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Inborn errors of carbohydrate metabolism

Last updated: March 8, 2021

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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.

Overview

Epidemiology

Pathophysiology

Types of GSD

Overview of types of GSD [2][3][4]
Relative frequency Gene defect and deficient enzyme Role of the enzyme Characteristic features
Type I (von Gierke disease) Type 1a
  • ∼ 25%
Type 1b
Type II (Pompe disease)
  • ∼ 15%
Type III (Cori disease)
  • ∼ 25%
Type IV (Andersen disease)
  • ∼ 3%
Type V (McArdle disease)
  • ∼ 2%
  • Generalized muscle weakness, exercise intolerance (with a second wind phenomenon): Symptoms of muscle fatigue disappear after a period of activity because of increased muscular blood flow.
  • Demanding physical exercise may cause rhabdomyolysis and myoglobinuria.
  • Electrolyte imbalances can trigger cardiac arrhythmias.
  • Normal serum glucose levels
  • Flat venous lactate curve with exaggerated elevations in blood ammonia during exercise
  • Glycogen accumulates in muscles, but can not be metabolized due to enzyme deficiency
Type VI (Hers disease)
  • ∼ 30%

The first six glycogen storage diseases can be remembered with the mnemonic “a Very Presumptuous Corgi Ambles in the Middle of the Highway.”

McArdle affects the Muscles.

Clinical features

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

Additional clinical manifestations

Pompe punishes pump, liver, and muscle.”

Diagnostics [6]

Therapy [6]

  • General
    • Most forms of GSD can be managed effectively with dietary therapy (e.g., uncooked corn starch, glucose preparations) with the aim of preventing hypoglycemia and/or muscle symptoms
    • Foods rich in fructose and galactose should be avoided in patients with GSD type I
  • Definitive therapy

Galactosemia refers to hereditary defects in enzymes that are responsible for the metabolism of galactose (galactose is a component of the disaccharide lactose, which is present in breast milk).

Overview of types of galactosemia [10]
Galactokinase deficiency Classic galactosemia Uridine diphosphate galactose-4-epimerase deficiency
Epidemiology
Mode of inheritance
Enzyme
  • Galactokinase
  • Galactose-1-phosphate uridyltransferase
Relative frequency
  • Rare
  • Rare
Role of enzyme
  • Converts galactose to galactose-1-phosphate
  • Converts galactose-1-phosphate to UDP-galactose
Disease severity
  • Mild
  • Severe
Effect of enzyme deficiency
  • Accumulation of galactitol in tissues
  • Galactose is present in blood and urine
  • Accumulation of toxic substances in tissues (e.g., galactitol in the lens)
Clinical features
Diagnostics
Treatment
  • Complete cessation of lactose-containing feeds and lifelong adherence to a galactose-free and lactose-free diet


Fruits from the Galapagos are kind” (galactokinase and fructokinase deficiencies present with mild symptoms).

Overview of disorders of fructose metabolism [6][12]
Hereditary fructose intolerance Essential fructosuria
Incidence
Gene defect
Mode of inheritance
Deficient enzyme
Role of enzyme
Effect of enzyme deficiency
Age of onset
  • Within the first months of life [15]
  • Symptoms begin when the child is weaned off breast milk and starts consuming food that contains sucrose (e.g., fruit, juice)
  • Asymptomatic
Clinical features
Diagnostics
Treatment
  • Lifelong adherence to a fructose-free, sorbitol-free, and sucrose-free diet
  • No treatment is required

  1. Ozen H. Glycogen storage diseases: new perspectives.. World journal of gastroenterology. 2007; 13 (18): p.2541-53. doi: 10.3748/wjg.v13.i18.2541 . | Open in Read by QxMD
  2. Glycogen Storage Diseases (GSD) in Children. http://www.chp.edu/our-services/transplant/liver/education/liver-disease-states/glycogen-storage-diseases. . Accessed: May 12, 2017.
  3. GYS1 Gene: Glycogen Synthase 1. https://ghr.nlm.nih.gov/gene/GYS1#location. Updated: May 9, 2017. Accessed: May 12, 2017.
  4. Glycogen Storage Disease Type 0. https://ghr.nlm.nih.gov/condition/glycogen-storage-disease-type-0. Updated: May 9, 2017. Accessed: May 12, 2017.
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  10. Kliegman R, Stanton B, St. Geme J, Schor N. Nelson Textbook of Pediatrics. Elsevier ; 2015
  11. Lebigot E, Brassier A, Zater M et al. . Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic features in French patients. Journal of Inherited Metabolic Disease. 2015; 38 (5): p.881-887. doi: 10.1007/s10545-014-9804-6 . | Open in Read by QxMD
  12. Baker P II, Ayres L, Gaughan S, et al. Hereditary Fructose Intolerance. GeneReviews. 1993 .
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  14. Hegde VS, Sharman T. Hereditary Fructose Intolerance. StatPearls. 2020 .
  15. Galactosemia. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=352. Updated: December 1, 2011. Accessed: January 29, 2018.
  16. Coelho AI, Rubio-Gozalbo ME, Vicente JB, Rivera I. Sweet and sour: an update on classic galactosemia.. J Inherit Metab Dis. 2017; 40 (3): p.325-342. doi: 10.1007/s10545-017-0029-3 . | Open in Read by QxMD
  17. Kasper DL, Fauci AS, Hauser S, Longo D, Jameson LJ, Loscalzo J . Harrisons Principles of Internal Medicine . McGraw-Hill Medical Publishing Division ; 2016