Extremes of a self-limiting diet in autism

I'll draw your attention to three papers in today's post which represent the extremes of where self-imposed dietary restrictions can potentially lead in relation to the autism spectrum disorders (ASDs). Issues with diet - outside of use of diet as an intervention measure - are something which have been talked about quite a bit in the autism research literature (see here).

"You look like a gangster"

The first paper by Baird & Ravindranath [1] describes a case report of an 11-year old with autism who became "critically ill" as a consequence of a diet exclusively limited to a single fast food, "a particular type of fried chicken". Liver dysfunction and "severe lactic acidosis" were listed as clinical findings ascribed to a diet "deficient in multiple micronutrients, including the B vitamins thiamine and pyridoxine". The authors reported some resolution of symptoms as and when B vitamin supplements were given including positive changes to "status epilepticus-with low serum pyridoxine- [which] resolved rapidly with pyridoxine". I might add that issues with lactate, elevated in lactic acidosis, are no stranger to autism research (see here and see here).

The second paper comes from Gulko and colleagues [2] and talks about "MRI findings of scurvy in four patients with autism or developmental delay". Scurvy, a condition characterised by a lack of vitamin C, is something which has cropped up before on this blog (see here) and as per the Gulko findings: "Despite its rarity, the radiologist must consider scurvy in a pediatric patient with a restricted diet presenting with arthralgia [joint pain] or myalgia [muscle pain]".

The final paper comes from Keown and colleagues [3] and describes the experiences of a young boy "identified to have a restricted diet" characterised among other things by consumption of "excessive quantities of carrot juice". As a result: "Blood investigations showed a raised serum carotene level and vitamin D deficiency". Vitamin D is something of an emerging area in relation to autism (see here).

Combined, these papers suggest yet another set of physiological variables which may require further clinical scrutiny as and when a child or adult presents with an ASD particularly where diet is mentioned as potentially being an accompanying issue. As per the findings from Marshall and colleagues [4], finding appropriate strategies to increase food variety (and not just food volume) remains an area in some need of further research.

----------

[1] Baird JS. & Ravindranath TM. Vitamin B Deficiencies in a Critically Ill Autistic Child With a Restricted Diet. Nutr Clin Pract. 2014 Aug 11. pii: 0884533614541483.

[2] Gulko E. et al. MRI findings in pediatric patients with scurvy. Skeletal Radiol. 2014 Aug 12.

[3] Keown K. et al. Nutritional implications of selective eating in a child with autism spectrum disorder. BMJ Case Rep. 2014 Mar 20;2014. pii: bcr2013202581.

[4] Marshall J. et al. Efficacy of interventions to improve feeding difficulties in children with autism spectrum disorders: a systematic review and meta-analysis. Child Care Health Dev. 2014 Jun 25.

-----------

Baird JS, & Ravindranath TM (2014). Vitamin B Deficiencies in a Critically Ill Autistic Child With a Restricted Diet. Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition PMID: 25112945



Gulko E, Collins LK, Murphy RC, Thornhill BA, & Taragin BH (2014). MRI findings in pediatric patients with scurvy. Skeletal radiology PMID: 25109378




Keown K, Bothwell J, & Jain S (2014). Nutritional implications of selective eating in a child with autism spectrum disorder. BMJ case reports, 2014 PMID: 24654242

Mitochondrial dysfunction as a neurobiological subtype of autism

The paper by Suzanne Goh and colleagues [1] reporting on "a possible neurobiological subtype of mitochondrial dysfunction in ASD [autism spectrum disorder]" is a worthy addition to the research roll call which has graced this blog down the years. Based on the analysis of brain lactate levels - a potential marker of mitochondrial dysfunction - via the analysis of lactate doublets on brain magnetic resonance spectroscopic imaging (MRSI), authors picked up a significantly higher rate of lactate in cases of autism spectrum disorder (ASD) when compared to age and sex-matched asymptomatic controls. I've talked lactate and autism before on this blog (see here) so very much welcomed this research looking specifically at brain levels of this stuff.

I'm writing this post having already scheduled a blog entry on the recent paper by Rose and colleagues [2] (open-access here) on the increasing complexity of mitochondrial dysfunction being seemingly present in some cases of autism. Given the findings from Goh et al I've decided to publish this entry first (just to confuse everyone even further) as yet again, my confusion on the topic of all-things mitochondrial has an opportunity to shine through.

So then, a few details from the Goh paper:

• Based on imaging and other data derived from 75 participants diagnosed with an ASD (aged 5-60 years) contrasted with 96 typically-developing controls, the authors set about "assessing in-vivo evidence of mitochondrial dysfunction directly in the brains of a large sample of children and adults with ASD".
• Whilst not an imaging man, I can tell you that they used proton multiplanar spectroscopic imaging (MPSI) to quantify endogenous brain chemistry and "regional cellular metabolism and function" specifically towards the detection of lactate. Actually, the talk of [lactate] doublets is not a million miles away from the results one gets as a consequence of a related chemical analytical technique, NMR, which brings back memories of some work from days gone by.
• After laying down quite a few ground rules for what was and wasn't a readable result, the authors concluded that: "Lactate doublets were present at a significantly higher rate in participants with ASD (13%) than in typically developing controls (1%) (P = .001), providing in vivo evidence for the presence of mitochondrial dysfunction in the brains of individuals with ASD". In-vivo by the way, means in the living and contrasts with science done in a test-tube (in-vitro).
• Age was a factor when it came to lactate levels, with elevations reported more often in adults than in children. This phenomenon has been talked about before in the research literature [3].
• The authors go on to discuss the implications of their results. Bearing in mind the various situations where elevated brain lactate levels have been noted outside of just ageing, including as a result of issues like anxiety or panic disorder [4], they reiterate how their "strict exclusion critera and careful scanning procedures made such explanations less likely". Further they highlight how: "individuals with ASD should undergo evaluation for mitochondrial dysfunction, as novel and promising treatments are under development for mitochondrial disorders".

As per my link above, this is not the first time that lactate has appeared in the autism research literature. I'll for example, draw your attention to the paper by Al-Mosalem and colleagues [4] and their reporting that: "Lactate as an important energy metabolite for the brain was significantly higher in autistic patients compared to control showing about 40% increase". Bear in mind however that this and other results [5] have tended to look in plasma rather than directly what's going on in the brain as Goh et al did.

There's little more for me to say on this area of research aside from the need for further replicative investigations and perhaps a little more inquiry into the subgroup of people with autism who fall into this mitochondrial dysfunction category bearing in mind the continued focus on the plurality of autism (the autisms). That there may be interventions available for mitochondrial disorder when present [6] is another important point. As per related research in other conditions with a potential mitochondrial aspect to them (see here), at least one of the interventions - Coenzyme Q10 (ubiquinol) - is being looked at with some autism in mind [7] (open-access here) bearing in mind no medical or clinical advice is given or intended.

Music then to close. I'm thinkin' of something with a candy orientation given the time of year, so again, ladies and gentlemen, Mr Sammy Davis Jnr and The Candy Man.. (he can you know).

-----------

[1] Goh S. et al. Mitochondrial Dysfunction as a Neurobiological Subtype of Autism Spectrum Disorder. Evidence From Brain Imaging. JAMA Psychiatry. 2014. April 9.

[2] Rose S. et al. Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines. Transl Psychiatry. 2014 Apr 1;4:e377.

[3] Ross JM. et al. High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio. PNAS. 2010; 10.1073/pnas.1008189107

[4] Al-Mosalem OA. et al. Metabolic biomarkers related to energy metabolism in Saudi autistic children. Clin Biochem. 2009 Jul;42(10-11):949-57.

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

[6] Parikh S. et al. A Modern Approach to the Treatment of Mitochondrial Disease. Curr Treat Options Neurol. Nov 2009; 11(6): 414–430.

[7] Gvozdjáková A. et al. Ubiquinol improves symptoms in children with autism. Oxid Med Cell Longev. 2014;2014:798957.

----------

Goh, S., Dong, Z., Zhang, Y., DiMauro, S., & Peterson, B. (2014). Mitochondrial Dysfunction as a Neurobiological Subtype of Autism Spectrum Disorder JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2014.179

Caution: mitochondrial disorder learner ahead

Learner @ Wikipedia  

I mentioned in a post on acyl-carnitines quite recently how I would be looking to eventually take on the whole issue of mitochondrial dysfunction in relation to cases of autism spectrum disorder (ASD) on this blog. The day of that mega-post is still on the horizon, but for now I want to run through some important terms and issues which might eventually feature in that future post. This post will also help me get things straight about the basics of mitochondrial disorder but please, don't take my word as Gospel.

To save any charges of plagiarism, my main reference for this paper is the excellent review article by Mary Kay Koenig* (open-access) on the presentation of mitochondrial disorders in childhood, which at a recent visit to the dentist of all places, I actually managed to read in detail and make some (semi-) legible notes.

So here goes.

I have already set some of the scene for mitochondria and their important effects on our lives in a few previous post looking at high lactate levels in cases of autism (see here) and also detailing some interesting midi-chlorian, sorry mitochondrial findings in relation to chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) (see here). Aside from the detail that approximately 20% of children with autism are estimated to present with high lactate levels, I introduced some of the ways and means that mitochondria work and in particular, their primary energy production aim.

It's in your D-D-DNA
The first thing to note about mitochondria is that they contain their own DNA, and most of it (all of it?) comes from your mother. Dad's sperm it seems, does not stand a chance in the most part. This distinction from nuclear DNA, is an important one, particularly to things like the science of molecular phylogenetics. It also means that one can to some extent distinguish between mitochondrial issues as a consequence of mitochondrial DNA (mtDNA) and those as a result of issues with nuclear DNA. As Dr Koenig notes: "the majority of cases of mitochondrial disorders in children result not from mitochondrial DNA mutations, but from nuclear DNA mutations". That being said, mtDNA has been implicated in cases of autism as per this paper by Napoli and colleagues** (open-access).

The next thing worth pointing out is that there is a symbiotic relationship between mitochondria and our cells. Mitochondria provide usable energy to the cell but the cell also nurtures the mitochondria with proteins and nutrients it needs too. A sort of 'you scratch my back and I'll scratch yours' relationship.

Processes and signs
OK, the processes involved is next in line. There are lots, but the electron transport chain is the primary one attached to mitochondrial dysfunction, all related to the production of adenosine triphosphate (ATP). ATP really is the bees knees when it comes to energy which cells need and use (as in the end product of cellular respiration). A shortage in the supply of ATP means that cells are not going to be able to complete their function optimally.

When it comes to the presentation of paediatric mitochondrial disorders, there are some interesting stats about the body systems most frequently showing signs and symptoms. To quote from the good Dr Koenig: "Approximately 45% of children present with neurologic signs" ranging from hypotonia to seizures. Additionally: "20% of patients demonstrate intellectual dysfunction or psychiatric disturbances". There are quite a few more somatic presentations in terms of liver and cardiac presentation but these seem to be slightly less frequently reported in the general literature apparently.

Diagnosis and assessment
Diagnosis of a mitochondrial disorder is not, it seems, totally straight forward. Without trying to make too much fuss, it also seems very 'spectrum-y' to me, in terms of the definition and laboratory diagnosis of a mitochondrial dysfunction which relies on various disciplines doing their diagnostic stuff and coming together to make the diagnosis.

Lactic acidosis is an important clinical finding, which includes measurement of plasma lactate as per that 1 in 5 kids with autism with high lactate levels. Lactic acidosis is all about what happens when there are low levels of ATP (that golden energy source) and how the body tries to compensate via up-regulation of glycolysis which in turn leads to an excess of pyruvate, which itself might lead to elevated levels of the amino acid alanine or lactate. As well as looking at lactate, one could perhaps therefore see some merit in looking at levels of pyruvate and alanine too.

Outside of just looking in blood/plasma, there is also some suggestion that looking at lactate levels in the brain might also be a good idea, as per the use of proton magnetic resonance spectroscopy. There are other potential markers and mediums to work with including lactate levels in urine and cerebrospinal fluid (bearing in mind how invasive this is) and muscle biopsy to look for ragged red muscle fibres using light microscopy. That alongside looking for mutations in nuclear and mitochondrial DNA. Indeed in saying all this, quite a nice roadmap of where and what to look at with autism and mitochondrial disorders in mind was provided by Weissman and colleagues*** (open-access) noting the high prevalence of gastrointestinal symptoms and indeed some more recent research**** including Dr Koenig on the authorship team.

I'm going to finish this very descriptive post at this point with a few choice pearls of wisdom from Dr Koenig. First, unexplained elevations of lactate in any medium "should raise suspicions for a mitochondrial disorder". Second, "mitochondrial disorders are progressive". Don't assume a one-off analysis rules anything out. Finally, "a mitochondrial disorder should be considered in any child presenting with nonspecific signs such as ... learning disorders [and] epilepsy".

'Nuff said (for now).

----------

* Koenig MK. Presentation and diagnosis of mitochondrial disorders in children. Pediatr Neurol. 2008; 38: 305-313.

** Napoli E. et al. Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism. Molecular Autism 2013; 4:2.

*** Weissman JR. et al. Mitochondrial disease in autism spectrum disorder patients: a cohort analysis. PLoS ONE. 2008; 3: e3815.

**** Bhardwaj J. et al. Impaired gastric emptying and small bowel transit in children with mitochondrial disorders. J Pediatr Gastroenterol Nutr. 2012; 55: 194-199.

***** Frye RE. et al. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Translational Psychiatry. January 2013.

----------

Koenig, M. (2008). Presentation and Diagnosis of Mitochondrial Disorders in Children Pediatric Neurology, 38 (5), 305-313 DOI: 10.1016/j.pediatrneurol.2007.12.001

High lactate levels reported in about 1 in 5 children with ASD

I'm quite conscious of the fact that my last post on aromatic amino acids and bacteria was quite technical and jargon-filled. I apologise to readers for this. I perhaps got a little bit carried away with an area close to my research heart. This post also deals with some complex issues; the difference being that this time I admit to being no expert on mitochondria, lactate or any related metabolite in relation to autism or anything else. I will try and describe some of the research leading to the post announcement but please don't take my word as gospel.

The sentence making up the title of this post was contained as part of this paper published by Dhillon and colleagues* (full-text). The manuscript is of the review-type looking at the various research on a possible relationship between mitochondrial DNA (mtDNA) and autism spectrum conditions and the 1 in 5 figure comes from this paper by Oliveira and colleagues**.

I guess it might be useful to introduce some basic information about lactate. First, don't confuse lactate with lactose or lactase mentioned in a previous posts on issues with milk. Neither be put off by all the jargon coming up - 'keep calm and carry on' as they say. It all starts with an energy source; in this case glucose, and how energy is released/metabolised via a process called glycosis; that is the conversion of glucose to pyruvate. I use the word pyruvate (and lactate) to generally mean pyruvic acid (or lactic acid) bearing in mind the chemistry of acids and bases in physiological terms.

Pyruvate forms an essential part of the Krebs cycle which onward ties into the electron transport chain and adenosine-5'-triphosphate (ATP), the energy transporter. There is quite a good graphical description of this process here. Pyruvate is also the important compound when it comes to lactate as a result of the enzyme lactate dehydrogenase making the change between the compounds under conditions without oxygen.  There is also some involvement with the coenzyme NAD+ (and NADH) but I don't want to complicate things any further. Pyruvate also cropped up in a previous post as one of five potential serum biomarkers for schizophrenia. Suffice to say that alterations in the levels of lactate might potentially indicate some pretty important things going on.

It was perhaps this paper by Coleman and Blass*** which really started the ball rolling with regards to lactate in which they reported an overlap between a diagnosis of autism and lactic acidosis. Lactic acidosis (high lactate levels and low pH levels) can result as a consequence of many different reasons including exercise and even that most final of processes rigor mortis; much to do with an absence of oxygen. Mitochondrial dysfunction has been suggested to be one source of this lack of oxygen (or at least issues with the Kreb's cycle functioning) as per the oft-cited review article by Rossignol and Frye.

Mary Coleman was again in many respects ahead of the game with her lactic acidosis findings in relation to cases of autism. Nearly 20 years after, Pauline Filipek and colleagues looked again at the whole pyruvate-lactate relationship in their study looking at carnitine deficiency and mitochondrial dysfunction in relation to autism. To quote: "Results for pyruvate, lactate, ammonia and alanine... collectively present a consistent picture of mild mitochondrial dysfunction". Don't even get me started on related findings on the amino acid alanine.

Other studies have suggested similar elevations in lactate although not universally so. Al-Mosalem and colleagues reported an approximate 40% increase in levels of lactate in children diagnosed with autism compared to controls. A finding similarly reported by some of the author group under separate cover. Indeed with these and various other reports I might be inclined to suggest that chronic elevations in lactate levels together with some of its relations might very well be important to the biology of at least some people with autism. As to how lactate levels may or may not directly impinge on the presented behaviours of autism is still a point of speculation.

To finish, the Cardigans in celebration of Valentines Day with Lovefool. Please don't forget that special someone (noting that flowers bought from the nearest petrol station are not generally that romantic).

-----------

* Dhillon S. et al. Genetics and mitochondrial abnormalities in autism spectrum disorders: a review. Current Genomics. 2011; 12: 322-332.

DOI: 10.2174/138920211796429745

** Oliveira G. et al. Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Developmental Medicine & Child Neurology. 2005; 47: 185-189

** Coleman M. & Blass JP. Autism and lactic acidosis. JADD. 1985;15: 1-8

----------

Oliveira, G., Diogo, L., Grazina, M., Garcia, P., Psych, A., Marques, C., Miguel, T., Borges, L., Vicente, A., & Oliveira, C. (2007). Mitochondrial dysfunction in autism spectrum disorders: a population-based study Developmental Medicine & Child Neurology, 47 (3), 185-189 DOI: 10.1111/j.1469-8749.2005.tb01113.x