FATTY ACIDS OF THE BRAIN IN PHENYLKETONURIA *

I N T R O D U C T I O N IN THE past several years, the nature of the enzymic defect associated with phenylketonuria (PKU) has been well defined (JERVIS, 1947; UDENFRIEND and BESSMAN, 1953; WALLACE, MOLDAVE and MEISTER, 1957; MITOMA, AULD and UDENFRIEND, 1957 ; KAUFMAN, 1961). However, a direct relationship between the absence of phenylalanine hydroxylase in the liver and mental deficiency remains to be demonstrated. Hypotheses relating the biochemical defect to the disease generally invoke competitive inhibition of an enzyme system by increased concentrations of one or more metabolites of the alternative pathways of phenylalanine metabolism (KNOX, 1960; PERRY, 1962). One characteristic of PKU is the irreversibility of the mental defect when dietary therapy is instituted after infancy. These early years are a period of active myelination. The possibility that PKU involves abnormal lipid metabolism is strengthened by reports of demyelination associated with PKU (ALVORD, STEVENSON, VOGEL and ENGLE, 1950; SCHOLZ, 1957; POSER and BOGAERT, 1959; CROME, TYMMS and WOOLF, 1962). Other cogent arguments for a lipid defect in this disease have been reviewed (KNOX, 1960, 1961). From the biochemical standpoint, a lipid disorder in PKU is suggested by the following: 1. Phenylacetic acid, a metabolite of phenylalanine, is present in increased amounts in PKU serum. The activation of phenylacetic acid to phenylacetyl CoA has been demonstrated in human liver (MOLDAVE and MEISTER, 1957). More recently, acylation of ethanolamine with phenylacetic acid, presumably via the CoA derivative, has been demonstrated (COLODZIN, BACHUR, WEISSBACH and UDENFRIEND, 1963). 2. The well known oxidation of w-phenyl fatty acids (KNOOP, 1904), together with the known reversibility of /3-oxidation (LYNEN, 1955), suggests that a phenyl fatty acid derivative such as phenylacetyl CoA may be lengthened by addition of 2-carbon units. 3. Fatty acid synthesis via malonyl CoA requires an end group of acetyl CoA which can to some extent be substituted. For example, propionyl CoA results in the formation of odd-numbered fatty acids (HORNING, MARTIN, KARMEN and VAGELOS, 1961 ; BRADY, BRADLEY and TRAMS, 1960; VAGELOS et al., 1961 ; WAKIL, 1961 ; HAJRA and RADIN, 1962). Also terminal branched-chain fatty acids are formed from branchedchain precursors (LENNARZ, 1961 ; HORNING et al., 1961 ; VAGELOS et al., 1961). These observations suggested that in PKU, w-phenyl fatty acids are formed as a result of an elevated phenylacetate concentration in the body. The derived fatty acids