• Clinical science

Inborn errors of carbohydrate metabolism

Abstract

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 0 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 VII (Tarui disease)
Type 0a Type 0b Type 1a Type 1b
Relative frequency
  • <1%
  • ∼25%
  • ∼15%
  • ∼25%
  • ∼3%
  • ∼2%
  • ∼30%
  • <1%
Gene defect
Deficient enzyme
  • Glucose-6-phosphate translocase
  • Muscle phosphofructokinase
Role of the enzyme
  • Glycogenesis in the liver
  • Glycogenesis in muscles
  • 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 0b, II, III, IV, V, VII, X, XI, XII, XIII, XIV, XV, phosphoglycerate kinase deficiency, RBCK1 deficiency

  • Two groups of skeletal muscle symptoms are seen:
    • Defects of muscle glycogenolysis and muscle glycolysis:
      • Easy fatiguability, exercise intolerance
      • Cramps
      • Rhabdomyolysismyoglobinuria (burgundy colored urine)
    • Defects of muscle glycogenesis (types IV and XV) 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 types 0b, II, and XV

Pompe trashes the Pump (heart)!

Liver involvement (liver GSD): Types 0a, I, III, IV, VI, IX, GLUT 2 deficiency

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 Uridine diphosphate galactose-4-epimerase
Relative frequency
  • Rare
  • Common (classic galactosemia)
  • Rare
Role of enzyme
  • Converts galactose to galactose-1-phosphate
  • Converts galactose-1-phosphate to UDP-galactose.
  • Converts UDP-galactose to glucose-1-phosphate
Disease severity
  • Mild
  • Severe
  • Usually asymptomatic
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 Fructose-1,6-biphosphatase deficiency
Incidence
  • 1 in 26,000 live births
  • 1 in 120,000 live births
  • 1 in 20,000 live births
Gene defect
Mode of inheritance
Deficient enzyme
  • Fructose-1,6-biphosphatase
Role of enzyme
  • Converts fructose-1-phosphate to glyceraldehyde and dihydroxyacetone phosphate
  • Converts fructose-1,6-biphosphate to fructose-6-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
  • ∼1 week after birth (in 50% of cases)
Clinical features
  • Episodic hypoglycemia
  • Lactic acidosis, ketoacidosis (especially after an illness)
  • Hepatomegaly
Diagnostics
  • Detection of reducing substances (fructose) in urine
  • Definitive diagnosis
    • Enzyme assay in leucocytes, liver biopsy and/or, intestinal biopsy samples
    • DNA testing for genetic defects
Treatment
  • Lifelong adherence to a fructose-free and sucrose-free diet
  • No treatment is required
  • Treat acute episodes with IV glucose
  • Lifelong adherence to a fructose-free and saccharose-free diet
  • Avoid prolonged fasting

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