Wednesday, 20 July 2011

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.