BCKDK mutations and autism continued?

February 19th 2014 (yesterday). Questioning Answers celebrates 3 years of life as a blog. Happy birthday. To quote from one website: "Congratulations, you have survived the "terrible two's!"'. Maybe I should start claiming some free early education for it too?

You are 3 @ Paul Whiteley

Anyhow...

Cast your mind back to September 2012 and the publication of a paper by Gaia Novarino and colleagues* which I posted about (see here) discussing some interesting observations with respect to a potentially treatable form of autism.

The main point of the Novarino research was how genetic mutations upset a delicate biochemical balance. Various 'inactivating' genetic mutations in respect of the BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) gene have knock-on implications for the production or rather non-production of BCKDK protein. Lower levels of this protein/enzyme left another important group of enzymes, the branched-chain keto-acid dehydrogenase complex (BCKD) to run unchecked which has implications for the metabolism and over-zealous degradation of branched-chain amino acids. The resulting lower levels of these branched-chain amino acids (BCAAs) seemed to correlate with presence of epilepsy and behavioural issues not a million miles away from those which characterise autism. Supplementation with BCAAs seemed to have a positive restorative effect on said behavioural issues. And rest.

Both then and now I consider these findings to be extremely interesting. As indicated on my post at the time, they hint at both some interesting roles for various amino acids in cases of autism (see here) and provided some exquisite evidence for the plurality of autism: the autisms (see here). That they also follow a pattern of inborn errors of metabolism being potentially linked to autism was also an important point.

Enter then another paper on BCKDK mutations by García-Cazorla and colleagues** found in two children presenting with "developmental delay, microcephaly and neurobehavioral abnormalities" also demonstrating the potential power of the BCAAs in affecting symptom presentation.

A few details about the latest study:

• It was a small study looking at two children who presented with "two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, [that] were identified at the homozygous state". Homozygous refers to the issue of genetic zygosity which, as the results go on to report, very much impacted on the function of BCKDK: "Mutation p.L389P showed total loss of kinase activity".
• Authors also confirmed how detrimental the mutations were based on analysis of "patient-derived fibroblasts" and how undetectable or barely detectable levels of BCKDK protein (the product of the BCKDK gene) resulted "in increased BCKD activity and the very rapid BCAA catabolism".
• They conclude that for one of the children who presented with undetectable levels of the BCKDK protein, use of a BCAA supplement "normalized plasma BCAA levels and improved growth, developmental and behavioral variables".

Obviously one has to be a little careful in extrapolating these results to the wider population of autism. This is a report of specific identified cases where genetic mutations of the BCKDK gene were found and the resultant biological effect of mutation confirmed. They don't imply that supplementing willy-nilly with BCAAs will impact on all cases of autism and neither am I suggesting they will. Autisms not autism...

That being said, there is another message to come from this paper on the value of keeping an open mind when it comes to look at the potential underlying genetics and biochemistry of autism. Not so long ago for example, I talked about the paper by Spilioti and colleagues (see here) on the presence of inborn errors of metabolism in their participant group diagnosed with autism. The message there was if you don't look, don't expect to find anything. Indeed, if you need some further evidence for this message I would also direct you to the work by Celestino-Soper and colleagues (see here) on another compound, carnitine, and their analysis of the gene Trimethyllysine Hydroxylase, Epsilon (TMLHE) in relation to carnitine and autism. Again, you've got to look to find or not find. And the papers keep coming***...

I'm going to keep my eye out for any further information on BCKDK mutations...

To close, no music link today but rather following some rather interesting conversations with my brood about winners and losers across the previous 6 films of the Star Wars saga, I vote for Darth Sidious as being the real winner... "unlimited power" and all that.

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* Novarino G. et al. Mutations in BCKD-kinase Lead to a Potentially Treatable Form of Autism with Epilepsy. Science. 2012; 338: 394-397.

** García-Cazorla A. et al. Two Novel Mutations in the BCKDK Gene (Branched-Chain Keto-Acid Dehydrogenase Kinase) are Responsible of a Neurobehavioral Deficit in two Pediatric Unrelated Patients. Hum Mutat. 2014 Jan 21. doi: 10.1002/humu.22513.

*** Helsmoortel C. et al. A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nature Genetics. 2014. 16 Feb.

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García-Cazorla A, Oyarzabal A, Fort J, Robles C, Castejón E, Ruiz-Sala P, Bodoy S, Merinero B, Lopez-Sala A, Dopazo J, Nunes V, Ugarte M, Artuch R, Palacín M, Rodríguez-Pombo P, & Working Group (2014). Two Novel Mutations in the BCKDK Gene (Branched-Chain Keto-Acid Dehydrogenase Kinase) are Responsible of a Neurobehavioral Deficit in two Pediatric Unrelated Patients. Human mutation PMID: 24449431