Inborn Errors of Metabolism - an Introduction

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Inborn errors of metabolism (IEMs) comprise a group of disorders in which a single gene defect causes a clinically significant block in a metabolic pathway resulting in either accumulation of substrate behind the block or deficiency of the product.

IEMs are defined by:

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

The incidence is 40 cases/100,000 live births in a Canadian study[1]. A much higher incidence of 1 in 784 live births has been reported from the West Midlands in the UK[2]. This is attributed to the effect of ethnicity and consanguinity in the local population. Likewise a high incidence of 150 cases per 100,000 live births has been reported from Saudi Arabia[3].

Most metabolic disorders present early in life although milder forms may remain undetected until adulthood. Various presentations are recognised:

  • A neonate or infant presenting with acute metabolic encephalopathy. The initial finding is usually poor feeding and lethargy as in any sick infant and the initial diagnosis is often sepsis. However, in the absence of risk factors for sepsis and poor response to treatment, metabolic disorder needs to be considered. Lethargy can progress to coma and other signs of CNS dysfunction such as abnormal tone or seizures may occur.
  • Persistent vomiting in infancy with no clear explanation should raise suspicion of IEM, possibly a defect of protein metabolism.
  • Presence of severe metabolic acidosis with increased anion gap should arouse suspicion of an IEM.
  • Hypoglycaemia and its associated symptoms such as lethargy or seizures may be a presenting feature in disorders of carbohydrate metabolism or fatty oxidation.
  • Jaundice or other evidence of liver dysfunction can be a presenting feature of IEMs such as galactosaemia and glycogen storage disorders.
  • Hepatomegaly in the neonatal period or infancy may be a presenting feature of storage disease.
  • Coarse facial features along with hepatosplenomegaly and skeletal abnormalities are typical of mucopolysaccharidosis.
  • A diagnosis of IEM should also be considered in children with cerebral palsy or developmental delay[5].
  • Abnormal body or urine odour - often noted by mothers or nurses - is an important feature of many IEMs.
  • IEMs may be an urecognised cause of intellectual disability in adults[6].
  • IEMs can also present with acidosis or renal stones.

The more common metabolic disorders include the following.

Defects in metabolism of amino acids

  • Phenylalanine - common disorder causing phenylketonuria (PKU):
    • An autosomal recessive disorder because of deficiency of enzyme phenylalanine hydroxylase.
    • This results in severe progressive intellectual disability, if untreated by diet[8].
    • 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 intellectual disability.
  • Tyrosine - tyrosinaemia, alkaptonuria and albinism[9].
  • Methionine - homocystinuria and hypermethioninaemia.
  • Cystine - cystinuria and cystinosis and sulfite oxidase deficiency.
  • Tryptophan - Hartnup's disorder[10].
  • Leucine, isoleucine and valine - maple syrup urine disease (MSUD)[11]:
    • This is a rare disorder due to deficiency of the enzyme branch chain alpha ketoacid dehydrogenase.
    • Affected infants are normal at birth, developing poor feeding and vomiting in the first week of life; lethargy and coma may develop in a few days.
    • Physical examination shows increased tone and muscular rigidity with opisthotonus which can often lead to a wrong diagnosis of sepsis with meningitis.
    • Diagnosis is often suspected because of the peculiar odour of maple syrup found in urine and sweat.
    • If left untreated, life-threatening neurological damage may result.
    • Treatment includes a special diet low in branched chain amino acids.
    • Strict compliance is necessary to prevent neurological damage.
  • Glycine - nonketotic hyperglycinaemia, or glycine encephalopathy:
    • It is caused by deficiency of the glycine cleavage multi-enzyme system.
    • Four forms have been identified including neonatal, infantile, late-onset and transient.
    • The neonatal form is the most common and most severe, with babies becoming very unwell in the first few days of life. Poor feeding, lethargy and hypotonia proceeds to coma and seizures with many babies dying and survivors left with profound psychomotor impairment.
  • Urea cycle and hyperammonaemia:
    • Catabolism of amino acids results in production of free ammonia which is very toxic to the CNS. The ammonia is detoxified to urea.
    • Five enzymes are involved in the synthesis of urea and deficiency of any of the individual enzymes can cause hyperammonaemia.
    • In neonates, symptoms of poor feeding, vomiting, lethargy progressing to coma and convulsions develop within days of starting feeding.
    • Clinical features of hyperammonaemia in older infants and children are vomiting and neurologic abnormalities such as ataxia, confusion, agitation and irritability. Coma can develop.
  • Lysine - glutaric aciduria type 1:
    • Affected infants may have normal development up to 2 years of age.
    • Macrocephaly is common.
    • Symptoms of hypotonia, choreoathetosis, seizures and generalised rigidity may develop suddenly after a minor infection.
  • Aspartic acid - Canavan's disease:
    • This is an autosomal recessive condition characterised by spongy degeneration of white matter of the brain, leading to a severe form of leukodystrophy.
    • Infants are usually normal until 3-6 months of age when they start developing progressive macrocephaly, hypotonia and developmental delay. Hypertonia, stiffness and contractures develop, as are seen in cerebral palsy.
    • Seizures and optic atrophy develop and most die in the first decade of life.

Defects in metabolism of lipids

These include:

  • Disorders of mitochondrial fatty acid beta-oxidation (particularly medium chain acetyl-CoA dehydrogenase (MCAD) deficiency now part of the newborn screening programme) See separate MCAD Deficiency article.[12, 13]. Mitochondrial beta-oxidation of fatty acids is an essential energy-producing pathway which ensures energy production during periods of starvation or low calorie intake as would happen during any illness.
  • Disorders of very long chain fatty acids (VLCFAs), which include disorders because of failure to form or maintain the peroxisome (eg, Zellweger's syndrome) or because of a defect in the function of a single peroxisomal enzyme (eg, adrenoleukodystrophy (ALD)):
    • Leukodystrophies cause damage to the myelin sheath.
    • People with ALD accumulate high levels of saturated 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.
    • 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.
  • Disorders of lipoprotein metabolism and transport causing various hyperlipoproteinaemias, including:
    • Familial hypercholesterolaemia
    • Familial dysbetalipoproteinaemia
    • Familial chylomicronaemia
  • Lipidoses, or lysosomal storage disorders, caused by inherited deficiency of a lysosomal hydrolase leading to intralysosomal accumulation of the substrate of that enzyme. These include:
    • GM1 gangliosidoses.
    • GM2 gangliosidoses (Tay-Sachs disease and Sandhoff's disease).
    • Gaucher's disease.
    • Niemann-Pick disease.
    • Anderson-Fabry disease.
  • Mucolipidoses - eg, I-cell disease.

Defects in metabolism of carbohydrates[15]

These include:

  • Galactosaemia (defects in galactose metabolism):
    • This involves the failure of breakdown of the carbohydrate galactose to glucose[16].
    • It can result in cataracts, an enlarged liver, an enlarged spleen and intellectual disability.
    • Typically, the disease is found in milk-fed infants shortly after birth (because milk contains large amounts of lactose which break down into glucose and galactose). A lactose-free infant formula is life saving in the neonate.
    • 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 intellectual disability to the fetus.
  • Glycogen storage diseases[17, 18]. These are inherited metabolic disorders of glycogen metabolism. There are more than 12 different types which are classified based on the enzyme deficiency and tissues involved.
  • Defects in fructose metabolism - eg, essential or benign fructosuria.
  • Defects in intermediary carbohydrate metabolism associated with lactic acidosis - eg, Leigh's disease.


These are inherited progressive diseases resulting from deficiency or absence of lysosomal enzymes needed to degrade glycosaminoglycans. Several different types are described, including Hurler's syndrome and Hunter's syndrome.

Purine and pyrimidine disorders

These include hyperuricaemia leading to gout and Lesch-Nyhan syndrome[19].

The porphyrias[20]

Porphyrias are a set of diseases caused by defects in one of the eight individual enzymes involved in the biosynthesis of haem:

  • Deficiency or inactivity of a specific enzyme in the haem production process results in accumulation of haem precursors, usually in the bone marrow or liver.
  • Some porphyrias result in photosensitivity because certain porphyrins are deposited in the skin.
  • In the acute neurological porphyrias symptoms are due to overproduction of neurotoxic precursor.
  • Acute intermittent porphyria is the most common type. It is inherited in an autosomal dominant manner and is characterised by recurrent attacks of abdominal pain, gastrointestinal dysfunction and neurological disturbances[21].

This includes acute and long-term management:

  • Acute management in the sick neonate or infant focuses on preventing the build-up of toxic metabolites. Feeds are stopped and 10% dextrose infusion commenced to promote anabolism. Toxic metabolites can be removed by using carnitine in organic acidaemias or by using filtration and dialysis[22].
  • Dietary modification is the mainstay of treatment. The aim is to avoid or minimise intake of substrate affected by impaired metabolism and to ensure that the diet is nutritionally adequate. This usually means using a low-protein diet with extra dietary supplements.
  • Replacement of missing enzyme, metabolite or cofactor. Enzyme replacement therapy is now a well established treatment for some metabolic disorders, most notably Pompe's disease.
  • Removal of toxic metabolite by peritoneal or haemodialysis. Approximately half of all inborn errors of metabolism can be treated biochemically, although the success of such treatment is variable[13].
  • Transplantation of bone marrow, liver or kidney[23].

Screening of all neonates, using blood spot for a wide range of errors, is the most effective method and screening for PKU was introduced in 1969. Screening for MCAD deficiency was added in 2009.

The scope of NHS newborn bloodspot screening was widened in July 2015 with the inclusion of testing for four more inborn errors of metabolism[13]

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Further reading and references

  1. Applegarth DA, Toone JR, Lowry RB; Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. 2000 Jan105(1):e10.

  2. Sanderson S, Green A, Preece MA, et al; The incidence of inherited metabolic disorders in the West Midlands, UK. Arch Dis Child. 2006 Nov91(11):896-9. Epub 2006 May 11.

  3. Moammar H, Cheriyan G, Mathew R, et al; Incidence and patterns of inborn errors of metabolism in the Eastern Province of Saudi Arabia, 1983-2008. Ann Saudi Med. 2010 Jul-Aug30(4):271-7. doi: 10.4103/0256-4947.65254.

  4. Burton BK; Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics. 1998 Dec102(6):E69.

  5. Leach EL, Shevell M, Bowden K, et al; Treatable inborn errors of metabolism presenting as cerebral palsy mimics: systematic literature review. Orphanet J Rare Dis. 2014 Nov 309(1):197.

  6. Hope S, Johannessen CH, Aanonsen NO, et al; The investigation of inborn errors of metabolism as an underlying cause of idiopathic intellectual disability in adults in Norway. Eur J Neurol. 2016 Jan23 Suppl 1:36-44. doi: 10.1111/ene.12884.

  7. Nelson Textbook of Pediatrics, ed 20, 2015

  8. Phenylketonuria, PKU; Online Mendelian Inheritance in Man (OMIM)

  9. Tyrosinemia, Type 1, TYRSN1; Online Mendelian Inheritance in Man (OMIM)

  10. Hartnup Disorder, HND; Online Mendelian Inheritance in Man (OMIM)

  11. Maple Syrup Urine Disease, MSUD; Online Mendelian Inheritance in Man (OMIM)

  12. Acyl-CoA Dehydrogenase, medium-chain, deficiency of, ACADMD; Online Mendelian Inheritance in Man (OMIM)

  13. Newborn Bloodspot Screening Programme; Public Health England

  14. Mayatepek E, Hoffmann B, Meissner T; Inborn errors of carbohydrate metabolism. Best Pract Res Clin Gastroenterol. 2010 Oct24(5):607-18. doi: 10.1016/j.bpg.2010.07.012.

  15. Galactosemia; Online Mendelian Inheritance in Man (OMIM)

  16. Ozen H; Glycogen storage diseases: New perspectives. World J Gastroenterol. 2007 May 1413(18):2541-53.

  17. Glycogen Storage Disease V, GSD5; Online Mendelian Inheritance in Man (OMIM)

  18. Lesch-Nyhan Syndrome, LNS; Online Mendelian Inheritance in Man (OMIM)

  19. Bissell DM, Wang B; Acute Hepatic Porphyria. J Clin Transl Hepatol. 2015 Mar3(1):17-26. doi: 10.14218/JCTH.2014.00039. Epub 2015 Mar 15.

  20. Porphyria, Acute Intermittent, AIP; Online Mendelian Inheritance in Man (OMIM)

  21. Champion MB; An approach to diagnosis of inherited metabolic disease Arch Dis Child Educ Pract Ed 2010

  22. Capelli I, Battaglino G, Baraldi O, et al; Kidney Transplantation and inborn errors of metabolism. G Ital Nefrol. 2015 Mar-Apr32(2). pii: gin/32.2.30.