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Disorders of Mitochondrial Long-Chain Fatty Acid Oxidation and the Carnitine Shuttle

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Disorders of Mitochondrial Long-Chain Fatty Acid Oxidation and the Carnitine Shuttle Reviews in Endocrine and Metabolic Disorders https://doi.org/10.1007/s11154-018-9448-1 Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle Suzan J. G. Knottnerus1,2 & Jeannette C. Bleeker1,2 & Rob C. I. Wüst2 & Sacha Ferdinandusse2 & Lodewijk IJlst2 & Frits A. Wijburg2 & Ronald J. A. Wanders2 & Gepke Visser1,2 & Riekelt H. Houtkooper2 # The Author(s) 2018 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. Keywords Mitochondrial long-chain fatty acid oxidation . ß-oxidation . Carnitine transport . Inborn errors of metabolism 1 Introduction carnitine transport and mitochondrial fatty acid oxidation, in- cluding long-chain fatty acid oxidation disorders (lcFAODs), Hypoglycemia is a common, and potentially dangerous, sign may be involved as cause. Plasma levels of free fatty acids in medical practice, with an extensive number of etiologies, (FFAs) are low in hyperinsulinism due to a suppression of especially in the neonatal period. When hypoglycemia is ac- lipolysis, while FFAs are generally high during hypoglycemia companied by a low concentration, or even absence, of ketone caused by lcFAODs. In lcFAODs, FFAs are mobilized during bodies in plasma and urine, hyperinsulinism and disorders of fasting but cannot be oxidized due to an autosomal recessive inherited deficiency of one of the mitochondrial ß-oxidation Suzan J. G. Knottnerus and Jeannette C. Bleeker contributed equally to enzymes. Hypoglycemia, however, is only one of the signs in this publication. lcFAODs. Before lcFAODs were included in newborn screen- ing (NBS) panels, a considerable number of patients was di- * Gepke Visser agnosed in adulthood and these patients typically presented [email protected] with different clinical presentations compared to patients who * Riekelt H. Houtkooper presented during childhood. Following the inclusion of [email protected] lcFAODs in NBS panels in many countries worldwide, the 1 Dutch Fatty Acid Oxidation Expertise Center, Department of number of patients diagnosed has significantly increased and Metabolic Diseases, Wilhelmina Children’s Hospital, University the clinical spectrum has expanded, necessitating new algo- Medical Center Utrecht, Lundlaan 6, 3584, EA Utrecht, rithms for choosing the optimal therapeutic strategy. This re- The Netherlands view aims to serve as a comprehensive reference for clinical 2 Dutch Fatty Acid Oxidation Expertise Center, Laboratory Genetic and laboratory findings for those who are confronted with Metabolic Diseases, Departments of Clinical Chemistry and pediatric and adult patients with a possible diagnosis of a Pediatrics, Emma Children’s Hospital, Academic Medical Center, Meibergdreef 9, 1105, AZ Amsterdam, The Netherlands mitochondrial lcFAOD. Rev Endocr Metab Disord 2 Mitochondrial long-chain fatty acid the scope of this review but are described elsewhere [11]. The oxidation MTP enzyme complex harbors activity for (a) long-chain enoyl-CoA hydratase (LCEH), (b) long-chain-(S)-3- Mitochondrial fatty acid oxidation is an important pathway for hydroxyacyl-CoA-dehydrogenase (LCHAD), and (c) long- maintaining energy homeostasis. Especially during fasting, chain-3-ketoacyl-CoA thiolase (LCKAT). These concerted ac- when glucose and glycogen stores are low, fatty acid oxidation tivities lead to the formation of a molecule of acetyl-CoA and a (FAO) is a significant source of energy provision in the form of shortened acyl-CoAwith two carbons less. The acetyl-CoA can adenosine triphosphate (ATP). The majority of fatty acids are enter the tricarboxylic acid (TCA) cycle for production of re- stored in the body, in particular in adipose tissue, as long-chain ducing equivalents for oxidative phosphorylation resulting in triglycerides (LCT). As blood glucose levels drop, triglycerides ATP production, or may enter the ketone body synthesis path- in adipose tissue are hydrolyzed and free fatty acids (FFAs) are way in the liver. The heart mostly depends on FAO (60–90%), mobilized in the blood stream and become available for other even when glucose levels are high [12]. In contrast, the brain tissues [1, 2]. The FFAs enter the cell via fatty acid transport mostly relies on the oxidation of glucose and ketone bodies. systems (FAT/CD36) (Fig. 1). Before degradation or elongation However, there is evidence of FAO in astrocytes derived from can take place, FFAs need to be activated to acyl-coenzyme A rat brain and expression of FAO enzymes in other parts of the (-CoA) esters by one of a variety of different chain-length- rat brain as well as in neural cells from human fetuses [13–15]. specific synthetases localized in distinct subcellular compart- ments [3]. Medium-chain fatty acids can freely diffuse into mitochondria, whereas long-chain acyl-CoAs cannot. Instead, 3 Clinical signs and symptoms long-chain fatty acids are esterified with carnitine in the cyto- plasm and then are transported by the carnitine shuttle. In this Inherited disorders for many of the enzymes of the FAO cas- shuttle, the CoA group is first exchanged for carnitine in a cade and carnitine shuttle have been described in the past reaction catalyzed by carnitine palmitoyltransferase 1 (CPT1), decades [16–19]. These disorders give rise to a variety of forming acylcarnitine. CPT1 is an important regulator of FAO clinical features especially in organs that rely on energy pro- as it is sensitive for inhibition by malonyl-CoA, formed by duction by FAO, such as the heart, skeletal muscle and liver. carboxylation of the product of fatty acid oxidation, acetyl- Signs and symptoms can manifest as early as a few hours after CoA. The acylcarnitines are imported into the mitochondrion birth, but may also only appear during adulthood, with a var- by carnitine acylcarnitine translocase (CACT) in exchange for iation in clinical severity between patients even within the a free carnitine molecule. Next, the intramitochondrial same family [20–26]. Patients with severe phenotypes can acylcarnitines are reconverted to acyl-CoAs by carnitine present in infancy with hypoglycemia and lactic acidosis. In palmitoyltransferase 2 (CPT2). The mitochondrial acyl-CoAs rare cases, patients also have low levels of ketones, which can subsequently be used for energy production that occurs via might therefore be misinterpreted as respiratory-chain defects degradation by a series of enzymes with different chain-length [27]. specificity. The first step concerns the dehydrogenation of acyl- The clinical presentation of lcFAODs is aspecific, but a CoAs by different acyl-CoA dehydrogenases. In humans, the characteristic feature of the signs and symptoms in lcFAODs key enzymes catalyzing this step for the different chain lengths is the fact that they can be provoked, or aggravated, by energy of fatty acids are very long-chain acyl-CoA dehydrogenase requiring states such as fasting, prolonged exercise, illness, (VLCAD), medium-chain acyl-CoA dehydrogenase (MCAD) fever or a combination of these factors. The most common and short-chain acyl-CoA dehydrogenase (SCAD) [4]. For clinical presentations in lcFAODs are hypoketotic hypoglyce- long-chain acyl-CoAs (chain length C14-C18), VLCAD is mia, cardiomyopathy and myopathy. These presentations oc- the main enzyme [5]. In rodents, the enzyme long-chain acyl- cur in combination but also isolated: CoA dehydrogenase (LCAD) can take over part of the VLCAD function, but in humans LCAD makes little contribution to & Hypoketotic hypoglycemia, sometimes resulting in convul- lcFAO [6]. Indeed, nine patients that were originally reported sions, coma and brain damage, is most often seen in infan- as LCAD-deficient, diagnosed by a reduction in palmitoyl- cy and the early years of childhood. Hypoketotic hypogly- CoA degradation [7], were reported to have normal LCAD cemia is often observed in combination with hepatomegaly, protein levels on western blot [8] and upon subsequent analyses elevated transaminases, and hyperammonemia. Hepatic many were in fact VLCAD-deficient [9]. Following the initial dysfunction is described in patients during episodes of met- dehydrogenation, the resulting long-chain enoyl-CoAs undergo abolic derangement [28] and can be fatal. Chronic liver hydration, a second dehydrogenation step, and finally thiolytic dysfunction is uncommon
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