Chapter 16 Inherited metabolic diseases
Introduction
Because they are individually rare, it is important for the clinician to have a high index of suspicion and actively consider the possibility that an illness may be caused by an inherited metabolic disease. Common clinical presentations of inherited metabolic diseases are indicated in Figure 16.2. Simple screening tests that should be performed when one of these conditions is suspected are discussed in Chapter 21. Most inherited metabolic diseases present in infancy and childhood (sometimes in association with specific events, e.g. weaning, puberty); their diagnosis and management is the province of paediatricians, albeit usually in close collaboration with the laboratory staff. With improving treatment, affected children with some conditions that hitherto were usually fatal in childhood are surviving into adulthood and being managed in dedicated adult metabolic clinics. Some inherited metabolic diseases usually present clinically only in adults, an important example being familial hypercholesterolaemia (see p. 248), although homozygotes for this dominantly inherited condition tend to present in their late teenage years and early twenties.
Inherited Metabolic Disorders
Galactosaemia
Three enzyme defects can cause galactosaemia, and exemplify the production of a clinical syndrome due to the accumulation of a substrate of the missing enzyme. The enzyme galactose 1-phosphate uridyl transferase is required for the conversion of galactose to glucose 1-phosphate (Fig. 16.6), thereby allowing galactose to be incorporated into glycogen, converted into glucose or to undergo glycolysis. Absence of the enzyme in classic galactosaemia results in the accumulation of galactose 1-phosphate. The clinical features of the condition are thought to be due directly to the toxicity of this metabolite. In addition, the plasma concentration of galactose is increased and galactose is excreted in the urine. Infants with galactosaemia present with failure to thrive, vomiting, hepatomegaly and jaundice. Septicaemia, particularly due to Escherichia coli, is also common. Cataracts may be present as a result of the conversion of excess galactose to galactitol in the lens. There may also be hypoglycaemia and impairment of renal tubular function. Galactose is a reducing sugar, and a positive test for urinary reducing substances in an infant presenting with such symptoms raises the possibility of galactosaemia. Galactose (and lactose, present in milk) should be withdrawn from the diet pending a definitive diagnosis, based on measurements of galactose 1-phosphate uridyl transferase in erythrocytes. The response to treatment (continued exclusion of galactose from the diet) is monitored by measuring galactose 1-phosphate in erythrocytes. A case of classic galactosaemia is presented in Case history 21.5. Deficiency of the enzyme UDP-galactose 4-epimerase causes a similar clinical syndrome, but is much less common. Deficiency of the enzyme galactokinase prevents the phosphorylation of galactose and leads to an increase in the plasma concentration of galactose and thus to galactosuria. Because galactose 1-phosphate formation is blocked, this metabolite does not accumulate and, although cataracts may occur, the other clinical features of classic galactosaemia are not seen in galactokinase deficiency.