General (medium-chain) acyl-CoA dehydrogenase deficiency (non-ketotic dicarboxylic aciduria): quantitative urinary excretion pattern of 23 biologically significant organic acids in three cases

doi:10.1016/0009-8981(83)90246-2

Clinica Chimica Acta

Volume 132, Issue 2, 15 August 1983, Pages 181-191

https://doi.org/10.1016/0009-8981(83)90246-2 Get rights and content

Abstract

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 ω- and ω-1 -oxidation systems are involved in the dicarboxylic and ω-1 -OH-monocarboxylic acids formation at c₁₀ and C₁₂ level and that the C₈–C₆-dicarboxylic and ω-1-OH-monocarboxylic acids are formed from higher chained acids by β-oxidation in both mitochondria and peroxisomes.

References (27)

S Kølvraa et al.
In vitro fibroblast studies in a patient with C₆–C₁₀-dicarboxylic aciduria: evidence for a defect in general acyl-CoA dehydrogenase
Clin Chim Acta
(1982)
N Gregersen et al.
Suberylglycine excretion in the urine from a patient with dicarboxylic aciduria
Clin Chim Acta
(1976)
N Gregersen et al.
Non-ketotic C₆–C₁₀-dicarboxylic aciduria: biochemical investigation of two cases
Clin Chim Acta
(1980)
RJW Truscott et al.
Dicarboxylic aciduria: the response to fasting
Clin Chim Acta
(1979)
PB Mortensen et al.
The biological origin of ketotic dicarboxylic aciduria. II. In vivo and in vitro investigations of the β-oxidation of C₈–C₁₆-dicarboxylic acids in unstarved, starved and diabetic rats
Biochim Biophys Acta
(1982)
PB Mortensen et al.
Cyanide insensitive and clofibrate enhanced β-oxidation of dodecanedioic acid in rat liver: evidence of peroxisomal β-oxidation of N-dicarboxylic acids
Biochim Biophys Acta
(1982)
K Tanaka
On the mode of action of hypoglycin A
J Biol Chem
(1972)
JE Pettersen et al.
The occurrence of adipic and suberic acid in urine from ketotic patients
Clin Chim Acta
(1972)
PB Lazarow
Rat liver peroxisomes catalyze the β-oxidation of fatty acids
J Biol Chem
(1978)
T Osumi et al.
Acyl-CoA oxidase of rat liver: a new enzyme for fatty acid oxidation
Biochem Biophys Res Comm
(1978)

M Bronfman et al.

Fatty acid oxidation by human liver peroxisomes

Biochem Biophys Res Comm

(1979)

H Przyrembel et al.

Glutaric aciduria type II: report on a previously undescribed metabolic disorder

Clin Chim Acta

(1976)

L Sweetman et al.

Glutaric aciduria type II

J Pediat

(1980)

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Triheptanoin (triheptanoylglycerol) has shown value as anaplerotic therapy for patients with long chain fatty acid oxidation disorders but is contraindicated in medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. In search for anaplerotic therapy for patients with MCAD deficiency, fibroblasts from three patients homozygous for the most common mutation, ACADM^G985A/G985A, were treated with fatty acids hypothesized not to require MCAD for their metabolism, including heptanoic (C7; the active component of triheptanoin), 2,6-dimethylheptanoic (dMC7), 6-amino-2,4-dimethylheptanoic (AdMC7), or 4,8-dimethylnonanoic (dMC9) acids. Their effectiveness as anaplerotic fatty acids was assessed in live cells by monitoring changes in cellular oxygen consumption rate (OCR) and mitochondrial protein lysine succinylation, which reflects cellular succinyl-CoA levels, using immunofluorescence (IF) staining. Krebs cycle intermediates were also quantitated in these cells using targeted metabolomics. The four fatty acids induced positive changes in OCR parameters, consistent with their oxidative catalysis and utilization. Increases in cellular IF staining of succinylated lysines were observed, indicating that the fatty acids were effective sources of succinyl-CoA in the absence of media glucose, pyruvate, and lipids. The ability of MCAD deficient cells to metabolize C7 was confirmed by the ability of extracts to enzymatically utilize C7-CoA as substrate but not C8-CoA. To evaluate C7 therapeutic potential in vivo, Acadm^-/- mice were treated with triheptanoin for seven days. Dose dependent increase in plasma levels of heptanoyl-, valeryl-, and propionylcarnitine indicated efficient metabolism of the medication. The pattern of the acylcarnitine profile paralleled resolution of liver pathology including reversing hepatic steatosis, increasing hepatic glycogen content, and increasing hepatocyte protein succinylation, all indicating improved energy homeostasis in the treated mice. These results provide the impetus to evaluate triheptanoin and the medium branched chain fatty acids as potential therapeutic agents for patients with MCAD deficiency.
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Biochemical testing typically shows elevations of medium-length acylcarnitines (C6–C10) with prominent octanoylcarnitine (C8) on acylcarnitine profile analysis.13 Urine organic acids show a characteristic pattern of elevated medium-length dicarboxylic acids (C6>C8>C10) with inappropriately low ketones.14 During an acute metabolic event, urine acylglycines will show elevations in hexanoylglycine, suberylglycine, and at times propionylglycine.11
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This is achieved by increasing feeding frequency with food containing a high starch content and a limited supply of medium chain triglyceride oils. Acute patients exhibit hyperamonemia and characteristic profile of elevated organic acids in urine – adipic, suberic, sebacic acids, hexanoic, octanoic acids [11] – and several other glycine conjugates – hexanoylglycine, 3-phenylpropionylglycine and suberylglycine [12]. This biochemical picture depends on the clinical status and can disappear during the period of normalcy.
Inborn errors of metabolism encompass a large group of diseases caused by enzyme deficiencies and are therefore amenable to metabolomics investigations. Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is a defect in β-oxidation of fatty acids, and is one of the most well understood disorders. We report here the use of liquid chromatography–mass spectrometry (LC–MS) based untargeted metabolomics and targeted flow injection analysis–tandem mass spectrometry (FIA–TMS) that lead to discovery of novel compounds of oxidative stress. Dry blood spots of controls (n=25) and patient samples (n=25) were extracted by methanol/water (1/1, v/v) and these supernatants were analyzed by LC–MS method with detection by an Orbitrap Elite MS. Data were processed by XCMS and CAMERA followed by dimension reduction methods. Patients were clearly distinguished from controls in PCA. S-plot derived from OPLS-DA indicated that medium-chain acylcarnitines (octanoyl, decenoyl and decanoyl carnitines) as well as three phosphatidylcholines (PC(16:0,9:0(COOH))), PC(18:0,5:0(COOH)) and PC(16:0,8:0(COOH)) were important metabolites for differentiation between patients and healthy controls. In order to biologically validate these discriminatory molecules as indicators for oxidative stress, a second cohort of individuals were analyzed, including MCADD (n=25) and control (n=250) samples. These were measured by a modified newborn screening method using FIA–TMS (API 4000) in MRM mode. Calculated p-values for PC(16:0,9:0(COOH)), PC(18:0,5:0(COOH)) and PC(16:0,8:0(COOH)) were 1.927×10⁻¹⁴, 2.391×10⁻¹⁵ and 3.354×10⁻¹⁵ respectively. These elevated oxidized phospholipids indeed show an increased presence of oxidative stress in MCADD patients as one of the pathophysiological mechanisms of the disease.
Medium-chain acyl-CoA-dehydrogenase (MCAD) deficiency: French consensus for neonatal screening, diagnosis, and management
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Le déficit en acyl-CoA-déshydrogénase des acides gras à chaîne moyenne (MCAD) est le plus fréquent des déficits de la bêta-oxydation mitochondriale des acides gras. La prévalence de ce déficit varie de 1/10 000 à 1/27 000 dans les pays limitrophes de la France. La Haute Autorité de santé (HAS) ayant récemment préconisé d’inclure le déficit en MCAD aux maladies dépistées en période néonatale, un groupe d’expert français a réalisé un consensus de prise en charge du déficit en MCAD que ce soit après diagnostic clinique ou après dépistage néonatal. Les patients peuvent présenter des épisodes de décompensation provoqués par le jeûne prolongé ou une infection intercurrente. Ces épisodes se caractérisent par une hypoglycémie avec hyperammoniémie entraînant des troubles neurologiques, souvent accompagnés d’une hépatomégalie. Des morts subites par troubles du rythme cardiaque peuvent également survenir. Le diagnostic est initialement suspecté grâce à l’analyse des acyl-carnitines plasmatiques ou des acides organiques urinaires. Ce diagnostic doit être confirmé par la biologie moléculaire et par une analyse de l’activité enzymatique si le patient n’est pas homozygote pour la mutation c.985A>G. Certains patients peuvent rester asymptomatiques tout au long de la vie. Le traitement consiste essentiellement à éviter les périodes de jeûne. La prescription de L-carnitine peut être proposée, surtout en cas de déficit en carnitine plasmatique. Cette prise en charge a radicalement modifié l’histoire naturelle des patients. Ce consensus permettra une prise en charge homogène une fois que le dépistage systématique de cette maladie sera effectivement mis en place dans notre pays.
MCAD deficiency is the most common fatty acid oxidation disorder, with the prevalence varying from 1/10,000 to 1/27,000 in the countries adjacent to France. As the High Authority for Health has recently proposed including MCAD deficiency in the panel of diseases neonatally screened for in France, a consensus was written for the management of MCAD deficiency diagnosed either clinically or by neonatal screening. Patients may present acutely with hyperammonemia, hypoglycemia, encephalopathy, and hepatomegaly, mainly after a prolonged fast of intercurrent infection. Sudden death related to heartbeat disorders may also occur. The diagnosis of MCAD deficiency is suspected on the plasma acylcarnitine and/or the urinary organic acid profile. The diagnosis is confirmed by molecular biology and the enzymatic activity for patients who are not homozygous for the main mutation c.985A>G. However, some MCAD-deficient individuals may remain asymptomatic throughout life. The mainstay of treatment consists in avoiding prolonged fast and prescribing l-carnitine for patients who exhibit a deficiency in plasma carnitine. This management has radically modified the natural history of MCAD deficiency. This consensus will allow homogeneous management of these patients once the neonatal screening of MCAD deficiency has been introduced in France.
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General (medium-chain) acyl-CoA dehydrogenase deficiency (non-ketotic dicarboxylic aciduria): quantitative urinary excretion pattern of 23 biologically significant organic acids in three cases

Abstract

Clin Chim Acta

Clin Chim Acta

Clin Chim Acta

Clin Chim Acta

Biochim Biophys Acta

Biochim Biophys Acta

J Biol Chem

Clin Chim Acta

J Biol Chem

Biochem Biophys Res Comm

Biochem Biophys Res Comm

Clin Chim Acta

J Pediat