What Are Common Fatty Acid Oxidation Metabolic Disorders?

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Patient Presentation
A 4-week-old male came to clinic for his well child visit. He had been a full-term infant with no known problems, but his parents had been called on day 3 of life for a possible fatty acid oxidation defect on his neonatal screening test. The genetic team evaluated him and additional testing had been sent and eventually was negative. He had always been a vigorous feeder and occasionally would have an effortless emesis after feeding. He did have mild jaundice in the first few days of life that resolved. The family history was negative for any neonatal or infant deaths. There was a paternal second cousin who died in a car accident but no unexplained sudden deaths. The mother had 1 previous first trimester spontaneous abortion. The review of systems was negative.

The pertinent physical exam showed a healthy appearing male with growth parameters in the 10-50%. Weight was 25-50%. He had no obvious abnormal stigmata on his face, head or extremities. Cardiac examination had normal S1, S2 without murmurs. Abdominal examination had no masses or hepatosplenomegaly. Tone and strength were normal.

The diagnosis of a healthy male was made. The parents related their story to the pediatrician and noted there had “been a lot of crying” about the possible diagnosis. “I’m still pretty vigilant watching him. I know that he doesn’t have it, but I worry about any little spit up or funny movement. I guess most parents do, and I know I’ll probably stop doing that as he gets bigger,” the mother stated. The pediatrician offered that these reactions were totally normal for a healthy baby, but with any child who has or could have a health problem, it usually makes the parents more concerned.

Discussion
All cells and particularly their mitochondria need an energy source. Glucose is one of the most common ones, but also fatty acids, lactate, pyruvate, ketones, and amino acids. Fatty acids are formed with a carboxylic acid with a long aliphatic carbon chain usually with even numbers of carbon atoms (usually 4-28 most commonly). Most are unbranched and in foods are usually found in the form of esters.

Fatty acids are important energy sources for the heart (50-70%) but also skeletal muscle where resting muscle uses both glucose and fatty acids. During fasting or increased stress fatty acids become a major source of energy in skeletal muscle. Regulation is by several factors including physiological state, organ system, substrate and co-substrate availability (such as oxygen or carnitine), blood supply, hormones, etc. Long-chain fatty acids need the carnitine transfer system to transport the substance across the outer mitochondrial membrane. Medium and short-chain fatty acids enter the mitochondria directly. Therefore carnitine availability and metabolism is vital for long-chain fatty acids metabolism but not for shorter ones.

Health problems occur when there is insufficient energy production and also build up of precursor metabolites.

With the increase and expansion of neonatal screening programs, especially the use of tandem mass spectrometry, in the US, most infants are screened at birth for fatty acid metabolism problems and therefore can be treated very early in life. However patients can present with arrhythmias, Reye’s syndrome like illnesses and/or even sudden death. Other people may not present until later with more exercise fatigue. Symptoms are generally worsened by stress including fasting, exercise, and illness.

Learning Point
Common fatty acid inborn errors of metabolism include:

  • Very-long chain acyl-CoA dehydrogenase deficiency (VLDCASD)
    • Initial step of β-oxidation of long-chain fatty acids for carbon lengths of 14-20
    • ADVL genes (autosomal recessive) with elevated metabolites with carbon chain lengths of 12, 14, and 16
    • Presents in first months of life usually if severe but can present later
      • Heart – cardiomyopathy and arrhythmias
      • Skeletal – hypotonia, later disease often with muscle fatigue and/or rhabdomyolysis
      • Liver – hypoglycemia, hepatomegaly, hyperammonemia, lactic acidosis, elevated transaminases
    • Treatment
      • Frequent feeding, glucose infusion, low fat formulas and increased medium-chain triglycerides
  • Medium-chain acyl-CoA dehydrogenase deficiency (MCAD)
    • **Most commonly diagnosed fatty acid oxidation disorder on neonatal screening
    • Initial step in dehydrogenation of fatty acids for carbon lengths of 4-12
    • ACADM with elevated metabolites with carbon chain lengths of 8 and 10
    • Presents in 3-24 months with “Reye-like” presentation
      • Liver – hypoketotic hypoglycemia, hepatomegaly, elevated transaminase
      • Neurological – lethargy, seizures
      • Sudden death
    • Treatment
        Avoid fasting, frequent feeding, glucose infusion, uncooked starch
  • Short chain acyl-CoA dehydrogenase deficiency (SCAD)
    • ACADS with elevated metabolites with carbon chain lengths of 4
  • Carnitine palmitoyltransferase I
    • CPT1A with elevated carnitine and decreased carbon chain lengths of 16 and 18
    • Presents < 24 months
      • Heart – cardiomyopathy and arrhythmias
      • Liver – hypoketotic hypoglycemia, hepatomegaly, elevated transaminase, hyperammonemia
      • Neurological – lethargy, seizures
      • Sudden death
    • Treatment
      • Carnitine supplementation, avoid fasting, frequent feeding, glucose infusion
  • Carnitine palmitoyltransferase II
    • CPT2 with decreased carnitine and decreased carbon chain lengths of 16 and 18
    • Presents neonatal to first year usually
      • Heart – cardiomyopathy and arrhythmias
      • Liver – hypoketotic hypoglycemia, hepatomegaly
      • Skeletal – hypotonia, later disease often with muscle fatigue and/or rhabdomyolysis
      • Neurological – lethargy, seizures
      • Sudden death
      • Cystic kidneys
    • Treatment
      • Avoid fasting, frequent feeding, glucose infusion, increased medium-chain triglycerides
  • Systematic primary carnitine deficiency
    • SLC22A5 with decreased total carnitine

Questions for Further Discussion
1. What are common presentations for inborn errors of metabolism? A review can be found here
2. What causes hyperammonemia? A review can be found here
3. What are emergency treatment plan elements that needed to be listed for a patient with a suspected or known inborn error of metabolism?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Lipid Metabolism Disorders

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

El-Hattab AW. Inborn errors of metabolism. Clin Perinatol. 2015;42(2):413-439, x. doi:10.1016/j.clp.2015.02.010

Longo N, Frigeni M, Pasquali M. Carnitine Transport and Fatty Acid Oxidation. Biochim Biophys Acta. 2016;1863(10):2422-2435. doi:10.1016/j.bbamcr.2016.01.023

El-Gharbawy A, Vockley J. Defects of Fatty Acid Oxidation and the Carnitine Shuttle System. Pediatr Clin North Am. 2018;65(2):317-335. doi:10.1016/j.pcl.2017.11.006

Fatty acid. In: Wikipedia. ; 2020. https://en.wikipedia.org/w/index.php?title=Fatty_acid&oldid=947595395.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

Published