Links to other pages within Patient UK which are related to this topic:
Experience | Leaflets | Support | Weblinks | News | Products | Other
Print options:   Other options:   (what's this?)

This is a PatientPlus article. PatientPlus articles are written for doctors and so the language can be technical. However, some people find that they add depth to the articles found in the other sections of this website which are written for non-medical people.

Inborn Errors of Metabolism - an Introduction

These 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.
Epidemiology

The incidence is 40 cases/100 000 live births in a Canadian study.1 In an Italian cohort of 1,935 cases, in the last 5 years the incidence was 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.

Presentation

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 (IEM).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.
  • IEMs can also present with acidosis or renal stones.
Classification

The more common metabolic disorders include defects in metabolism of:

Amino acids

  • Phenylalanine - common disorder causing phenylketonuria:
    • 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 prevent mental retardation.
  • Tyrosine - tyrosinaemia,6 alcaptonuria and albinism
  • Methionine - homocystinuria is most common form
  • Cystine - cystinuria and cystinosis and sulphite oxidase deficiency
  • Tryptophan - Hartnup disorder7
  • Leucine, isoleucine and valine - maple syrup urine disease: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 - non-ketotic glycinaemia:
    • This also called glycine encephalopathy.
    • It is caused by deficiency of the glycine cleavage multienzyme system.
    • The gene is thought to be located on the short arm of chromosome 9.
  • Hyperammonaemia - due to defect in detoxification of ammonia to urea
  • Aspartic acid - Canavan 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.

Lipids

These include disorders of:

  • Mitochondrial fatty acid oxidation (particularly medium chain acetyl-CoA dehydrogenase deficiency - MCAD Deficiency10)
  • Very long chain fatty acids e.g. peroxysomal disorders and adrenoleukodystrophy (ALD):
    • Leukodystrophies cause damage to the myelin sheath.
    • People with ALD accumulate high levels of saturated, very long chain fatty acids (VLCFA) 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.11
    • 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 docosahexanoic acid (DHA) may help infants and children with neonatal ALD.
  • Lipoprotein metabolism and transport causing the hypolipidaemias
  • Lipidoses - lipid storage disorders, mucolipidoses

Carbohydrates

These include:

  • Galactosaemia:
    • This involves the failure of breakdown of the carbohydrate galactose to glucose.12
    • 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, 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 diseases13,14
  • Essential benign pentosuria
  • Disorders of glycoprotein metabolism
  • Mucopolysaccharidoses - caused by deficiency of enzymes responsible for breakdown of glycosaminoglycans

Purine and pyrimidine disorders

These include hyperuricaemia leading to gout and Lesch-Nyhan syndrome.15

The porphyrias

Caused by deficiency of enzymes involved in 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.16
  • Some porphyrias result in abdominal pain and liver damage.17
Management

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.18
  • Transplantation of bone marrow or liver
Prevention

Screening of all neonates for a wide range of errors.18,19


Document references
  1. Applegarth DA, Toone JR, Lowry RB; Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. 2000 Jan;105(1):e10. [abstract]
  2. Velazquez A, Vela-Amieva M, Ciceron-Arellano I, et al; Diagnosis of inborn errors of metabolism. Arch Med Res. 2000 Mar-Apr;31(2):145-50. [abstract]
  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. [abstract]
  4. Weiner D; Paediatrics, Inborn Errors of Metabolism; eMedicine (2005); Overview of Inborn Errors of metabolism
  5. Phenylketonuria, Online Mendelian Inheritance in Man (OMIM)
  6. Tyrosinaemia type 1, Online Mendelian Inheritance in Man (OMIM)
  7. Hartnup Disorder, Online Mendelian Inheritance in Man (OMIM)
  8. Maple Syrup Urine Disease, Online Mendelian Inheritance in Man (OMIM)
  9. Medline Plus; Inborn Errors of Metabolism. October 2007.
  10. MCAD Deficiency, Online Mendelian Inheritance in Man (OMIM)
  11. National Institute of Neurological Disorders and Stroke; Adrenoleukodystrophy information page. October 2007.
  12. Galactosemia, Online Mendelian Inheritance in Man (OMIM)
  13. Ozen H; Glycogen storage diseases: New perspectives. World J Gastroenterol. 2007 May 14;13(18):2541-53. [abstract]
  14. Glycogen Storage Disease V, Online Mendelian Inheritance in Man (OMIM)
  15. Lesch Nyhan Syndrome, Online Mendelian Inheritance in Man (OMIM)
  16. Acute Intermittent Porphyria, Online Mendelian Inheritance in Man (OMIM)
  17. Merck Manual; Porphyrias. February 2003.
  18. UK Newborn Screening Policy.; Newborn Screening Programme Centre Website.
  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. [abstract]

Internet and further reading
  • King M; Bioresearch Website Index page to all Inborn Errors of Metabolism.
  • Nelson Textbook of Pediatrics. 16th Edition. Behrman RE et al. WB Saunder Co. 2000.
Acknowledgements EMIS is grateful to Dr Hayley Willacy for writing this article. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2008.
DocID: 1561
Document Version: 22
DocRef: bgp357
Last Updated: 30 Jul 2008
Review Date: 30 Jul 2010

The authors and editors of this article are employed to create accurate and up to date content reflecting reliable research evidence, guidance and best clinical practice. They are free from any commercial conflicts of interest.

Find out more about updating.

(what's this?)

Patient UK Current Health News

Advertisements











Disclaimer: Patient UK has no control over the content of any external links above. Inclusion does not imply endorsement by Patient UK.

Want to advertise on this site? Find out how >>

Clicking here will take you to the foot of this page where you'll find a list of Information Leaflets which are related to the topic you are currently viewing
Clicking here will take you to the foot of this page where you'll find a list of Support Groups which are related to the topic you are currently viewing
Clicking here will take you to the foot of this page where you'll find a list of Medicines & Drugs which are related to the topic you are currently viewing
Clicking here will take you to the foot of this page where you'll find a list of diagrams which are related to the topic you are currently viewing
Clicking here will take you to the foot of this page where you'll find a list of PatientPlus (detailed reference) articles which are related to the topic you are currently viewing
Clicking here will take you to the foot of this page where you'll find a list of UK Guidelines which are related to the topic you are currently viewing
Clicking here will take you to the foot of this page where you'll find a list of other selected websites which are related to the topic you are currently viewing
Clicking here will take you to the foot of this page where you'll find a list of Poems and Stories which are related to the topic you are currently viewing
Clicking here will take you to the foot of this page where you'll find a list of Operations and Procedures which are related to the topic you are currently viewing
Clicking here will take you to the foot of this page where you'll find a list of Online Videos which are related to the topic you are currently viewing
Clicking here will take you to the foot of this page where you'll find links through to our interactive forum.
Here you can follow a link to view existing patient experiences on this subject, or to add your own
Clicking here will take you to the foot of this page where you'll find links to news stories on this subject in our Online Newspaper
Clicking here will take you to the foot of this page where you'll find links to related products
Clicking here will take you to the foot of this page where you'll find links to other useful sources of information
Click here to open a printer-friendly version of this document, in a new window, together with the print dialogue box
Click here to open this document in PDF format
This will offer you the usual PDF options i.e. document navigation, search, zoom and formatted print
Note: this is the best way to print the document
Click here to listen to the MP3 audio recording of this document
Click here to download the audio recording of this document as a podcast, for listening to at your leisure
Click here to open our Dictionaries and Glossaries page
Click here to see related products in our Online Pharmacy
Note: this will open in a new window
Click here to add this page to a social bookmarking site of your choice
Click here if you want to find out more about social bookmarking. This link will take you to the Wikipedia explanation
Note: this will open in a new window
Click here to return to the home page
Click here to read our 'About Us' page
Go to the Emis Access website, where you can book an appointment with your GP, order a repeat prescription or view you medical record online.
Note: this will open in a new window
View and/or join in discussion about health, lifestyle and disease in our interactive forum.
Note: this will open in a new window
Go to our online pharmacy where you can buy over-the-counter products for home delivery.
Note: this will open in a new window
Go to our online newspaper for current medical news and commentary.
Note: this will open in a new window
Adverts on this site do not influence the medical content. Click to read more.
Adverts on this site do not influence the medical content. Click to read more.