Methyl B12 for autism? Placebo-controlled results say maybe...

"Methyl B12 treatment improved clinician-rated symptoms of ASD [autism spectrum disorder] that were correlated with improvements in measures of methionine metabolism and cellular methylation capacity."

Those were the very encouraging results published by Robert Hendren and colleagues [1] who can now update their ClinicalTrials.gov study entry (see here). Building on the ideas that: "Children with autism spectrum disorder (ASD) have been reported to have reduced ability to methylate DNA and elevated markers of oxidative stress" (topics that have been covered on this blog before), researchers undertook a gold-standard trial - randomised, placebo-controlled - to ascertain the effect (if any) of "8 weeks of treatment with methyl B12 (75 μg/kg) or saline placebo every 3 days in a subcutaneous injection." The success of the treatment was measured by "the Clinical Global Impressions-Improvement (CGI-I) score" accompanied by "changes in the Aberrant Behavior Checklist (ABC) and the Social Responsiveness Scale (SRS)" scores. At the same time, researchers also looked at various biochemical parameters pertinent to "methionine methylation and antioxidant glutathione metabolism."

Based on the 50 children ("mean age 5.3 years") who completed the study, researchers reported a trend of improvement in autistic and related behaviours following the methyl B12 injections. Importantly, the primary outcome measure - the CGI-I scores - rated by clinicians, showed a trend of being "statistically significantly better (lower) in the methyl B12 group (2.4) than in the placebo group (3.1) (0.7 greater improvement in the methyl B12 group, 95% CI 1.2-0.2, p = 0.005)." Biological parameters also showed changes: "increases in plasma methionine (p = 0.05), decreases in S-adenosyl-l-homocysteine (SAH) (p = 0.007) and improvements in the ratio of S-adenosylmethionine (SAM) to SAH (p = 0.007), indicating an improvement in cellular methylation capacity" following the use of methyl B12 compared with placebo.

Accepting that 'subcutaneous injection' of methyl B12 is hardly a 'user-friendly' option and may very well scupper plans to use this particular intervention option for quite a few, these are potentially important results. I'm really quite interested in how vitamin B12 'vitamers' might show some links to at least some 'types' of autism (see here) including the measurement of 'brain levels' of the stuff (see here). The Hendren results suggest that quite a few more research resources might be needed in this area. I wonder also if this future research agenda would include the 'baby and bathwater' compound that is methylmalonic acid in relation to autism too (see here)?

I do also have to point out that previous research from members of this research team has not been so complimentary about the use of methyl B12 in cases of autism [2] despite the idea that there may be 'responders' to this type of intervention. To quote: "methyl B12 may alleviate symptoms of autism in a subgroup of children, possibly by reducing oxidative stress. An increase in glutathione redox status (GSH/GSSG) may provide a biomarker for treatment response to methyl B12." Such differences in reported results are not unfamiliar to autism research (the rule rather than the exception) but perhaps provides a further focus for clarification of effect.

----------

[1] Hendren RL. et al. Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism. J Child Adolesc Psychopharmacol. 2016 Feb 18.

[2] Bertoglio K. et al. Pilot study of the effect of methyl B12 treatment on behavioral and biomarker measures in children with autism. J Altern Complement Med. 2010 May;16(5):555-60.

----------

Hendren RL, James SJ, Widjaja F, Lawton B, Rosenblatt A, & Bent S (2016). Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism. Journal of child and adolescent psychopharmacology PMID: 26889605

Maternal folate status and offspring autism risk: where are we up to?

I'd like to briefly draw your attention to the review published by Elizabeth DeVilbiss and colleagues [1] today, covering "what is known about the role of folate in the aetiology of neurodevelopmental disorders."

Folate, is a topic that has graced this blog a few times with autism in mind (see here for example) based on various ideas that folate status during pregnancy might have the ability to modify offspring risk of autism [2] alongside the idea that autoimmune processes might act on folate receptors in some cases of autism (see here) and what this might subsequently mean for pathology / management. The specific idea that folate levels and folate supplementation during pregnancy might influence autism risk has garnered the most research attention, seemingly also crossing geographies too [3].

The DeVilbiss review is quite comprehensive in its scope and material covered, summarising "relevant biological, genetic and epigenetic mechanisms" and the various science that has been done so far on this topic. I would certainly agree with their sentiments that "existing evidence is inconclusive" (as previously indicated) in light of the numerous confounding variables also potentially linked to offspring autism risk. That being said, and acknowledging where folate metabolism sits in terms of areas such as MTHFR genetics (see here) and the whole vitamin B12 story (see here) and perhaps beyond (see here), I do think there is more to see in this area and perhaps outside of autism and related neurodevelopmental conditions (see here). Without jumping on the whole epigenetics bandwagon, the link between the folate cycle and DNA methylation in particular (see here) offers a whole slew of research ideas ripe for further investigation.

Music: Lost Frequencies - Are You With Me.

----------

[1] DeVilbiss EA. et al. Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence. Br J Nutr. 2015 Aug 5:1-10.

[2] Schmidt RJ. et al. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. Am J Clin Nutr. 2012 Jul;96(1):80-9.

[3] Surén P. et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 2013 Feb 13;309(6):570-7.

----------

DeVilbiss EA, Gardner RM, Newschaffer CJ, & Lee BK (2015). Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence. The British journal of nutrition, 1-10 PMID: 26243379

Homocysteine and autism: yet more...

It's been a while since I've discussed the issue of homocysteine - that's homocysteine not homocystine - with autism in mind, so consider this short blog entry a bit of an update to previous discussions (see here and see here).

In case you need to know it, homocysteine is an important component of the trans-sulfuration pathway intersecting with both the methione cycle and the folate cycle. Collectively, these biological processes have important functions for various aspects of biology including the process of methylation and the issue of oxidative stress leading into the important role of glutathione (see here) for example.

I was brought to this post following the publication of two recent paper from Carmen Puig-Alcaraz and colleagues [1] and from Yu Han and colleagues [2] that both reported on elevated levels of homocysteine to be present in their cohorts of children diagnosed with an autism spectrum disorder (ASD) compared with asymptomatic controls. These findings are pretty much in line with what most other research has reported in this area.

Puig-Alcaraz et al reported that alongside an overall increased level of urinary homocysteine in their cohort, there seemed to be something of a relationship between elevated urinary homocysteine with "the severity of the deficit in communication skills" in their participant group. Something that was not seen when looking at the other core areas of autism (social interaction and repetitive/restricted behaviour). I'm intrigued at the prospect that specific traits may be linked to something like elevated levels of homocysteine although recognise the need for far greater scrutiny of this finding with larger cohorts. That this group only measured homocysteine in urine is another issue that needs to be further explored.

Han et al report results based on Chinese children. This in itself is an important cohort suggesting that issues with homocysteine might cross geography and ethnicity when it comes to autism on the basis of other studies looking at different populations. Alongside reporting on elevations in homocysteine, researchers also noted that total levels of glutathione and cysteine were lower in the autism group; findings that accord with meta-analyses of glutathione and related compounds with autism in mind (see here). Further: "Hcy [homocysteine] levels correlated significantly with increasing CARS [Childhood Autism Rating Scale] scores and GSSG [oxidized glutathione] levels in children with ASD" with the proviso that further investigations are needed in this area.

The peer-reviewed evidence is indeed stacking up for something potentially fundamental at work when it comes to autism and homocysteine. At this stage it would be difficult to tease apart homocysteine alone as being 'linked' to [some] autism given the myriad of other compounds/pathways also potentially implicated as per the literature on the B vitamins and their important links to homocysteine. I'm also wondering whether another relation of one of the B vitamins, methylmalonic acid, that has languished in the autism science desert for far too long might also need resurrecting in future studies on the 'big H' and autism?

And yes, screening is important [3]...

----------

[1] Puig-Alcaraz C. et al. Increased homocysteine levels correlate with the communication deficit in children with autism spectrum disorder. Psychiatry Res. 2015 May 29. pii: S0165-1781(15)00290-5.

[2] Han Y. et al. Abnormal transsulfuration metabolism and reduced antioxidant capacity in Chinese children with autism spectrum disorders. International Journal of Developmental Neuroscience. 2015. July 3.

[3] Ranjan S. & Nasser JA. Nutritional Status of Individuals with Autism Spectrum Disorders: Do We Know Enough? Adv Nutr. 2015 Jul 15;6(4):397-407.

----------

Puig-Alcaraz C, Fuentes-Albero M, Calderón J, Garrote D, & Cauli O (2015). Increased homocysteine levels correlate with the communication deficit in children with autism spectrum disorder. Psychiatry research PMID: 26070768





Han, Y., Xi, Q., Dai, W., Yang, S., Gao, L., Su, Y., & Zhang, X. (2015). Abnormal transsulfuration metabolism and reduced antioxidant capacity in Chinese children with autism spectrum disorders International Journal of Developmental Neuroscience DOI: 10.1016/j.ijdevneu.2015.06.006

Vitamin B12 and autism: more to do

The short report by Malhotra and colleagues* linking a case of the regressive condition childhood disintegrative disorder, CDD (otherwise known as Heller's syndrome) with vitamin B12 deficiency and hyperhomocysteinemia has grabbed my attention.

Malhotra et al report that following the identification of said nutritional issues, supplementation with vitamin B12 and a few other nutrients, seemed to correlate with some improvements in the 14 year old at the centre of this paper, according to parental reports. The authors suggest: "A case is made for vitamin B12 deficiency syndrome presenting as CDD".

Methyl Curt Cobain... er, cobalamin @ Wikipedia  

Bearing in mind the overlap between CDD with autism or autistic-like behaviours, and that the Malhotra paper was a case report (good news when it comes to the autism and n=1 philosophy), one has to caution against making any sweeping generalisations to the autisms as a whole. That being said and bearing in mind others have talked about developmental regression** being linked to hypocobalaminemia, it did make me take a look at some of the other scientific literature on any link between vitamin B12 and autism.

I have actually talked about vitamin B12 before on this blog. A few times in fact; ranging from vitamin B12 optic neuropathy presenting in cases of autism (see here and the paper is here), to vitamin B12 deficiency being picked up in cases of autism (see here), to the very much under-investigated issue of methylmalonic acid (MMA) alongside cases of autism (see here). Slightly outside of autism research, vitamin B12 has also been discussed with thin-fat bodies in mind (see here) and its relationship with the epigenome.

Given also the connection between vitamin B12 and that other B-vitamin of the moment with autism in mind, folic acid, this post turns out to be quite timely.

Whilst there is not a great expanse of literature on the topic of vitamin B12 and autism, there are a few other points worth noting:

• Not all vitamin B12 is equal (or some are more equal than others, to coin a phrase). As with the example of folic acid, vitamin B12 can appear in more than one form (the so-called vitamers) seemingly also related to how we ingest/supplement with the stuff and what form our body actually use.
• Methyl B12 (methylcobalamin) has been looked at as a possible intervention for cases of autism as per the study by Bertoglio and colleagues***. The results on that occasion were not exactly universally successful in terms of behavioural outcomes, although there was the suggestion of a sub-group of possible responders to this intervention. Indeed based on an abstract presented at IMFAR 2012, it appears that responders might be linked to another favourite topic of this blog, glutathione (see here).
• The combinatorial use of methylcobalamin and another compound of interest, folinic acid (see this post) has also been the topic of some investigation with autism in mind as reported by Jill James and colleagues**** (open-access). The intervention appeared to affect several important biochemical parameters but some unanswered questions on clinical outcome remained.
• Although seemingly unrelated to vitamin B12, I was alerted to a recent study by Parks and colleagues***** on how specific strains of bacteria have the ability to turn inorganic mercury into methylmercury. Whilst this biochemical process may not initially seem particularly exciting or relevant to this post, when you conisder the role of cobalmin (vitamin B12) in this process (as per the result reported by Choi and Bartha****** for example and the action of being a methyl donor), one becomes slightly more interested in light of reports of elevated heavy metals being present in cases of autism and of course all that gut bacteria work being undertaken. I'm not making too much of this research at the moment despite it being mentioned by others, aside from illustrating how even vitamins are pharmaceutics and their use should be treated as such.

Accepting again that the literature on vitamin B12 and autism is not exactly voluminous, there are some interesting strands of research which potentially connect the two things together requiring much greater study. Outside of the autism connection (or not), vitamin B12 has some interesting links with other things such as propionic acid for example (itself covered in separate posts on this blog, see here and here) which might also be a source of discussion.

One of the main drawbacks of supplementing with vitamin B12 (or specifically methyl B12) where indicated is the requirement for delivery by subcutaneous injection. This might be OK if you are used to repeated injections such as those required for type 1 diabetes for example, but probably a little more invasive if you're not used to having them, given also that children with autism in particular might not be too taken with visiting the doctor or indeed other healthcare professionals such as the dentist.

Without making any recommendations or anything like that, one would assume that some kind of reformulation might be possible to 'rebrand' methly B12 to make it more palatable, either based on a cream, even something like a microneedle preparation or some other transdermal delivery system******* as per other recent news in an unrelated area.

The emphasis however has to be on the requirement for further research in this area and an extension of the notion that a diagnosis of autism or conditions which manifest as autistic symptoms, are seemingly protective of nothing when it comes to other conditions or physiological states including the presence of things like vitamin B12 deficiency.

A song to finish. Sunday Bloody Sunday by U2.

----------

* Malhotra S. et al. Brief report: Childhood disintegrative disorder as a likely manifestation of vitamin B12 deficiency. J Autism Dev Disord. January 2013.

** Dror DK. & Allen LH. Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev. 2008; 66: 250-255.

*** Bertoglio K. et al. Pilot study of the effect of methyl B12 treatment on behavioral and biomarker measures in children with autism. J Altern Complement Med. 2010; 16: 555-560.

**** James SJ. et al. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. Am J Clin Nutr. 2009; 89: 425-430.

***** Parks JM. et al. The genetic basis for bacterial mercury methylation. Science. January 2013.

****** Choi S-C. & Bartha R. Cobalamin-mediated mercury methylation by
Desulfovibrio desulfuricans LS. Appl Environ Microbiol. 1993; 59: 290-295.

******* Madhaiyan K. et al. Vitamin B(12) loaded polycaprolactone nanofibers: A novel transdermal route for the water soluble energy supplement delivery. Int J Pharm. January 2013.

----------

Malhotra S, Subodh BN, Parakh P, & Lahariya S (2013). Brief Report: Childhood Disintegrative Disorder as a Likely Manifestation of Vitamin B12 Deficiency. Journal of autism and developmental disorders PMID: 23334842

Methylmalonic acid and autism: baby and bathwater?

To 'throw the baby out with the bathwater' is perhaps one of more common mistakes we humans tend to make, alongside our tendency to generalise. The theory goes something like this: concept/product/idea X is put forward. It contains more than one element. One of the elements is found to be potentially wrong or show some error. Ergo, all of concept/product/idea X is wrong.

You can see such an idea at work nearly every day. Your TV stops working just after the warranty expires - your response: 'I'm never going to buy that brand of TV set again'. It couldn't just be that yours is [individually] a dodgy TV set? No, of course not; it has to be the whole brand at fault. Without wishing to get all political and certainly without offering any opinion, take also the recent Climategate arguments and the University of East Anglia and how this was used to in certain circles. Baby and bathwater.

In the post titled: should I mention gastrointestinal symptoms in autism? I talked briefly about co-morbid inflammatory bowel disease and autism, and the fact that such findings in some cases of autism have been reported by more than one team. The controversy around one paper, the original paper, has however raised debates after debates which have far extended beyond that one paper to have more wide-reaching effects on how we view autism and its various gastrointestinal (GI) co-morbidities - indeed how we manage (or don't) such co-morbidity when present. Baby and bathwater?

I have picked on the GI area because alongside the original (now retracted) bowel findings presented in the 1998 Lancet paper, there was another potentially important area of research: methylmalonic acid [and vitamin B12 (cobalamin)] which seems to have joined sulphate in its path towards autism research oblivion as a result of the various debates on the bowel findings and their suggested implications. A sort of death by association?

Methylmalonic acid (MMA) is quite an interesting compound. I am not for one minute suggesting that I am an expert on MMA, certainly nowhere near as in the same league as these chaps. Indeed Messers Bhatt and Linnell have quite an extensive history when it comes to MMA and vitamin B12, publishing in some pretty decent journals. I had the good fortune to meet with John Linnell many, many years ago and talk to him about some of his work at the vitamin B12 unit at the Chelsea & Westminster Hospital after its closure. He was a very nice chap and knew what he was talking about when it came to B12 and MMA.

Methylmalonic acidemia  is another example of an inborn error of metabolism (alongside things like PKU). There is quite a good technical overview of the various possible reasons for the condition and the various phenotypes here. The basic effect of this condition is an increase in the levels of MMA in various biological fluids. Treatment is, depending on disease type, via dietary management, vitamin B12 injections and interestingly related to my previous post, supplementation with carnitine. In much the same way as with the management of PKU, a few adjustments can make a world of difference. Vitamin B12 (as methylcobalamin) has also received some interest in autism previously albeit not entirely efficaciously.

The retracted 1998 Lancet paper carries the only peer-reviewed published reference to the measurement of MMA in autism that I have found in the research literature; where all of the children included for study who were tested (n=8) showed elevated levels of urinary MMA against age-matched controls. Similar elevations of MMA have been reported in other conditions including schizophrenia. In amongst the various commentaries, one letter (from Ray Bhatt) questioned several aspects of the MMA findings in relation to autism, and certainly reading the detailed description of methylmalonic acidemia, some of them seem valid.

I would perhaps argue that MMA and cobalamin metabolism in general is still an unexplored avenue in relation to autism spectrum conditions. Knowing that our old friend homocysteine might show some link to at least some cases of autism, and the relationship between MMA and homocysteine, there is perhaps something that could be learned from a little more inquiry and a little less baby and bathwater.