New developments in the diagnosis and investigation of mitochondrial fatty acid oxidation disorders

Abstract

Since the discovery of muscle carnitine palmitoyltransferase deficiency in 1973, a dozen separate defects of mitochondrial fatty acid beta-oxidation in man have been identified. With the exception of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, which occurs with a frequency approaching 1:10,000 among Caucasians of Northern European origin, the other defects are quite rare. Collectively, however, they are common causes of disease resembling Reye syndrome in early life, and some have a later and more chronic presentation with cardiomyopathy and skeletal muscle weakness. They also represent a small, but significant, proportion of cases of sudden and unexplained death within the first 2 years of life. Diagnosis of these disorders has become increasingly sophisticated, with the advent of new analytical technologies and an increased awareness of the appropriate clinical and laboratory investigations needed in order to evaluate potential defects of this pathway. The combination of provocative testing (e.g., carnitine loading, phenylpropionic acid loading, long-chain fat loading) and advanced analytical techniques for the measurement of blood and urinary metabolites (e.g., tandem fast atom bombardment-mass spectrometry, stable isotope dilution gas chromatography-mass spectrometry) permits a specific diagnosis in the case of several, although not all, of the disorders of this pathway. Methods for the measurement of all of the enzymes of beta-oxidation are now available to enhance this diagnostic capability. There remain, however, many patients in whom clinical and laboratory signs point to a defect in beta-oxidation, but in whom no specific diagnosis has yet been made.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of medium-chain acyl-coenzyme A esters in mouse tissues by liquid chromatography–electrospray ionization mass spectrometry

“…On the other hand, the control of the enzymes influencing fatty acid metabolism may be perturbed by disease and drugs. Medium-chain acyl-CoA dehydrogenase deficiency, which causes a ReyeÕs syndrome-like disease, is an inherited metabolic disorder affecting b-oxidation of fatty acids [8,9]. Salicylate, which serves a causal role in the development of ReyeÕs syndrome [10], has been reported to inhibit b-oxidation of long-chain fatty acids (in vivo) and medium-chain fatty acids (in vitro) [11].…”

Metabolic function and liver histopathology in Reye‐like illnesses

“…Muscle carnitine palmitoyltransferase deficiency and defects of mitochondrial fatty acid /&oxidation are common causes of diseases resembling RS in early life. and are also responsible for certain sudden and unexplained death within the first 2 years of life (17). Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency was highly suspected in four cases of our series.…”

cis-4-decenoic acid provokes mitochondrial bioenergetic dysfunction in rat brain

“…cis-4-decenoic acid (cDA) accumulates in the tissue and body fluids of patients affected by MCADD and is considered the pathognomonic metabolite of this disease. Clinical management relies on the administration of high glucose and Lcarnitine amounts during the acute episodes, as well as fat restriction and L-carnitine supplementation after recovery (Coates 1994;Roe and Ding 2001).…”