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

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.

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[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.

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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).

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[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.

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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

Treatable inborn errors of metabolism in cases of autism

Happy New Year! Καλή Χρονιά (in Greek).

Welcome back to Questioning Answers in 2014. Let's continue our journey across the autism research landscape.

Party time, excellent @ Wikipedia 

Holidays. Whilst never regretting the opportunity to go on holiday/vacation, I am the type of person who has a strong desire to stay connected to the (research) world. I wouldn't necessarily say that I'm a product of the age of social media, more of late convert who ran enthusiastically towards the light.

A few months back however, I missed something important. It was the chance to peer review the paper by Martha Spilioti and colleagues* (open-access here) and some very interesting information following the screening of 187 children presenting with an autism spectrum disorder (ASD) for the signs and symptoms of various inborn errors of metabolism.

Actually it wasn't all my fault that I didn't accept this review. Granted I didn't access my email on holiday as often as I do when working, but more than that, the publishing journal seemed to expect quite a prompt reply on whether or not I was willing to review. I didn't reply in time, so I missed out. That's what happens in August, the holiday month, the time the kids are off school, y'know, the summer (at least here in my part of the World). No mind, I am happy to see that the Spilioti paper has seen the light of scientific day and hence become fodder for this blog.

Anyhow, inborn errors of metabolism. I've talked about them before in relation to autism (see here and here) and how at least some of them might actually be pretty revealing when it comes to at least some autism (as per those interesting findings in relation to the branched-chain amino acids). More recently I've been reading the paper by Stockler-Ipsiroglu and colleagues** talking about outcomes with regards to a diagnosis of guanidinoacetate methyltransferase (GAMT) deficiency which included some chatter on autistic behaviours (or should that just be autism?) as being involved.

The Spilioti paper evaluated 187 Greek children diagnosed with an autism spectrum condition on the basis of quite a few parameters. We're told that alongside taking quite a bit of information about family history and dietary habits, quite a few laboratory investigations were initiated, too numerous to all mention here. I have to say I was particularly impressed by the authors talking about a glucose loading test (with mitochondrial issues in mind) alongside serum and urine amino and organic acid screens; even looking at carnitine levels. The Greeks seem to be taking a lead in this 'look-see' approach when it comes to the autisms.

Their results: well, only a small proportion of their cohort turned up an inborn error of metabolism. Two participants with Lesch-Nyhan syndrome linked to the overproduction of uric acid (see here for a post of impulsivity and uric acid). Two further participants were identified with succinic semialdehyde dehydrogenase (SSADH) deficiency (which is a very, very rare condition indeed). One child was also diagnosed with PKU (see here).

Perhaps of more interest were the findings related to that glucose loading test and the suggestion that there was an increase in serum beta hydroxybutyrate (β-OH-b) in around 8% of participants. Although not an expert on this particular metabolite, I understand that elevations can indicate one or several possible scenarios (see here). The authors elaborate that some of those with elevations in β-OH-b also "manifested exacerbation of symptoms during high carbohydrate intake" which brings in an interesting dietary element. Indeed, further when a ketogenic diet (high fat, low carbohydrate intake) was initiated in [some of] those with increased β-OH-b, some interesting behavioural changes were reported; one participant was reported to show "remarkable improvement" in his CARS scores, which was followed by a cessation of medication and attendance at a "public elementary school without clinical problems". Yes, I know this was a case series (an optimal outcomer?) and not a controlled trial of the ketogenic diet where increased serum β-OH-b levels have been identified. Perhaps this is the next experimental step?

Other interesting findings. Well, yes. Around 7% of participants also showed elevated levels of urinary 3-hydroxyisovaleric acid (3-OH-IVA). Assuming that these child participants were not smokers (see here***) we are also told that none of these 7% were also "undergoing valproate intervention" which is another potential way of elevating 3-OH-IVA (see here****). And when it came to intervening with biotin as a function of the connection between 3-OH-IVA and biotin*****, authors again reported some interesting outcomes leading to "clear therapeutic benefit" noted in CARS scores for some. Please note I'm not suggesting anything based on these findings as per my caveat about no medical or clinical advice given or intended.

There is a lot more, data-wise, in the Spilioti paper which I've not been able to include in this post. As per the growing literature on autism perhaps being better defined as the 'autisms' I would echo the sentiments of Spilioti and colleagues when they say: "further consideration be given to the selected analysis of IEM [inborn errors of metabolism] in ASD". That dietary and nutritional supplementation might also be a road to improvement in the presentation of symptoms for some on the spectrum with identified metabolic parameters is also a very important consideration too.

Some music to close, and for those of who watched the New Year festivities from the comfort of your own home like I did to the tune of offspring chatter of 'can I stay up late please?', Alfie and Gary sing a classic...

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* Spilioti M. et al. Evidence for Treatable Inborn Errors of Metabolism in a Cohort of 187 Greek Patients with Autism Spectrum Disorder (ASD). Front. Hum. Neurosci. 2013; 7:858. doi: 10.3389/fnhum.2013.00858

** Stockler-Ipsiroglu S. et al. Guanidinoacetate methyltransferase (GAMT) deficiency: Outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab. 2013 Nov 7. pii: S1096-7192(13)00366-1. doi: 10.1016/j.ymgme.2013.10.018.

*** Sealey WM. et al. Smoking accelerates biotin catabolism in women. Am J Clin Nutr. 2004 Oct;80(4):932-5.

**** Mock DM. et al. Disturbances in biotin metabolism in children undergoing long-term anticonvulsant therapy. J Pediatr Gastroenterol Nutr. 1998 Mar;26(3):245-50.

***** Mock NI. et al. Increased urinary excretion of 3-hydroxyisovaleric acid and decreased urinary excretion of biotin are sensitive early indicators of decreased biotin status in experimental biotin deficiency. Am J Clin Nutr. 1997; 65: 951-958.

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Martha Spilioti, Athanasios Evangeliou, Despoina Tramma, Zoe Theodoridou, Spyridon Metaxas, Eleni Michailidi, Eleni Bonti, Helen Frysira, Katerina Haidopoulou, Despoina Asprangathou, Aggelos Tsalkidis, Panagiotis Kardaras, Ron Wevers, Cornelis Jakobs, & Michael Gibson (2013). Evidence for Treatable Inborn Errors of Metabolism in a Cohort of 187 Greek Patients with Autism Spectrum Disorder (ASD) Front. Hum. Neurosci.

Gastrointestinal comorbidity for World Autism Awareness Day

Today (Tuesday 2 April 2013) is World Autism Awareness Day (WAAD).

I don't exactly know how one is supposed to communicate this message ('Happy world autism awareness day' just doesn't roll off the tongue). So I guess all I will say is to reiterate the subtext of this blog on what the spectrum - the very wide spectrum - means: "To some it means a need for life-long support. To others it is part of the varied tapestry of humanity. To all it means a need to foster a welcoming society with appropriate support and opportunities."

Onwards. Having discussed the latest paper from Drs Stephen Walker and Arthur Krigsman on bowel pathology in cases of autism potentially denoting a distinct condition from other inflammatory bowel diseases and stumbling upon the paper by Peeters and colleagues* on functional defecation disorder and autistic traits, I thought it appropriate to pop into the DeLorean and revisit a paper which never really received the recognition it deserved.

The subject matter for today is the paper by Karoly Horvath and colleagues** published in 1999 as we begin another trip down the autism research memory lane, same as I did when covering the the Mary Goodwin paper from 1971 on the gut-brain axis and autism (see here) and the John Money autism and autoimmunity paper also from 1971 (see here).

Hadrian's Wall @ Wikipedia  

Remember my name
The name Karoly Horvath will probably be familiar to quite a few people who've been on the autism research scene for a while. Another of Dr Horvath's papers*** created a bit of stir a while back based on some very preliminary findings on the use of the digestive hormone, secretin for cases of autism.

Following some initial reports of "transient, marginally significant improvements in autistic behaviors" in some cases as per studies like the one from Coniglio and colleagues****, a whole slew of subsequent trials have painted a rather less positive picture on the use of secretin for autism as per the review by Krishnaswami and colleagues***** (open-access) which quite emphatically stated that "secretin as a treatment approach for ASDs warrants no further study".

I'm not one to normally challenge paper conclusions - particularly systematic reviews - but will perhaps contrast that quote with the closing remarks made by the Cochrane Library review of Williams and colleagues******. They left the secretin research door slightly ajar for those who were potentially able to  identify "important subgroups of children with ASD who could benefit from secretin because of a proven link between the action of secretin and the known cause of their ASD, or the type of problems they are experiencing". I'm a great believer in subgroups when it comes to autism, or rather the autisms, and how a diagnosis of autism is seemingly protective of nothing when it comes to other conditions/states, so you can perhaps assume which quote was my preference.

Factoids
Anyhow, back to the Horvath 1999 paper. A few interesting factoids from their report:

• Thirty-six children all diagnosed with an autism spectrum disorder (ASD), mean age 5.7 years, formed the participant group. Children were all referred to the gastroenterology (GI) clinic where the authors worked following the presence of various GI symptoms ranging from abdominal pain to chronic diarrhoea and various other presentations.
• As well as quite a bit of review of participants' medical history, various clinical investigations were undertaken which included a "full upper gastrointestinal workup", analysis of digestive enzyme function in the small intestine and some histological examination.
• Results: quite a few important findings. Reflux esophagitis was present in nearly 70% of participants (25/36). Chronic inflammation of the gastric mucosa was determined in 15 children. Reduced disaccharidase activity was present in approximately 60% of children, and in particular low lactase levels. Following administration of secretin, participants with autism and diarrhoea comorbid showed signs of increased pancreatico-biliary fluid output potentially indicative of "upregulation of the secretin receptors" itself potentially related to "either a defect in secretin production or a problem of release from the intestinal S cells".
• "There was no evidence of either fungal or bacterial overgrowth in the duodenum" was another finding.

I know there is a lot to take in from those results so I'm going to try and put them into some kind of perspective with some of the other related literature in the peer-reviewed domain.

Lactose intolerance
I'll start with the disaccharidase activity side of things. The Horvath results were in some respects ahead of their time with their findings in this area. I've talked previously about the Rafail Kushak paper and their findings of the frequency "of lactase deficiency was 58% in autistic children ≤ 5 years old and 65% in older patients". Notice the similarity in the percentages between Horvath and Kushak. Indeed, this whole area of carbohydrate malabsorption present in cases of autism was very nicely continued by the Brent Williams paper looking at enzyme activity and autism. I know a few people have talked about how some of these findings might overlap with for example, the various reports on the use and effectiveness of a gluten- and casein-free (cereal grains and mammalian dairy free) diet in some cases of autism. Certainly, I wouldn't rule out a possible overlap to account for any results.

Reflux and GERD
Gastroesophageal reflux and reflux esophagitis - states pertaining to inflammation of the esophagus - were also commonly reported in the participant group and indeed also correlated with various behavioural manifestations noted in some cases (nighttime wakening, signs of irritability, abdominal discomfort) which are "typically reported by non-autistic children with esophagitis". A little reading around this topic suggests that many cases of such esophagitis are tied into things like GERD - gastroesophageal reflux disease - which is basically about stomach acid rising up instead of staying where it should be and causing damage. That being said, other explanations have also surfaced to potentially account for the damage done during GERD (see the paper by Souza and colleagues*******) highlighting a possible role for cytokines in this process. I'm also conscious of the findings of eosinophilic esophagitis being reported in individual cases of autism (see here). In terms of management options and without heading down any medical advice giving path, I was very interested to see a body of work appearing supporting the use of baclofen for cases of GERD********, a derivative of which - arbaclofen - has recently been touted as a potential intervention option for cases of autism. One has to wonder whether kum-ba-arbaclofen might be doing so much more than just affecting GABA receptors?

I'm going to stop there with the Horvath paper and its quite important observations. Once again it is a good example of how, just because we see a rising tide of new findings on autism or any other condition or state, we shouldn't neglect the older literature (published pre-social media) and the valuable insights that it has provided. Indeed, I am going to champion the paper by Horvath et al as an important one; particularly when it came to the assessment of carbohydrate digestive enzyme activity because it was truly ahead of its time and very possibly something that you might hear more about in the coming years of autism research.

Importantly for WAAD, the Horvath paper is a stark reminder that awareness of the autism spectrum should extend beyond just the triad (very soon to be dyad) of core symptoms and into the range of often very pronounced comorbidities which can also exist and affect quality of life. And just in case you need a more recent example of this, have a look at this paper from Francisca van Steensel and colleagues********* (open-access) and their findings on the over 50% rate of psychiatric comorbidity reported in their pediatric cohort. Their focus on 'anxiety disorders' does not need any more chatter from me.

To close, something musically, a little more contemporary. Bruno Mars and Locked Out Of Heaven.

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* Peeters B. et al. Autism spectrum disorders in children with functional defecation disorders. J Pediatr. March 2013.

** Horvath K. et al. Gastrointestinal abnormalities in children with autistic disorder. J Pediatr. 1999; 135: 559-563.

*** Horvath K. et al. Improved social and language skills after secretin administration in patients with autistic spectrum disorders. J Assoc Acad Minor Phys. 1998; 9: 9-15.

**** Coniglio SJ. et al. A randomized, double-blind, placebo-controlled trial of single-dose intravenous secretin as treatment for children with autism. J Pediatr. 2001; 138: 649-655.

***** Krishnaswami S. et al. A systematic review of secretin for children with autism spectrum disorders. Pediatrics. 2011; 127: e1322–e1325.

****** Williams K. et al. Intravenous secretin for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2012; 4: CD003495.

******* Souza RF. et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology. 2009; 137: 1776-1784.

******** Cossentino MJ. et al. Randomised clinical trial: the effect of baclofen in patients with gastro-oesophageal reflux - a randomised prospective study. Aliment Pharmacol Ther. March 2012.

********* van Steensel FJA. et al. Psychiatric comorbidity in children with autism spectrum disorders: a comparison with children with ADHD. J Child Fam Stud. 2013; 22: 368–376.

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Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, & Tildon JT (1999). Gastrointestinal abnormalities in children with autistic disorder. The Journal of pediatrics, 135 (5), 559-63 PMID: 10547242

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).

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* 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.

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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

Mitochondrial dysfunction and ME/CFS

I continue my interest in research examining chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) in this post looking at what might turn out to be quite an important paper by Booth and colleagues* (full-text) on a potential role for mitochondrial dysfunction.


Where to start....

Mitochondria (plural) are not to be confused with the midi-chlorians of a Galaxy far, far away. A few associated words: organelles, eukaryotic cell, the power plant of cells, cellular respiration (this link carries a really easy to understand description of this process). In short, mitochondria provide energy to the cell in the form of ATP. Cells like most thing need energy to function properly; where insufficient energy is produced... well, cells don't work as well as they should and the results can be serious and wide-ranging.

I've kinda eluded to mitochondrial function, or rather dysfunction, in posts like this one on lactate levels in autism although I dare say that as some point I will come back to the topic in more detail. Indeed elevations in lactate levels do seem to indicate some potential issue with mitochondrial dysfunction as per studies like this one from Magner and colleagues**.

I digress. Booth et al have previously reported on mitochondrial dysfunction in cases of CFS/ME in this paper*** (full-text); the current study being a sort of extension and elaboration effort. I might add that they are by no means the first to suggest that there may be some mitochondrial 'involvement' in cases of CFS/ME (see here and here). Low carnitine levels? Now where have I heard that before?

Their latest paper is full-text and contains quite a bit of data but a short summary is perhaps in order:

• The ATP profile features quite strongly in the paper. This is described as containing among other things, ATP concentration in blood neutrophils (in the presence of excess magnesium, deficiencies of which have been linked to CFS) and is a part of a so-called mitochondrial energy score (MES). In their previous paper (***) the authors reported an impressive correlation between MES and CFS Ability as described using the Bell Ability Scale, a rough and ready measure of the level of disability as a consequence of the condition (see here). 
• It looks like there were a few elements to this paper including a reanalysis of the cohort reported in their previous paper - cohort 1 (minus 10 participants who were outside of the age range of controls, again taken from their original publication) and analysis of a new participant group - cohort 2 - made up of 138 participants aged between 18-65, mean age 41 years.
• Similar to the last paper, the MES showed a pretty good correlation with CFS Ability (correlation coefficient = 0.80). I have to admit that quite a lot of the rest of the results are beyond the limits of my biochemistry as various measures of ATP inhibition, functionality of the translocator proteins (e.g. ANT) and efficiency of oxidative phosphorylation are tested ( I think!). The end result is that the mitochondrial dysfunction noted by the authors in this patient group seems to (a) frequent, very frequent and (b) particularly involves issues with the translocator protein (TL) regulating the passage of ATP and ADP across mitochondrial membranes (see here - no endorsement intended). Other preliminary studies of oxidative phosphorylation capacity in CFS for example, suggested that this is probably not the main reason for mitochondrial dysfunction**** (full-text).
• The authors conclude: "Taken together, these measurements show that ME/CFS is a serious illness which may affect every cell in the body".

And relax. 

I should point out that my interpretation of the Booth results should not be taken as Gospel or anything like that. I do however believe that these results are important for CFS/ME and potentially represent at least one part of the puzzle that is this debilitating set of conditions. Independent replication of the Booth results is the next step.

I was drawn to the fact that other conditions presenting with a fatigue component such as fibromyalgia have also been suggested to be linked to issues with mitochondria as per this case study by Abdullah and colleagues***** (full-text). The 'solution' to their reported case was supplementation with various compounds including coenzyme Q10, creatine and carnitine among other things. Whilst I am not in a position to endorse anything like such a treatment protocol (please do speak to your healthcare provider first), I note that supplements like coenzyme Q10 have cropped up more than once in relation to CFS/ME as per articles like this one****** from a familiar name to this area of study, Michael Maes and colleagues.

ME/CFS are a heterogeneous set of conditions which, similar to the description of autism, probably include quite a few different paths to the development of symptoms. Whilst the area of mitochondrial dysfunction is an attractive potential marker showing involvement in cases - at least some cases - the question of whether this is a 'core' aspect of the conditions still remains to be seen alongside its connection with other pathways of interest. 


To finish, Kate Bush sings Wuthering Heights. A lesson in the art of dance and music (and its absolutely fantastic).

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* Booth NE. et al. Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). International Journal of Clinical & Experimental Medicine. 2012; 5: 208-220.


** Magner M. et al. Elevated CSF-lactate is a reliable marker of mitochondrial disorders in children even after brief seizures. European Journal of Paediatric Neurology. 2011; 15: 101-108.

*** Myhill S. et al. Chronic fatigue syndrome and mitochondrial dysfunction. International Journal of Clinical & Experimental Medicine. 2009; 2: 1-16.

**** Vermeulen RC. et al. Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. Journal of Translational Medicine. 2010; 8: 93.

***** Abdullah M. et al. Mitochondrial myopathy presenting as fibromyalgia: a case report. Journal of Medical Case Reports. 2012; 6: 55.

****** Maes M. et al. Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinology Letters. 2009; 30: 470-476.

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).

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* 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

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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