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

ABSTRACT: 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, two 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. In plasma 832 metabolites were identified, 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 metabolite 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 new clinical tools capable of confirming or diagnosing FAOD, even in subjects with a mild phenotype, and may provide clues regarding the biochemical and metabolic impact of FAOD that is relevant to the etiology of FAOD symptoms.

SUBMITTER: McCoin CS

PROVIDER: S-EPMC4851894 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

McCoin Colin S CS Piccolo Brian D BD Knotts Trina A TA Matern Dietrich D Vockley Jerry J Gillingham Melanie B MB Adams Sean H SH

Journal of inherited metabolic disease 20160223 3

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, two CPT2) and 11 healthy age-, sex-, and body mass index (BMI)-match ...[more]

PMID: 26907176

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Project description:Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of rare, autosomal recessive genetic disorders that impair conversion of long-chain fatty acids into energy. Here we describe the impact of LC-FAOD in terms of effects on work and school, absenteeism and presenteeism at work, importance of symptoms, physical activity, participation in social activities, and quality of life (QoL). A convenience sample of adults (≥18 years) and caregivers of patients with LC-FAOD was invited to take the online survey (Confirmit). To be included, patients must have been receiving medical care from a healthcare provider for their LC-FAOD, and caregivers must not have been compensated for their care. Degree of physical activity, represented by metabolic equivalents (METs), was calculated using the NHANES Physical Activity Questionnaire. Absenteeism and presenteeism at work were calculated using the WHO Health Productivity Questionnaire. QoL was assessed using the 12-Item Short Form of the Medical Outcomes Survey. Significance was assessed using two tailed independent sample t-tests and z-tests at α = 0.1. Fourteen adults and 30 caregivers of LC-FAOD patients (answering for 37 patients) answered the survey (51 unique respondents). 59.2% of LC-FAOD patients experienced effects on their schooling due to LC-FAOD. 84.2% of working patients experienced effects on their work due to LC-FAOD. 70% of caregivers experienced effects on their work due to their child's LC-FAOD. Unique respondents report that muscle weakness (69%), physical fatigue (49%), and rhabdomyolysis (39%) are the most impactful symptoms of LC-FAOD. Adults (n = 14) scored significantly below the normalized average (50) on both physical (34.51, p < 0.001) and mental (45.27, p = 0.04) component scores of the SF-12 health-related quality of life measure. LC-FAOD impart a high disease impact on patients and their caregivers. In particular, symptoms relating to energy production were rated as highly impactful and limiting. Activities that may be considered normal for many people can prove to be very difficult or impossible for respondents with LC-FAOD, with respondents reporting lower physical and mental health-related quality of life measures than the average American.

Project description:BackgroundFatty acid oxidation (FAO) defects have been implicated in experimental models of acute lung injury and associated with poor outcomes in critical illness. In this study, we examined acylcarnitine profiles and 3-methylhistidine as markers of FAO defects and skeletal muscle catabolism, respectively, in patients with acute respiratory failure. We determined whether these metabolites were associated with host-response ARDS subphenotypes, inflammatory biomarkers, and clinical outcomes in acute respiratory failure.MethodsIn a nested case-control cohort study, we performed targeted analysis of serum metabolites of patients intubated for airway protection (airway controls), Class 1 (hypoinflammatory), and Class 2 (hyperinflammatory) ARDS patients (N = 50 per group) during early initiation of mechanical ventilation. Relative amounts were quantified by liquid chromatography high resolution mass spectrometry using isotope-labeled standards and analyzed with plasma biomarkers and clinical data.ResultsOf the acylcarnitines analyzed, octanoylcarnitine levels were twofold increased in Class 2 ARDS relative to Class 1 ARDS or airway controls (P = 0.0004 and < 0.0001, respectively) and was positively associated with Class 2 by quantile g-computation analysis (P = 0.004). In addition, acetylcarnitine and 3-methylhistidine were increased in Class 2 relative to Class 1 and positively correlated with inflammatory biomarkers. In all patients within the study with acute respiratory failure, increased 3-methylhistidine was observed in non-survivors at 30 days (P = 0.0018), while octanoylcarnitine was increased in patients requiring vasopressor support but not in non-survivors (P = 0.0001 and P = 0.28, respectively).ConclusionsThis study demonstrates that increased levels of acetylcarnitine, octanoylcarnitine, and 3-methylhistidine distinguish Class 2 from Class 1 ARDS patients and airway controls. Octanoylcarnitine and 3-methylhistidine were associated with poor outcomes in patients with acute respiratory failure across the cohort independent of etiology or host-response subphenotype. These findings suggest a role for serum metabolites as biomarkers in ARDS and poor outcomes in critically ill patients early in the clinical course.

Project description:IntroductionDetermining the epidemiology of disease is critical for multiple reasons, including to perform risk assessment, compare disease rates in varying populations, support diagnostic decisions, evaluate health care needs and disease burden, and determine the economic benefit of treatment. However, establishing epidemiological measures for rare diseases can be difficult owing to small patient populations, variable diagnostic techniques, and potential disease and diagnostic heterogeneity. To determine the epidemiology of rare diseases, investigators often develop estimation models to account for missing or unobtainable data, and to ensure that their findings are representative of their desired patient population.MethodsA modeling methodology to estimate the prevalence of rare diseases in one such population-patients with long-chain fatty acid oxidation disorders (LC-FAOD)-as an illustrative example of its applicability.ResultsThe proposed model begins with reliable source data from newborn screening reports and applies to them key modifiers. These modifiers include changes in population growth over time and variable standardization rates of LC-FAOD screening that lead to (1) a confirmed diagnosis and (2) improvements in standards of care and survival estimates relative to the general population. The model also makes necessary assumptions to allow the broad applicability of the estimation of LC-FAOD prevalence, including rates of diagnosed versus undiagnosed patients in the USA over time.ConclusionsAlthough each rare disease is unique, the approach described here and demonstrated in the estimation of LC-FAOD prevalence provides the necessary tools to calculate key epidemiological estimates useful in performing risk assessment analyses; comparing disease rates between different subgroups of people; supporting diagnostic decisions; planning health care needs; comparing disease burden, including cost; and determining the economic benefit of treatment.

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

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

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