Inborn error of metabolism

Inborn error of metabolism
Inborn error of metabolism
Classification and external resources
ICD-10 E70-E90
ICD-9 270-279
MedlinePlus 002438
eMedicine emerg/768
MeSH D008661

Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic diseases.

The term inborn error of metabolism was coined by a British physician, Archibald Garrod (1857–1936), in the early 20th century (1908). He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism was published in 1923.


Major categories of inherited metabolic diseases

Traditionally the inherited metabolic diseases were categorized as disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases. In recent decades, hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated. Following are some of the major classes of congenital metabolic diseases, with prominent examples of each class. Many others do not fall into these categories. ICD-10 codes are provided where available.


In a study in British Columbia, the overall incidence of the inborn errors of metabolism were estimated to be 70 per 100,000 live births or 1 in 1,400 births,[1] overall representing more than approximately 15% of single gene disorders in the population.[1]

Type of inborn error Incidence
Disease involving amino acids (e.g. PKU), organic acids,
primary lactic acidosis, galactosemia, or a urea cycle disease
24 per 100 000 births[1] 1 in 4,200[1]
Lysosomal storage disease 8 per 100 000 births[1] 1 in 12,500[1]
Peroxisomal disorder ~3 to 4 per 100 000 of births[1] ~1 in 30,000[1]
Respiratory chain-based mitochondrial disease ~3 per 100 000 births[1] 1 in 33,000[1]
Glycogen storage disease 2.3 per 100 000 births[1] 1 in 43,000[1]

Manifestations and presentations

Because of the enormous number of these diseases and wide range of systems affected, nearly every "presenting complaint" to a doctor may have a congenital metabolic disease as a possible cause, especially in childhood. The following are examples of potential manifestations affecting each of the major organ systems: many manifestations may develop

Diagnostic techniques

Dozens of congenital metabolic diseases are now detectable by newborn screening tests, especially the expanded testing using mass spectrometry. This is an increasingly common way for the diagnosis to be made and sometimes results in earlier treatment and a better outcome. There is a revolutionary GC/MS based technology with an integrated analytics system, which has now made it possible to test a newborn for over 100 genetic metabolic disorders.

Because of the multiplicity of conditions, many different diagnostic tests are used for screening. An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis.

Common screening tests used in the last sixty years:

Specific diagnostic tests (or focused screening for a small set of disorders):


In the middle of the 20th century the principal treatment for some of the amino acid disorders was restriction of dietary protein and all other care was simply management of complications. In the past twenty years, enzyme replacement, gene transfer, and organ transplantation have become available and beneficial for many previously untreatable disorders. Some of the more common or promising therapies are listed:

  • Dietary restriction
    • E.g., reduction of dietary protein remains a mainstay of treatment for phenylketonuria and other amino acid disorders
  • Dietary supplementation or replacement
  • Vitamins
  • Intermediary metabolites, compounds, or drugs that facilitate or retard specific metabolic pathways
  • Dialysis
  • Enzyme replacement E.g. Acid-alpha glucosidase for Pompe disease
  • Gene transfer
  • Bone marrow or organ transplantation
  • Treatment of symptoms and complications
  • Prenatal diagnosis and avoidance of pregnancy or abortion of an affected fetus


For clinicians and scientists in the field of inborn errors of metabolism, good resources include books by Scriver,[2] Fernandes,[3] Clarke,[4] Blau (diagnosis),[5] Blau (treatment),[6] Lyon,[7] Nyhan,[8] Hoffmann,[9] and Zschocke.[10] Other resources include genetests, orphanet, OMIM, Metab-L, societies such as the SSIEM, the SIMD and links therein. For medical students and clinicians looking for overviews of the field, such reviews can be found on pubmed and in good pediatric textbooks (e.g. articles by Saudubray,[11] Ellaway,[12] Raghuveer[13] or Burton,[14] and textbooks by Hay[15] or Behrman[16]).

For patients, their families or other individuals seeking good information and support groups, the National Institutes of Health offers the office of rare diseases, genetics home reference, medlineplus and health information. The National Human Genome Research Institute hosts an information center, a section for patients and the public and additional educational resources. Support groups can be found at NORD, Genetic Alliance and Orphanet. The genetic education center at the KUMC has many more useful links.


  1. ^ a b c d e f g h i j k l Applegarth DA, Toone JR, Lowry RB (January 2000). "Incidence of inborn errors of metabolism in British Columbia, 1969-1996". Pediatrics 105 (1): e10. doi:10.1542/peds.105.1.e10. PMID 10617747. 
  2. ^ Charles Scriver, Beaudet, A.L., Valle, D., Sly, W.S., Vogelstein, B., Childs, B., Kinzler, K.W. (accessed 2007). The Online Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill. - Summaries of 255 chapters, full text through many universities. There is also the OMMBID blog.
  3. ^ Fernandes, J.; Saudubray, J.M.; van den Berghe, G.; Walter, J.H. (2006). Inborn Metabolic Diseases : Diagnosis and Treatment (4th ed.). Springer. p. 561 p. 
  4. ^ Clarke, J.T.R. (2005). A Clinical Guide to Inherited Metabolic Diseases (3rd ed.). Cambridge: Cambridge University Press. p. 358 p. doi:10.2277/0521614996. ISBN 978-0521614993. 
  5. ^ Blau, N.; Duran, M.; Blaskovics, M.E.; Gibson, K.M. (2002). Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases (2nd ed.). Springer. p. 716 p. ISBN 978-3-540-42542-7. 
  6. ^ Blau, N; Hoffmann, G.F.; Leonard, J.; Clarke, J.T.R. (2006). Physician's Guide to the Treatment And Follow-up of Metabolic Diseases (1st ed.). Springer. p. 416 p. ISBN 3-540-22954-X. 
  7. ^ Lyon, G.; Kolodny, E.H.; Pastores, G. (2006). Neurology of Hereditary Molecular & Metabolic Disease of Children (3rd ed.). McGraw-Hill Professional. p. 500p. 
  8. ^ Nyhan, W.L.; Barshop, B.; Ozand, P.T. (2005). Atlas of Metabolic Diseases (2nd ed.). Oxford University Press. p. 800 p. 
  9. ^ Hoffmann, G.F; Nyhan, W.L.; Zschocke, J.; Kahler, S.G; Mayatepek, E. (2001). Inherited Metabolic diseases. Lippincott Williams & Wilkins. p. 448 p. 
  10. ^ Zschocke, J; Hoffmann, G.F. (2004). Vademecum Metabolicum (2nd ed.). Schattauer GmbH. p. 176 p. 
  11. ^ Saudubray J, Sedel F, Walter J (2006). "Clinical approach to treatable inborn metabolic diseases: an introduction". J Inherit Metab Dis 29 (2–3): 261–74. doi:10.1007/s10545-006-0358-0. PMID 16763886. 
  12. ^ Ellaway C, Wilcken B, Christodoulou J (2002). "Clinical approach to inborn errors of metabolism presenting in the newborn period". J Paediatr Child Health 38 (5): 511–7. doi:10.1046/j.1440-1754.2002.00047.x. PMID 12354271. 
  13. ^ Raghuveer T, Garg U, Graf W (2006). "Inborn errors of metabolism in infancy and early childhood: an update". Am Fam Physician 73 (11): 1981–90. PMID 16770930. 
  14. ^ Burton B (1998). "Inborn errors of metabolism in infancy: a guide to diagnosis". Pediatrics 102 (6): E69. doi:10.1542/peds.102.6.e69. PMID 9832597. 
  15. ^ Hay, W.H., Jr.; Levin, M.J.; Sondheimer, J.M.; Deterding, R.R. (2006). Current Pediatric Diagnosis and Treatment (18th ed.). McGraw-Hill. p. 1306 p. 
  16. ^ Behrman, R.E.; Kliegman, R.M.; Jenson, H.B. (2004). Nelson Textbook of Pediatrics (17th ed.). Elsevier. p. 2672 p. 

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