers were able to classify some important details: "vitamin supplements were classified as FA and/or multivitamin supplements, an FA supplement, and a multivitamin supplement" and the timing of their dispensation: "before pregnancy (540-271 days before childbirth) and during pregnancy (270 days before childbirth up to the date of childbirth)." This is something rather different from some other previous research attempts that have for example, tended to rely on maternal recall of pregnancy supplements.

Results: "This study of 45 300 children revealed a decreased risk of ASD in children born to mothers who used FA and/or multivitamin supplements before and/or during pregnancy compared with those who had not." Among all supplement combinations - FA and/or Multivitamin Supplements, FA Supplements, Multivitamin Supplements - there was a reduced relative risk (RR) of offspring autism compared with 'unexposed' children that was present both before pregnancy and during pregnancy supplementation and took into account various covariates such as "sex, birth year, socioeconomic status (high vs low),17 a maternal and paternal psychiatric diagnosis by childbirth (present or absent), maternal and paternal age at childbirth, and parity." The sorts of risk reduction statistics being talked about - above 50% and even approaching that 75% risk reduction - are not to be sniffed at.

Although quite a good study design, the Levine results are to be treated with some caution. Not least that the authors noted: "causality cannot be inferred from observational epidemiologic studies such as this one" so one has to be careful.

But... yet again, this is further research talking about pregnancy folic acid and offspring autism. This is an area that requires further investigation in relation to possible mechanisms (or combinations of mechanisms) [2] potentially involved. Also, whether specific groups of women taking other important medicines during pregnancy, might benefit from something like folic acid supplementation in the context of enhanced offspring risk of autism [3].

To close, a musical choice to mark the passing of Mark E Smith: Mr Pharmacist (my favourite) or the more widely known, Hit the North?

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[1] Levine SZ. et al. Association of Maternal Use of Folic Acid and Multivitamin Supplements in the Periods Before and During Pregnancy With the Risk of Autism Spectrum Disorder in Offspring. JAMA Psychiatry. 2018. Jan 3.

[2] Goodrich AJ. et al. Joint effects of prenatal air pollutant exposure and maternal folic acid supplementation on risk of autism spectrum disorder. Autism Res. 2017 Nov 9.

[3] Bjørk M. et al. Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero. JAMA Neurol. 2017 Dec 26.

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From limp to scurvy in the context of autism

"A panel of nutritional markers was sent, and a presumptive diagnosis of scurvy was made."

So said the case report detailed by Adam Yan and colleagues [1] as, yet again (see here and see here), the topic of scurvy in the context of autism appears in the peer-reviewed science literature. Scurvy, a condition affecting various tissues of the body, comes about as a result of a lack of adequate vitamin C in the diet. It's thought of as a rare disease nowadays, following on from some 'limey' historical observations (see here).

I say that scurvy is a rare disease, but as per the other blogging occasions when it's received attention, for those diagnosed on the autism spectrum it's not as rare as it should be. Indeed, even Yan et al note that "scurvy is increasingly identified in children with ASD [autism spectrum disorder] and developmental delay who consume restrictive diets, often lacking in fruits and vegetables." Their case report highlights how clinicians need to be observant...

The subject of the Yan case report was a young boy diagnosed with autism who was described as non-verbal. He came to clinical attention following "a 2-week history of limp and oral mucosal bleeding." Unfortunately, his first contact with medical professionals resulted in less-than-revealing typical test results that meant he was discharged with "a referral to dentistry to address the oral mucosal changes." Things did not improve. He presented again to hospital, this time "with new onset of fevers for 1 week, ongoing limp that had progressed to complete refusal to weight bear, and persistent bleeding from his oral mucosa." This second time a few more investigations were ordered and a very (VERY) low level of vitamin C (ascorbic acid) was detected: "The low ascorbic acid level confirmed the diagnosis of scurvy with a concomitant diagnosis of anemia." Treatment in the form of vitamin C and an iron supplement (alongside a multivitamin) did the trick in terms of the limp/leg problem and bleeding gums.

What are the lessons from this case report? Well, yet again, the realisation that issues such as those related to feeding problems present quite widely in relation to autism (see here) and can very much impact on health is paramount. Indeed, it should really be part of standard medical care to monitor and keep monitoring children in particular, with a diagnosis of autism to ensure that their nutritional needs are being met in many areas (see here). If they're not, supplement (under appropriate medical guidance) and don't be afraid to do so, keeping in mind that each person/child is different (see here).

I'm also minded to mention that when medical and other allied healthcare practitioners are faced with a child/adult with autism that is non-verbal and presenting with 'symptoms', the onus really should be on medicine to turn investigator to find out 'hows-and-whys' rather than discharging with a 'we don't know' sentiment. I say this in the context that a diagnosis of autism is seemingly not protective against any other condition/label/disease occurring, and noting other, more catastrophic, examples where this has happened (see here). And minus any sweeping generalisations, a few correctly framed questions can sometimes be enlightening [2] for all-manner of different issues pertinent to autism...

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[1] Yan A. et al. Limp in a Child With Autism Spectrum Disorder. Global Pediatric Health. 2017. Nov 30.

[2] Cohen S. et al. Sleep patterns predictive of daytime challenging behavior in individuals with low-functioning autism. Autism Res. 2017 Dec 1.

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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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ADHD and vitamin levels

"ADHD [attention-deficit hyperactivity disorder] patients were overrepresented in the group with low levels of some vitamins, possibly indicative of inadequate dietary intake of these micronutrients in a subgroup of patients. It is important to identify these patients in dietary intervention trials of ADHD."

So said the study findings reported by Elisabeth Toverud Landaas and colleagues [1] (open-access) providing some potentially important data on how nutritional factors might intersect with the diagnosis of ADHD. So: "Owing to the important and neurologically relevant functions of vitamins and the lack of studies exploring this topic in ADHD, we measured serum levels of the major vitamin classes in a sample of adult ADHD patients and controls to determine whether vitamin levels are associated with ADHD diagnosis and psychiatric symptoms." Said participants (n=133) were young adults and most were listed as having ADHD according to a "Norwegian national registry of adult ADHD patients." Vitamin levels were assessed from blood samples and compared with results for 131 control participants as per other studies on this cohort from this authorship group [2]. It's worth pointing out that samples were in deep freeze storage for between 2-9 years between collection and thawing for analysis.

Various vitamins were measured in those samples (vitamins A, B6, , B9, B12 and D to name a few) alongside levels of cotinine "to assess [tobacco] smoking status." The analytical assay(s) of choice was, in the most part, a familiar one to this blog: liquid- or gas chromatography-tandem mass spectrometry.

Results: "The concentrations of vitamins B2, B6 and B9 were all significantly lower in the ADHD group." When results were analysed according to percentiles based on blood levels of the various vitamins results similarly showed that those with ADHD were 'over-represented' in the lower levels bandings of those previously described vitamins. Smokers, as defined by a "widely used cut-off of 80 nmol/L" of blood cotinine, were also over-represented in the ADHD group (66%) compared with control participants' samples (12%). The authors reported that: "vitamin B6 and B9 levels were significantly higher in non-smoking ADHD patients compared with smokers" suggesting that lifestyle choices may play a role in some of the results obtained. Finally, when it came to looking at any possible association(s) between measured vitamin levels and behaviours pertinent to ADHD (derived from responses to the Adult ADHD Self-report Scale (ASRS), the authors report some preliminary observations but I'd like to see a little more data before anything further is made of this.

These are interesting results (aren't they always!). I note that the authors make reference to the findings reported by Julia Rucklidge and colleagues on a vitamin-mineral mix for ADHD (see here) and the idea that correcting vitamin deficiencies might have effects beyond just the somatic. There are however caveats to the latest results: "The reason why we observed association between lower levels of some vitamins and ADHD is uncertain and probably multifactorial. Regrettably, we do not have information on lifestyle and nutrient intake from the participants to help in the interpretation of our observations. It is reasonable to think that differences in dietary factors may partly be responsible for the differences." Indeed.

There is also one final observation to touch upon in the Landaas results concerning the vitamin/hormone of the hour: vitamin D. Although there was no overall difference in vitamin D concentrations in the ADHD and not-ADHD group samples, the authors did observe that: "for vitamin D, ADHD patients were significantly overrepresented both in the lowest and highest 10th percentile groups." Bearing in mind past research has suggested that ADHD might be yet another diagnosis/label where vitamin D deficiency might be a feature (see here) it is pertinent that the authors suggest: "One reason for the overabundance of ADHD patients in the highest 10th percentiles of vitamin D may thus be that relatively more ADHD patients take vitamin D supplements, either as part of an experimental treatment of symptoms or as a consequence of a diagnosed vitamin D deficiency."

Finally: "It is possible that low levels of certain vitamins may contribute to ADHD symptoms. Dietary intervention trials have shown promising effects in ADHD. Thus, identification and correction of low vitamin levels could be beneficial in treatment of ADHD. Further studies are warranted for replication and for examination of the underlying mechanisms."

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[1] Landaas ET. et al. Vitamin levels in adults with ADHD. BJPsych Open. 2016 Dec 13;2(6):377-384.

[2] Aarsland TI. et al. Serum concentrations of kynurenines in adult patients with attention-deficit hyperactivity disorder (ADHD): a case-control study. Behav Brain Funct. 2015 Nov 5;11(1):36.

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Landaas ET, Aarsland TI, Ulvik A, Halmøy A, Ueland PM, & Haavik J (2016). Vitamin levels in adults with ADHD. BJPsych open, 2 (6), 377-384 PMID: 27990293

Vitamin D toxicity and autism: a case report

"Alternative medicine treatment put four-year-old boy in A&E [accident & emergency / emergency room]" went the recent BBC headline talking about the case report published by Drs Catriona Boyd and Abdul Moodambail [2].

Describing the experiences of a 4-year old boy who attended A&E (the emergency room) following an extended period of "vomiting, loss of appetite, constipation, polyuria, polydipsia and loss of 3kg in weight" in previous weeks, the authors report how after an unremarkable series of test results, parents disclosed that "for a number of months he had been taking 12 different holistic supplements recommended to the family by a naturopath to help with his autism."

Coinciding with the detected presence of hypercalcaemia - high calcium levels in the blood - and a circulating vitamin D level that was pretty much off the scale ("Vitamin D level was checked and was 2130 nmol/L (normal range: 50-150 nmol/L)") authors set about correcting such issues and eventually reported that he "has had no further problems since stopping the supplements." His symptoms by the way, matched other reports of vitamin D toxicity present in the peer-reviewed literature [2]. Insofar as any long-term side-effects associated with this case, well, we just don't know yet.

Whilst this is an unfortunate incident, there are a number of important wider points potentially raised from such a case report worth mentioning. So, treading very carefully:

1. Quite a lot of the media chatter about the Boyd/Moodambail report has focused on the more general role of complementary and alternative medicine (CAM) particularly when applied to autism (see here). The authors, in that BBC news report, stress as much with comments like: "When some complementary and alternative therapies are suggesting they can cure these situations, these parents get a hope - which is probably a false hope." Bearing in mind what was actually being reported on in their paper - hypercalcaemia and vitamin D toxicity - primarily due to either/combined excessive calcium intake and vitamin D supplementation and as far as I can see, no mention of the word 'cure' in the case report when it comes to the reasoning behind their use, one has to be a little cautious about turning such reports into something more than they are. Vitamin D - the sunshine vitamin/hormone - is an important nutrient as science and (UK) Government health policy is starting to realise (see here) and this includes that research potentially relevant to [some] autism (see here). Indeed, a response to the Boyd/Moodambail paper highlights this fact. This case report highlights how we should be treating our nutritional supplements as what they are - medicines - and how professional medical advice should always be sought when it comes to their use including that related to dosage and importantly, any contraindications. I might also suggest that this case highlights the value of screening before and during supplementation [3] - "obtaining serum 25-hydroxyvitamin D levels in infants and children who receive long-term vitamin D supplementation at or above the upper level intake that is currently recommended". The further question of 'whether vitamin D actually comes under the auspice of CAM' also surfaces. I'm sure many people will have different opinions about this but like other important vitamins (e.g. folic acid) where specific government advice is available, I'd be inclined to say not anymore.

2. There were some rather extreme reactions to this paper/story when it broke. Despite the fact that "The safeguarding team became involved as well as the police to investigate the naturopath who had advised the therapies" some people were calling the parent's actions as being tantamount to 'child abuse'. I however go with the authors on this one where the parents were naive at worst and perhaps far too trusting. Such a response does however intersect with various other thoughts and opinions in relation to autism and its' 'treatment' and calls by some for more regulation when it comes to the vast number of interventions being put forward 'for autism'. There are no easy answers to this because as well as balancing parental responsibility with the health and wellbeing of the child, blanket calls to 'ban all nutritional supplements for children/adults with autism' for example, are neither practical nor enforceable. Indeed, it could be viewed as discriminatory given our population habits when it comes to such pharmaceutics. I might also add that if one assumes that 'autism' should be replaced by the more plural 'autisms', peer-reviewed science has actually suggested that the presentation of some of the 'autisms' may be potentially amenable to certain dietary or nutritional intervention as function of their underlying genetics/biology (see here for example). The bottom line is that as long as autism remains a 'singular mysterious condition' where very little information about aetiology and life course exists, so these sorts of scenarios will unfortunately continue to occur.

3. Finally, very little discussion has centred on the individual supplements 'recommended' in this case outside of those containing calcium and vitamin D. Cod liver oil is mentioned "(containing 1000IU vitamin D") alongside camel milk, zinc, Epsom salts baths and something called AFP peptizyde. I'm sure some people might see these kinds of interventions as pure 'woo' when it comes to autism but it's perhaps important to realise that there is some preliminary peer-reviewed science behind some elements of them (see here and see here for example). Focusing specifically on cod liver oil and the idea that as well as containing vitamin A (be careful with that one) and vitamin D it contains some of those essential fatty acids that everyone keeps going on about these days, the suggestion that certain facets of cognition could be 'affected' by their inclusion as a supplement for some continues to gain scientific ground (see here). Obviously quite a lot more investigation needs to be put into the 'hows and whys' of their possible actions and mechanisms of effect with a specific focus on autism, onwards to the identification of criteria for potential best or non-responder to such approaches.

The Boyd/Moodambail report represents an important example of how supplements that can be easily purchased in-store or on-line are not just benign tablets or pills but can have very real physical effects if used inappropriately or without the right medical consultation. I certainly don't want to downplay the 'suffering' that the child in their report went through which ultimately led him to be hospitalised with some pretty serious health issues. I do however object to the 'throwing the baby out with the bathwater' sentiments that potentially stem from the translation of reports such as these, where important research on something like vitamin D and autism (which continues on at a pace [4] I might add) could easily become 'vilified' as a result of the actions of one or two parties at fault.

And perhaps it is timely to report that at least in the United States, dietary supplement use remains pretty high among the adult population albeit with a changing pattern of consumption not so dissimilar to that highlighted in the Boyd/Moodambail paper...

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[1] Boyd C. & Moodambail A. Severe hypercalcaemia in a child secondary to use of alternative therapies. BMJ Case Reports. 2016; Oct 6.

[2] Kaur P. et al. Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency. Clin Endocrinol (Oxf). 2015 Sep;83(3):327-31.

[3] Vogiatzi MG. et al. Vitamin D supplementation and risk of toxicity in pediatrics: a review of current literature. J Clin Endocrinol Metab. 2014 Apr;99(4):1132-41.

[3] Mazahery H. et al. Vitamin D and omega-3 fatty acid supplements in children with autism spectrum disorder: a study protocol for a factorial randomised, double-blind, placebo-controlled trial. Trials 2016; 17:295.

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Boyd, C., & Moodambail, A. (2016). Severe hypercalcaemia in a child secondary to use of alternative therapies BMJ Case Reports DOI: 10.1136/bcr-2016-215849

Pregnancy multivitamins 'are a waste of money' (except when they're not)

Science headlines eh? Who would trust them and their sometimes inflated press releases?

I start today with a science headline taken from the BBC website reading: "Pregnancy multivitamins 'are a waste of money'" based on the findings of a review article [1] published in the journal Drug and Therapeutics Bulletin.

In it we are told that complex multi-vitamin and mineral supplements are 'unlikely to be needed and are an unnecessary expense' during the nine months that made us. Further that certain vitamins are not indicated for supplementation during pregnancy including that contributory to excess vitamin A. All pregnant women have to do, we are told is "to have a healthy, varied diet including fresh fruit and vegetables" and avoid the old phrase 'eating for two'. What could be simpler?

The irony behind such findings and those BBC and other media headlines is that although one needs to be careful about one's vitamin and mineral intake (treat them as what they are, medicines) there is a long tradition of vitamin supplementation being indicated when it comes to that special time called pregnancy. Indeed, and I quote from the BBC article: "pregnant women should make sure they take folic acid and vitamin D, as well as eating a well-balanced diet, as per NHS guidelines, they add."

So let me get this straight: don't take a multi-vitamin supplement but makes sure that you take a (multi) supplement containing folic acid and vitamin D? You can perhaps see how confusing such headlines are and how grandiose ideas that every woman pre-conceptual and during pregnancy is feasting down on 5-a-day (or even 8-a-day if you actually believe it will make you happier!) are not necessarily based in reality. We would all love to think that important health messages about maternal fruit and vegetable consumption during pregnancy for example, are being heard loud and clear but the reality is that they aren't for everyone. The reality is that people are using vitamin and mineral supplements to supplement their dietary needs for whatever reasons and headlines further confusing the population about such supplementation being a 'waste of money' is only likely to put more people off using them without perhaps giving greater thought about the ways and means to help people alter their diet accordingly. The net result: more pregnant women potentially becoming deficient in certain core nutrients during pregnancy and more potential effects/risks for her and her offspring.

I do have a bee in my bonnet about this issue because time after time the research evidence points to how important pregnancy nutrition is for a variety of maternal and offspring outcomes [2]. Outside of folic acid and vitamin D, various other nutrients are also pretty important during pregnancy (i.e. iodine - 'good for baby, good for the economy') and the unfortunate reality is that most people can't or don't get enough of them from their diet alone. The late David Barker was a pioneer in the area of foetal programming including that related to pregnancy nutrition; one can only wonder what he would make of the suggestion that universally, supplementary multivitamin use during pregnancy is a 'waste of money'?

And finally, you want more people to eat fruit and vegetables? Don't focus too much on just price and positioning at the supermarket, focus on home economics (or just cookery!) classes at school [3] for starters and make fruit and vegetables interesting...

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[1] Vitamin supplementation in pregnancy. Drug & Therapeutics Bulletin. 2016. July 11.

[2] Harding JE. The nutritional basis of the fetal origins of adult disease. Int J Epidemiol. 2001 Feb;30(1):15-23.

[3] McMorrow L. et al. Perceived barriers towards healthy eating and their association with fruit and vegetable consumption. J Public Health (Oxf). 2016 May 24.

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Drug and Therapeutics Bulletin (2016). Vitamin supplementation in pregnancy Drug and Therapeutics Bulletin DOI: 10.1136/dtb.2016.7.0414

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

More extremes of a limiting diet and autism

In a previous post a while back, I discussed some examples in the peer-reviewed literature of where a self-limiting diet in the extreme can lead to with autism in mind. Today, I'm adding a further example of what food faddism might mean, to further forward the point that "a low threshold for vitamin level testing should be undertaken in autistic spectrum disorder cases, highlighting the importance of enquiring about dietary habits."

That last quote comes from the paper in question by Emma Duignan and colleagues [1] (open-access available here) who describe two case reports of teenagers with autism "with a background of moderate autistic spectrum disorder who were diagnosed with a multivitamin deficiency, including vitamin A." Said nutritional deficiency manifested as ophthalmic issues - relating to the physiology of the eye - that importantly seemed to abate following vitamin supplementation.

Aside from the idea that several factors might align to bring a person diagnosed with autism to a deficiency state, I was interested in the Duignan results for a few other reasons. I've talked about vitamin and mineral deficiencies a few times on this blog; more generally as per the results from Jim Adams and colleagues back in 2011 (see here) following the publication of their double-blind, placebo-controlled trial of supplementation through to more specific issues with something like the vitamin-of-the-hour, vitamin D (see here) or even the scurvy-preventer that is vitamin C (see here). There is quite a bit of literature out there to suggest that particularly in cases where dietary issues are noted to accompany a diagnosis of autism or autism spectrum disorder (ASD), one perhaps should expect nutritional deficiencies to follow.

The other thing that struck me about the Duignan results was the focus on ophthalmic issues as manifestations of those vitamin deficiency issues. It's not new news that among the various effects linked to something like vitamin A deficiency for example, vision and eye health may suffer. Although still in need of quite a bit of research, issues related to the eyes and knock-on effects for things like visual perception are no stranger to autism research as per my ramblings about the findings reported by Ikeda and colleagues [2]. The paper from Pineles and colleagues [3] on optic neuropathy due to vitamin B12 deficiency in cases of autism is also worth mentioning at this point and the question of whether at least some of the visual perceptual issues discussed with autism in mind might have a nutritional link?

We don't currently know how widespread nutritional deficiencies are when a diagnosis of autism is received because, at the moment, this is not something that is routinely tested for. On the basis of the Duignan and other results, I'd be minded to repeat my suggestion that where dietary issues are present for people on the autism spectrum, modern medicine could do a lot worse than find out whether there may be biological effects to come from a limited or restricted diet save any further charges of health inequality being levelled...

Music to close. Paul Simon - Me and Julio Down by the Schoolyard.

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[1] Duignan E. et al. Ophthalmic manifestations of vitamin a and d deficiency in two autistic teenagers: case reports and a review of the literature. Case Rep Ophthalmol. 2015 Jan 24;6(1):24-9.

[2] Ikeda J. et al. Brief report: incidence of ophthalmologic disorders in children with autism. J Autism Dev Disord. 2013 Jun;43(6):1447-51.

[3] Pineles SL. et al. Vitamin B12 optic neuropathy in autism. Pediatrics. 2010 Oct;126(4):e967-70.

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Duignan, E., Kenna, P., Watson, R., Fitzsimon, S., & Brosnahan, D. (2015). Ophthalmic Manifestations of Vitamin A and D Deficiency in Two Autistic Teenagers: Case Reports and a Review of the Literature Case Reports in Ophthalmology, 6 (1), 24-29 DOI: 10.1159/000373921

Persistent hyperlactacidemia in cases of autism

The paper from José Guevara-Campos and colleagues [1] (open-access can be downloaded here) is fodder for today's short post, and a topic that has not been seen on this blog for quite a while: hyperlactacidemia (elevated plasma lactate levels) and autism.

Previous mentions of lactate and autism on this blog (see here and see here) were potentially pretty important; specifically, how elevated plasma lactate levels might (a) not be an unfamiliar finding for quite a few people on the autism spectrum [2] and (b) might provide further evidence for the involvement of mitochondria in cases of autism among other things [3]. Mitochondria and autism, I might add, is still quite a complicated topic but a research area in the ascendancy.

Guevara-Campos et al reported on case reports for "three patients diagnosed with developmental delay, ID [intellectual disability] and ASD [autism spectrum disorder], and also with a possible mitochondrial disease accompanied by an ETC [electron transport chain] deficiency accompanied by hyperlactacidemia." There are various data provided following some clinical investigations including that based on muscle biopsy data. Just as important are some of the details on 'pharmacological treatment' of said issues and the observed impact on presented symptoms. Without cherry-picking too much, carnitine, a vitamin B complex, co-enzyme Q10 and folic acid combined seemed to have quite an effect on participants, particularly on "intellectual abilities". Some of these interventions have been trialled in other conditions where mitochondria or their important processes are suspected to show involvement (see here). I say this without providing endorsement or recommendation.

Appreciating that there is quite a bit more to do (experimentally) when it comes to "suspected mitochondrial involvement" specifically where autism is mentioned, and in particular, the need for quite a bit more controlled study on how such interventions might impact on symptoms in this group, I'm interested in the Guevara-Campos report. How many people on the autism spectrum their results hold true for is as yet unknown. With the growth in this area of research however, I'd be minded to suggest that we should really start directing a lot more resources to trying to answer that question if we are indeed going to start taking the plural autisms a little more seriously. Oh, and as per the sentiments of the paper by Zilberter and colleagues [4] there may yet be related factors which might be of "potential therapeutic significance."

Music: Roots Manuva - Witness. Brilliant.

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[1] Guevara-Campos J. et al. Autism and Intellectual Disability Associated with Mitochondrial Disease and Hyperlactacidemia. Int J Mol Sci. 2015 Feb 11;16(2):3870-3884.

[2] Oliveira G. et al. Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Dev Med Child Neurol. 2005 Mar;47(3):185-9.

[3] Andersen LW. et al. Etiology and therapeutic approach to elevated lactate levels. Mayo Clin Proc. 2013 Oct;88(10):1127-40.

[4] Zilberter Y. et al. A unique array of neuroprotective effects of pyruvate in neuropathology. Front. Neurosci. 2015. Feb 17.

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Guevara-Campos J, González-Guevara L, & Cauli O (2015). Autism and Intellectual Disability Associated with Mitochondrial Disease and Hyperlactacidemia. International journal of molecular sciences, 16 (2), 3870-3884 PMID: 25679448