A recent study by Celestino-Soper and colleagues* (full-text) continues the interest in carnitine and autism with the suggestion that issues with a gene, trimethyllysine hydroxylase, epsilon (TMLHE) involved in the biosynthesis of carnitine, might be associated with some cases of autism.
I was drawn to this paper on several levels, not least further evidence that amino acid chemistry might show some involvement to cases of autism and the authors' suggestion of another in-born error of metabolism to be added to a growing list in general medicine. The authorship content of the current paper is a veritable who's who in autism genetic research (here and here for example) bearing in mind some overlap with the recent Nature de novo papers.
The paper is full-text but here are a few highlights:
- Based on previous findings of potential issues with TMLHE in cases of autism (here), the frequency of mutations in TMLHE was analysed in cases of autism and controls. Various sources were used to acquire participants including the Simons Simplex Collection (SSC) and the Autism Genetic Resource Exchange (AGRE) covering both simplex (one child in the family with autism) and multiplex families (more than one child diagnosed with autism).
- Deletions of exon 2 seemed to be relatively common in both autism and control groups. So of the control male participants examined, roughly 1 in 366 showed deletions of exon 2. Looking at simplex participants in the autism group, the rate was 1 in 323 presenting with a deletion. When it came to looking at multiplex families, the rate of deletions in the autism group became stronger, estimated at 1 in 130.
- Based on this cumulative data, the authors write "The frequency of TMLHE deﬁciency is startling" suggesting that this in-born error of metabolism is relatively common, approximately 20 times more frequent than phenylketonuria (PKU) in males.
- When it came to looking at the functional biological effects of exon 2 deletions, based on the activity of 6-N-trimethyllysine dioxygenase (TMLD), enzyme activity was low or undetectable for those carrying the deletion.
- Urinary and plasma analysis for related metabolites, 6-N-trimethyllysine (TML) 3-hydroxy-6-N-trimethyllysine (HTML) and 4-N-trimethylaminobutyric acid [γ-butyrobetaine (γBB)] suggested alterations in the levels detected according to the presence of TMLHE exon 2 deletions. Some of these metabolites were even suggested to have 'diagnostic potential' for TMLHE deficiency.
- Cognitive function did not seem to determine TMLHE deletions, varying widely among those with deletions.
- The authors conclude that TMLHE deficiency is likely to be a risk factor for autism although with low genetic penetrance.
As per just about every genetics paper that I have ever attempted to read, this is quite a complex story to follow if you are not a molecular biologist or at least with some detailed interest in the ways and means of genetics research. It's not quite the dark art of EEG reading, but pretty close.
The authors make some interesting remarks in the manuscript discussion relating to their findings.
First, they talk about the disparity in their results when it came to simplex and mulitplex family findings. Without making too sweeping a generalisation, the argument goes something like this: having more than one child with autism in the family is more likely to represent a stronger genetic component to aetiology as being involved than those cases of a simplex child, bearing in mind the snapshot and 'what if' scenarios of future offspring attached to looking at simplex families. I can see the logic in this argument about single and multiple instances, and how, when it comes to the eternal question of genes vs. environment as per Trading Places and the $1 bet, the heterogeneity of autism might, to some degree become more homogeneous if autism research were to start looking at simplex vs. multiplex autism rather than bundling it all together.
Second, the authors talk about whether or not the 'risk' of autism could potentially be modified by dietary carnitine intake from birth in the early years, perhaps even prenatally and during gestation when it comes to mum's diet. With some degree of caution, I find myself interested in this suggestion, particularly with all the recent interest in epigenetics and how issues like maternal diet might have the propensity to modify offspring risk for lots of different conditions not just autism. I know epigenetic modification is not a large part of the current study but still, genetics is an awfully complicated business where genes being switched on or off by means other than mutation or deletion might be pertinent.
Finally, this is probably not the last we are going to hear about this area of research by this group. Two studies are being initiated we are told, one looking at carnitine metabolites in cerebrospinal fluid (CFS) of infants with autism with or without TMLHE deficiency; a second following on from other research by Geier and colleagues** on the supplementation of L-carnitine or γBB for cases of autism again with and without TMLHE deficiency. A case of watch this space.
Regular readers to this blog will perhaps know that the genetics of autism are becoming more and more complicated as more research emerges. The concept of an 'autism gene' is becoming an ever more distant memory as a result of the cumulative findings and a realisation that autism is an extremely nebulous condition. What I do like about the current paper is that not only does it detail results based on genetic findings, but more than that, it goes through how those findings relate to biochemistry (expression of the gene) and, in this case, the possibility that there may be ways to 'rescue' some of that biological functioning. I also wonder if through epigenetic means, issues with carnitine biosynthesis might also be present in cases of autism without the underlying genetic structural issues and what those all-important modifying variables might be. All that and the need to screen cases for those ever-so important in-born errors of metabolism, I'll be keeping a look out for further results from this group.
To finish something a little less mind-boggling but nevertheless with some bite: The Clash (the law won y'know and don't they keep telling us).
* Celestino-Soper PBS. et al. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. PNAS. May 2012.
** Geier DA. et al. A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders. Medical Science Monitor. 2011; 17: 15-23