MCAD Deficiency

oPatientPlus 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.

Synonyms: medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, ACADM deficiency

This is an autosomal recessive inherited disorder of fatty acid metabolism, caused by a mutation of the medium-chain acyl-CoA dehydrogenase gene (ACADM) on chromosome 1. The gene has been mapped to locus 1p31; several allelic variations have been reported. The most common mutation is called G985. This is because of a substitution of a guanine for an adenine nucleotide at the 985th residue.

Fatty acids are unable to be metabolised beyond the medium-chain size (8-12 carbon stage), and gluconeogenesis is effectively inhibited. In response to any fasting or metabolic stress (eg, illness) the body is unable to metabolise fat (so no ketones are produced), and continues to metabolise glucose producing hypoglycaemia.[1] The clinical result is severe hypoglycaemia and hypoketonuria, with accumulation of monocarboxylic fatty acids and dicarboxylic organic acids.

The incidence is up to 1 in every 12,000 births.[2] 

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Typically this presents clinically with failure of fatty acid oxidation after fasting and an inability to generate energy during periods of increased energy demand. This may cause variable presentation, including symptomatic hypoglycaemia, hepatic encephalopathy or sudden unexpected infant death. Most cases present before 2 years of age (mean age 13 months), although a variable spectrum of disease is increasingly recognised, with presentations both in the neonatal period and in adulthood.

About a third of affected individuals remain asymptomatic throughout life but may be at risk of metabolic decompensation in periods of critical energy supply - eg, during infection or prolonged fasting.[3] 

  • Age at presentation is quite variable.
  • It most commonly presents in infants aged >3 months, when overnight feeds reduce in frequency. The gap between feeds is then long enough for acute hypoglycaemia to occur, producing symptoms of preprandial irritability, drowsiness, jitteriness, sweating, coma and seizures.
  • It can present as sudden death in adults. There is a 25% mortality rate in undiagnosed cases.
  • It can present with:
    • Life-threatening hypoketotic hypoglycaemic coma.
    • Metabolic acidosis.
    • Encephalopathy.
    • Hepatomegaly and fatty infiltration of viscera.
  • In later childhood it may present with episodic hypoglycaemia - eg, with sweating, collapse, confusion, or developmental delay.
  • It has been reported presenting after a first episode of alcohol intoxication.[4]
  • It very occasionally presents in adulthood with muscle weakness and fatigue.
  • Survivors of acute episodes may have severe hypoglycaemia-induced brain damage.

These may be normal in between attacks.

  • Acutely - hypoglycaemia.
  • U&E may show high or low bicarbonate and reduced anion gap.
  • LFTs may show elevated enzymes, low plasma carnitine.
  • Urine - medium-chain dicarboxylic aciduria and absent ketones.

Skin biopsy can be performed to confirm diagnosis of primary carnitine deficiency - demonstrating reduced carnitine transport in fibroblasts. Fibroblasts may be used for fatty acid oxidation studies or enzyme assay.

  • Avoidance of fasting.[5] A maximum duration of fasting in children with MCAD deficiency of:[6] 
    • Between 6 months and 1 year of age - eight hours.
    • In the second year of life - ten hours.
    • Thereafter - twelve hours.
    • There are no firm guidelines on the duration of fasting during situations of intercurrent illness, especially with fever.
  • Because the fundamental biochemical defect is in fatty acid oxidation, the composition of the diet should be adjusted to provide greater calories in carbohydrates and proteins, while minimising lipids.
  • Daily carnitine supplementation may be required.[7] 
  • Genetic counselling should be provided for family members.
  • The heterozygous state is quite common. Testing for the gene should be offered to first-degree relatives of an affected child.
  • Frequent episodes of severe hypoglycaemia carry a risk of adverse effects in the CNS.
  • Hypoglycaemia and hyperammonaemia may cause cerebral oedema and prolonged coma.

About 25% of patients with undiagnosed MCAD deficiency die at or shortly after the first presentation. A further large group of undiagnosed patients presents too late to prevent long-term neurological disability.

If the diagnosis is made early, children with this deficiency can expect to lead a full and normal life, with simple dietary treatment aimed mainly at the avoidance of fasting.

This is technically possible by demonstrating a marked reduction in octanoate oxidation in cultured amniotic cells obtained via amniocentesis.

Biochemically, MCAD deficiency is characterised by elevated medium-chain acylcarnitines in blood, particularly octanoylcarnitine. It can be identified by screening of dried blood spots via quantitative detection of acylcarnitines using mass spectrometry.[8] 

The Department of Health introduced routine MCAD deficiency screening in the neonatal blood spot screen from February 2009.[9]

Further reading & references

  1. Acyl-CoA Dehydrogenase, medium-chain, deficiency of, ACADMD; Online Mendelian Inheritance in Man (OMIM)
  2. Carroll JC, Gibbons CA, Blaine SM, et al; Genetics: newborn screening for MCAD deficiency. Can Fam Physician. 2009 May;55(5):487.
  3. Loughrey C, Bennett MJ; Screening for MCAD deficiency in newborns. BMJ. 2009 Mar 12;338:b971. doi: 10.1136/bmj.b971.
  4. Mayell SJ, Edwards L, Reynolds FE, et al; Late presentation of medium-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2006 Nov 30;.
  5. Touw CM, Smit GP, Niezen-Koning KE, et al; In vitro and in vivo consequences of variant medium-chain acyl-CoA dehydrogenase genotypes. Orphanet J Rare Dis. 2013 Mar 20;8:43. doi: 10.1186/1750-1172-8-43.
  6. Derks TG, van Spronsen FJ, Rake JP, et al; Safe and unsafe duration of fasting for children with MCAD deficiency. Eur J Pediatr. 2007 Jan;166(1):5-11. Epub 2006 Jun 21.
  7. Couce ML, Sanchez-Pintos P, Diogo L, et al; Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: regional experience and high incidence of carnitine deficiency. Orphanet J Rare Dis. 2013 Jul 10;8:102. doi: 10.1186/1750-1172-8-102.
  8. Kennedy S, Potter BK, Wilson K, et al; The first three years of screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) by newborn screening ontario. BMC Pediatr. 2010 Nov 17;10:82. doi: 10.1186/1471-2431-10-82.
  9. NHS Newborn Bloodspot Screening Programme; Public Health England

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:
Peer Reviewer:
Dr Adrian Bonsall
Last Checked:
20/06/2014
Document ID:
2438 (v24)
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