Clinical manifestations and management of fatty acid oxidation disorders

Merritt, J. Lawrence; MacLeod, Erin; Jurecka, Agnieszka; Hainline, Bryan E.

doi:10.1007/s11154-020-09568-3

Cited by 54 publications

(53 citation statements)

References 76 publications

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“…(39) Intriguingly, clinical manifestations of fatty acid oxidation disorders include neuropsychological and behavioral symptoms present in depression and other psychiatric disorders, such as cognitive impairments, mood alterations, irritability, sleep and appetite dysregulations and low energy. (40) Recent metabolomics analyses(13) in a population-based sample showed that subjects with elevated depressive symptoms, as compared to healthy controls, had lower levels of medium-chain ACs such as decanoylcarnitine (C10) and dodecanoylcarnitine (C12), a finding that seem in contrast with the present MR results. Nevertheless, discrepancies between observational and genetic estimates are not uncommon (e.g.…”

Section: Discussioncontrasting

confidence: 97%

Genomics-based identification of a potential causal role for acylcarnitine metabolism in depression

Milaneschi

Arnold

Kastenmüller

et al. 2021

Preprint

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Altered metabolism of acylcarnitines – transporting fatty acids to mitochondria – may represent a mechanism linking cellular energy dysfunction to depression. We examined the potential causal role of acylcarnitine metabolism in depression by leveraging genomics and Mendelian randomization. Summary statistics were obtained from large GWAS: the Fenland Study (N= 9,363), and the Psychiatric Genomics Consortium (246,363 depression cases and 344,901 controls). Two-sample Mendelian randomization analyses tested the potential causal link of 15 endogenous acylcarnitines with depression. In univariable analyses, genetically-predicted lower levels of short-chain acylcarnitines C2 (Odds Ratio [OR] 0.97, 95% Confidence Intervals [CIs] 0.95-1.00) and C3 (OR 0.97, 95%CIs 0.96-0.99) and higher levels of medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.01-1.06) and C10 (OR 1.04, 95%CIs 1.02-1.06) were associated with increased depression risk. No reverse potential causal role of depression genetic liability on acylcarnitines levels was found. Multivariable analyses showed that the association with depression was driven by the medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.02-1.06) and C10 (OR 1.04, 95%CIs 1.02-1.06), suggesting a potential causal role of these acylcarnitines in the risk of depression. Causal estimates for C8 (OR=1.05, 95%CIs=1.02-1.07) and C10 (OR=1.05, 95%CIs=1.02-1.08) were confirmed in follow-up analyses using genetic instruments derived from a GWAS meta-analysis including up to 16,841 samples. Accumulation of medium-chain acylcarnitines is a signature of inborn errors of fatty acid metabolism and age-related metabolic conditions. Our findings point to a link between altered mitochondrial energy production and depression pathogenesis. Acylcarnitine metabolism represents a promising access point for the development of novel therapeutic approaches for depression.

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Section: Discussioncontrasting

confidence: 97%

Genomics-based identification of a potential causal role for acylcarnitine metabolism in depression

Milaneschi

Arnold

Kastenmüller

et al. 2021

Preprint

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“…The clinical spectrum and prognosis are both highly variable, depending on the enzyme deficiency and the age of the patient, from paucisymptomatic cases or cases with mild symptoms under conditions of fasting or metabolic stress, to more severe affectations. A common feature of all these disorders (except the short or sometimes medium chain) is fasting hypoketotic hypoglycemia [ 8 , 9 ]. Approximately 5% of sudden deaths in childhood are secondary to FAODs [ 10 ], most of which are diagnosed postmortem.…”

Section: Introductionmentioning

confidence: 99%

Biochemical Markers for the Diagnosis of Mitochondrial Fatty Acid Oxidation Diseases

Ruíz-Sala

Quintana

2021

JCM

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Mitochondrial fatty acid β-oxidation (FAO) contributes a large proportion to the body’s energy needs in fasting and in situations of metabolic stress. Most tissues use energy from fatty acids, particularly the heart, skeletal muscle and the liver. In the brain, ketone bodies formed from FAO in the liver are used as the main source of energy. The mitochondrial fatty acid oxidation disorders (FAODs), which include the carnitine system defects, constitute a group of diseases with several types and subtypes and with variable clinical spectrum and prognosis, from paucisymptomatic cases to more severe affectations, with a 5% rate of sudden death in childhood, and with fasting hypoketotic hypoglycemia frequently occurring. The implementation of newborn screening programs has resulted in new challenges in diagnosis, with the detection of new phenotypes as well as carriers and false positive cases. In this article, a review of the biochemical markers used for the diagnosis of FAODs is presented. The analysis of acylcarnitines by MS/MS contributes to improving the biochemical diagnosis, both in affected patients and in newborn screening, but acylglycines, organic acids, and other metabolites are also reported. Moreover, this review recommends caution, and outlines the differences in the interpretation of the biomarkers depending on age, clinical situation and types of samples or techniques.

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“…Short-chain acyl-CoA dehydrogenase deficiency is an autosomal recessive inborn-error metabolic disease of mitochondrial FAO (3,(14)(15)(16). The pathogenic gene is traditionally considered to be ACADS, and the biochemical signatures of defects in short-chain acyl-CoA dehydrogenase (SCAD) result in the accumulation of plasma C4 and urine EMA (17,18).…”

Section: Introductionmentioning

confidence: 99%

Quantification of Differential Metabolites in Dried Blood Spots Using Second-Tier Testing for SCADD/IBDD Disorders Based on Large-Scale Newborn Screening in a Chinese Population

Zhou

Cai

Li³

et al. 2021

Front. Pediatr.

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Background: Although newborn screening (NBS) for metabolic defects using the marker butyl carnitine (C4) combined with the C4-to-acetylcarnitine ratio is adequate, the incorporation of novel parameters may improve differential testing for these disorders without compromising sensitivity.Methods: Analytical and clinical performance was evaluated by MS/MS using 237 initially positive neonatal samples between March 2019 and March 2020 at the Newborn Screening Center of Xuzhou Maternity and Child Health Care Hospital. Additionally, second-tier testing by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) combined with the quantification of ethylmalonate (EMA) or isobutyryl-glycine (IBG) in dried blood spots (DBSs) was performed to reduce the false-positive rate.Results: We reviewed initial MS/MS data for DBSs from 469,730 neonates, and a second-tier test was performed using 237 samples that exceeded the C4 concentration cutoff value. Eleven variants of the ACADS gene were identified, with c.1031A>G (p.E344G) being the most common. Fifteen ACAD8 mutations were identified in seven patients, and Swiss modeling and amino acid conservation analyses were conducted for the novel variants. Based on a retrospective analysis of EMA and IBG, the application of second-tier tests before the release of neonatal screening results reduced referrals by over 91.89% and improved the positive predictive value (PPV) for short-chain acyl-CoA dehydrogenase deficiency/isobutyryl-CoA dehydrogenase deficiency (SCADD/IBDD) screening.Conclusion: A screening algorithm including EMA/IBG improves target differential testing for NBS and may eliminate unnecessary referrals while maintaining 100% sensitivity. Second-tier screening using UPLC-MS/MS as a rapid and convenient supplemental DNA sequencing method may be beneficial for differential detection.

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Clinical manifestations and management of fatty acid oxidation disorders

Cited by 54 publications

References 76 publications

Genomics-based identification of a potential causal role for acylcarnitine metabolism in depression

Genomics-based identification of a potential causal role for acylcarnitine metabolism in depression

Biochemical Markers for the Diagnosis of Mitochondrial Fatty Acid Oxidation Diseases

Quantification of Differential Metabolites in Dried Blood Spots Using Second-Tier Testing for SCADD/IBDD Disorders Based on Large-Scale Newborn Screening in a Chinese Population

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