The genetics of metabolic disorders.

Abstract

THE first work on the genetics of metabolic disorders in Man was of course carried out by that great pioneer Sir Archibald Garrod at the turn of the present century (Garrod, 1902). From a study of the hereditary background of a small series of patients with a rare disorder, alcaptonuria, he discovered the first example of recessive Mendelian inheritance in Man and with remarkable foresight he suggested that this unusual condition was an example of 'chemical individuality'-an inborn alteration in the metabolism of tyrosine. He also suggested that other conditions such as albinism and cystinuria could be manifestations of inborn changes or defects in metabolism. He called them 'freaks' or 'sports' of metabolism. This was as long ago as 1902-almost 70 years ago. A few years later in the Croonian lectures, Garrod (1908) developed the subject further and formulated a theory to account for the metabolic freaks or 'inborn errors of metabolism' as he now called them. His idea was that in each of these conditions there was a specific congenital enzyme defect at some point in the normal metabolic chain. This deficiency could lead either to an accumulation of intermediary metabolites which might be toxic or to the failure of adequate synthesis of some essential final product and thus in various ways result in pathological changes. Arguing from the pedigree data he put forward the view that the congenital deficiency of a specific enzyme was due to the presence of an abnormal Mendelian factor or what we would now call a gene. Implicit in his argument was the idea that the normal gene directed the synthesis of the enzyme in the healthy individual. Thus, well before his time, Garrod formulated the now well recognized concept that genes exert their effects in an organism by directing the synthesis ofenzymes and other proteins. Garrod also predicted that in due course other inherited metabolic disorders would be found and with a similar underlying basis. Since that time, ample evidence has accumulated to support this view and numerous fresh examples of inborn errors have been described and the specific enzyme deficiencies recognized. In a recent publication (Harris, 1970) more than sixty such disorders were listed and further examples are regularly being reported. It is interesting to note that there is no one particular aspect of metabolism which seems peculiarly susceptible to genetic variation of this kind. Nor is there any indication that enzymes catalysing particular types of reaction or utilizing specialized cofactors are more prone. On the one hand we have disorders like acatalasia in which there is a deficiency of catalase, the enzyme responsible for the simple reaction splitting hydrogen peroxide to water and oxygen, and on the other hand we have the glycogen diseases in which there are deficiencies of one or other of the enzymes involved in the synthesis or degradation of the rather complex molecule glycogen. There is a great variation too in the clinical manifestations of these metabolic disorders ranging from the severe and incapacitating mental retardation which may be a feature of phenylketonuria, to the benign and symptomless passage of fructose in the urine in benign fructosuria. In other cases, like glucose-6-phosphate dehydrogenase deficiency, the metabolic disorder may come to light in the presence of specific unusual environmental factors such as particular foodstuffs in the diet or perhaps drugs given for therapeutic purposes. Such people may lead completely normal lives and be untroubled and unaware of their metabolic 'abnormality'. And the existence of this type of metabolic disorder is exactly in accord with an earlier prediction of Garrod that genetically determined differences in enzyme activity may occur without obvious symptoms and be detected only by specialized techniques.