Understanding LC-FAOD mechanism of disease (MOD)

Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of autosomal recessive genetic disorders caused by defects in mitochondrial ß-oxidation enzymes, characterized by metabolic deficiencies in which the body is unable to efficiently convert long-chain fatty acids into energy.1

These defects impact both the carnitine cycle and the intramitochondrial ß-oxidation cycle, resulting in the2

  • Accumulation of fatty acid intermediates, which conjugate with carnitine and may cause cytotoxicity3
  • Inability to complete the conversion of intramitochondrial ß-oxidation cycle into acetoacetate
  • Overall energy deficit in the cell
            *CACT=carnitine-acyl carnitine translocase deficiency.

The inability to efficiently metabolize long-chain fatty acids can lead to a severe energy deficit. Beginning from early in life to as late as adulthood, patients with LC-FAOD may present with acute crises of energy metabolism and energy deficiency. This often leads to potentially severe comorbidities, such as1,4

  • Rhabdomyolysis
  • Hypoglycemia
  • Hypotonia
  • Cardiomyopathy

FAOD affect 1 in 4600 people in the United States5,6
Long-chain FAOD (LC-FAOD) are a specific group of FAOD. The most common types of LC-FAOD are

  • Very long–chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency
  • Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency
  • Trifunctional protein (TFP) deficiency
  • Carnitine palmitoyltransferase I and II (CPT I and II) deficiency

LC-FAOD are included in newborn screening panels across the United States and in certain European countries.7

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References: 1. Roe CR, Sweetman L, Roe DS, David F, Bruengraber H. Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain triglyceride. J Clin Invest. 2002;110(2):259-269. doi:10.1172/JCI200215311. 2. Vockley J, Charrow J, Ganesh J, et al. Response to compassionate use of triheptanoin in infants with cardiomyopathy due to long chain fatty acid oxidation defects (LC-FAODs). Poster presented at: Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium; September 1-4, 2015; Lyon, France. Poster P-349. 3. Koves TR, Ussher JR, Noland RC, et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 2008;7(1):45-56. doi:10.1016/j.cmet.2007.10.013. 4. MCAD and other fatty acid oxidation disorders. Illinois Department of Public Health: Genetics and Newborn Screening. http://www.idph.state.il.us/HealthWellness/fs/mcad.htm. Accessed August 17, 2016. 5. Lindner M, Hoffmann GF, Matern D. Newborn screening for disorders of fatty-acid oxidation: experience and recommendations from an expert meeting. J Inherit Metab Dis. 2010;33(5):521-526. 6. Ultragenyx announces initiation of phase 2 study for patients with long-chain fatty acid oxidation disorders [press release]. Novato, CA: Ultragenyx Pharmaceutical Inc.; February 12, 2014. http://ir.ultragenyx.com/releasedetail.cfm?releaseid=824776. Accessed August 17, 2016. 7. Rocha H, Castiñeiras D, Delgado C, et al. Birth prevalence of fatty acid β-oxidation disorders in Iberia. JIMD Reports. 2014;16:89-94. doi:10.1007/8904_2014_324.