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Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle.

ABSTRACT: Mitochondrial fatty acid oxidation is an essential pathway for energy production, especially during prolonged fasting and sub-maximal exercise. Long-chain fatty acids are the most abundant fatty acids in the human diet and in body stores, and more than 15 enzymes are involved in long-chain fatty acid oxidation. Pathogenic mutations in genes encoding these enzymes result in a long-chain fatty acid oxidation disorder in which the energy homeostasis is compromised and long-chain acylcarnitines accumulate. Symptoms arise or exacerbate during catabolic situations, such as fasting, illness and (endurance) exercise. The clinical spectrum is very heterogeneous, ranging from hypoketotic hypoglycemia, liver dysfunction, rhabdomyolysis, cardiomyopathy and early demise. With the introduction of several of the long-chain fatty acid oxidation disorders (lcFAOD) in newborn screening panels, also asymptomatic individuals with a lcFAOD are identified. However, despite early diagnosis and dietary therapy, a significant number of patients still develop symptoms emphasizing the need for individualized treatment strategies. This review aims to function as a comprehensive reference for clinical and laboratory findings for clinicians who are confronted with pediatric and adult patients with a possible diagnosis of a lcFAOD.

SUBMITTER: Knottnerus SJG

PROVIDER: S-EPMC6208583 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle.

Knottnerus Suzan J G SJG Bleeker Jeannette C JC Wüst Rob C I RCI Ferdinandusse Sacha S IJlst Lodewijk L Wijburg Frits A FA Wanders Ronald J A RJA Visser Gepke G Houtkooper Riekelt H RH

Reviews in endocrine & metabolic disorders 20180301 1

Mitochondrial fatty acid oxidation is an essential pathway for energy production, especially during prolonged fasting and sub-maximal exercise. Long-chain fatty acids are the most abundant fatty acids in the human diet and in body stores, and more than 15 enzymes are involved in long-chain fatty acid oxidation. Pathogenic mutations in genes encoding these enzymes result in a long-chain fatty acid oxidation disorder in which the energy homeostasis is compromised and long-chain acylcarnitines accu ...[more]

PMID: 29926323

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Project description:Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. It can be synthesized by the body or assumed with the diet from meat and dairy products. Defects in carnitine biosynthesis do not routinely result in low plasma carnitine levels. Carnitine is accumulated by the cells and retained by kidneys using OCTN2, a high affinity organic cation transporter specific for carnitine. Defects in the OCTN2 carnitine transporter results in autosomal recessive primary carnitine deficiency characterized by decreased intracellular carnitine accumulation, increased losses of carnitine in the urine, and low serum carnitine levels. Patients can present early in life with hypoketotic hypoglycemia and hepatic encephalopathy, or later in life with skeletal and cardiac myopathy or sudden death from cardiac arrhythmia, usually triggered by fasting or catabolic state. This disease responds to oral carnitine that, in pharmacological doses, enters cells using the amino acid transporter B(0,+). Primary carnitine deficiency can be suspected from the clinical presentation or identified by low levels of free carnitine (C0) in the newborn screening. Some adult patients have been diagnosed following the birth of an unaffected child with very low carnitine levels in the newborn screening. The diagnosis is confirmed by measuring low carnitine uptake in the patients' fibroblasts or by DNA sequencing of the SLC22A5 gene encoding the OCTN2 carnitine transporter. Some mutations are specific for certain ethnic backgrounds, but the majority are private and identified only in individual families. Although the genotype usually does not correlate with metabolic or cardiac involvement in primary carnitine deficiency, patients presenting as adults tend to have at least one missense mutation retaining residual activity. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

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: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.

Dataset Information

Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle.

Publications

Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle.

Similar Datasets

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