Impaired arachidonic (20 : 4n-6) and docosahexaenoic (22 : 6n-3) acid synthesis by phenylalanine metabolites as etiological factors in the neuropathology of phenylketonuria

The recent literature on polyunsaturated fatty acid metabolism in phenylket onuria (PKU) is critically analyzed. The data suggest that developmental im pairment of the accretion of brain arachidonic (20:4n-6) and docosahexaenoi c (22:6n-3, DHA) acids is a major etiological factor in the microcephaly an d mental retardation of uncontrolled PKU and maternal PKU. These fatty acid s appear to be synthesized by the recently elucidated carnitine-dependent, channeled, mitochondrial fatty acid desaturases for which alpha -tocopherol quinone (alpha -TQ) is an essential enzyme cofactor. alpha -TQ can be synth esized either de novo or from alpha -tocopherol. The fetus and newborn woul d primarily rely on de novo alpha -TQ synthesis for these mitochondrial des aturases because of low maternal transfer of alpha -tocopherol. Homogentisa te, a pivotal intermediate in the de novo pathway of alpha -TQ synthesis, i s synthesized by 4-hydroxyphenylpyruvate dioxygenase. The major catabolic p roducts of excess phenylalanine, viz, phenylpyruvate and phenyllactate, are proposed to inhibit alpha -TQ synthesis at the level of the dioxygenase re action by competing with its 4-hydroxyphenylpyruvate substrate, thus leadin g to a developmental impairment of 20:4n-6 and 22:6n-3 synthesis in uncontr olled PKU and fetuses of PKU mothers. The data suggest that dietary supplem entation with carnitine, 20:4n-6, and 22:6n-3 may have therapeutic value fo r PKU mothers and for PKU patients who have been shown to have a low plasma status of these essential metabolites. (C) 2001 Academic Press.