No abstract

From the time of its discovery in 1905 until the first description of its deficiency in 1973, the role of carnitine in intermediary metabolism was decidedly vague. Identification of carnitine acyl transferases and their products, acylcarnitines, have paved the way to the confirmation of the importance of carnitine in the transfer of fatty acid CoAs into the mitochondrion for beta-oxidation and energy production. The elucidation of defects in fatty acid oxidation together with the concept of carnitine therapy in certain organoacidaemias have given a new meaning to the term acylcarnitine. Not only are these compounds of diagnostic importance, their formation may be part of a secondary carnitine depletion which may be brought about as a result of various medications. Recent evidence suggests that long-chain acylcarnitines are responsible for cardiac arrhythmias and other effects, both good and bad, will certainly be found. This review will attempt to highlight the importance of acylcarnitines, from their production, the difficulties in analysis, the diagnostic possibilities and their positive and negative effects on intermediary metabolism.

Ethylmalonic encephalopathy (EE) is a rare, recently defined inborn error of metabolism which affects the brain, gastrointestinal system and peripheral blood vessels and is characterized by a unique constellation of clinical and biochemical features. A 7-month-old male, who presented with psychomotor retardation, chronic diarrhea and relapsing petechiae is described with the objective of highlighting the biochemical and neuroradiological features of this disorder as well as the effect of high-dose riboflavin therapy. Urinary organic acid analysis revealed markedly increased excretion of ethylmalonic acid, isobutyrylglycine, 2-methylbutyrylglycine and isovalerylglycine. Acylcarnitine analysis in dried blood spots showed increased butyrylcarnitine. Short-chain acyl-CoA dehydrogenase (SCAD) activity in muscle was normal as were mitochondrial OXPHOS enzyme activities in cultured skin fibroblasts. In skeletal muscle the catalytic activity of complex II was decreased. Brain MRI revealed bilateral and symmetrical atrophy in the fronto-temporal areas, massive enlargement of the subarachnoid spaces and hyperdensities on T (2) sequences of the basal ganglia. Mutation analysis of the ETHE1 gene demonstrated homozygosity for the Arg163Gly mutation, confirming the diagnosis of EE at a molecular level. On repeat MRI, a significant deterioration was seen, correlating well with the clinical deterioration of the patient.

The aim of the study was to investigate the effect of carnitine supplementation of valproic acid (VPA) treated patients presenting with increased plasma ammonia concentrations. Plasma ammonia concentrations were recorded in 69 children and young adults on VPA monotherapy (25.6 +/- 9.2 mg VPA/kg per day; mean plasma VPA concentration 68.8 +/- 27.6 mg/l). Their mean plasma ammonia concentration was 80.2 +/- 32.1 micrograms/dl (median 73.1 microgram/dl). A total of 24 patients (35.3%) presenting with ammonia concentrations > 80 microgram/dl were considered hyperammonaemic. Of these, 15/24 (22.1%) showed ammonia concentrations > 100 microgram/dl, even up to 194 micrograms/dl. In 48/69 patients, plasma carnitine concentrations could be determined. The plasma total carnitine (TC) concentrations were rather low (26.9 +/- 8.8 mumol/1) compared to normal values obtained in our laboratory (40.9 +/- 7.2 mumol/1). The percentage of free carnitine was considered decreased (< 75% TC) in 13/48 samples (27%). Fourteen hyperammonaemic patients and one with a plasma ammonia level of 60 micrograms/dl agreed to be supplemented with L-carnitine (1 g/m2 per day divided into two equal doses). Their plasma ammonia and carnitine concentrations were re-evaluated after a mean of 9.1 +/- 4.0 days (median 9.0 days) and in 9 patients again after a mean of 79.6 +/- 30.1 days (median 75 days) of L-carnitine supplementation. Plasma ammonia concentrations decreased in all 15 patients. The decrease was 25.4 +/- 11.2% (median 28.3%) after a mean of 9.1 +/- 4.0 days and amounted to 46.0 +/- 17.2% (median 48%) after 79.6 +/- 30.1 days. L-Carnitine supplementation led to an increase in plasma free carnitine of 11.6 +/- 13.0% (median 15.6%) and to a further increase of 11.1 +/- 8.4% (median 11.5%) when re-evaluated a second time. The plasma ammonia concentrations were significantly correlated with the percentage of free plasma carnitine (r = -0.67; p < 0.0001). The results show that carnitine supplementation is a means of normalizing elevated plasma ammonia concentrations. However, we cannot conclude from our results whether this lowers the risk of developing a VPA-induced Reye's-like syndrome.