Autism in phenylketonuria (PKU)

"Autism has been reported in untreated patients with phenylketonuria."

Indeed it has, as the paper by Sameh Khemir and colleagues [1] revisits something of a long known about association whereby the archetypal inborn error of metabolism that is phenylketonuria (PKU) has been linked to the presentation of autism or autistic traits [2].

Looking at 18 participants diagnosed with PKU, Khemir et al "report their clinical, biochemical and molecular peculiarities" (authors words not mine) and how 15 of the 18 presented with autism as per assessment with "The Childhood Autism Rating Scale and the Autism Diagnostic Interview-Revised." Following some molecular biological analysis specifically with the "phenylalanine hydroxylase gene" in mind (a key player in PKU), the authors reported on various potentially important issues but "no correlation between autism and mutations affecting the phenylalanine hydroxylase gene."

I have a lot of time for PKU on this blog. Not only because PKU represents one of the best examples of how certain foods for some can affect development and onwards mental health (see here) but also because some of the other intervention options for PKU (outside of low phenyalanine diet) might hold some promise for some autism too (see here). Indeed, the idea that tetrahydrobiopterin (BH4) - an important cofactor for phenyalanine hydroxylase and related aromatic amino acid hydroxylase enzymes - might be quite good at helping to mop up excess phenylalanine and other compounds continues to find favour in some autism research circles. Dare I also mention the effects of BH4 on tryptophan and 5-HTP as potentially being relevant to some autism too? (see here)

In many parts of the world, the advent of the newborn screening program (built on the genius of people like Robert Guthrie and others) has all but eradicated untreated PKU and perhaps impacted on the number of people presenting with autism too. There remain however, challenges in certain areas of the globe, where people are not so fortunate to have such screening measures in place. Indeed, Khemir and colleagues report their results based in Tunisia and Algeria; other geographically related areas might also benefit from the implementation of such screening practices [3].    

Just before I go, there is one last comment to make on something discussed by Khemir and colleagues: "age of diet onset was the determining factor in autistic symptoms' evolution." Diet, as I've mentioned, refers to the low phenylalanine (low protein) diet commonly used to manage PKU. It appears that there might be more to see in terms of how long PKU goes untreated and the progression of autistic traits similar to other descriptions, particularly the findings reported by Baieli and colleagues [4]: "None out of 62 patients with classic PKU diagnosed early met criteria for autism. In the group of 35 patients diagnosed late, two boys (5.71%) ages 16 and 13 years fulfilled the diagnostic criteria for autism."

Diet potentially affecting the presentation of autism eh? I'll be coming to the paper by Oyarzabal and colleagues [5] soon enough built on some related research...

Music: Led Zeppelin - Rock And Roll.

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[1] Khemir S. et al. Autism in Phenylketonuria Patients: From Clinical Presentation to Molecular Defects. J Child Neurol. 2016 Jan 12. pii: 0883073815623636.

[2] Miladi N. et al. Phenylketonuria: an underlying etiology of autistic syndrome. A case report. J Child Neurol. 1992 Jan;7(1):22-3.

[3] Saad K. et al. ADHD, autism and neuroradiological complications among phenylketonuric children in Upper Egypt. Acta Neurol Belg. 2015 Dec;115(4):657-63.

[4] Baieli S. et al. Autism and phenylketonuria. J Autism Dev Disord. 2003 Apr;33(2):201-4.

[5] Oyarzabal A. et al. Mitochondrial response to the BCKDK-deficiency: Some clues to understand the positive dietary response in this form of autism. Biochim Biophys Acta. 2016 Jan 22. pii: S0925-4439(16)30003-5.

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Khemir S, Halayem S, Azzouz H, Siala H, Ferchichi M, Guedria A, Bedoui A, Abdelhak S, Messaoud T, Tebib N, Belhaj A, & Kaabachi N (2016). Autism in Phenylketonuria Patients: From Clinical Presentation to Molecular Defects. Journal of child neurology PMID: 26759449