The Genetics of Metabolic Disorders* D

Postgrad Med J: first published as 10.1136/pgmj.48.558.207 on 1 April 1972. Downloaded from Postgraduate Medical Journal (April 1972) 48, 207-2,11. The genetics of metabolic disorders* D. A. HOPKINSON M.A., M.D. MRC Human Biochemical Genetics Unit, Galton Laboratory, University College London THE first work on the genetics of metabolic disorders tion (Harris, 1970) more than sixty such disorders in Man was of course carried out by that great were listed and further examples are regularly being pioneer Sir Archibald Garrod at the turn of the reported. present century (Garrod, 1902). From a study of the It is interesting to note that there is no one hereditary background of a small series of patients particular aspect of metabolism which seems with a rare disorder, alcaptonuria, he discovered the peculiarly susceptible to genetic variation of this first example of recessive Mendelian inheritance in kind. Nor is there any indication that enzymes Man and with remarkable foresight he suggested catalysing particular types of reaction or utilizing that this unusual condition was an example of specialized cofactors are more prone. On the one 'chemical individuality'-an inborn alteration in the hand we have disorders like acatalasia in which metabolism of tyrosine. He also suggested that other there is a deficiency of catalase, the enzyme res- conditions such as albinism and cystinuria could be ponsible for the simple reaction splitting hydrogen manifestations of inborn changes or defects in meta- peroxide to water and oxygen, and on the other hand bolism. He called them 'freaks' or 'sports' of meta- we have the glycogen diseases in which there are bolism. This was as long ago as 1902-almost 70 deficiencies of one or other of the enzymes involved years ago. in the synthesis or degradation of the rather complex A few years later in the Croonian lectures, Garrod molecule glycogen. copyright. (1908) developed the subject further and formulated There is a great variation too in the clinical mani- a theory to account for the metabolic freaks or festations of these metabolic disorders ranging from 'inborn errors of metabolism' as he now called the severe and incapacitating mental retardation them. His idea was that in each of these conditions which may be a feature of phenylketonuria, to the there was a specific congenital enzyme defect at benign and symptomless passage of fructose in the some point in the normal metabolic chain. This urine in benign fructosuria. In other cases, like glu- deficiency could lead either to an accumulation of cose-6-phosphate dehydrogenase deficiency, the intermediary metabolites which might be toxic or metabolic disorder may come to light in the presence http://pmj.bmj.com/ to the failure of adequate synthesis of some essential of specific unusual environmental factors such as par- final product and thus in various ways result in ticular foodstuffs in the diet or perhaps drugs given pathological changes. for therapeutic purposes. Such people may lead com- Arguing from the pedigree data he put forward pletely normal lives and be untroubled and unaware the view that the congenital deficiency of a specific of their metabolic 'abnormality'. And the existence enzyme was due to the presence of an abnormal of this type of metabolic disorder is exactly in Mendelian factor or what we would now call a gene. accord with an earlier prediction of Garrod that on September 27, 2021 by guest. Protected Implicit in his argument was the idea that the normal genetically determined differences in enzyme activity gene directed the synthesis of the enzyme in the may occur without obvious symptoms and be healthy individual. Thus, well before his time, detected only by specialized techniques. Garrod formulated the now well recognized concept that genes exert their effects in an organism by directing the synthesis ofenzymes and other proteins. Genetic heterogeneity with the 'inborn errors of Garrod also predicted that in due course other metabolism' inherited metabolic disorders would be found and A point ofconsiderable interest which is beginning with a similar underlying basis. to emerge from the progressive analysis and detailed Since that time, ample evidence has accumulated characterization of the inborn errors of metabolism to support this view and numerous fresh examples of is the remarkable degree of genetic heterogeneity inborn errors have been described and the specific which appears to exist. Quite often it has been found enzyme deficiencies recognized. In a recent publica- that what appeared to be a single disease entity, with perhaps rather variable clinical manifestations, * Shortened version of a talk given at the Symposium on is in reality a number of distinct conditions, each Medical Gernetics, University of Sllssex, 26-27 March 1971. due to the deficiency of a different enzyme. This is Postgrad Med J: first published as 10.1136/pgmj.48.558.207 on 1 April 1972. Downloaded from 208 D. A. Hopkinson true for example in the group of disorders affecting dozens of different variant forms of glucose-6-phos- glycogen metabolism where there are several different phate dehydrogenase which have now been reported forms of glycogen disease due to deficiencies in one (Motulsky & Yoshida, 1969; Kirkman, 1971). Each or another of the enzymes involved in the synthesis variant may be attributed to a different mutant allele or degradation of the macromolecule glycogen. at the same structural gene locus and appears to be a The point is also illustrated by the series of con- structurally different form of the enzyme protein genital haemolytic anaemias, which are clinically with its own characteristic properties. In some cases fairly homogeneous, but are now known to be due to the variants result in chronic haemolytic anaemia, specific deficiencies of different enzymes normally which may be mild or very severe depending on the concerned with catalysing successive steps in red cell degree of enzyme deficiency. In other cases the glycolysis (Valentine, 1968, Brain, 1971). variant may appear to be quite harmless until the This is perhaps hardly surprising if one looks at affected individual comes into contact with particular the principal pathways of metabolism in red cells drugs or foodstuffs, in which event haemolysis may (Fig. 1). Glucose is the main source of energy for occur. In yet other cases the variants seem to be quite the erythrocytes and this energy is generated by innocuous. glycolysis and also in the hexose monophosphate For various reasons glucose-6-phosphate de- shunt pathway. There are no citric acid cycle enzymes hydrogenase has been studied more extensively than present in the red cell or other alternative means of any other human enzyme and it may be supposed ATP synthesis on the required scale. Similarly there that the many variants which have been described are no other effective ways of generating the reduced are somewhat exceptional. However, this does not coenzymes NADH or NADPH. Thus, a deficiency seem to be true. Many similar variants of other of virtually any one of the enzymes in the glycolytic enzymes have been discovered and glucose-6-phos- sequence or the hexose monophosphate shunt phate dehydrogenase does not appear to be a special pathway might be expected to have the same effects case. If we look again (Fig. 1) at the main metabolic -depletion of ATP and depletion of reduced pathway ofthe red cell for example we can easily find coenzyme concentrations and hence premature lysis several other good examples of multiple variants of copyright. of the red cells. In other words, the clinical signs and particular enzymes. For instance, several different symptoms of haemolytic anaemia would be expected kinds of red cell hexokinase deficiency have been and do indeed occur from deficiencies of red cell encountered in patients with congenital non- hexokinase, phosphohexose isomerase, glucose-6- spherocytic haemolytic anaemia (Necheles, Rai & phosphate dehydrogenase, pyruvate kinase and Cameron, 1970), and similar heterogeneity due to several other enzymes, due to the occurrence of multiple allelism has been encountered in phospho- mutant alleles at the various structural loci which hexose isomerase deficiency (Baughan et al., 1968; determine these particular enzymes. Paglia et al., 1969; Detter et al., 1968) and also in http://pmj.bmj.com/ In addition to this kind of genetic heterogeneity pyruvate kinase deficiency (Valentine, 1968). within the inborn errors of metabolism, that is variation at separate gene loci leading to the same or similar clinical syndromes, another type of hetero- Practical considerations geneity exists. This is allelic variation at the same The occurrence of several different mutant alleles genetic locus and this kind of heterogeneity may at a given locus, each resulting in marked deficiency well prove to be the rule rather than exception for the of the specific enzyme coded, means that certain genetically determined metabolic disorders. It ideas about the inborn errors of metabolism have to on September 27, 2021 by guest. Protected seems that very often different cases of a particular be altered. For example in the past it was generally metabolic disorder may be attributable to different assumed that individuals with such disorders show- abnormal alleles at the same gene locus, each allele ing the well known familial pattern of autosomal causing the enzyme defect in its own characteristic recessive inheritance were invariably homozygous manner. Sometimes the different patients may for a

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