Around the turn of the century Garrard established the concept of an inborn error of metabolism using his study on alcaptonuria to exemplify his hypothesis that a considerable number of metabolic disorders with clearly defined clinical, pathologic, and biochemical abnormalities arise because an enzyme governing a single metabolic step is either reduced in activity or missing altogether. He pointed out the familial distribution of alcaptonuria and later showed that the inheritance could be explained on mendelian principles, ie, the affected individual was homozygous for the abnormal gene and that the inheritance was recessive, both parents being heterozygous for the disorder. He suggested that the accumulation of homogentisic acid in alcaptonuria was evidence that this substance is a normal metabolite in the degradation of tyrosine and attributed this accumulation to a failure of oxidation of homogentisic acid. In addition to alcaptonuria he described cystinunia, pentosuria, and albinism. This work was the forerunner of the classic studies of Beadle and Tatum on mutants of Neurospora crassa which led to the one gene-one enzyme concept. DETECTION Different groups require special attention: the family at risk because of previously affected individuals, those with unusual features suggestive of metabolic disorders, and sick newborns. Screening of normal newborns requires a different approach.