PKU children who are compliant with the recommended low protein diet are devoid of natural dietary sources of n-3 LCPUFA, as LCPUFA rich foods also contain high amounts of protein. Accordingly, blood concentrations of n-3 LCPUFA and especially of docosahexaenoic acid (DHA) are reduced in plasma and red blood cell phospholipids of PKU children relative to omnivorous children [
10‐
12] with a more marked relative depletion of DHA than arachidonic acid, the major n-6 LCPUFA, throughout childhood. LCPUFA with 20 and 22 carbon atoms are metabolically derived from α-linolenic acid (ALA) and linoleic acid (LA) by consecutive enzymatic desaturation and chain elongation. Although LCPUFA including DHA (22:6n-3) and AA (20:4n-6) can be synthesized from ALA and LA in mammals, respectively, the activity of conversion is low in humans particularly for the synthesis of DHA, which is formed through a far more complex and indirect metabolic pathway than AA [
13]. Blood levels of AA are influenced by polymorphisms of the fatty acid desaturase genes to a far greater degree than DHA levels (around 28-30% vs 2-3%) [
14], which also points towards a low contribution of endogenous n-3 conversion to DHA and the importance of a preformed dietary intake of DHA. There is increasing awareness of the importance of DHA for optimal neurological function in humans. DHA status during prenatal and postnatal development has been linked to benefits for child outcomes in several studies [
15]. In particular the striking variations that have been found in the DHA content of prefrontal brain cortex in breastfed compared with formula-fed infants provide convincing evidence of the effects of a dietary supply of LCPUFA on the structure of the brain [
16]. The extremely low dietary DHA intake in PKU children, with resulting low blood and presumably tissue DHA contents, may have adverse consequences for central nervous function, which might contribute to learning difficulties, behavioral abnormalities and visual problems found in PKU patients [
17‐
19]. Early dietary treatment of PKU prevents severe neurological damage and generally leads to normal cognitive development, but subtle neurological deficits persist [
5]. Poorer school performance of PKU children was reported, with significantly lower academic performance, initiative and progress than in age matched omnivorous children [
6]. These subtle functional deficits in early and well treated individuals with PKU are not explained by variations in plasma Phe levels, and it is plausible that a low DHA supply induced by the extremely restricted diet contributes to neurological abnormalities.