It is now only four decades since Folling’s original description of the condition he termed Imbecillitas phenylpyrouvica,(1) or phenylpyruvic oligophrenia, which was the first clear association of an inherited disorder of amino acid metabolism with brain dysfunction. The precise identification by Jervis of the enzymatic etiology, the deficiency of Phenylalanine 4-hydroxylase (EC 1.14.16.1),(2,3)1 waited two decades. In the subsequent two decades a large number of inherited disorders have been described, and in many cases the enzymatic etiology has been defined. So far, all of these disorders have involved defects in the pathways of degradation or in the conversion of one amino acid to another. In many, but not in all, the deficient enzyme is extracerebral—at least there has been no definite evidence of an intracerebral enzymatic defect. In parallel with this recent explosion of information on genetic etiology, there has been an explosion of information in neurobiology. However, information relating these two areas—i.e., how the enzymatic deficiency results in the brain disease—has not been clear-cut. Indeed, in no instance are we able to relate clearly the inherited enzymatic defect with the neurological deficit.