• Clinical science

Inborn errors of carbohydrate metabolism

Summary

All classic disorders of carbohydrate metabolism result from a specific enzyme defect. Almost all of these enzyme defects are inherited in an autosomal recessive fashion. These metabolic diseases may be classified into three main groups, affecting the metabolism of glycogen, galactose, and fructose. Clinical manifestations are variable and range from occasional innocuous hypoglycemia to severe cognitive impairment and death within a few weeks of birth. Newborn screening enables the early detection of metabolic diseases and early initiation of appropriate dietary restrictions helps prevent disease manifestations.

Glycogen storage disorders (GSD)

Glycogen storage disorders (GSD, glycogenoses) are hereditary defects in enzymes that are responsible for either glycogenolysis or glycolysis.

Epidemiology

  • Incidence: 1 per 20,000 live births
  • Age of onset: presentation during infancy or childhood
  • Sex: =
  • Mode of inheritance: mostly autosomal recessive

Pathophysiology

Defects in enzymes that are responsible for either glycolysis or glycogenolysis↑ storage of either normal or abnormal glycogen; Since the liver, heart, and muscles are the most common sites of glycogen storage, they are the ones most commonly affected.

Overview of the various types of GSD

Type of GSD Type I (von Gierke disease) Type II (Pompe disease) Type III (Cori disease) Type IV (Andersen disease) Type V (McArdle disease) Type VI (Hers disease)
Type 1a Type 1b
Relative frequency
  • ∼25%
  • ∼15%
  • ∼25%
  • ∼3%
  • ∼2%
  • ∼30%
Deficient enzyme
  • Glucose-6-phosphate translocase
Role of the enzyme
  • Hydrolysis of glucose-6-phosphate to glucose and inorganic phosphate
  • Glycogenolysis
  • Glycogenesis
  • Glycogenolysis
  • Glycogenolysis
Characteristic features
  • Generalized muscle weakness, exercise intolerance (with a second wind phenomenon) ,
  • Rhabdomyolysis and myoglobinuria
  • Flat venous lactate curve with exaggerated elevations in blood ammonia during exercise

The first six glycogen storage diseases can be remembered with the mnemonic “Very POMPous CORI ANDERSON Met Her”.

Summary of clinical features

Glycogen storage disorders can be classified based on the presenting symptoms as muscle and/or liver GSD.

Muscle involvement (muscle GSD): Types II, III, IV, V

  • Two groups of skeletal muscle symptoms are seen:
    • Defects of muscle glycogenolysis and muscle glycolysis:
      • Easy fatiguability, exercise intolerance
      • Cramps
      • Rhabdomyolysis → myoglobinuria (burgundy colored urine)
    • Defects of muscle glycogenesis (type IV) and lysosomal glycogenolysis; (type II): progressive weakness of extremities and trunk (proximal myopathy)
  • Cardiac involvement (hypertrophic cardiomyopathy and/or conduction defects) is seen only in type II

Pompe trashes the Pump (heart)!

Liver involvement (liver GSD): Types I, III, IV

Additional clinical manifestations

Types III and IV (late-onset type) may present with both muscle and liver involvement!

Diagnostics

Therapy

  • Most forms of GSD can be managed effectively with dietary therapy (e.g., corn starch, glucose preparations) with the aim of prevent hypoglycemia and/or muscle symptoms
  • Fructose and galactose-containing food should be avoided in patients with Type I GSD
  • Definitive therapy

References:[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]

Galactosemia

  • Galactosemia refers to hereditary defects in enzymes that are responsible for the metabolism of galactose
  • Epidemiology
    • Incidence: 1 in 60,000 live births
    • Sex: =
    • Age of onset: infancy
  • Mode of inheritance: autosomal recessive
  • Types of galactosemia
Deficient enzyme Galactokinase Galactose-1-phosphate uridyltransferase
Relative frequency
  • Rare
  • Common (classic galactosemia)
Role of enzyme
  • Converts galactose to galactose-1-phosphate
  • Converts galactose-1-phosphate to UDP-galactose.
Disease severity
  • Mild
  • Severe
Clinical features
  • Diagnostics
  • Treatment: complete cessation of lactose-containing feeds and lifelong adherence to a galactose-free and lactose-free diet

References:[1][28][29]

Disorders of fructose metabolism

Disorder Hereditary fructose intolerance Essential fructosuria
Incidence
  • 1 in 26,000 live births
  • 1 in 120,000 live births
Mode of inheritance
Deficient enzyme
Role of enzyme
  • Converts fructose-1-phosphate to glyceraldehyde and dihydroxyacetone phosphate
Effect of enzyme deficiency
  • Increased conversion of fructose to fructose-6-phosphate by hexokinase
  • Remaining excess fructose → excretion of fructose in urine
Age of onset
  • 6 months
  • Asymptomatic
Clinical features
Diagnostics
  • Detection of reducing substances (fructose) in urine
Treatment
  • Lifelong adherence to a fructose-free and sucrose-free diet
  • No treatment is required

References:[30][9][31][32]