FAODs: the interrupted pathways of β-oxidation
beta - Oxidation

Author: Stefano Vigo
Date: 04/12/2014



FAOD is an acyromym for fatty acid oxidation disorder. FAODs are genetic disorders that result from the inability to breakdown fats in the body Fatty acid Beta oxidation (FAO) is a key metabolic pathway for maintaining energy homeostasis in humans, and its importance is dependent on the organ and physiological state. It is particularly important for some high-energy-requiring organs, such as heart and skeletal muscle, and provides the main energy supply for organisms during prolonged fasting After a meal the body uses the energy from the food directly, and stores what is unused as glycogen in the liver. If the short-term energy supply of the body is depleted (such as fasting overnight), fatty acids are broken down to create energy. Skeletal muscle and the heart use fatty acids as a major source of energy. There are many different enzymes involved in the breakdown of fats for energy. If any of the enzymes is not working properly, the result is an FAOD. Each enzyme is responsible for a different FAOD.


The most common FAOD is called MCAD (medium chain acyl-CoA dehydorgenase) deficiency . Predominant hepatic symptoms were observed in 89% of patients regardless of the underlying defect. The most frequent symptoms observed were hepatomegaly (92%), increased blood alanine aminotransferase (ALAT) level (82%), and steatosis (88%). Other frequent features included Reye syndrome (49%), increased gamma-glutamyltranspeptidase (37%), and liver failure (27%). Hypoglycemia (75%), neurological (64%), muscle (61%), or cardiac features (55%) as either cardiomyopathy (47%) or arrhythmias (31%)] were frequently documented. Hemodynamic events (41%) were represented by shock(circulatory) (31%) or sudden death (35%). Hyperammonemia (73%) and hyperlactacidemia (57%) were the two main biochemical features.
Total, very-long-chain acyl-CoA dehydrogenase ( VLCADD ), longchain 3-hydroxyacylCoA dehydrogenase ( LCHADD ), and medium-chain acyl-CoA dehydrogenase ( MCADD ) deficiency mortality rates were 48%, 60%, 63%, and 20% respectively.
FAODs are relatively common inherited metabolic diseases with serious life-threatening symptoms, such as hypoketotic hypoglycemia, acute encephalopathy, cardiomyopathy, myolysis, metabolic acidosis and liver dysfunction. A cardiac presentation is usually observed in newborns or in infancy.
In infancy, a hepatic presentation with hypoketotic hypoglycemia and Reye-like syndrome can occur. Triggering events, including febrile illness, vomiting, or fasting, can lead to severe complications, such as neurological damage or sudden death.
In adolescence and adulthood,milder clinical forms with a mostly muscular presentation are frequent.
A number of patient never develop symtomps, either because they have a mild defect or because they are not exposed to the necessary environmental stress; these patients have mainly been identified since the introduction of newborn screening and it is not yet clear how many will remain asymptomatic throughout life.



In various developed countries, early diagnosis of these defects has been introduced in the form of various population-based newborn screening programs ( NSP ). These programs have dramatically decreased the number of acute decompensations and mortality rate. Notwithstanding the progress made in diagnosis and molecular analyses of FAODs, detailed clinical descriptions remain incomplete. MCADD was the most frequent FAOD, followed by LCHADD and VLCADD. Carnitine shuttle deficiencies ( CPTI , CACT, CPTII ) accounted for 19% of the diagnosis. The first symptoms appeared usually after 1 year for MCADD, CPTI deficiencies, and CTD. CACT deficiency was frequently symptomatic a few hours after birth.

Newborn screening tests


Most patient with FAOD need to avoid prolonged fasting and require careful management during acute illnesses to prevent metabolic decompensation. Long-term dietary treatment is needed in patient with severe long-chain FAODs. Carnitine and riboflavin are indicated in specific disorders and various forms of treatment have been proposed for exercise-induced symtoms.
Carnitine treatment is very effective in patients with carnitine transporter deficiency. The cardiomyopathy and weakness resolve within a few months and there are no further episodes of hypoglycaemia. With the usual dose of 100mg/kg/day, plasma concentrations my reach the lower part of the normal range, but muscle carnitine concentrations remain less than 5% of normal. The value of carnitine therapy in other FAODs in controversial.
In LC-FAOD the current standard of care includes diligent prevention of fasting combined with the use of low-fat/high-carbohydrate diets and medium-chain triglyceride oil supplementation. A phase 2 study is evaluating the efficacy of Triheptanoin , a medium-chain triglyceride of three seven-carbon fatty acids designed to provide substrate replacement for both fatty acid metabolism and the Krebs cycle.

Triheptanoin for Long-Chain Fatty Acid Oxidation Disorders

Clinical and biological features at diagnosis in mitochondrial fatty acid beta-oxidation defects: a French pediatric study of 187 patients. 2013

AddThis Social Bookmark Button