Accumulation of Odd-Numbered Long-Chain Fatty Acids in Fetuses and Neonates with Inherited Disorders of Propionate Metabolism

Wendel, U.; Baumgartner, R.; Sb, van der Meer; Lj, Spaapen

doi:10.1203/00006450-199104000-00015

Cited by 20 publications

(18 citation statements)

References 8 publications

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“…This suggests the maternal circulation does not completely "detoxify" the fetus. This finding is in agreement with the observed elevation of odd-numbered long-chain fatty acids in fetuses in disorders of propionate metabolism, reflecting the ongoing in utero elevation of propionyl-CoA despite the maternal circulation (15). The significance of this to the health of the developing fetus is unclear at this stage.…”

Section: Discussionsupporting

confidence: 88%

A Knock-out Mouse Model for Methylmalonic Aciduria Resulting in Neonatal Lethality

Peters

Nefedov

Sarsero

et al. 2003

Journal of Biological Chemistry

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Methylmalonic aciduria is a human autosomal recessive disorder of organic acid metabolism resulting from a functional defect in the activity of the enzyme methylmalonyl-CoA mutase. Based upon the homology of the human mutase locus with the mouse locus, we have chosen to disrupt the mouse mutase locus within the critical CoA binding domain using gene-targeting techniques to create a mouse model of methylmalonic aciduria. The phenotype of homozygous knock-out mice (mut ؊/؊ ) is one of early neonatal lethality. Mice appear phenotypically normal at birth and are indistinguishable from littermates. By 15 h of age, they develop reduced movement and suckle less. This is followed by the development of abnormal breathing, and all of the mice with a null phenotype die by 24 h of age. Urinary levels of methylmalonic and methylcitric acids are grossly increased. Measurement of acylcarnitines in blood shows elevation of propionylcarnitine with no change in the levels of acetylcarnitine and free carnitine. Incorporation of [ 14 C]propionate in primary fibroblast cultures from mut ؊/؊ mice is reduced to approximately 6% of normal level, whereas there is no detectable synthesis of mut mRNA in the liver. This is the first mouse model that recapitulates the key phenotypic features of mut 0 methylmalonic aciduria.Methylmalonic aciduria (MMA, 1 MIM 251000) is an autosomal recessive inborn error of organic acid metabolism. The true incidence of the disorder has been difficult to determine, and variable figures have been reported. A recent review of newborn screening data indicates an incidence of isolated MMA (mutase and cobalamin A/B) in the order of 1 in 140,000 in Australia (1). The condition results from a functional defect in the enzyme methylmalonyl-CoA mutase (MCM, EC 5.4.99.2) either due to a defect in the mutase (mut) gene itself (designated mut o or mut Ϫ ) or from a defect in the metabolism of the cofactor adenosylcobalamine. MCM is a nuclear-encoded mitochondrial enzyme that catalyzes the conversion of L-methylmalonyl-CoA to succinyl-CoA, which then enters the citric acid cycle. L-Methylmalonyl-CoA is predominantly derived from the catabolism of branched chain amino acids in the diet, odd chain fatty acids via propionyl-CoA, and propionate synthesized from gut flora.Following normal pregnancy and delivery-affected individuals with the mut 0 form typically present in the newborn period with overwhelming illness consisting of acidosis, vomiting, poor feeding, hypotonia, and lethargy. Untreated, there is progression to coma and death. The mut 0 form may have a less severe phenotype. Aggressive supportive therapy results in survival. However, any intercurrent illness or "metabolic stress" may lead to metabolic instability characterized by repeat recurrent life-threatening episodes of metabolic decompensation.Currently, the mainstay of treatment for MMA is strict dietary restriction and drug manipulation. The aim of such treatment is to control methylmalonate (MM) and propionate production by limiting dietary intake of precur...

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Section: Discussionsupporting

confidence: 88%

A Knock-out Mouse Model for Methylmalonic Aciduria Resulting in Neonatal Lethality

Peters

Nefedov

Sarsero

et al. 2003

Journal of Biological Chemistry

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“…Most cellular FAs contain even-numbered chain-lengths. However, odd-numbered FAs also exist, albeit at much lesser levels compared with evennumbered FAs [1][2][3][4] .…”

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confidence: 99%

Identification of the phytosphingosine metabolic pathway leading to odd-numbered fatty acids

et al. 2014

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The long-chain base phytosphingosine is a component of sphingolipids and exists in yeast, plants and some mammalian tissues. Phytosphingosine is unique in that it possesses an additional hydroxyl group compared with other long-chain bases. However, its metabolism is unknown. Here we show that phytosphingosine is metabolized to odd-numbered fatty acids and is incorporated into glycerophospholipids both in yeast and mammalian cells. Disruption of the yeast gene encoding long-chain base 1-phosphate lyase, which catalyzes the committed step in the metabolism of phytosphingosine to glycerophospholipids, causes an B40% reduction in the level of phosphatidylcholines that contain a C15 fatty acid. We also find that 2-hydroxypalmitic acid is an intermediate of the phytosphingosine metabolic pathway. Furthermore, we show that the yeast MPO1 gene, whose product belongs to a large, conserved protein family of unknown function, is involved in phytosphingosine metabolism. Our findings provide insights into fatty acid diversity and identify a pathway by which hydroxyl group-containing lipids are metabolized.

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“…Based on findings in two fetuses with PA we suggested that during early postnatal life, when fatty acids are mobilized from stored triglycerides, the breakdown of adipose tissue might greatly contribute to the mitochondrial accumulation of toxic propionyl-CoA and thus to the severity of illness in newborns affected with PA an MMA [6]. We are now able to demonstrate directly a very high content of OLCFA in the subcutaneous adipose tissue of affected neonates, which is the source of circulating free OLCFA.…”

Section: Introductionmentioning

confidence: 86%

“…One patient was responsive to vitamin B12 (Cbl A variant). His data have been reported previously [6]. Venous blood samples were drawn in newborns between 3 and 9 days of age and again at the age of 2 to 3 months.…”

Section: Patientsmentioning

confidence: 99%

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

1993

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Newborns with disturbed propionate metabolism (propionic and methylmalonic acidaemias) accumulate during fetal life large amounts of odd-numbered long-chain fatty acids in adipose tissue (8% to 10% of total fatty acids vs 1% in normal controls) and other body lipids. During periods of acute catabolism, such as in the early days of life, mobilization and oxidation of odd-chain fatty acids from adipose tissue yield extensive amounts of toxic propionyl-CoA in the mitochondria and thus might contribute to the severe illness of the patients. Our data suggest that not only catabolism of protein but also that of adipose tissue has to be avoided in order to alleviate the neonatal illness of patients with propionic and methylmalonic acidaemias. It seems prudent to avoid prolonged fasting during the 1st year of life.

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Accumulation of Odd-Numbered Long-Chain Fatty Acids in Fetuses and Neonates with Inherited Disorders of Propionate Metabolism

Cited by 20 publications

References 8 publications

A Knock-out Mouse Model for Methylmalonic Aciduria Resulting in Neonatal Lethality

A Knock-out Mouse Model for Methylmalonic Aciduria Resulting in Neonatal Lethality

Identification of the phytosphingosine metabolic pathway leading to odd-numbered fatty acids

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

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