Historical aspects of inborn errors of metabolism.

An inborn error of metabolism is a metabolic defect caused by an abnormality in one or more genes. An abnormality present at birth is not necessarily inborn: the foetus may acquire congenital disease such as syphilis or deformity through intrauterine injury. Of more direct nutritional interest are the diseases of the newborn that occur through administration of substances to the pregnant woman : malformations of infants may be caused by the antivitamin aminopterin (Warkany, Beaudry & Hornstein, 1959) or by tolbutamide given to a diabetic mother (Larrson & Sterky, I 960) ; the analogue of vitamin K, naphthaquinone, can cause hyperbilirubinaemia and even kernicterus in the newborn (Crosse, Meyer & Gerrard, 1955; Allison, 1955; Meyer & Angus, 1956). Until a century ago, physicians paid a great deal of attention to constitution in disease. From ancient times it has been known that a tendency to a certain disease is inherited since certain diseases run in families and tend to be commoner in persons of particular constitutions. The Hippocratic work, I l ~ p l XvpGv, states : ‘As to the modes of diseases, it is possible by enquiry to discover that some are inborn, others due to the country, others to the body, and some due to food and the condition of the disease or seasonal.’ It was easy to recognize that structural defects could be inherited, such as extra fingers, hare-lip or achondroplasia. Other inherited abnormalities, such as haemophilia or colour-blindness, appeared to be functional rather than structural. As knowledge advanced, the distinction between structure and function became less: albinism, at first regarded as an inherited structural abnormality of hair, became recognized as very probably caused by insufficiency of the enzyme tyrosinase. As we shall see later, this may be a structural defect at the molecular level. A remarkable book was published in 1814 (Adams, 1814) which distinguished diseases that were inherited from those that were familial but not inherited; it also distinguished between dominant and recessive inheritance, and