The diagnosis of inborn errors of metabolism by examination of the genotype

Abstract

In the Croonian Lectures of 1908 [1], Archibald Garrod described the work that had led'him to conclude that alkaptonuria, albinism, pentosuria and: cystinuria were inherited conditions, that their patterns of inheritance ~,,.~:'.d be explained by Mendel's laws, that each was caused by a reduction in, or complete absence of, the activity of an enzyme that governs a single metabolic step and that these characteristics made them examples of a new classification of disease that he named the 'inborn errors of metabolism'. Garrod's hypothesis that enzyme activity, or, more generally speaking, normal protein function, is genetically determined, provided the intellectual foundation for the studies of Beadle and Tatum which, in 1941, culminated with their 'one gene one enzyme' hypothesis [2]. For example, in his review of 1945 [3] Beadle refers to Garrod's work directly when he states that his own work on tryptophan metabolism in Neurospora was '... almost exactly analogous to the classical experiments on alkaptonuria in man...'. Beadle's work, in turn, came at the beginning of, and provided the foundation for, the investigations that over the past 50 years, have been aimed at elucidating the exact nature of the biochemical processes that ,govern the relationship between the nucleic acids of genetic material and proteins, the rema~'k~ble success of which has provided results that ~tot only support the one gene one enzyme hyl~othesis, but also