Metabolic effects of carnitine medication in a patient with multiple acyl-CoA dehydrogenation deficiency.
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Amino Acids, Branched-Chain↗
Biomedical subjects
N Gregersen
Publications and source records attributed to N Gregersen.
Medium-chain acyl-CoA dehydrogenase deficiency in two siblings with a Reye-like syndrome.
An increasing number of reports indicate that patients with some inherited metabolic diseases may have symptoms resembling those of Reye syndrome. We describe two siblings who developed a Reye-like syndrome at ages 16 and 18 months, respectively, after a viral illness and salicylate therapy. Both had fasting hypoglycemia and hypoketonemia. At the time of the acute episode and after ingestion of a medium-chain triglyceride load, one of them excreted large amounts of abnormal metabolites derived from the omega- and (omega-1)-oxidation of medium-chain fatty acids. Medium-chain acyl-CoA dehydrogenase activity was lower than 20% of control values in fibroblasts from both patients. This enzyme defect should be considered in children with a Reye-like syndrome with these distinctive manifestations.
Acyl-CoA Dehydrogenase↗
The acyl-CoA dehydrogenation deficiencies. Recent advances in the enzymic characterization and understanding of the metabolic and pathophysiological disturbances in patients with acyl-CoA dehydrogenation deficiencies.
Acyl-CoA dehydrogenation deficiencies are defined as disorders of the metabolism of branched chain and straight chain acyl-CoA esters and of glutaryl-CoA. The acyl-CoA dehydrogenation process is comprised of three enzymes, i.e. acyl-CoA dehydrogenase (isovaleryl-CoA, isobutyryl-CoA/2-Me-butyryl-CoA, short-chain acyl-CoA, general (medium-chain) acyl-CoA, long-chain acyl-CoA or glutaryl-CoA), electron transfer flavoprotein (ETF) and electron transfer flavoprotein dehydrogenase (ETF DH). Patients with isovaleryl-CoA dehydrogenase deficiency, glutaryl-CoA dehydrogenase deficiency and general (medium-chain) acyl-CoA dehydrogenase deficiency have been reported. Assays for the enzymatic diagnosis in cells from such patients (especially cultured skin fibroblasts) have been developed and the different methods are reviewed. Patients with apparent defects in all acyl-CoA dehydrogenation processes, designated multiple acyl-CoA dehydrogenation deficiencies, have also been found. I. e. glutaric aciduria type II, ethylmalonicadipic aciduria and riboflavin responsive multiple acyl-CoA dehydrogenation defect. The enzymatic diagnosis has not yet been performed in any of these cases, but the different approaches in this respect are discussed. The excretion pattern of organic acids in urine from patients with acyl-CoA dehydrogenation deficiencies - as measured by means of gas chromatography/mass spectrometry - offers in most cases a tentative diagnosis of the enzyme defect. These excretion patterns are characterized by the presence in urine of different compounds originating from the primary accumulated acyl-CoA ester(s). The most important biochemical processes involved in the formation of these patterns seem to be glycine conjugation, omega-and omega-1-oxidation, carboxylation and dioxygenation. The enzymatic basis for these processes is discussed with respect to the enzyme affinities for acyl-CoA esters relevant to the acyl-CoA dehydrogenation deficiencies. And the knowledge gained from such affinity studies is used to explain the excretion pattern in the different patients, thus increasing the diagnostic power of the gas chromatographic/mass spectrometric analyses. The pathophysiological manifestations in patients with acyl-CoA dehydrogenation deficiencies resemble in many respect those seen in patients with Reye's syndrome, in which the fatty acid oxidation also seems to be compromised. Ethiological factors have not been identified in Reye's syndrome, but in many patients blood accumulation of short- and medium-chain fatty acids has been found.(ABSTRACT TRUNCATED AT 400 WORDS)
Acidosis↗
Medium chain acyl-CoA dehydrogenase deficiency: apparent Km and Vmax values for fibroblast acyl-CoA dehydrogenase towards octanoyl CoA in patient and control cell lines.
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Acyl Coenzyme A↗
In vivo studies on the metabolic derangement in a patient with D-glyceric acidaemia and hyperglycinaemia.
In a mentally retarded boy, who excreted elevated amounts of glycine, D-glyceric acid and acylglycines and whose cells exhibited diminished D-glycerate dehydrogenase and glycine cleavage activity, investigations have been undertaken aiming at characterizing the relationship between the different accumulations. This was done in vivo by trying in a specific manner to alter in turn the degree of accumulation of each of the three classes of compounds and then monitoring changes in the others. The results suggest, that the D-glyceric acid accumulation is directly caused by the genetic defect, since the D-glyceric acid excretion was not altered by changes in degree of accumulation of either glycine or acylglycines. Similarly alterations in acylglycine excretion caused alterations in glycine but not in D-glyceric acid excretion. Based on these findings a model for the pathogenesis behind the accumulations of acylglycines and glycine is proposed.
Amino Acid Metabolism, Inborn Errors↗
Fatty acyl-CoA dehydrogenase deficiency: enzyme measurement and studies on alternative metabolism.
Fatty acyl-CoA dehydrogenase deficiencies are defined as disorders of the metabolism of straight chain acyl-CoA esters at the level of short chain acyl-CoA, general (medium chain) acyl-CoA and long chain acyl-CoA dehydrogenases. Patients with proven or indicated defects in either general (medium chain) or long chain acyl-CoA dehydrogenase have been reported. In recent years assays for the enzymatic diagnosis in cells, especially cultured skin fibroblasts, from such patients have been developed. The different methods are reviewed. The urinary excretion profile of organic acids from patients with fatty acyl-CoA dehydrogenase deficiencies are characterized by the presence of different compounds originating from the primary accumulated acyl-CoA ester(s). The most important biochemical processes involved in the formation of these compounds are glycine conjugation and omega/omega-1 oxidation. The biochemistry of these pathways is discussed and the knowledge gained from in vitro and in vivo studies is used to explain the excretion pattern in some of the patients with general (medium chain) acyl-CoA dehydrogenase deficiency.
Acids↗
Glutaric aciduria type II: evidence for a defect related to the electron transfer flavoprotein or its dehydrogenase.
Incubation of intact fibroblasts from a patients with glutaric aciduria type II with [2-14C]riboflavin showed normal synthesis of flavin mononucleotide and flavin adenine dinucleotide. This is taken as evidence for normal transport of riboflavin into the cells and normal activity of riboflavin kinase (EC 2.7.1.26) and flavin mononucleotide adenylyltransferase (EC 2.7.7.2). The ability of intact fibroblasts to oxidize 1-14C-fatty acids and [6-14C]lysine is impaired in the patient which together with the urinary excretion pattern of organic acids indicates a defective dehydrogenation of fatty acid acyl-CoAs and glutaryl-CoA. However, dehydrogenation of (C6-C10) fatty acid acyl-CoA derivatives and glutaryl-CoA was normal when the dehydrogenases were measured in fibroblast homogenate with artificial electron acceptors. In vivo, these dehydrogenases transfer their electrons to CoQ10 in the main electron transport chain via electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase. Glutaric aciduria type II fibroblasts showed very diminished activity when the glutaryl-CoA dehydrogenase activity was measured without artificial electron acceptor but with intact endogenous electron transport system. As the NADH and succinate oxidation seems normal in glutaric aciduria type II patients, this is strong evidence for a defect in either the electron transfer flavoprotein or the electron transfer flavoprotein dehydrogenase.
Amino Acid Metabolism, Inborn Errors↗
General (medium-chain) acyl-CoA dehydrogenase deficiency (non-ketotic dicarboxylic aciduria): quantitative urinary excretion pattern of 23 biologically significant organic acids in three cases.
Urinary analysis of the pattern of 23 organic acid metabolites derived from fatty acids in three patients with general (medium-chain) acyl-CoA dehydrogenase deficiency was performed. Although there exist quantitative differences in the excreted amounts of the different metabolites in the three patients the qualitative picture was the same. The excretion of adipic, suberic and sebacic acids was substantial, whereas that of dodecanedioic acid was within or just above control limit. The monounsaturated C6-C10-dicarboxylic acid excretion was only marginally or not increased. 5-OH-hexanoic acid and hexanoylglycine were excreted in excessive amounts, whereas 7-OH-octanoic acid, 9-OH-decanoic acid, octanoylglycine and decanoylglycine were excreted in limited amounts. The excreted amounts of 6-OH-hexanoic, 8-OH-octanoic and 10-OH-decanoic acids were not or only marginally elevated compared to controls. In one of the patients the excretion of ethylmalonic and methylsuccinic acids was enhanced, whereas the excretion of these two acids in the two other patients was comparable to that in controls. The urinary excretion of hexanoic, octanoic, decanoic and dodecanoic acids was just a little above the control limit, whereas the esterified hexanoic and octanoic acids were excreted in appreciable amounts. It is argued that the microsomal omega- and omega-1-oxidation systems are involved in the dicarboxylic and omega-1-OH-monocarboxylic acids formation at C10 and C12 level and that the C8-C6-dicarboxylic and omega-1-OH-monocarboxylic acids are formed from higher chained acids by beta-oxidation in both mitochondria and peroxisomes.
Acyl-CoA Dehydrogenase↗
Dicarboxylic aciduria due to medium chain acyl CoA dehydrogenase defect. A cause of hypoglycemia in childhood.
Dicarboxylic aciduria was found during hypoglycemic episode in a 14 months old girl. Her brother had died at the age of 4 years during febrile illness. A ketogenic diet induced in this patient a severe hypoglycemia. Urinary organic acid profile exhibited abnormal excretion of the C6-C10 dicarboxylic acids (adipic-suberic-sebacic) and related metabolites (5 hydroxyhexanoic, hexanoylglycine, suberyl glycine). This pattern suggested a defect in fatty acids beta oxidation. Plasma carnitine values was within control limits. Similar clinical findings and urinary organic acids excretion have been described in 6 patients since the initial case of Gregersen. Enzymatic studies on cultivated fibroblasts from our patient showed a defect in medium chain CoA dehydrogenase. The treatment of this disease consists of glucose infusion during attacks and prevention of fasting. This rare disease must be considered in a child with non ketotic hypoglycemia or Reye's syndrome.
Acyl-CoA Dehydrogenases↗
On the biologic origin of C6-C10-dicarboxylic and C6-C10-omega-1-hydroxy monocarboxylic acids in human and rat with acyl-CoA dehydrogenation deficiencies: in vitro studies on the omega- and omega-1-oxidation of medium-chain (C6-C12) fatty acids in human and rat liver.
C6-C10-dicarboxylic acid C6-C10-omega-1-hydroxy monocarboxylic acids were measured in postmitochondrial (10,000 g) fractions of rat liver after incubation with hexanoic, octanoic, and decanoic acids. In livers both from fed and starved rats, the proportion of decanoic acid converted to sebacic acid was high (approximately 25%) with only minor accumulation of the intermediate 10-hydroxy decanoic acid (1-2%). The conversion of octanoic and hexanoic acids to suberic and adipic acids, respectively, was low (less than 1%). The intermediate 8-hydroxy octanoic and 6-hydroxy hexanoic acids were also accumulated in very small amounts (less than 1%). It was concluded that cytochrome-P-450-mediated omega-hydroxylation was of decisive importance for the production rate of the dicarboxylic acids. Analysis of kinetic parameters of human and rat liver microsomal omega- and omega-1-hydroxylation of hexanoic, octanoic, decanoic, and dodecanoic acids gave the following results: in rats, the apparent Km values for the omega-hydroxylation for dodecanoic and decanoic acids are low, ie., 171 and 3.1 mumole/liter, respectively, whereas they are high for octanoic and hexanoic acids (8211 and 8822 mumole/liter, respectively). In two different humans, the corresponding Km values for dodecanoic, decanoic, octanoic, and hexanoic acids are 3.6-186, 522-247, 4861-3892, and 6825-10400 mumole/liter, respectively. Based on these results, it is argued that adipic and suberic acids found in urine from rats and humans with acyl-CoA dehydrogenation deficiencies are not biosynthesized by direct omega-oxidation of hexanoic and octanoic acids, but most probably by means of beta-oxidation of sebacic and dodecanedioic acids, produced by direct omega-oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
Adipates↗
In vitro fibroblast studies in a patient with C6-C10-dicarboxylic aciduria: evidence for a defect in general acyl-CoA dehydrogenase.
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Acyl-CoA Dehydrogenases↗
Cyanide-insensitive and clofibrate enhanced beta-oxidation of dodecanedioic acid in rat liver. An indication of peroxisomal beta-oxidation of N-dicarboxylic acids.
The beta-oxidation rate of dodecanedioic acid in rat liver homogenates (600 X g supernatant fraction) was determined by simultaneous measurements of the C6-C12-dicarboxylic acids, i.e., adipic, suberic, sebacic and dodecanedioic acids, in relation to time in assays incubated with dodecanedioic acid. Measurements were performed by a combined gas chromatographic-mass spectrometric technique, i.e., selected ion-monitoring. The beta-oxidation rate was registered as the consumption rate of dodecanedioic acid and as the initial rise in the concentrations of C6-C10-dicarboxylic acids. The beta-oxidation rate of C8-C12-dicarboxylic acids was increased many times in homogenates from clofibrate-treated rats. Moreover, it was unexpectedly found that 2.0 mM cyanide was unable to inhibit the beta-oxidation rate of the dicarboxylic acids in vitro, but in fact caused a minor increase in the rate of beta-oxidation in homogenates from both normal and clofibrate-treated rats. It was concluded that the present results strongly indicate the existence of a peroxisomal beta-oxidation of dicarboxylic acids.
Animals↗
The biological origin of ketotic dicarboxylic aciduria. II. In vivo and in vitro investigations of the beta-oxidation of C8-C16-dicarboxylic acids in unstarved, starved and diabetic rats.
The beta-oxidation of C8-C16-dicarboxylic acids to short-chain dicarboxylic acids was investigated in vivo and in rat liver homogenate. The beta-oxidation in vivo was evaluated from the excretions of C6-C10-dicarboxylic acids in urine from rats given C8-C16-dicarboxylic acids. Correspondingly, the beta-oxidation in vitro was determined from the rise in concentration of C6-C10(12)-dicarboxylic acids in the postnuclear (600Xg) fraction of rat liver homogenates incubated with C8-C16-dicarboxylic acids. The results showed that C10-C14-dicarboxylic acids were far better substrates for beta-oxidation than were C8- and C16-dicarboxylic acids. In particular, hexadecanedioic acid could only be beta-oxidized to a minor degree, and, in contrast to the other dicarboxylic acids, it was toxic for starved rats. The activity of the lipid metabolism (unstarved, starved and diabetic ketotic rats) was of decisive significance for the quantity and pattern of the C6-C10-dicarboxylic acids present both in vivo and in vitro, since adipic acid was increased and sebacic acid decreased with increasing lipid catabolism, i.e. the adipic: sebacic acid ratio increased with increasing rates of beta-oxidation. On comparison with earlier investigations on the chain-length dependency of the omega-oxidation of monocarboxylic acids it was concluded that the biological origin of the ketotic C6-C8 -dicarboxylic aciduria is C10-C14-monocarboxylic acids, and that an elevated beta-oxidation rate is important for the formation of C6-C8-dicarboxylic aciduria.
Acidosis↗
C6-C10-dicarboxylic aciduria: investigations of a patient with riboflavin responsive multiple acyl-CoA dehydrogenation defects.
The abnormal metabolites-adipic, suberic, and sebacic acids-were detected in large amounts in the urine of a boy during a Reye's syndrome-like crisis. Substantial amounts of 5-OH-caproic acid, caproylglycine, glutaric acid, and 3-OH-butyric acid and moderately elevated amounts of ethylmalonic acid, methylsuccinic acid, 3-OH-isovaleric acid, and isovalerylglycine were also found. These metabolites were consistently present in urine samples collected in the boy's habitual condition after the attack. 1-[14C]-Palmitic acid was oxidized at a normal rate, whereas U-[14C]-Palmitic acid was oxidized at a reduced rate in cultured skin fibroblasts from the patient, thus indicating a defect at the level of medium- and/or short-chain fatty acid oxidation. Riboflavin medication (100 mg three times a day) significantly reduced the excreted amounts of pathologic metabolites, suggesting a flavineadeninedinucleotide-related acyl-CoA dehydrogenation defect as the cause of the disease. Carnitine in plasma was low in the patient (6 mumole/liter, controls 26-74 mumole/liter), suggesting carnitine deficiency as a secondary effect of the acyl-CoA dehydrogenation deficiency. The present patient, who presented with a Reye's syndrome-like attack, suffers from impaired dehydrogenation of acyl-CoA resulting in accumulation of acyl-CoA in the cells. Attacks with similar symptoms are seen in other acyl-CoA dehydrogenation deficiencies, such as glutaric aciduria types I and II, other types of C6-C10-dicarboxylic acidurias and isovaleric acidemia. Reduced flow through the acyl-CoA dehydrogenation steps may therefore be an ethiologic factor in Reye's syndrome. Several of the accumulated acyl-CoA's are toxic and may be responsible for some of the symptoms. The low carnitine level in plasma and the elevated esterified carnitine excretion in the present patient indicate that acyl-CoA accumulation may cause a functional carnitine deficiency by sequestration of carnitine as acyl-carnitines. As the inborn defect, systemic carnitine deficiency may exhibit symptoms like those of Reye's syndrome, it may be speculated whether functional carnitine deficiency in patients with accumulated acyl-CoA is another causal factor in the development of the symptoms during attacks.
Acyl Coenzyme A↗
C6-C10-dicarboxylic aciduria: biochemical considerations in relation to diagnosis of beta-oxidation defects.
By means of gas chromatographic methods substantial amounts of the C6-C10-dicarboxylic acids, i.e. adipic, suberic and sebacic acids, have been found in the urine from children with unexplained attacks of lethargy and hypotonia, presumably related to episodes of fever and/or insufficient food intake. The course have once been fatal and is often characterized by severe hypoglycemia without ketonuria. Systematic gas chromatographic/mass spectrometric determinations of selected organic acid metabolites in the urine, together with enzymatic measurements in fibroblasts and clinical data from 4 patients of this category, have shown that the biochemical basis of this syndrome can be inborn errors of the beta-oxidation of fatty acids, localized to the medium-chain acyl-CoA dehydrogenation system. The biosynthesis of adipic, suberic and sebacic acids was studied using ketotic rats as the model, since ketosis in rats and humans is accompanied by excessive urinary excretion of adipic and suberic acids. A probable pathway for the production of the three dicarboxylic acids was found to be an initial omega-oxidation of the medium-chain C10-C14-monocarboxylic acids followed by beta-oxidation of the resulting medium-chain dicarboxylic acids. It is argued that the source of the omega-oxidizable monocarboxylic acids in ketosis most probably is the fat deposites, and it is speculated that the patients with beta-oxidation defects supplement this source with beta-oxidation intermediate medium-chain monocarboxylic acids, accumulated as a result of the defect. The ratio between the excreted amounts of adipic acid and sebacic acid in the urine from the patients with beta-oxidation defects is less than 50. This is in contrast to the ratio in urine from ketotic patients, where it is greater than 100. Adipic acid/sebacic acid ratio-measured by means of a gas chromatographic analysis-is therefore suggested as a tool in the diagnosis of dicarboxylic acidurias. Based on the clinical picture and the pattern of a series of organic acids in the urinary metabolic profile our four patients can be divided in two types of dicarboxylic aciduria. The two types have different therapeutic implications.
Adipates↗
The biological origin of ketotic dicarboxylic aciduria. In vivo and in vitro investigations of the omega-oxidation of C6-C16-monocarboxylic acids in unstarved, starved and diabetic rats.
The conversion of radioactive C6-C16-monocarboxylic acids to urinary adipic, suberic, sebacic and 3-hydroxybutyric acids was investigated in vivo in unstarved, starved and diabetic ketotic rats. Hexanoic, octanoic and decanoic acids were converted to C6-, C6-C8- and C6-C10-dicarboxylic acids, respectively, in fed and 72-h-starved rats. Lauric acid was converted to C6-C8-dicarboxylic acids in starved rats but not in unstarved rats. Decanoic and lauric acids were converted to relatively high amounts of C6-C8-dicarboxylic acids compared with myristic acid in myristic acid in ketotic diabetic rats, while radioactivity from [1-14C]-and [16-(14)] palmitic acid was not incorporated into C6-C8-dicarboxylic acids in diabetic ketotic rats. C6-C12-monocarboxylic acids in hydrolysed rat adipose tissue wee determined by gas-liquid chromatography-mass spectrometry (selected ion monitoring). Decanoic and lauric acids were found in amounts of 7.6-9.1 and 85.9-137.5 micrometers/100 mg tissue, respectively, whereas the amounts of hexanoic and octanoic acids were negligible. It is concluded that the biological origin of the C6-C8-dicarboxylic aciduria seen in ketotic rats are C10-C14-monocarboxylic acids, which are initially omega-oxidised solely or partly as free acids and subsequently beta-oxidised to adipic and suberic acids. The in vitro omega-oxidation of C6-C16-monocarboxylic acids to corresponding dicarboxylic acids in the 100,000 Xg supernatant fraction of rat liver homogenate was measured by selected ion monitoring. 0.09, 0.14, 16.1, 5.8, 7.0 and -6.9% of, respectively, hexanoic, octanoic, decanoic, lauric, myristic and palmitic acid were omega-oxidised to dicarboxylic acids of corresponding chain lengths after 90 min of incubation, when correction for the production of dicarboxylic acids in control assays was made. An in vitro production of C12-C16-dicarboxylic acids was detected in all assays ()including control assays), probably formed from"endogenous' monocarboxylic acids preexistent in the homogenate. Ths "endogenous' production of dicarboxylic acids was inhibited by C10-C16-monocarboxylic acids, where palmitic acid had the strongest effect. In fact, palmitic acid inhibited its own omega-oxidation when added in concentrations above 0.6 mM. Starvation of rats for 72 h did not alter the "endogenous' in vitro production of hexadecanedioic acid.
Animals↗
Urinary excretion of succinylacetone and delta-aminolevulinic acid in patients with hereditary tyrosinemia.
Succinylacetone was excreted in the urine from four patients, with hereditary tyrosinemia i.e., two patients with the severe infantile type with fatal outcome and two patients with less severe juvenile form. In the urine from two patients with neonatal transient tyrosinemia and from normal individuals succinylacetone was not detectable. The urinary excretion of delta-aminolevulinic acid was also increased in all patients with hereditary tyrosinemia compared to patients with neonatal transient tyrosinemia and to normal individuals. The results presented support the hypothesis of a deficiency of fumarylacetoacetase in hereditary tyrosinemia. Furthermore an analytical method for the quantitative determination of succinylacetone in urine using GC-MS is described.
Acetoacetates↗
The specific inhibition of the pyruvate dehydrogenase complex from pig kidney by propionyl-CoA and isovaleryl-Co-A.
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Acyl Coenzyme A↗