Introduction

Many inherited diseases are known to be due to the genetically determined absence or modification of specific proteins. For example, in sickle cell anaemia, the protein is haemoglobin; in agammaglobulinaemia, antibody production is defective. However, in the majority of such diseases, the protein in question is an enzyme, and the effect is to cause a metabolic disorder. Other inherited metabolic diseases may be due to defective receptor synthesis (e.g. familial hypercholesterolaemia, which affects the receptor for low density lipoprotein) or to defects involving carrier proteins (e.g. cystinuria, in which renal tubular reabsorption of cystine is impaired). Whatever the cause, the clinical features of inherited metabolic diseases stem directly from the metabolic abnormalities to which they give rise. Although individually these conditions are rare (Fig. 16.1), they are of considerable significance; the consequences of many of them are potentially severe, but may, in some cases, be ameliorated if an early diagnosis is made and the appropriate treatment instituted.

Figure 16.1 Approximate incidences of some inherited metabolic diseases. Note that there is considerable variation in the incidence of these conditions in different countries and in different ethnic groups.

In recent years, application of the techniques of molecular genetic analysis has massively increased our understanding of these conditions. Whereas it used to be thought that each condition was the result of a single mutation, it is now clear that many inherited metabolic diseases can arise because of one of a number of genetic defects. Furthermore, it is clear that the concept of ‘one gene, one enzyme’ is no longer generally applicable. Although many inherited metabolic diseases (e.g. phenylketonuria) are a consequence of a mutation in a single gene affecting the synthesis of one enzyme, there are many exceptions. For example, one polypeptide chain can occur in more than one enzyme: an example is the β-subunit of hexosaminidase A (one α-, one β-chain) and B (two β-chains), deficiency of which causes Sandhoff disease, one of the gangliosidoses; inherited deficiency of the α-chain affects only hexosaminidase A, and causes a related but distinct disorder, Tay–Sachs disease. Or the active form of an enzyme may consist of subunits coded by different genes, an example being propionyl CoA carboxylase: mutations in either gene can lead to deficiency of the enzyme, causing propionic acidaemia. Another variant is that one polypeptide chain may have more than one enzyme activity, as is the case with two enzymes involved in pyrimidine metabolism, orotate phosphoribosyltransferase and orotidine 5′-monophosphate decarboxylase, deficiency of which causes orotic aciduria.

Most inherited metabolic diseases show autosomal recessive inheritance; heterozygotes are usually phenotypically normal although they are carriers of the condition. Familial hypercholesterolaemia and most of the porphyrias are important exceptions, being inherited as autosomal dominant conditions.

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.

Figure 16.2 Common clinical features of inherited metabolic diseases presenting in childhood. Features may be provoked by a specific stimulus, for example feeding or a lack of feeding.

The techniques of molecular genetic analysis are now also being increasingly used in the screening and diagnosis of inherited metabolic diseases (although with genetically heterogeneous diseases, phenotypic diagnosis may still be more reliable). These techniques, for example mutational analysis using the polymerase chain reaction, and the detection of restriction fragment length polymorphisms, are discussed in detail in textbooks of basic biochemistry and molecular biology, and are not discussed further here.

In a book of this size, it is only possible to discuss a selection of the many hundreds of inherited metabolic diseases that have been described. The ones that have been chosen are either among the more common, or illustrate important general principles with regard to presentation, diagnosis and management, or both. Many others are discussed in other chapters of this book (Fig. 16.3).

Figure 16.3 Inherited metabolic diseases that are discussed in other chapters of this book.

Effects of enzyme defects

Figure 16.4A shows a hypothetical metabolic pathway involving the synthesis of product D from substrate A by successive, enzyme-catalysed reactions through intermediates B and C. If the formation of B from A, catalysed by enzyme a, is rate limiting, as the first step unique to a metabolic pathway frequently is, then the concentrations of intermediates B and C will normally be low. The formation of product E from C, catalysed by enzyme c′, is normally a minor pathway, only a small amount of E being formed.

Figure 16.4 Effects of enzyme defects. (A) Product D is synthesized from A by a series of reactions catalysed by enzymes a, b and c. Enzyme c′ catalyses the formation of a small amount of product E in a minor pathway. (B) In the absence of the enzyme c, no D is synthesized. (C) If the conversion of C to D is blocked, the concentration of the intermediate C, and possibly other precursors, may increase. (D) Increased formation of E may occur if the concentration of C increases and conversion of C to D is blocked.

Three distinct sequelae of a lack of enzyme can be envisaged; these could occur alone or in combination.

Decreased formation of the product

Decreased formation of the product of a reaction is the most obvious consequence of a lack of enzyme c (see Fig. 16.4B). If enzyme c is defective, D cannot be synthesized or may only be synthesized in small amounts. Clinical features will arise if product D has an essential function and there is no alternative pathway for its synthesis.

Accumulation of the substrate

Accumulation of the substrate (C) of the missing enzyme would also be expected (see Fig. 16.4C). If this is biologically active, clinical manifestations will result. Other, earlier substrates may also accumulate if the reactions prior to the one blocked are reversible. This will occur particularly if there is negative feedback by the product on an early reaction in the pathway because, with decreased formation of the product, feedback will be lost, thus reversing the inhibition and stimulating the formation of the intermediate substrates.

Increased formation of other metabolites

Increased formation of E, the product of a minor pathway, may occur if the concentration of C is increased as a result of the enzyme deficiency, the reaction being promoted by a mass action effect (see Fig. 16.4D). If product E is biologically active, a clinical syndrome will result.

Inherited Metabolic Disorders

Glucose 6-phosphatase deficiency

Glucose 6-phosphatase deficiency (glycogen storage disease type IA) exemplifies the development of a clinical syndrome due to lack of formation of the product of an enzyme-catalysed reaction. Glucose synthesis from glycogen or by gluconeogenesis is blocked (Fig. 16.5). Children with this disorder are prone to severe fasting hypoglycaemia, because their only source of glucose is dietary carbohydrate and the small amounts of glucose that can be liberated from glycogen by debranching enzyme.

Figure 16.5 Glucose production by glycogenolysis and gluconeogenesis. Glucose 6-phosphate is an essential intermediate in the production of glucose by either glycogenolysis or gluconeogenesis. In the absence of glucose 6-phosphatase, glucose cannot be formed from glucose 6-phosphate.

Acute hypoglycaemia is treated with intravenous glucose infusion. Maintenance treatment is with frequent daytime feeding and overnight constant intragastric infusion with a glucose/glucose polymer feed. Older children are given uncooked corn starch, from which glucose is released only slowly in the gut.

Glucose 6-phosphatase deficiency also exemplifies the consequences of accumulation of a precursor other than the immediate substrate of the defective enzyme. Glycogen accumulates in the liver, causing hepatomegaly. The block in gluconeogenesis results in an accumulation of lactate, and lactic acidosis is a common finding. Hyperlipidaemia results from increased fat synthesis, and hyperuricaemia is also frequently present. Accumulation of glycogen in platelets leads to disordered platelet function and a bleeding tendency. Due to the enzyme block, neither glucagon nor adrenaline (epinephrine) increases the blood glucose in glucose 6-phosphatase deficiency, but the definitive diagnosis is made by demonstrating lack of enzyme activity in a sample of liver obtained by biopsy. In glycogen storage disease types IB and IC, similar clinical and metabolic abnormalities occur (with an additional impairment of immune function) as a result of defects in the translocases involved in the transport of glucose 1-phosphate (type IB) and phosphate (IC) in the endoplasmic reticulum.

Nine other glycogen storage diseases (GSDs) are known, each due to the deficiency of an enzyme related to glycogen metabolism and, with one exception, leading to glycogen accumulation; glycogen synthase deficiency (GSD type 0) does not result in excessive glycogen accumulation but is included in the classification.

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.

Figure 16.6 Metabolic pathway for the conversion of galactose to glucose. UDP, uridine diphosphate.

Phenylketonuria

Phenylketonuria (PKU) is another condition in which the accumulation of the substrate of the missing enzyme gives rise to a clinical syndrome. The enzyme concerned is phenylalanine hydroxylase, which hydroxylates phenylalanine to form tyrosine (Fig. 16.7).

Figure 16.7 Metabolic pathway for the conversion of phenylalanine to tyrosine. The site of action of phenylalanine hydroxylase, the enzyme deficient in phenylketonuria (PKU), is shown.

Phenylalanine accumulates in the blood and if the condition is untreated it results in severe learning difficulties, thought to be due directly to the effect of excess phenylalanine on the developing brain. The name of the condition derives from the urinary excretion of phenylpyruvic acid, a phenylketone. This is normally a minor metabolite of phenylalanine but is produced in excess when the major metabolic pathway is blocked. Many children with PKU have fair hair and blue eyes, owing to defective melanin synthesis: tyrosine, the formation of which is blocked, is a precursor of this pigment. The diagnosis depends on the demonstration of an abnormally high concentration of phenylalanine in the blood: neonatal screening for the condition is discussed below.

The management involves restricting the dietary intake of phenylalanine using diets based on special proteins and pure amino acids. The plasma concentration of phenylalanine should be maintained between 120 and 360 µmol/L during infancy and childhood, when there is rapid brain development. The diet is unpalatable, and compliance can be a major problem. Although there has been a tendency to allow less rigorous dietary restriction after the age of ten, most paediatricians now advocate a policy of ‘diet for life’. Strict dietary control is essential when a woman with PKU becomes pregnant, as maternal hyperphenylalaninaemia has been shown to affect the fetus in utero even if the fetus itself does not have PKU.

As phenylalanine is an essential amino acid, a certain amount must be provided in the diet, and while tyrosine is not normally an essential amino acid, it becomes so when the intake of phenylalanine is limited: adequate quantities must therefore be provided. Dietary treatment is monitored by measuring both phenylalanine and tyrosine concentrations in finger-prick blood spot samples. Thus treated, most children in whom a diagnosis of PKU is made shortly after birth will grow and develop normally. Untreated, they rarely achieve an IQ of above 70, and usually require life-long institutional care.

Variants and related conditions

The enzyme phenylalanine hydroxylase has tetrahydrobiopterin as a coenzyme. A number of variant forms of PKU have been described, some involving a defect in the metabolism of this coenzyme. Several other inherited metabolic diseases are associated with abnormalities of phenylalanine and tyrosine metabolism, including tyrosinaemia and alkaptonuria.

Tyrosinaemia type 1 (due to deficiency of fumaryl-acetoacetate hydrolase, a late enzyme in tyrosine degradation) causes liver damage, leading to cirrhosis, and renal tubular damage, resulting in Fanconi syndrome. Alkaptonuria (due to deficiency of homogentisic acid oxidase) causes accumulation of homogentisic acid (a metabolite of phenylalanine and tyrosine). This polymerizes in skin and sclerae, causing brown-black discolouration (ochronosis), and in fibrous tissue and cartilage, including articular cartilage, where it can cause arthritis. Homogentisic acid is colourless but it becomes oxidized in urine, causing it to become brown-black on standing.

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