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 Disorders of carbohydrate metabolism 

 Disorders of carbohydrate metabolism
Chapter:
 Disorders of carbohydrate metabolism
Author(s):

Robin H. Lachmann

DOI:
10.1093/med/9780199235292.003.1250
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Introduction

Many disorders of carbohydrate metabolism are characterized by hypoglycaemia and attacks of neuroglycopenia. Hypoglycaemia can also be caused by disorders affecting the use of other fuels, such as those producing fatty acids and ketone bodies which are important alternative sources of energy. Thus when investigating a patient with hypoglycaemia it is necessary to investigate not only pathways that provide glucose directly, but also those which spare glucose utilization and thus provide defence mechanisms when carbohydrate energy sources become depleted. The defence mechanisms that are activated during fasting to preserve blood glucose are:

  • glycogenolysis—glucose liberation from glycogen degradation

  • gluconeogenesis—glucose production from pyruvate/lactate and from noncarbohydrate sources such as glucogenic amino acids and glycerol

  • fatty acid β‎-oxidation—catabolism of triglycerides to acetyl-CoA and ketone bodies

The interrelation between these glucose generating pathways is shown in Fig. 12.3.1.1.


Fig. 12.3.1.1 Main pathways of carbohydrate metabolism and relation with lipid metabolism. Acetyl-CoA, acetyl-coenzyme A; G-1-P, glucose-1-phosphate; G-6-P, glucose-6-phosphate; GLUT, glucose transporter; triose-P, triose phosphate.

Fig. 12.3.1.1
Main pathways of carbohydrate metabolism and relation with lipid metabolism. Acetyl-CoA, acetyl-coenzyme A; G-1-P, glucose-1-phosphate; G-6-P, glucose-6-phosphate; GLUT, glucose transporter; triose-P, triose phosphate.

Although there is much overlap, the activation of these defence mechanisms during fasting is sequential. The first defence mechanism, glycogenolysis, is exhausted within 8–12 h of fasting. The second and third defence mechanisms provide glucose once glycogen stores have been depleted. In a patient with glycogen storage disease (GSD) where glycogenolysis is blocked, gluconeogenesis and fatty acid oxidation are activated immediately on fasting and can only maintain normoglycaemia for a few hours. In patients with defects affecting gluconeogenesis or fatty acid oxidation, hypoglycaemia does not occur until glycogen stores have been depleted. When more than one pathway is affected, as in GSD I, where neither glycogenolysis nor gluconeogenesis can release glucose into the circulation, patients can be entirely dependent on oral carbohydrate intake to maintain normoglycaemia. These pathways are also susceptible to hormonal influences. Insulin in particular inhibits all three pathways and stimulates some enzymes of the reverse pathways: glycogen synthesis, glycolysis, and fatty acid synthesis. Therefore hyperinsulinaemia of whatever cause leads to severe hypoglycaemia which is resistant to treatment. Other hormones, such as glucagon, adrenaline, and growth hormone, also activate some enzymes of glucose homoeostasis, though less markedly. This is discussed elsewhere.

The metabolism of the other monosaccharides, galactose and fructose, is connected with that of glucose. As well as causing hypoglycaemia, inherited defects that affect the metabolism of these sugars lead to the accumulation of toxic metabolites which also contribute to pathology (see below).

Glycogen storage diseases

The GSDs are caused by enzyme defects involved in the first defence system of glucose homoeostasis, glucose production from glycogen. The principal tissues that use glycogen as a source of glucose are liver and muscle. The enzymology of glycogenolysis differs somewhat between these two tissues and therefore GSDs, which are due to inherited deficiencies of these enzymes, can be classified according to whether they affect the liver, the muscle, or both. Liver involvement results in hepatomegaly, hypoglycaemia, and a range of metabolic disturbances, while muscle involvement presents as rhabdomyolysis or as myopathy. Multiorgan involvement can either be secondary to metabolic derangements, or the direct result of storage in other tissues (e.g. kidney storage in GSD I) (1).

This chapter is limited to a discussion of hepatic GSDs. The most important hepatic GSDs are glucose-6-phosphatase EC 3.1.3.9 deficiency (GSD Ia, MIM 232200) and debranching enzyme EC 3.2.1.33 deficiency (GSD III, 232400). Less common are deficiencies of the phosphorylase cascade, that is, phosphorylase-b-kinase EC 2.7.11.19 deficiency (GSD IX MIM 306000) and phosphorylase EC 2.4.1.1 deficiency (GSD VI, MIM 232700) (Fig. 12.3.1.2). These hepatic GSDs share a number of clinical features and will be discussed together.


Fig. 12.3.1.2 The enzymatic processes of glycogen synthesis and breakdown in the liver.

Fig. 12.3.1.2
The enzymatic processes of glycogen synthesis and breakdown in the liver.

Clinical presentation

The main clinical features are abdominal distension due to hepatomegaly, hypoglycaemia, often severe enough to present with seizures and growth retardation (1). Without hepatomegaly, which is due to glycogen storage in hepatocytes, the diagnosis of an hepatic GSD is highly unlikely. Over time, for reasons which are not well understood, hepatic adenomas can develop in patients with GSD I (and less often in patients with GSD III) and there is a risk of malignant transformation (2, 3). Cirrhosis is rare.

In GSD III there is also skeletal and cardiomyopathy while renal involvement is a feature of GSD I. As well as renal enlargement due to storage, the kidneys develop focal glomerulosclerosis, very similar to that seen in people with diabetes, which evolves gradually to renal insufficiency (4). GSD Ib, caused by deficiency of glucose-6-phosphate translocase (GSD Ib), is characterized by neutropenia, leading to recurrent bacterial infections and inflammatory bowel disease. The main clinical and enzymatic abnormalities of the other GSDs are summarized in Table 12.3.1.1.

Table 12.3.1.1 Classification of hepatic glycogen storage diseases (GSDs)

Type

Defective enzyme or transporter

Tissue involved

Main clinical symptoms

Ia

Glucose-6-phosphatase

Liver, kidney

Hepatomegaly, hypoglycaemia, lactic acidosis, hyperlipidaemia, hyperuricaemia liver adenoma, focal glomerulosclerosis

Ib

Glucose-6-phosphatase translocases

Liver, leucocytes

In addition: neutropenia, infections, inflammatory bowel disease

III

Debranching enzyme

Liver, muscle

Hepatomegaly, hypoglycaemia, hyperlipidaemia, myopathy

IV

Branching enzyme

Liver

Hepatosplenomegaly, cirrhosis

VI

Phosphorylase

Liver

Hepatomegaly, hypoglycaemia

IX

Phosphorylase b kinase

Liver

Hepatomegaly, hypoglycaemia

GSD 0

Glycogen synthase

Liver

Hypoglycaemia

GLUT2, glucose transporter 2.

Metabolic derangements

The main metabolic abnormalities seen in GSDs stem from the deficiency of glucose production in the liver. In GSD I, the primary deficiency of glucose-6-phosphatase not only blocks glucose production from glycogenolysis, but also from gluconeogenesis. This is due to the role of glucose-6-phosphatase in the formation of glucose from glycogen and pyruvate via glucose-6-phosphate (Fig. 12.3.1.2). This suppression of both the first and second defence mechanism against the development of hypoglycaemia makes GSD I the most severe of all the GSDs. Although glucose production from glucose-6-phosphate is blocked, glycogen degradation towards pyruvate and lactate continues, and may even be enhanced, presumably secondary to hormonal stimulation. This results in lactic acidosis. In addition, there is increased lipogenesis, which gives rise to hyperlipidaemia. There is also increased hepatic production of uric acid which, combined with decreased renal excretion due to competition with lactic acid and reduced glomerular filtration rate (GFR, leads to hyperuricaemia and gout (1).

In deficiencies of debranching enzyme (GSD III) and of the phosphorylase system (GSD VI and GSD IX), gluconeogenesis is not affected and fasting hypoglycaemia tends to be milder and is accompanied by ketosis, rather than lactic acidosis. A mild carbohydrate-induced hyperlipidaemia is observed, but the secondary metabolic derangements are much less severe than in GSD I (1).

Diagnosis

A diagnosis based on the clinical and biochemical features must be confirmed by analysis of the relevant enzymes and/or DNA. Leucocyte enzyme assays can confirm the diagnosis in most cases, but glucose-6-phosphatase is only expressed in hepatocytes, and a liver biopsy is required for the enzymatic diagnosis of GSD I. Nowadays, the diagnosis can be made by molecular analysis of the glucose-6-phosphatase and glucose-6-phosphate translocase genes and liver biopsy is not necessary.

Treatment

The only means to prevent hypoglycaemia and suppress secondary metabolic derangements is to ensure regular carbohydrate intake. In the past this involved frequent high-carbohydrate meals: young children with GSD I would often need to eat every 2 h, through the night as well as during the day. The introduction of drip feeding via a nasogastric tube during the night has improved outcomes, particularly in terms of growth, and quality of life for these families (5).

A second innovation has been the use of uncooked cornstarch as a ‘slow-release’ form of carbohydrate, allowing less frequent meals during the day (6). The frequency of cornstarch required to maintain normoglycaemia can be assessed by monitoring glucose and lactate levels following a cornstarch load. Fasting capacity increases with age and for many adults a cornstarch load last thing at night will allow them to sleep through until the morning without the need for tube feeding. The administration of uncooked cornstarch before the night can also prevent hypoglycaemia in disorders of gluconeogenesis, and even in patients with diabetes mellitus (7).

The dietary regimen for patients with disorders other than GSD I is less extreme. Although children may require overnight tube feeding, most adult patients with GSD III or phosphorylase disorders can manage an 8-h night-time fast thanks to the activation of gluconeogenesis and fatty acid oxidation.

Proper dietary treatment of children with GSD results in improved growth and there is no place for hormonal treatment. The development of kidney disease can be attenuated if angiotensin-converting enzyme inhibitors are used at an early stage. Allopurinol is important in preventing clinical attacks of gout. In GSD Ib, the use of recombinant human granulocyte colony-stimulating factor improves leucocyte counts and reduces infections and inflammatory bowel disease (8).

Prognosis

Follow-up studies in adults have allowed the effects of dietary and other treatments on frequently occurring complications to be evaluated (9, 10). For GSD I patients catch-up growth was shown to occur, but not in all (11), liver adenomata usually remained constant in adults (3), deterioration of renal glomerulosclerosis could be halted or delayed by an inhibitor of angiotensin-converting enzyme, and survival and quality of life improved considerably.

Although the metabolic derangements in GSD III are less severe, the muscle disease can be progressive and skeletal and cardiomyopathy are long-term complications (3, 10, 12).

Deficiencies of the phosphorylase system are the most benign of all hepatic GSDs. Normal height is often attained (13), the liver enlargement disappears, usually before puberty, and complications such as myopathy are rare.

Genetics

All GSDs have an autosomal recessive inheritance except phosphorylase-b-kinase deficiency, which usually has an X-linked inheritance. Most enzyme defects show large genetic and clinical heterogeneity.

Disorders of gluconeogenesis

Gluconeogenesis is the second defence mechanism of the body against hypoglycaemia during fasting. It involves the formation of glucose from lactate/pyruvate, glycerol and some glucogenic amino acids, mainly alanine. Gluconeogenesis involves the same enzymes as glycolysis, working in reverse, except for those that catalyse the four irreversible steps which convert pyruvate to glucose: pyruvate carboxylase (EC 6.4.1.1), phosphoenolpyruvate carboxykinase (EC 4.1.1.38) (PEPCK), fructose-1,6-bisphosphatase and glucose-6-phosphatase (Fig. 12.3.1.3). Gluconeogenesis is restricted to the liver and the kidney cortex, as only these two organs possess high levels of glucose-6-phosphatase. Defects are known of all four enzymes. As glucose-6-phosphatase deficiency is dealt with under glycogen storage diseases, and fructose-1,6-bisphosphatase deficiency under disorders of fructose metabolism, the discussion below is limited to deficiencies of pyruvate carboxylase and PEPCK.


Fig. 12.3.1.3 Gluconeogenesis and glycolysis. 1, pyruvate carboxylase deficiency; 2m and 2c, mitochondrial and cytosolic phosphoenol pyruvate carboxykinase deficiency, respectively; 3, fructose-1,6-bisphosphatase deficiency; 4, glucose-6-phosphatase deficiency; for other abbreviations, see Fig. 12.3.1.1.

Fig. 12.3.1.3
Gluconeogenesis and glycolysis. 1, pyruvate carboxylase deficiency; 2m and 2c, mitochondrial and cytosolic phosphoenol pyruvate carboxykinase deficiency, respectively; 3, fructose-1,6-bisphosphatase deficiency; 4, glucose-6-phosphatase deficiency; for other abbreviations, see Fig. 12.3.1.1.

Clinical presentation

Pyruvate carboxylase (MIM 266150) and PEPCK (MIM 261680) deficiencies are both rare and present with hypoglycaemia and lactic acidosis, which causes hyperventilation. The first episode may occur in the neonatal period or in infancy and is usually triggered by fasting and vomiting associated with an intercurrent illness. Both are severe multisystem disorders with microcephaly, myopathy, cardiomyopathy, hepatocellular damage, and renal tubular acidosis, leading to early death.

Metabolic derangements

In disorders of gluconeogenesis fasting hypoglycaemia is generally more severe the later the block in the pathway occurs (14, 15). Systemic toxicity, particularly to the brain, liver, and kidneys, is more severe the closer the enzyme defect is located to pyruvate. In the absence of hypoxia, the combination of a low plasma glucose concentration and elevated levels of lactate, pyruvate, and alanine indicates a problem with gluconeogenesis. The urea cycle may be secondarily compromised and this is reflected by increased levels of ammonia, citrulline, and lysine.

Diagnosis

Traditionally, the pathway of gluconeogenesis was explored using a tolerance test with a gluconeogenic substrate. Such tests involved risk of toxicity when elevated levels of the substrate already existed and have therefore been abandoned. Instead, a stable isotope test with [2H2]glucose is used and this allows the rate of total glucose production and the contribution from the glucose–lactate cycle to be calculated (16). In case of a disrupted glucose–pyruvate cycling, the enzymes of gluconeogenesis should be assayed.

Treatment and prognosis

The results of treatment are poor. In case of acute hypoglycaemia, high doses of intravenous glucose (up to 10–12 mg/kg bodyweight per min of a 10% solution) and sodium bicarbonate are indicated. Maintenance treatment consists of high-carbohydrate feeding, nocturnal gastric drip feeding and/or uncooked cornstarch (see Glycogen storage diseases above). These diseases are usually fatal in early infancy.

Disorders of galactose metabolism

The disaccharide lactose, which is the most important carbohydrate in both human and cow’s milk, is formed from glucose and galactose. Galactose therefore forms a large part of the energy intake of infants. There are three inborn errors of galactose metabolism, as shown in Fig. 12.3.1.4.


Fig. 12.3.1.4 Galactose metabolism. 1, galactokinase; 2, galactose-1-phosphate uridyltransferase; 3, UDP galactose 4′-epimerase; 4, UDP glucose (UDP galactose) pyrophosphorylase; 5, aldose reductase. The three enzyme defects are depicted by solid bars across the arrows. Gal-1-P, galactose-1-phosphate; G-1-P, glucose-1-phosphate; G-6-P, glucose-6-phosphate; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced NADP; UDPG, uridine diphosphoglucose; UDPGal, uridine diphosphogalactose. (With permission from Gitzelmann R. Disorders of galactose metabolism. In: Fernandes J, Saudubray J-M, van den Berghe G, eds. Inborn Metabolic Diseases. 3rd edn. Heidelberg, Springer-Verlag, 2000.)

Fig. 12.3.1.4
Galactose metabolism. 1, galactokinase; 2, galactose-1-phosphate uridyltransferase; 3, UDP galactose 4′-epimerase; 4, UDP glucose (UDP galactose) pyrophosphorylase; 5, aldose reductase. The three enzyme defects are depicted by solid bars across the arrows. Gal-1-P, galactose-1-phosphate; G-1-P, glucose-1-phosphate; G-6-P, glucose-6-phosphate; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced NADP; UDPG, uridine diphosphoglucose; UDPGal, uridine diphosphogalactose. (With permission from Gitzelmann R. Disorders of galactose metabolism. In: Fernandes J, Saudubray J-M, van den Berghe G, eds. Inborn Metabolic Diseases. 3rd edn. Heidelberg, Springer-Verlag, 2000.)

Galactokinase deficiency

Clinical presentation

The only abnormality is cataract, which usually develops within the first weeks of life if the infant consumes lactose-containing milk. The cataract is formed by the accumulation of galactitol in the lens, causing osmotic swelling of lens fibres and denaturation of proteins.

Metabolic derangements

Deficiency of galactokinase (EC 2.7.1.6, MIM 230200), the first enzyme of galactose metabolism, causes accumulation of its substrate, galactose (Fig. 12.3.1.4, enzyme 1). Some of this galactose is reduced to galactitol by aldose reductase, a normally ‘dormant’ metabolic pathway (Fig. 12.3.1.4, enzyme 5). Both galactose and galactitol are excreted in the urine.

Diagnosis

In several countries, disorders of galactose metabolism are part of the newborn screening programme. If an increased blood galactose concentration is the only abnormality detected in the pathway, then urine should be tested for galactose and the lens inspected for cataract. Galactokinase deficiency is highly probable if these abnormalities are found in an otherwise healthy infant and the diagnosis should be confirmed by enzyme analysis of erythrocytes or fibroblasts. In countries where newborn screening for galactose abnormalities does not exist, the diagnosis rests on the ability to detect developing cataracts in the young infant. Any chance finding of a reducing substance in the urine of infants or young children requires further investigation, particularly for the reducing sugars glucose and galactose.

Treatment and prognosis

Elimination of milk (human and cow’s) from the diet is sufficient in galactokinase deficiency. The small amount of galactose derived from other sources, such as dairy products, legumes, and green vegetables, is metabolized or excreted without causing harm. Calcium supplements should be given to prevent osteoporosis. Cataracts do not develop or may disappear completely if the diagnosis is made and treatment started early.

Genetics

The inheritance is autosomal recessive and several gene mutations have been found (17). The incidence is very low, in the order of 1:150 000 births or less, except in the Balkan countries.

Galactosaemia or galactose-1-phosphate uridyltransferase deficiency

Clinical presentation

Infants with classic galactosaemia (MIM 230400), caused by severe deficiency of galactose-1-phosphate uridyltransferase (transferase, EC 2.7.7.10) (Fig. 12.3.1.4, enzyme 2) appear normal at birth but rapidly become very unwell. Refusal to feed and vomiting are accompanied by signs of liver disease: jaundice, hepatomegaly, oedema, and ascites. Cataracts appear within a few days or weeks. Left untreated, liver and kidney failure develop and, along with sepsis are rapidly fatal (17).

Partial transferase deficiency is usually asymptomatic. It is commoner than classic galactosaemia but only detected in countries with newborn screening programmes (18).

Metabolic derangements

Galactose-1-phosphate, which accumulates before the metabolic block (Fig. 12.3.1.4, enzyme 2), is toxic for many organs and tissues, mainly the liver, kidney, and brain. It suppresses the activities of some enzymes of glycogenolysis and gluconeogenesis, which may lead to hypoglycaemia. It is not known whether galactose itself, which accumulates too, adds to galactose-1-phosphate toxicity. Galactitol, produced from galactose excess, leads to cataract formation and is excreted in the urine. As well as being derived from exogenous sources of galactose, galactose-1-phosphate is also produced endogenously from glucose-1-phosphate, by a reversal of the pyrophosphorylase-epimerase pathway (Fig. 12.3.1.4, enzymes 3 and 4) (17). This ‘self-intoxication’ may contribute to late complications, such as ovarian failure and neurological disease, which can develop despite a strict lactose-free diet.

Diagnosis

As classical galactosaemia presents very early in life it can be argued that it is not suitable for a newborn screening programme. However, screening results may still speed diagnosis, and can be important in detecting milder forms presymptomatically. Diagnosis otherwise rests on the detection of galactose in urine and should be confirmed by enzyme assays of whole blood, an erythrocyte lysate or fibroblasts, and DNA analyses.

Treatment

The dietary treatment of patients with classic galactosaemia due to a (near) total transferase defect is much more demanding than that of patients with galactokinase deficiency. It aims at total exclusion of all sources of lactose. For the galactosaemic infant the earliest possible introduction of a lactose-free milk is essential. At weaning, patients need to be established on a lactose-free diet (17, 19). This is not as straightforward as it seems as many manufactured foods contain milk products. In contrast, some mature cheeses are actually lactose-free, as all the sugars have been cleared by fermenting bacteria. In the UK, the Galactosaemia Support Group produces a list of foods known to be suitable for individuals with galactosaemia and which is regularly updated. Calcium needs to be supplemented.

For patients with a partial transferase deficiency detected at newborn screening, a pragmatic approach is recommended. It consists of a lactose-free milk during the first 4 months, followed by a slow introduction of lactose-containing milk. If all relevant biochemical parameters remain normal, a normal diet can be commenced.

Prognosis

Currently it is recommended that a lactose-free diet is maintained for life, but there is little evidence to support this. There are reports of patients with galactosaemia who have relaxed their diets and not experienced any ill effects. Equally, there are patients who remain on a strict diet but go on to develop neurological symptoms. Cognitive dysfunction, speech abnormalities, a declining DQ or IQ occur frequently in older children (20). Similarly, all female patients develop premature ovarian failure and very few manage to start families. Early hormone replacement therapy is required (19).

These ongoing deficiencies might be due to continuous intoxication with galactose-1-phosphate, either produced endogenously or derived from complex sugars such as raffinose and stachyose by bacterial fermentation in the gut. In fact, it is possible that these effects are not related to the build-up of toxic metabolites at all, but actually reflect a generalized defect in glycosylation of proteins (21). Patients with congenital glycosylation defects demonstrate similar clinical features including hypogonadotropic premature ovarian failure, which is thought to relate to lack of glycosylation of follicle-stimulating hormone.

Genetics

Galactosaemia is inherited as an autosomal recessive trait. The incidence of galactosaemia is approximately 1: 55 000. Many cases of severe disease are associated with homozygosity for the ‘classic’ allele.

Disorders of fructose metabolism

Fructose is found in fruits, vegetables, and honey. With glucose, it forms the disaccharide sucrose, which is an important carbohydrate in many foods and beverages. Sucrose is hydrolysed into its two monosaccharides by the enzyme sucrase (EC 3.2.1.48) on the small intestinal mucosa. Another source of fructose is sorbitol, which is widely distributed in fruits and vegetables. It is converted in the liver into fructose by the enzyme sorbitol dehydrogenase (EC 1.1.1.14). The three inborn errors of fructose metabolism are shown in Fig. 12.3.1.5.


Fig. 12.3.1.5 Fructose metabolism. 1, fructokinase; 2, aldolase B; 3, fructose-1,6-bisphosphatase; 4, phosphofructokinase; 5, sorbitol dehydrogenase. The enzyme defects are depicted by solid bars across the arrows. ADP, adenosine diphosphate; ATP, adenosine triphosphate; DHA-P, dihydroxyacetone phosphate; F-1-P, fructose-1-phosphate; F-6-P, fructose-6-phosphate; F-1,6-P2, fructose-1,6-bisphosphate; G-6-P, glucose-6-phosphate; Pi, inorganic phosphate; GAH-3-P, glycer-aldehyde-3-phosphate.

Fig. 12.3.1.5
Fructose metabolism. 1, fructokinase; 2, aldolase B; 3, fructose-1,6-bisphosphatase; 4, phosphofructokinase; 5, sorbitol dehydrogenase. The enzyme defects are depicted by solid bars across the arrows. ADP, adenosine diphosphate; ATP, adenosine triphosphate; DHA-P, dihydroxyacetone phosphate; F-1-P, fructose-1-phosphate; F-6-P, fructose-6-phosphate; F-1,6-P2, fructose-1,6-bisphosphate; G-6-P, glucose-6-phosphate; Pi, inorganic phosphate; GAH-3-P, glycer-aldehyde-3-phosphate.

Essential fructosuria

This is a rare ‘non-disease’, which does not show any clinical symptoms. It is caused by a deficiency of fructokinase (EC 2.7.1.4) (Fig. 12.3.1.5, enzyme 1), which is normally found in liver, kidney, and small intestinal mucosa. Thus, fructose cannot be phosphorylated into fructose-1-phosphate. Instead, it is slowly phosphorylated into fructose-6-phosphate by the enzyme hexokinase in adipose tissue and muscle with the excess being excreted in the urine. The resultant fructosuria is the only finding. A discrepancy between a positive test for reducing sugars and a negative reaction with glucose oxidase should allow the identification of fructose as a nonglucose-reducing sugar. Dietary treatment is unnecessary.

Hereditary fructose intolerance

Clinical presentation

Deficiency of aldolase-B (EC 4.1.2.13, MIM 229600), the second enzyme of the fructose pathway (Fig. 12.3.1.5, enzyme 2) causes fructose-1-phosphate to accumulate after consumption of fructose containing foods (22). The mechanism of toxicity of fructose-1-phosphate is like that of galactose-1-phosphate in classical galactosaemia and there are some clinical similarities between the two disorders. When fructose/sucrose containing foods are introduced into the diet at weaning, the infant starts to vomit and refuse food, and develops failure to thrive with jaundice, hepatomegaly, oedema, ascites, and a bleeding tendency, reflecting liver dysfunction. Urinary findings are mellituria, proteinuria, and aminoaciduria, reflecting renal proximal tubular dysfunction. Diarrhoea and malabsorption reflect small intestinal involvement. Lethargy, tremor, and convulsions are due to hypoglycaemia (see Metabolic derangements below). The larger the fructose load and the younger the infant, the more acute the symptoms of intolerance. Older children may selectively refuse fructose containing products and never present in acute crisis. In these cases the diagnosis may be made by their dentist due to a complete freedom of dental caries.

Metabolic derangements

Fructose-1-phosphate, which accumulates due to the aldolase-B defect, is toxic. It causes hypoglycaemia by inhibiting enzymes of both glycogenolysis and gluconeogenesis: not only is the splitting of fructose-1-phosphate into three-carbon sugars impaired (Fig. 12.3.1.5, enzyme 2), but also the condensation of the three-carbon sugars into fructose-1,6-bisphosphate (Fig. 12.3.1.5, enzyme 3). The accumulation of fructose-1-phosphate also leads to the sequestration of inorganic phosphate, which is then not available for the regeneration of ATP from ADP, causing a generalized energy defect in the cell. This provokes the catabolism of adenine nucleotides, which leads to the overproduction of uric acid.

Diagnosis

The clinical picture, combined with the finding of a combination of fructosuria and disturbed liver function tests, should lead to the suspicion of hereditary fructose intolerance Traditionally an intravenous fructose tolerance test was performed, but assay of aldolase-B activity in a biopsy of liver, jejunal mucosa or kidney cortex, or DNA analysis is simpler and safer.

Treatment and prognosis

All sources of fructose, sucrose, and sorbitol (which can be present in many products such as medicines) should be excluded from the diet. They should be replaced by glucose, maltose, and starch. This elimination diet rapidly corrects all abnormalities except the hepatomegaly, which is more slow to resolve. If small amounts of fructose remain in the diet growth may remain slow, but will catch up after further adjustment of the diet and overall, with treatment, the prognosis is excellent (22).

Genetics

Hereditary fructose intolerance is an autosomal recessive disorder with a large heterogeneity. Its incidence is estimated at 1:20 000.

Fructose-1,6-bisphosphatase deficiency (MIM 229700)

Clinical presentation

Fructose-1,6-bisphosphatase (EC 3.1.3.11) has a role both in the conversion of fructose to glucose (Fig. 12.3.1.5, enzyme 3) and in gluconeogenesis, in which fructose-1,6-bisphosphatase is the third unidirectional enzyme (Fig. 12.3.1.3, enzyme 3). Therefore, deficiency of the enzyme leads to abnormalities due to the impairment of both pathways, though those of failing gluconeogenesis are more serious than those of impaired fructose conversion. Hypoglycaemia, associated with lactic acidosis, occurs in the neonatal period and can recur in later childhood. It usually develops after prolonged fasting or with an intercurrent febrile illness. The clinical symptoms of hypoglycaemia (lethargy, irritability, apnoea, coma, and convulsions) are accompanied by hyperpnoea, somnolence, and vomiting due to the lactic acidosis. Attacks may also occur after ingestion of fructose or sucrose. The frequency of attacks decreases with increasing age. A mild hyperlactacidaemia may persist between episodes. Growth and psychomotor development are usually normal (22).

Metabolic derangements

As gluconeogenesis is blocked, glucose cannot be synthesized from lactate, pyruvate, alanine, glycerol, or fructose. The patient depends on exogenous glucose and galactose and endogenous glycogen for their glucose requirements. On fasting, hypoglycaemia and lactic acidosis develop, sometimes accompanied by hyperketonaemia. Lactate, pyruvate, alanine, glycerol, and glycerol-3-phosphate accumulate in blood and urine.

Diagnosis

The enzymatic assay of fructose-1,6-bisphosphatase in a biopsy of the liver, jejunal mucosa, or kidney cortex is the only reliable means for the diagnosis.

Treatment and prognosis

The acute, life-threatening attack is treated with an intravenous glucose drip: an intravenous glucose bolus (200 mg glucose/kg bodyweight over 5 min) followed by a continuous infusion (c. 12 mg glucose/kg bodyweight per min). Sodium bicarbonate may be given to treat the lactic acidosis. In order to prevent further attacks it is important to avoid prolonged fasting. An emergency regimen consisting of frequent carbohydrate is given during intercurrent infection. In small children a restriction (not elimination) of fructose, sucrose, and sorbitol is recommended. The tolerance for fasting improves with age and the prognosis is good if adequate treatment is introduced in infancy.

Genetics

Various mutations underlying this autosomal recessive disorder exist. Its incidence is not known.

References

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