Özge’s background is in research; she holds a MSc. in Molecular Genetics from the University of Leicester and a PhD. in Developmental Biology from the University of London. Özge worked as a bench scientist for six years in the field of neuroscience before embarking on a career in science communication. She worked as the research communication officer at MDUK, a UK-based charity that supports people living with muscle-wasting conditions, and then a research columnist and the managing editor of resource pages at BioNews Services before joining Rare Disease Advisor.
Long chain fatty acid oxidation disorder (LCFAOD) is a group of autosomal recessive genetic conditions characterized by the impairment of long chain fatty acid metabolism and associated with significant morbidity and mortality.1
History of Long Chain Fatty Acid Oxidation Disorder Diagnosis
Historically, LCFAODs could only be diagnosed based on symptoms after sudden death or near death. Later, with the development of mass spectrometric acylcarnitine analysis, asymptomatic patients could also be diagnosed. However, physicians had to have a suspicion of the disease in order to use this approach.2
In more recent years, the addition of fatty acid oxidation disorders to newborn screening programs has dramatically increased the ability to identify patients with the disease before any symptoms develop.
Newborn Screening for Fatty Acid Oxidation Disorders
Newborn screening tests for LCFAODs include tests for carnitine update defects, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, trifunctional protein (TFP) deficiency, and very-long-chain acyl-coenzyme A (CoA) dehydrogenase (VLCAD) deficiency.3
Because the management of LCFAOD mostly focuses on dietary interventions, early detection of the disease is of paramount importance.
Newborn screening has dramatically improved outcomes for affected babies in terms of symptomatic manifestation rates, neurodevelopmental impairment, and death.4
Following a positive result in the newborn screening test, confirmatory testing must be conducted to reach a final diagnosis of LCFAODs and determine the disease type.
Types of Long Chain Fatty Acid Oxidation Disorders
There are six main types of LCFAODs each caused by a mutation in a gene encoding one of the enzymes that are necessary for the transport of long chain fatty acids to the mitochondria and their breakdown.
Read more about LCFAOD etiology.
These are carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II deficiency (CPT II), CACT deficiency, VLCAD deficiency, LCHAD deficiency, and TFP deficiency.
CPT I binds long chain fatty acids to carnitine so they can be shuttled across the mitochondrial membrane. CACT transports the long chain fatty acid-carnitine complex inside the mitochondria, and CAT II removes the carnitine molecule from long chain fatty acids once inside the mitochondria so they can be metabolized.
Mutations in the gene encoding for any one of these enzymes disrupt the carnitine shuttle and lead to long chain fatty acids not being able to enter the mitochondria, thereby accumulating and causing damage.
VLCAD is required for the beta-oxidation of fatty acids inside the mitochondria. LCHAD is part of the TFP complex, which also plays a role in fatty acid metabolism inside the mitochondria.
The deficiency of any one of these enzymes is established by the detection of biallelic pathogenic variants in encoding genes with molecular genetic testing. When molecular genetic testing is not conclusive, enzyme activity can be assessed on skin fibroblast cultures, muscles, or lymphocytes.5,6,7
An algorithm flowchart developed by the American College of Medical Genetics and Genomics (ACMG) is available to determine the final diagnosis in infants with a positive newborn screening test result.8
The ACMG also has newborn screening ACT sheets available detailing the actions that need to be taken if a baby’s newborn screening test results are positive.
These include contacting the family about the newborn screening result and ascertaining clinical status, consulting with a pediatric metabolic specialist, evaluating the patient, educating the family about the need to avoid fasting, and reporting the findings to the newborn screening program.
Diagnostic Workup by LCFAOD Type
Patients with CPT I will have elevated free carnitine C0 with low or normal long-chain
acylcarnitines in the plasma acylcarnitine test. A newborn with this feature should be evaluated for lethargy, hepatomegaly, and seizures. A CPT I enzyme assay and CPT1a gene sequencing can confirm the diagnosis.9
In CPT II deficiency, the plasma acylcarnitine test shows high levels of C16 and/or C18:1. Urine organic acid tests show high levels of lactic acid and dicarboxylic acids. The patient should be evaluated for hepatomegaly, cardiac insufficiency, and dysmorphic facies. The sudden unexpected death of a sibling should also be investigated.10
In VLCAD deficiency, the plasma acylcarnitine test may reveal high C14:1 acylcarnitine. Infants may present with poor feeding, lethargy, hypotonia, hepatomegaly, arrhythmia, and evidence of cardiac decompensation. Mutation analysis of the VLCAD gene can confirm the diagnosis.11
Elevated C16-OH +/- C18 and other long chain acylcarnitines are indicative of LCHAD or TFP deficiency. Further biochemical and molecular genetic testing is necessary to differentiate between the two disorders. Healthcare professionals should evaluate the infant in terms of hepatomegaly, cardiac insufficiency, and hypoglycemia. Maternal liver disease during pregnancy and the unexpected sudden death of a sibling should also be investigated.12
- Merritt JL, Norris M, Kanungo S. Fatty acid oxidation disorders. Ann Transl Med. 2018;6(24): 473. doi:10.21037/atm.2018.10.57
- Vockley J. Long-chain fatty acid oxidation disorders and current management strategies. Am J Manag Care. 2020;26(7 Suppl):S147-S154. doi:10.37765/ajmc.2020.88480
- Treatment of fatty acid oxidation disorders. March of Dimes. January 2014. Accessed June 7, 2021.
- Marsden D, Bedrosian DL, Vockley J. Impact of newborn screening on the reported incidence and clinical outcomes associated with medium- and long-chain fatty acid oxidation disorders. Genet Med. 23,816–829 (2021). doi:10.1038/s41436-020-01070-0
- Bennett MJ, Santani AB. Carnitine Palmitoyltransferase 1A Deficiency. GeneReviews. March 17, 2016. Accessed June 7, 2021.
- Wieser T. Carnitine Palmitoyltransferase II Deficiency. GeneReviews. January 3, 2019. Accessed June 7, 2021.
- Leslie ND, Valencia A, Strauss AW, Zhang K. Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. GeneReviews. May 13, 2021. Accessed June 7, 2021.
- ACT Sheets and Algorithms. American College of Medical Genetics and Genomics. Accessed June 7, 2021.
- Newborn Screening ACT Sheet. [Elevated C0/C16+C18] Carnitine PalmitoylTransferase 1 Deficiency (CPT1). American College of Medical Genetics and Genomics, 2012. Accessed June 7, 2021.
- Newborn Screening ACT Sheet. [Elevated C16 and/or C18:1 Acylcarnitine] Carnitine Palmitoyltransferase 2 (CPT2) Deficiency. American College of Medical Genetics and Genomics. 2010. Accessed June 7, 2021.
- Newborn Screening ACT Sheet. [Elevated C14:1 +/- other long-chain Acylcarnitines] Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency. American College of Medical Genetics and Genomics. 2012. Accessed June 7, 2021.
- Newborn Screening ACT Sheet. [Elevated C16-OH +/- C18 and Other Long Chain Acylcarnitines] Long-chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD). American College of Medical Genetics and Genomics. 2012. Accessed June 7, 2021.
Reviewed by Harshi Dhingra, MD, on 7/1/2021.