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Inborn Errors of Metabolism - an Introduction

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PatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.

See also: Glycogen Storage Disorders written for patients

Inborn errors of metabolism (IEMs) are defined by:

  • Their clinical features
  • Specific enzyme affected
  • Their pattern of inheritance

They show considerable variation in the way they present because of:

  • Different parts of a single enzyme are affected by different mutations of the same gene.
  • Different genes affecting different enzymes with similar functions.
  • Overall differences in the patient's genetic make-up.
  • Environmental factors.
  • Mutations can either change the protein structure of the enzyme or the quantity of enzyme produced and their effects can vary from mild to fatal. Those that present in newborns are normally severe and may prove fatal if not treated promptly. Other milder forms may not be diagnosed for months or years.

The incidence is 40 cases/100,000 live births in a Canadian study.[1] In an Italian cohort of 1,935 cases, the last 5 years showed an incidence of 36.25/100,000.[2] This showed an increase on previous years, possibly reflecting improved diagnostic facilities, better coverage, increased medical awareness and newly discovered diseases.

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Suspect this is the cause in:

  • Children with neurological abnormalities, delayed development or feeding difficulties, especially when several systems are involved with acute symptoms.[3]
  • 20% of term infants who develop symptoms of sepsis without known risk factors, may have an inborn error of metabolism.[4]
  • Hepatomegaly is common.
  • An unusual smell to the urine can be indicative of a problem.
  • There may also be periods of vomiting with no clear explanation.
  • Inborn errors of metabolism (IEMs) can also present with acidosis or renal stones.

The more common metabolic disorders include defects in metabolism of:

Amino acids

  • Phenylalanine - common disorder causing phenylketonuria (PKU):
    • This results in severe progressive mental retardation, if untreated by diet.[5]
    • Newborn screening for PKU has been performed by heel prick since 1969.
    • A low phenylalanine diet is required.
    • Strict compliance to the diet is necessary to reduce or to prevent mental retardation.
  • Tyrosine - tyrosinaemia,[6] alkaptonuria and albinism.
  • Methionine - homocystinuria is the most common form.
  • Cystine - cystinuria and cystinosis and sulphite oxidase deficiency.
  • Tryptophan - Hartnup disorder.[7]
  • Leucine, isoleucine and valine - maple syrup urine disease (MSUD):[8]
    • This is a rare disorder involving the breakdown of the branch chain amino acids.
    • Typically, it is found shortly after birth and is characterised by maple syrup odour of the urine, vomiting, refusing to eat and increased reflex actions.[9]
    • If left untreated, life-threatening neurological damage may result.
    • Treatment includes a special diet.
    • Strict compliance is necessary to prevent neurological damage.
  • Glycine - nonketotic glycinaemia:
    • This also called glycine encephalopathy.
    • It is caused by deficiency of the glycine cleavage multi-enzyme system.
    • The gene is thought to be located on the short arm of chromosome 9.
  • Hyperammonaemia - due to a defect in detoxification of ammonia to urea.
  • Aspartic acid - Canavan's disease.
    • The clinical features include onset in early infancy, atonia of neck muscles, hypotonia, hyperextension of legs and flexion of arms, blindness, severe mental defects, megalocephaly and usually death by 18 months old.
    • The neurological findings are due to demyelination and leukodystrophy.


These include disorders of:

  • Mitochondrial fatty acid oxidation (particularly medium chain acetyl-CoA dehydrogenase deficiency - see separate article MCAD Deficiency - now part of the newborn screening programme).[10][11]
  • Very long chain fatty acids, eg peroxisomal disorders and adrenoleukodystrophy (ALD):
    • Leukodystrophies cause damage to the myelin sheath.
    • People with ALD accumulate high levels of saturated, very long chain fatty acids (VLCFAs) in the brain and adrenal cortex.
    • The loss of myelin and the progressive dysfunction of the adrenal gland are the primary characteristics of ALD. Treatment with adrenal hormones can be lifesaving.
    • There is evidence that a mixture of oleic acid and erucic acid, 'Lorenzo's Oil', can reduce or delay the appearance of symptoms when given to boys with X-linked ALD.[12]
    • Bone marrow transplants may provide long-term benefit to boys who have early evidence of X-linked ALD; however, the procedure carries risks and is not recommended for those whose symptoms are already severe, or who have the adult-onset or neonatal forms.
    • Oral administration of docosahexaenoic acid (DHA) may help infants and children with neonatal ALD.
  • Lipoprotein metabolism and transport causing the hypolipidaemias.
  • Lipidoses - lipid storage disorders, mucolipidoses.


These include:

  • Galactosaemia:
    • This involves the failure of breakdown of the carbohydrate galactose to glucose.[13]
    • It can result in cataracts, enlarged liver, enlarged spleen and mental retardation.[9]
    • Typically, the disease is found in milk-fed infants shortly after birth (because milk contains large amounts of galactose).
    • Food sources of galactose include mammalian milks, dairy products and foods containing them.
    • It is recommended that milk and milk products should be avoided, including yoghurt, cheese, and ice cream. Galactose and lactose-free milk substitutes and foods should be used.
    • Other sources of galactose may include sugar beets, gums, seaweed, flaxseed, mucilage, whey, some vegetables, etc.
    • Women who carry the genetic trait should also follow the diet since galactose may cause mental retardation to the fetus.
  • Glycogen storage diseases.[14][15]
  • Essential benign pentosuria.
  • Disorders of glycoprotein metabolism.
  • Mucopolysaccharidoses - caused by deficiency of enzymes responsible for the breakdown of glycosaminoglycans.

Purine and pyrimidine disorders

These include hyperuricaemia leading to gout and Lesch-Nyhan syndrome.[16]

The porphyrias

Porphyrias are caused by deficiency of enzymes involved in the biosynthesis of haem:

  • The result is a deficiency or inactivity of a specific enzyme in the haem production process, with resulting accumulation of haem precursors.
  • Some porphyrias result in photosensitivity, because certain porphyrins are deposited in the skin.
  • When exposed to light and oxygen, these porphyrins can generate a charged, unstable form of oxygen, capable of damaging the skin.
  • Nerve damage, leading to pain and even paralysis, can also occur in some porphyrias.[17] 
  • Some porphyrias result in abdominal pain and liver damage.[18]

There are various approaches:

  • Restriction of dietary intake.
  • Replacement of missing enzyme, metabolite or cofactor.
  • Removal of toxic metabolite - approximately half of all inborn errors of metabolism can be treated biochemically, although the success of such treatment is variable.[11]
  • Transplantation of bone marrow or liver.

Screening of all neonates for a wide range of errors.[11][19] [X20038]

Further reading & references

  • King MW©; King MW©, Bioresearch Website Index page to all Inborn Errors of Metabolism
  1. Applegarth DA, Toone JR, Lowry RB; Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. 2000 Jan;105(1):e10.
  2. Dionisi-Vici C, Rizzo C, Burlina AB, et al; Inborn errors of metabolism in the Italian pediatric population: a national J Pediatr. 2002 Mar;140(3):321-7.
  3. Calvo M, Artuch R, Macia E, et al; Diagnostic approach to inborn errors of metabolism in an emergency unit. Pediatr Emerg Care. 2000 Dec;16(6):405-8.
  4. Weiner D; Paediatrics, Inborn Errors of Metabolism, eMedicine, Mar 2009
  5. Phenylketonuria, PKU; Online Mendelian Inheritance in Man (OMIM)
  6. Tyrosinemia; Type 1, Online Mendelian Inheritance in Man (OMIM)
  7. Hartnup Disorder, Online Mendelian Inheritance in Man (OMIM)
  8. Maple Syrup Urine Disease, MSUD; Online Mendelian Inheritance in Man (OMIM)
  9. Inborn Errors of Metabolism, MedlinePlus, October 2007
  10. Acyl-CoA Dehydrogenase, medium-chain, deficiency of, ACADMD; Online Mendelian Inheritance in Man (OMIM)
  11. NHS Newborn Bloodspot Screening Programme; Public Health England
  12. Adrenoleukodystrophy, National Institute of Neurological Disorders and Stroke
  13. Galactosemia; Online Mendelian Inheritance in Man (OMIM)
  14. Ozen H; Glycogen storage diseases: New perspectives. World J Gastroenterol. 2007 May 14;13(18):2541-53.
  15. Glycogen Storage Disease V, GSD5; Online Mendelian Inheritance in Man (OMIM)
  16. Lesch Nyhan Syndrome, LNS; Online Mendelian Inheritance in Man (OMIM)
  17. Porphyria, Acute Intermittent, AIS; Online Mendelian Inheritance in Man (OMIM)
  18. Porphyrias, Merck Manual, February 2003
  19. Wilcken B, Wiley V, Hammond J, et al; Screening newborns for inborn errors of metabolism by tandem mass spectrometry. N Engl J Med. 2003 Jun 5;348(23):2304-12.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Hayley Willacy
Current Version:
Document ID:
1561 (v25)
Last Checked:
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