Thursday 6 September 2012

BCKDK mutations: a treatable form of autism?

The Nature headline reads: Amino-acid deficiency underlies rare form of autism. My interest is piqued. The paper by Novarino and colleagues* suggests "autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome". My interest is most definitely piqued. Hence therefore this very quick post (yeah right!) on some potentially very important results.

Let's rewind a bit first. I've talked about amino acids and autism (and schizophrenia) quite a bit already on this blog as per this Godzilla post and this one on those very, very interesting aromatic amino acids. Generally speaking, issues with specific amino acids related to paediatric mental health fall into the category of an in-born error of metabolism; where phenylketonuria (PKU) represents the archetypal 'diet can affect mental health' condition. I say generally but am willing to concede if I am wrong.

Anyway, I'm still in the process of trying to get the full-text paper by Gaia Novarino et al and indeed get my head around the findings, but from what I gather this was a multi-faceted study:

  • To start with they sequenced the genomes (exome sequencing) of six children with autism from three families where mum and dad were first cousins and focused in on mutation related to the BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) gene. The gene ties into a protein which inactivates an enzyme, or complex of enzymes called branched chain ketoacid dehydrogenase (BCKDH) related to the degradation of a certain family of amino acids, called branched-chain amino acids including valine, leucine and isoleucine. Issues with the BCKDHA gene (one of the enzyme subunit genes) is linked to another inborn error of metabolism, maple syrup urine disease, so named because of the distinctive smell of the urine of those with the condition as a result of the build up of these branched-chain amino acids.
  • Anyway, these amino acids are essential in that they cannot be synthesised endogenously so must be derived from food or other nutrient sources. The suggestion being that with BCKDH running unchecked as a result of issues with BCKDK, functional levels of these branched chain amino acids are also going to be reduced.
  • Sure enough those participants who presented homozygously (see zygosity) with the BCKDK mutation/s showed "reductions in BCKDK mRNA and protein, E1-α phosphorylation, and plasma branched chain amino acids".
  • Next, the authors working with an engineered strain of mouse with the same issue with the BCKDK gene (knockout mice) reported that the mice showed certain traits similar to those noted in the human participants with regards to seizures and importantly also showed low levels of the branched-chain amino acids.
  • A diet enriched with said amino acids seemed to 'abate' some of these symptoms in the mice; or as the authors put it they "respond to dietary supplementation". Ipso facto, autism and epilepsy associated with issues with BCKDK might also be treatable by such amino acid supplementation.

I don't claim to have provided a definitive overview of the findings here but I think this is pretty close to what has been reported. In essence the checks and balances which are supposed to keep the levels of these branched-chain amino acids within tolerance are disrupted, but rather than the maple syrup urine disease scenario, lower levels of these essential amino acids seem also to have some potential effect.

There are bound to be quite a few discussions about this new research and its implications as it filters through both the scientific and lay community. I would stress that at the current time, I advocate nothing based on these results until the appropriate safety and efficacy studies are undertaken on the appropriate group.

If anything however, this study reiterates a few things: (i) autisms is probably a better description than autism, and (ii) don't underestimate the power of the amino acids.



Novarino G. et al. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science. September 2012.

---------- Gaia Novarino,Paul El-Fishawy, Hulya Kayserili, Nagwa A. Meguid, Eric M. Scott, Jana Schroth1, Jennifer L. Silhavy1, Majdi Kara, Rehab O. Khalil, Tawfeg Ben-Omran, A. Gulhan Ercan-Sencicek, Adel F. Hashish, Stephan J. Sanders, Abha R. Gupta, Hebatalla S Hashem, Dietrich Matern, Stacey Gabriel, Larry Sweetman, Yasmeen Rahimi, Robert A. Harris, Matthew W. State, & Joseph G. Gleeson (2012). Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy Science : 10.1126/science.1224631


  1. I am doing my senior thesis over this topic and emailed Dr. Novarino at her work email and she emailed me the full paper + supplements.

  2. Many thanks for dropping by Katheryne.

    If you publish some of your work in this area, please do let me know.


Note: only a member of this blog may post a comment.