Contribution of odd-numbered fatty acid oxidation to propionate production in neonates with methylmalonic an propionic acidaemias

Wendel, U.; Zass, R.; Leupold, D.

doi:10.1007/bf01957229

Cited by 8 publications

(5 citation statements)

References 6 publications

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“…The presence of large amounts of odd-numbered long-chain fatty acids in adipose tissue (from 8% to 10% of total fatty acids vs 1% in normal controls) during fetal life in newborns suffering of propionate metabolism defects has been largely reported from Wendel and collaborators (15–17). During periods of acute catabolism, such as in the early days of life, the mobilization and the oxidation of odd-chain fatty acids from adipose tissue leads to the production of extensive amounts of toxic propionyl-CoA in the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Heptadecanoylcarnitine (C17) a novel candidate biomarker for newborn screening of propionic and methylmalonic acidemias

Malvagia

Haynes²,

Grisotto

et al. 2015

Clinica Chimica Acta

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Background 3-hydroxypalmitoleoyl-carnitine (C16:1-OH) was recently reported to be elevated in acylcarnitine profile of propionic acidemia (PA) or methylmalonic acidemia (MMA) patients during expanded newborn screening (NBS). High levels of C16:1-OH, combined with other hydroxylated long chain acylcarnitines are related to long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). Methods The acylcarnitine profile of two LCHADD patients was evaluated using liquid chromatography-tandem mass spectrometric method. A specific retention time was reported for each hydroxylated long chain acylcarnitine. The same method was applied to some neonatal dried blood spots (DBS) from PA and MMA patients presenting abnormal C16:1-OH concentrations. Results The final retention time of the peak corresponding to C16:1-OH in LCHADD patients differed from those in MMA and PA patients. Heptadecanoylcarnitine (C17) has been identified as the novel biomarker specific for PA and MMA patients through high resolution mass spectrometry (Orbitrap) experiments. We found that 21 out of 23 neonates (22 MMA, and 1PA) diagnosed through the Tuscany region NBS program had significantly higher levels of C17 compared to levels detected in controls. Twenty-three maternal deficiencies (21 vitamin B12 deficiency, 1 homocystinuria and 1 gastrin deficiency) and 82 false positive for propionylcarnitine (C3) results were also analyzed. Conclusions This paper reports on the characterization of a novel biomarker able to detect propionate disorders during expanded newborn screening (NBS). The use of this new biomarker may improve the analytical performances of NBS programs especially in laboratories where second tier tests are not performed.

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Section: Discussionmentioning

confidence: 99%

Heptadecanoylcarnitine (C17) a novel candidate biomarker for newborn screening of propionic and methylmalonic acidemias

Malvagia

Haynes²,

Grisotto

et al. 2015

Clinica Chimica Acta

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“…Although most fatty acids have an even number of carbon atoms and are metabolized via ␤-oxidation, odd-chain fatty acids represent a small percentage of fatty acids in normal brain. This percentage increases in pathological states and during development (Kishimoto et al, 1973;Rosenberg, 1983;Wendel et al, 1993;Sbai et al, 1994). Odd-chain fatty acids are metabolized via ␣-oxidation to acetyl CoA and propionyl CoA.…”

Section: Discussionmentioning

confidence: 99%

Methylmalonyl-CoA Mutase Induction by Cerebral Ischemia and Neurotoxicity of the Mitochondrial Toxin Methylmalonic Acid

et al. 1996

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Differential screening of gerbil brain hippocampal cDNA libraries was used to search for genes expressed in ischemic, but not normal, brain. The methylmalonyl-CoA mutase (MCM) cDNA was highly expressed after ischemia and showed a 95% similarity to mouse and 91% similarity to the human MCM cDNAs. Transient global ischemia induced a fourfold increase in MCM mRNA on Northern blots from both hippocampus and whole forebrain. MCM protein exhibited a similar induction on Western blots of gerbil cerebral cortex 8 and 24 hr after ischemia. Treatment of primary brain astrocytes with either the branched-chain amino acid (BCAA) isoleucine or the BCAA metabolite, propionate, induced MCM mRNA fourfold. Increased concentrations of BCAAs and odd-chain fatty acids, both of which are metabolized to propionate, may contribute to inducing the MCM gene during ischemia. Methylmalonic acid, which is formed from the MCM substrate methylmalonyl-CoA and which inhibits succinate dehydrogenase (SDH), produced dose-related cell death when injected into the basal ganglia of adult rat brain. This neurotoxicity is similar to that of structurally related mitochondrial SDH inhibitors, malonate and 3-nitropropionic acid. Methylmalonic acid may contribute to neuronal injury in human conditions in which it accumulates, including MCM mutations and B12 deficiency. This study shows that methylmalonyl-CoA mutase is induced by several stresses, including ischemia, and would serve to decrease the accumulation of an endogenous cellular mitochondrial inhibitor and neurotoxin, methylmalonic acid.

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“…These fatty acids are incorporated in lipids, which may be found in cellular membranes, but also in plasma. Accordingly, high levels of OLCFAs have been detected in patients with these disorders as well as in fetuses affected with PA and MMA (Wendel et al, 1991(Wendel et al, , 1993. It remains to be established whether fetal accumulation of OLCFAs has a deleterious effect on the development of neural tissue.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, these OLCFAs are present in many tissues and body fluids in abnormal amounts, usually expressed as a percentage of the total C,,C,, fatty acids. The accumulated OLCFAs contribute to the formation of propionate during a period of catabolism associated with metabolic decompensation (Wendel et al, 1993). This accumulation of OLCFAs starts in utero, as exemplified by the finding of OLCFAs in fetal tissues (Wendel et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Amniotic Fluid Odd-Chain Fatty Acids Are Increased in Propionic Acidaemia

et al. 1996

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Odd‐chain (C15 and C17) fatty acids have been reported to accumulate in tissues and body fluids of patients with propionic and methylmalonic acidaemia. We investigated the occurrence of these substances in amniotic fluid samples. The odd‐chain fatty acid levels (expressed as the percentage of total C12–C20 fatty acids) in eight control samples ranged from 3·7 to 12·5 per cent. Three samples from affected propionic acidaemia pregnancies had values of 15·3–22·9 per cent; one methylmalonic acidaemia sample had a normal level of 9·3 per cent. These results supply further evidence of the prenatal accumulation of odd‐chain fatty acids in propionic acidaemia.

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Contribution of odd-numbered fatty acid oxidation to propionate production in neonates with methylmalonic an propionic acidaemias

Cited by 8 publications

References 6 publications

Heptadecanoylcarnitine (C17) a novel candidate biomarker for newborn screening of propionic and methylmalonic acidemias

Heptadecanoylcarnitine (C17) a novel candidate biomarker for newborn screening of propionic and methylmalonic acidemias

Methylmalonyl-CoA Mutase Induction by Cerebral Ischemia and Neurotoxicity of the Mitochondrial Toxin Methylmalonic Acid

Amniotic Fluid Odd-Chain Fatty Acids Are Increased in Propionic Acidaemia

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