Oxidized phosphatidylcholines suggest oxidative stress in patients with medium-chain acyl-CoA dehydrogenase deficiency

Najdekr, Lukáš; Gardlo, Alžběta; Mádrová, Lucie; Friedecký, David; Janečková, Hana; Correa, Elon; Goodacre, Royston; Adam, Tomáš

doi:10.1016/j.talanta.2015.02.041

Cited by 39 publications

(38 citation statements)

References 37 publications

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“…A recent manuscript by Najdekr et al showed elevated oxidized phosphatidylcholines in patients with medium-chain acyl-CoA dehydrogenase deficiency [11], a result not seen in this study. Nevertheless, our findings and those of Najdekr et al indicate that compromised mitochondrial fatty acid oxidation clearly impacts complex lipid homeostasis.…”

Section: Discussioncontrasting

confidence: 76%

Unique plasma metabolomic signatures of individuals with inherited disorders of long‐chain fatty acid oxidation

McCoin

Piccolo

Matern³

et al. 2016

J of Inher Metab Disea

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Blood and urine acylcarnitine profiles are commonly used to diagnose long-chain fatty acid oxidation disorders (FAOD: i.e., long-chain hydroxy-acyl-CoA dehydrogenase [LCHAD] and carnitine palmitoyltransferase 2 [CPT2] deficiency), but the global metabolic impact of long-chain FAOD has not been reported. We utilized untargeted metabolomics to characterize plasma metabolites in 12 overnight-fasted individuals with FAOD (10 LCHAD, 2 CPT2) and 11 healthy age-, sex-, and body mass index (BMI)-matched controls, with the caveat that individuals with FAOD consume a low-fat diet supplemented with medium-chain triglycerides (MCT) while matched controls consume a typical American diet. 832 metabolites were identified in plasma, and partial least squared-discriminant analysis (PLS-DA) identified 114 non-acylcarnitine variables that discriminated FAOD subjects and controls. FAOD individuals had significantly higher triglycerides and lower specific phosphatidylethanolamines, ceramides and sphingomyelins. Differences in phosphatidylcholines were also found but the directionality differed by species. Further, there were few differences in non-lipid metabolites indicating the metabolic impact of FAOD specifically on lipid pathways. This analysis provides evidence that LCHAD/CPT2 deficiency significantly alters complex lipid pathway flux. This metabolic signature may provide powerful clinical tools capable of confirming or diagnosing FAOD, even in subjects with a mild phenotype, and provide clues regarding the biochemical and metabolic impact of FAOD that could be relevant to the etiology of FAOD symptoms.

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Section: Discussioncontrasting

confidence: 76%

Unique plasma metabolomic signatures of individuals with inherited disorders of long‐chain fatty acid oxidation

McCoin

Piccolo

Matern³

et al. 2016

J of Inher Metab Disea

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“…Besides energy production defects, other pathogenic mechanisms have also been reported. The increased oxidative stress in MCADD patients contributes to the phenotypes, which suggests that antioxidative treatment could be useful in MCADD individuals. Also, accumulation of decanoic and cis‐4‐decanoic acids in MCADD patient tissues disturbs mitochondrial function in the brain and liver, and is possibly involved in the neuropathology and liver dysfunction …”

Section: Discussionmentioning

confidence: 99%

Medium‐chain acyl‐coenzyme A dehydrogenase deficiency: Six cases in the Chinese population

Zhu

Liu

et al. 2019

Pediatrics International

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Background Medium‐chain acyl‐coenzyme A dehydrogenase deficiency (MCADD) is a rare autosomal recessive disorder that affects the degradation of medium‐chain fatty acids. Few cases of MCADD have been documented to date in mainland China. Methods Medium‐chain acyl‐coenzyme A dehydrogenase deficiency was diagnosed in six patients (three girls and three boys) from six unrelated Chinese families at ages ranging from 10 days to 3 years old. The diagnosis was confirmed by the identification of a primary biomarker of serum octanoyl‐carnitine (C8) and genetic pathogenic mutations. Results Only two patients were admitted because of vomiting, diarrhea, myasthenia, and coma; the other four patients were diagnosed via the newborn screening process. Six mutations were found in acyl‐CoA dehydrogenase medium chain (ACADM). One mutation (c.727C>T) was novel and the others (c.158G>A, c.387+1delG, c.449_452del, c.1045C>T, and c.1085G>A) have been previously reported. Conclusions Six Chinese cases of MCADD were identified. One novel mutation was found. c.449_452del and c.1085G>A were common mutations in this study.

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“…Furthermore, increased oxidative stress, due to the disruption of OXPHOS, may also be contributing to MCAD deficiency disease pathogenesis. Increased ROS production has been reported in patients with MCAD deficiency [86,87], while cells lacking MCAD expression exhibit elevated ROS generation associated with increased sensitivity to OXPHOS complex III inhibition [24].…”

Section: Emerging Links Between B-fao and Oxphos In Pathophysiologymentioning

confidence: 99%

Understanding the role of OXPHOS dysfunction in the pathogenesis of ECHS1 deficiency

Burgin

McKenzie

2020

FEBS Letters

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Mitochondria provide the main source of energy for eukaryotic cells, oxidizing fatty acids and sugars to generate ATP. Mitochondrial fatty acid β‐oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two key pathways involved in this process. Disruption of FAO can cause human disease, with patients commonly presenting with liver failure, hypoketotic glycaemia and rhabdomyolysis. However, patients with deficiencies in the FAO enzyme short‐chain enoyl‐CoA hydratase 1 (ECHS1) are typically diagnosed with Leigh syndrome, a lethal form of subacute necrotizing encephalomyelopathy that is normally associated with OXPHOS dysfunction. Furthermore, some ECHS1‐deficient patients also exhibit secondary OXPHOS defects. This sequela of FAO disorders has long been thought to be caused by the accumulation of inhibitory fatty acid intermediates. However, new evidence suggests that the mechanisms involved are more complex, and that disruption of OXPHOS protein complex biogenesis and/or stability is also involved. In this review, we examine the clinical, biochemical and genetic features of all ECHS1‐deficient patients described to date. In particular, we consider the secondary OXPHOS defects associated with ECHS1 deficiency and discuss their possible contribution to disease pathogenesis.

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Oxidized phosphatidylcholines suggest oxidative stress in patients with medium-chain acyl-CoA dehydrogenase deficiency

Cited by 39 publications

References 37 publications

Unique plasma metabolomic signatures of individuals with inherited disorders of long‐chain fatty acid oxidation

Unique plasma metabolomic signatures of individuals with inherited disorders of long‐chain fatty acid oxidation

Medium‐chain acyl‐coenzyme A dehydrogenase deficiency: Six cases in the Chinese population

Understanding the role of OXPHOS dysfunction in the pathogenesis of ECHS1 deficiency

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