Inborn Errors of Carbohydrate Metabolism

Inborn errors of carbohydrate metabolism are a subgroup of inborn errors of metabolism. Each results from deficiency of an enzyme required for normal carbohydrate metabolism. Prompt recognition matters because of the risk of severe, sometimes life-threatening acute complications.

The main groups are the glycogen storage disorders, galactosaemia and hereditary fructose intolerance. Each has a characteristic presentation that follows from the point of metabolic blockade and the resulting substrate accumulation or product deficiency.

• Glycogen storage disorders reflect impaired glycogen synthesis or breakdown. Glycogen storage disease type I (von Gierke disease) is the commonest and most extensively characterised subtype.
• Galactosaemia results from impaired galactose metabolism, most commonly deficiency of galactose-1-phosphate uridyltransferase.
• Hereditary fructose intolerance results from deficiency of fructose-1,6-bisphosphate aldolase B.

In several conditions, dietary modification is essential. Long-term organ damage occurs if the condition remains unrecognised and untreated.

Classification and pathophysiology

• Glycogen storage disease type I (von Gierke disease) results from deficiency of glucose-6- phosphatase. This enzyme catalyses the final step of both glycogenolysis and gluconeogenesis. During fasting, glucose cannot be mobilised from either pathway, causing profound, severe fasting hypoglycaemia. Accumulated glucose-6-phosphate shunts toward alternative pathways, causing lactic acidosis, hyperlipidaemia and hyperuricaemia.
• Galactosaemia, most commonly from galactose-1-phosphate uridyltransferase deficiency (classic galactosaemia), causes accumulation of galactose-1-phosphate after ingestion of galactose. Galactose derives predominantly from dietary lactose, the disaccharide of glucose and galactose present in breast milk and standard infant formula. The accumulated metabolite is directly toxic to the liver, kidney and brain.
• Galactosaemia has a specific, well recognised association with Escherichia coli sepsis. This is believed to reflect impaired neutrophil function related to the metabolic derangement.
• Hereditary fructose intolerance results from deficiency of aldolase B, the enzyme that metabolises fructose-1-phosphate. This toxic intermediate accumulates after ingestion of fructose. Fructose is present in fruit and in sucrose, and historically in some infant formula sweetened with sucrose rather than lactose. It produces severe hypoglycaemia and hepatic and renal toxicity.
• Affected infants remain entirely well while fructose is avoided. Symptoms emerge when fructose-containing foods are introduced, typically with weaning foods or fruit-containing preparations.

• Glycogen storage disease type I typically presents in infancy with hepatomegaly, from glycogen accumulation in the liver. Recurrent, severe hypoglycaemia is pronounced even during relatively brief fasts, because glucose homeostasis cannot be maintained by glycogenolysis or gluconeogenesis.
• Affected infants frequently have a characteristic "doll-like" facial appearance, reflecting fat deposition in the cheeks. Growth is impaired if the condition is inadequately managed.
• Classic galactosaemia typically presents within the first days to weeks of life, as milk feeding starts (breast milk or standard, lactose-containing infant formula). Features are jaundice, hepatomegaly, vomiting, poor feeding and lethargy.
• If unrecognised, galactosaemia progresses to liver failure and coagulopathy, with increased susceptibility to Escherichia coli sepsis.
• Long-term complications of galactosaemia can occur if dietary management is inadequate, and in some cases despite adequate management. They include cataract (from galactitol accumulation within the lens) and premature ovarian insufficiency in affected females. Ovarian insufficiency is an important complication that occurs despite adequate dietary galactose restriction.
• Hereditary fructose intolerance presents with acute, severe symptoms triggered by fructose ingestion. These are vomiting, hypoglycaemia and lethargy. With continued or repeated exposure, hepatic and renal dysfunction progress.
• Affected infants develop a strong, protective aversion to sweet, fructose-containing foods once old enough to choose. In older children presenting for the first time, this aversion is a useful, though retrospective, clue alongside relevant biochemical findings.
• The common feature across the group is a direct temporal relationship between symptom onset and exposure to the relevant dietary carbohydrate. The triggers are fasting for glycogen storage disease type I, milk or lactose introduction for galactosaemia, and fructose or sucrose introduction for hereditary fructose intolerance. This is a useful diagnostic clue.

• Newborn screening for galactosaemia is included in many, though not all, established programmes. It allows identification and prompt dietary intervention before significant symptoms in screened populations.
• Clinical presentation can still occur before screening results are available, or where screening for this condition is not established. Ongoing clinical awareness is needed.
• Diagnosis of glycogen storage disease type I is supported by the characteristic presentation and biochemical pattern: severe fasting hypoglycaemia with lactic acidosis, hyperlipidaemia and hyperuricaemia. Confirm with enzyme activity assay or genetic testing.
• Diagnosis of galactosaemia is supported by measurement of galactose-1-phosphate uridyltransferase enzyme activity together with galactose-1-phosphate level. Genetic testing gives definitive molecular confirmation.
• Prompt diagnosis and dietary intervention are essential. A symptomatic, milk-fed infant with unrecognised galactosaemia can deteriorate rapidly and severely.
• Diagnosis of hereditary fructose intolerance is supported by a history of symptoms related to fructose exposure, together with genetic testing for aldolase B mutations.
• A formal fructose tolerance test was used historically. It is now generally avoided because it risks provoking a severe, acute hypoglycaemic reaction. Genetic testing is the safer, preferred approach.
• Severe, rapid deterioration is possible. Any infant with the characteristic clinical pattern, particularly with a clear temporal relationship to feeding or a specific dietary exposure, needs urgent clinical suspicion and prompt diagnostic evaluation.
• Where severity of presentation indicates, start empirical dietary modification pending definitive confirmation.

• Glycogen storage disease type I management centres on preventing hypoglycaemia through frequent feeding. This structured dietary and feeding approach is essential to maintain normal blood glucose and prevent metabolic complications.
• Avoid simple sugars. Through alternative metabolic pathways, they can exacerbate the lactic acidosis and metabolic derangement.
• Give regular uncooked cornstarch, which is particularly important for maintaining normoglycaemia overnight and during any prolonged period without feeding. It provides a slow-release source of glucose because of its gradual digestion and absorption.
• Galactosaemia management requires immediate, strict elimination of galactose from the diet. This includes lactose, since galactose is a constituent of this disaccharide.
• Substitute a soy-based or other galactose-free infant formula for breast milk or standard, lactose-containing formula. Continue the restriction lifelong, as no curative treatment exists.
• Galactosaemia needs ongoing, structured surveillance for longer-term complications that can occur despite adequate, lifelong dietary management. These are cataract, developmental outcome and, in females, ovarian function.
• Hereditary fructose intolerance management is strict, lifelong avoidance of dietary fructose and sucrose.
• Affected individuals generally adapt well once the diagnosis is established and dietary guidance is given, since many develop a natural aversion to these foods. Prognosis is generally favourable with strict avoidance.
• Dietetic input and structured nutritional support are an integral component of management. Monitor growth and nutritional adequacy carefully, given the significant dietary restrictions. Specialist metabolic dietetic services with expertise in these conditions should deliver this.
• Educate patients and families on the specific dietary restrictions. Give clear guidance on reading food labels and identifying hidden sources of the restricted carbohydrate in processed foods and medications. Plan emergency management for any acute presentation or intercurrent illness.
• Offer genetic counselling to the family on the autosomal recessive inheritance pattern and recurrence risk for future pregnancies.