LC-FAOD are a group of rare, often severe, and life-threatening autosomal recessive disorders that result from defective enzymes involved in the transport and catabolism of long-chain fatty acids (LCFAs).1-4
LC-FAOD include the following types4:
Carnitine palmitoyltransferase I (CPT I) deficiency
CPT I deficiency is caused by mutations in the CPT1A gene encoding CPT IA, a liver isoform, preventing LCFAs from entering mitochondria for fatty acid β-oxidation. Key signs and symptoms usually appear in childhood and are related to liver function. They include hepatic encephalopathy, hypoketotic hypoglycemia, seizures, and sudden unexpected death in infancy; muscle and heart symptoms are absent.1,5,6
Carnitine-acylcarnitine translocase (CACT) deficiency
CACT deficiency is caused by mutations in the SLC25A20 gene encoding CACT, leading to disruption of LCFAs mitochondrial import for β-oxidation. Key signs and symptoms include hypoketotic hypoglycemia, respiratory distress, seizures, hypotonia, bradycardia/other arrhythmias, cardiac failure, and hyperammonemia; often fatal at birth or early infancy.7,8
Carnitine palmitoyltransferase II (CPT II) deficiency
CPT II deficiency is caused by mutations in the CPT2 gene encoding CPT II, preventing LCFAs from being transported into mitochondria for fatty acid β-oxidation. Key signs and symptoms of the neonatal and infantile forms include hypoketotic hypoglycemia, cardiomyopathy, and seizures. Symptoms of the myopathic form include muscle pain and weakness after exercise.7,9
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency
VLCAD deficiency is caused by mutations in the ACADVL gene encoding VLCAD and is the most common form of LC-FAOD. VLCAD catalyzes the initial rate-limiting step in mitochondrial fatty acid β-oxidation. VLCAD deficiency is clinically heterogenous, with three major phenotypes: a severe early childhood onset form with high rates of both cardiomyopathy and mortality; a milder, later childhood onset form that mainly presents with hypoketotic hypoglycemia and has low rates of mortality and cardiomyopathy; and an adult form with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria that are usually triggered by exercise or fasting.3,7,10
Trifunctional protein (TFP) deficiency
TFP deficiency is heterogeneous, with mutations identified in both the HADHA and HADHB genes, leading to defects in the 3 enzymes that comprise the TFP complex. Key signs and symptoms include heart disease, skeletal myopathy, peripheral myopathy, and pigmentary retinopathy.11-13
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
LCHAD deficiency is caused by mutations in the HADHA gene encoding the α subunit of trifunctional protein (TFP). It prevents the breakdown of 3-hydroxyacyl-CoA to 3-ketoacyl-CoA, causing an accumulation of acylcarnitines and other fatty acids. Key signs and symptoms include hypoketotic hypoglycemia, liver disease, cardiomyopathy, skeletal myopathy, peripheral neuropathy, and pigmentary retinopathy.1,11-16
1. Knottnerus SJG, Bleeker JC, Wüst RCI, et al. Rev Endocr Metab Disord. 2018;19(1):93-106. 2. Wajner M, Amaral AU. Biosci Rep. 2015;36(1):e00281. 3. Lindner M, Hoffmann GF, Matern D. J Inherit Metab Dis. 2010;33(5):521-526. 4. Wanders RJ, Ruiter JP, IJLst L, Waterham HR, Houten SM. J Inherit Metab Dis. 2010;33(5):479-494. 5. Bennett MJ, Santani AB. Carnitine Palmitoyltransferase 1A Deficiency. July 27, 2005 [Updated March 17, 2016]. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. 6. Ogawa E, Kanazawa M, Yamamoto S, et al. J Hum Genet. 2002;47(7):342-347. 7. Pennisi EM, Garibaldi M, Antonini G. J Clin Med. 2018;7(12):E472. 8. Vitoria I, Martín-Hernández E, Peña-Quintana L, et al. JIMD Rep. 2015;20:11-20. 9. Wieser T. Carnitine Palmitoyltransferase II Deficiency. August 27, 2004 [Updated January 3, 2019]. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. 10. Andresen BS, Olpin S, Poorthuis BJ, et al. Am J Hum Genet. 1999;64(2):479-494. 11. De Biase I, Viau KS, Liu A, et al. JIMD Rep. 2017;31:63-71. 12. Rinaldo P, Matern D, Bennett MJ. Annu Rev Physiol. 2002;64:477-502. 13. Ibdah JA, Bennett MJ, Rinaldo P, et al. N Engl J Med. 1999;340(22):1723-1731. 14. den Boer ME, Wanders RJ, Morris AA, IJlst L, Heymans HS, Wijburg FA. Pediatrics. 2002;109(1):99-104. 15. Raval DB, Cusmano-Ozog KP, Ayyub O, et al. Mol Genet Metab Rep. 2016;10:8-10. 16. Fletcher AL, Pennesi ME, Harding CO, Weleber RG, Gillingham MB. Mol Genet Metab. 2012;106(1):18-24. 17. Saudubray JM, Martin D, de Lonlay P, et al. J Inherit Metab Dis. 1999;22(4):488-502. 18. Shekhawat PS, Matern D, Strauss AW. Pediatr Res. 2005;57(5 Pt 2):78R-86R. 19. Vockley J, Burton B, Berry GT, et al. Mol Genet Metab. 2017;120(4):370-377. 20. Siddiq S, Wilson BJ, Graham ID, et al. Orphanet J Rare Dis. 2016;11(1):168.
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