The inborn errors of mitochondrial fatty acid oxidation

Abstract

To date, seven inborn errors of mitochondrial fatty acid oxidation have been identified. A total of about 100 patients in the world have been reported. Clinically the beta-oxidation defects are more often characterized by episodic hypoglycaemia leading to a coma mimicking Reye's syndrome. The hypoglycaemia is non-ketotic since the synthesis of ketone bodies is deficient. Periods of decompensation occur when carbohydrate supply is poor, e.g. prolonged fasting, vomiting, or increased caloric requirements, as and when lipid stores are used. Defects in beta-oxidation have also been reported to be one cause of sudden infant death syndrome. The diagnosis of these inborn errors is by biochemical investigation since where symptoms suggest such a defect, the precise aetiology cannot be assessed. The biochemical diagnosis is based firstly on identification of abnormal plasma and of urinary metabolites during acute attacks. Derivatives of the omega-oxidation and omega-1-oxidation of medium chain fatty acids have been identified, as well as acylglycine and acylcarnitine conjugates. These metabolites are nearly always absent when patients are in good clinical condition. Secondly, the diagnosis must be based on the identification of the enzymatic defects: this involves global assays which allow a localization of the 'level' of the defect (i.e. the oxidation of long, medium or short chain fatty acids) and specific measurement of enzyme activities (acyl-CoA dehydrogenases and electron carriers: ETF and ETF-DH). The diagnosis of these disorders is of prime importance because of the severity of the clinical symptoms. These can be prevented, in some cases, by an appropriate diet (a high carbohydrate, low fat diet, sometimes supplemented with L-carnitine). In other cases, genetic counselling can be offered.

Medium chain acyl-CoA dehydrogenase deficiency: Human genome epidemiology review

“…Touma and Charpentier (1992) reviewed outcomes for 65 MCADD patients identified upon acute onset of the disease at hospitals who had their MCADD diagnosis confirmed by GCIMS.28 A third study summarized the outcomes of the first 23 reported cases of MCADD in the world (mostly from Europe), which were compiled from published case reports of each individual. 29 The prevalence of clinical symptoms reported for patients in all three studies are summarized in Table 2. It is important to note that there is overlap between the studies referenced in Table 2.…”

Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency in Mice

“…Rodents more readily produce butyrylglycine than primates for reasons that remain unclear. However, the production of butyrylglycine as an alternative pathway to eliminate excess butyrylCoA is analogous to the production of suberylglycine and hexanoylglycine in MCAD deficiency (19) and isovalerylglycine in isovaleryl-CoA dehydrogenase deficiency (20) of humans. As discussed for isovaleric acidemia (20), glycine conjugation is a critical alternative pathway and is probably a major factor in determining the clinical severity of the disease.…”

Binding of straight-chain saturated dicarboxylic acids to albumin.

“…Only 5-10% of FFA are metabolized by this pathway in ketotic rats (1). However, dicarboxylic acids have recently been shown to be a prominent feature of several diseases, including Reye's syndrome (2)(3)(4), neonatal adrenoleukodystrophy (5), Zellweger's syndrome (5), and defects of fatty acid metabolism (6,7). In Reye's syndrome, dicarboxylic acids make up as much as 55% of the total serum FFA (4).…”