Paeds · genetics-dysmorphology-and-metabolism
Fatty-acid oxidation disorders
Also known as FAOD · Fatty acid beta-oxidation disorders · Medium-chain acyl-CoA dehydrogenase deficiency · MCAD deficiency · MCADD · Long-chain fatty acid oxidation disorders · LC-FAOD · VLCAD deficiency · LCHAD deficiency
A fellowship approach to the fatty-acid oxidation disorders: recognise the child who cannot switch to fat-burning during fasting and so presents with hypoketotic hypoglycaemia, cardiomyopathy, rhabdomyolysis or sudden death; treat the acute crisis with intravenous glucose to shut off fatty-acid mobilisation; confirm with plasma acylcarnitines and molecular testing; and prevent recurrence with avoidance of fasting, an emergency sick-day plan, and for long-chain defects triheptanoin and carnitine.
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Target exams
Red flags
- A child with fasting- or illness-induced hypoketotic hypoglycaemia — the glucose is low but ketones are inappropriately absent, meaning the body cannot burn fat to compensate
- An infant or child with cardiomyopathy, liver dysfunction and skeletal-muscle pain during intercurrent illness — the energy failure of a long-chain fatty-acid oxidation defect
- Exercise-induced recurrent rhabdomyolysis with myoglobinuria in an older child or adolescent — think very long-chain acyl-CoA dehydrogenase deficiency or CPT II deficiency
- A previously well child found dead after a period of fasting or viral illness, especially if labelled sudden unexpected death — undiagnosed MCAD deficiency was historically a leading cause
- An infant with hypotonia, cardiomyopathy and liver steatosis — the presentation of a severe neonatal-onset long-chain defect or glutaric acidemia type II
- A mother who develops acute fatty liver of pregnancy or HELLP syndrome — screen the infant for LCHAD deficiency
Life stages
Care settings
Clinical exam formats
Board mappings
- Hypoketotic hypoglycaemia as a metabolic emergency clue
- Initial metabolic work-up of the child with fasting intolerance
- Principles of acute management with intravenous glucose
- Classification of fatty-acid oxidation disorders by chain length and enzyme defect
- Acylcarnitine profiling and molecular confirmation
- Triheptanoin and long-term management of long-chain defects
- Recognising and stabilising a child with a suspected fatty-acid oxidation defect
- Interpreting plasma acylcarnitines
- Building an emergency sick-day plan to prevent catabolism
- Acute case of an infant with hypoketotic hypoglycaemia and encephalopathy
- Long case of a child with a long-chain defect discussing exercise tolerance and triheptanoin
- Metabolic emergencies presenting with hypoglycaemia
- Investigation of the acutely unwell child
- Inherited metabolic disease and family implications
- Fatty-acid beta-oxidation biochemistry and the major enzyme defects
- Acute and long-term management of FAODs
- Newborn screening and genetic counselling
- Resuscitation of the metabolic collapse
- Communicating a fatty-acid oxidation disorder diagnosis to parents
- Inborn errors of metabolism presenting with hypoglycaemia
- Medium-chain acyl-CoA dehydrogenase deficiency and sudden unexpected death
- Long-chain defects and cardiomyopathy
- Fatty-acid oxidation disorders
- Hypoketotic hypoglycaemia diagnosis and emergency management
- Multidisciplinary care of inherited metabolic disease
- Neonatal and childhood hypoglycaemia of metabolic origin
- Long-term outcomes and newborn screening for FAODs
The fellowship mark goes to the candidate who thinks in three layers simultaneously. The first is the child in front of you: a hypoglycaemic, encephalopathic infant after a viral illness, or an adolescent with exercise-induced muscle pain and dark urine. The immediate question is not which enzyme is defective but whether the child can make ketones. The second is the physiology: fasting triggers lipolysis, fatty acids enter the mitochondrion via the carnitine shuttle, and beta-oxidation trims two carbons at a time to generate acetyl-CoA, ketone bodies and ATP. A block anywhere in this chain produces an energy deficit and, in the long-chain defects, toxic accumulation. The third is the family: these are autosomal recessive conditions, newborn screening detects most of them, and a well-constructed sick-day plan is what keeps the child safe between episodes. [1] [4]
Overview & Definition
The fatty-acid oxidation disorders are a group of inherited metabolic diseases caused by defects in the transport of fatty acids into the mitochondrion or in their subsequent beta-oxidation to generate energy. The pathway begins with the carnitine shuttle — carnitine palmitoyltransferase I (CPT I), the carnitine-acylcarnitine translocase (CACT), and carnitine palmitoyltransferase II (CPT II) — which ferries long-chain fatty acids across the impermeable inner mitochondrial membrane. Once inside, the beta-oxidation spiral progressively shortens the fatty-acyl chain through a repeating cycle of dehydrogenation, hydration, dehydrogenation and thiolysis, with each enzyme class acting on a different chain-length range: very long-chain acyl-CoA dehydrogenase (VLCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD, part of the mitochondrial trifunctional protein), medium-chain acyl-CoA dehydrogenase (MCAD), and short-chain acyl-CoA dehydrogenase (SCAD). [1] [4]
Clinically, the fatty-acid oxidation disorders sit within the family of fasting-induced energy-failure inborn errors: conditions in which a blocked catabolic pathway prevents the body from using its largest energy reserve — stored fat — during periods of caloric deficit. This framing matters because it dictates both the presentation (crisis during fasting, infection or exercise) and the management (prevent catabolism, provide alternative fuel). Medium-chain acyl-CoA dehydrogenase deficiency is by far the most common, accounting for the majority of diagnosed cases, and it was the first condition for which newborn screening by tandem mass spectrometry demonstrated a clear outcome benefit. The long-chain defects (VLCAD, LCHAD, CPT I, CPT II, CACT) are individually rare but collectively important because they cause cardiomyopathy, liver dysfunction and rhabdomyolysis in addition to hypoglycaemia. [1] [7]
References12ShowHide
- [1]Merritt JL 2nd, Norris M, Kanungo S. Fatty acid oxidation disorders. Ann Transl Med, 2018.PMID 30740404
- [2]Vockley J Long-chain fatty acid oxidation disorders and current management strategies. Am J Manag Care, 2020.PMID 32840329
- [3]Spiekerkoetter U, Lindner M, Santer R, et al. Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop. J Inherit Metab Dis, 2009.PMID 19399638
- [4]Houten SM, Wanders RJ A general introduction to the biochemistry of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis, 2010.PMID 20195903
- [5]Wilcken B. Fatty acid oxidation disorders: outcome and long-term prognosis. J Inherit Metab Dis, 2010.PMID 20049534
- [6]Derks TG, Reijngoud DJ, Waterham HR, et al. The natural history of medium-chain acyl CoA dehydrogenase deficiency in the Netherlands: clinical presentation and outcome. J Pediatr, 2006.PMID 16737882
- [7]Wilcken B, Haas M, Joy P, Wiley V, Bowling FG, Carpenter KH, et al. Expanded newborn screening: outcome in screened and unscreened patients at age 6 years. Pediatrics, 2009.PMID 19620191
- [8]Vockley J, Marsden D, McCracken E, et al. Long-term major clinical outcomes in patients with long chain fatty acid oxidation disorders before and after transition to triheptanoin treatment. Mol Genet Metab, 2015.PMID 26116311
- [9]Vockley J, Burton BK, Berry G, et al. Triheptanoin for the treatment of long-chain fatty acid oxidation disorders: Final results of an open-label, long-term extension study. J Inherit Metab Dis, 2023.PMID 37276053
- [10]Mason E, Hindmarch CCT, Dunham-Snary KJ Medium-chain acyl-CoA dehydrogenase deficiency: pathogenesis, diagnosis, and treatment. Endocrinol Diabetes Metab, 2023.PMID 36300606
- [11]Tein I. Disorders of fatty acid oxidation. Handb Clin Neurol, 2013.PMID 23622388
- [12]Pandor A, Eastham J, Beverley C, Chilcott J, Paisley S. Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review. Health Technol Assess, 2004.PMID 14982654