A chemical investigation of the defects of myelination in phenylketonuria.

The relationship between the metabolic abnormality and the mental deficiency characteristic of phenylketonuria has been the subject of speculation and experiment since the condition was first discovered. An 'intoxication' has been postulated (Woolf and Vulliamy, 1951) and it has been shown that the functioning of a number of different enzymes present in the brain is affected. However, at least in some cases, the actual morphology of the brain appears to be altered and the occurrence of these neural lesions must be fitted into the overall picture. The suggestion that the mental and neurological effects of phenylketonuria were due to intoxication by phenylalanine or its metabolites appears to have been confirmed by the success of a diet low in phenylalanine in preventing or ameliorating, in some cases, the mental deficiency and neurological abnormalities (Woolf and Vulliamy, 1951; Bickel, Gerrard, and Hickmans, 1953; Woolf, Griffiths, and Moncrieff, 1955; Armstrong and Tyler, 1955; Blainey and Gulliford, 1956; Homer and Streamer, 1956; Low, Bosma, and Armstrong, 1957; Woolf, Griffiths, Moncrieff, Coates, and Dillistone, 1958; Brimblecombe, Stoneman, and Maliphant, 1959; Murphy, 1959). The concentrations in the blood of noradrenaline and 5-hydroxytryptamine are reduced in phenylketonuria (Weil-Malherbe, 1955; Pare, Sandler, and Stacey, 1957, 1959). The enzymes DOPA-decarboxylase, 5-hydroxytryptophan decarboxylase, and glutamic acid decarboxylase are partly inhibited by some of the abnormal metabolites of phenylalanine present in phenylketonurics, and it has been suggested that the mental abnormalities are due to the consequent partial inhibition of synaptic transmission (Fellman, 1956; Davison and Sandler, 1958; Sandler, Davies, and Rimington, 1959; Hanson, 1959; Tashian, 1961). The question of the occurrence of neural lesions in the brains of phenylketonurics is particularly important. Not only might such lesions help to explain the main clinical features of the condition, but their absence or presence in a particular case