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Carnitine Inborn Errors of Metabolism

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Carnitine Inborn Errors of Metabolism molecules Review Carnitine Inborn Errors of Metabolism Mohammed Almannai 1, Majid Alfadhel 2,3,4 and Ayman W. El-Hattab 5,* 1 Section of Medical Genetics, Children’s Hospital, King Fahad Medical City, Riyadh 11525, Saudi Arabia 2 Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia 3 King Abdullah International Medical Research Center (KAIMRC), Riyadh 11426, Saudi Arabia 4 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11426, Saudi Arabia 5 Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, UAE * Correspondence: [email protected]; Tel.: +971508875123 Academic Editors: Cesare Indiveri and Lara Console Received: 7 August 2019; Accepted: 4 September 2019; Published: 6 September 2019 Abstract: Carnitine plays essential roles in intermediary metabolism. In non-vegetarians, most of carnitine sources (~75%) are obtained from diet whereas endogenous synthesis accounts for around 25%. Renal carnitine reabsorption along with dietary intake and endogenous production maintain carnitine homeostasis. The precursors for carnitine biosynthesis are lysine and methionine. The biosynthetic pathway involves four enzymes: 6-N-trimethyllysine dioxygenase (TMLD), 3-hydroxy-6-N-trimethyllysine aldolase (HTMLA), 4-N-trimethylaminobutyraldehyde dehydrogenase (TMABADH), and γ-butyrobetaine dioxygenase (BBD). OCTN2 (organic cation/carnitine transporter novel type 2) transports carnitine into the cells. One of the major functions of carnitine is shuttling long-chain fatty acids across the mitochondrial membrane from the cytosol into the mitochondrial matrix for β-oxidation. This transport is achieved by mitochondrial carnitine–acylcarnitine cycle, which consists of three enzymes: carnitine palmitoyltransferase I (CPT I), carnitine-acylcarnitine translocase (CACT), and carnitine palmitoyltransferase II (CPT II). Carnitine inborn errors of metabolism could result from defects in carnitine biosynthesis, carnitine transport, or mitochondrial carnitine–acylcarnitine cycle. The presentation of these disorders is variable but common findings include hypoketotic hypoglycemia, cardio(myopathy), and liver disease. In this review, the metabolism and homeostasis of carnitine are discussed. Then we present details of different inborn errors of carnitine metabolism, including clinical presentation, diagnosis, and treatment options. At the end, we discuss some of the causes of secondary carnitine deficiency. Keywords: carnitine; trimethyllysine (TML) dioxygenase; carnitine transporter; carnitine palmitoyltransferase 1. Introduction Carnitine (l-3-hydroxy-4-N,N,N-trimethylaminobutyrate), is an essential water soluble molecule that has many biological functions. One of these major functions is shuttling long-chain fatty acids across the mitochondrial membrane from the cytosol into the mitochondrial matrix for β-oxidation, and hence, cellular energy production. Carnitine also modulates the acyl-CoA/CoA ratio, thereby regulating the activity of several mitochondrial enzymes [1]. The acetylated form of carnitine, acetyl-carnitine, is involved in energy storage. Carnitine conjugates with partially metabolized acyl groups and allows their excretion as carnitine esters in urine [2–4]. More roles of carnitine being identified include anti-inflammatory and antioxidant properties [5–7], and improving insulin resistance [2,8]. Meat, poultry, fish, and dairy products are major sources of carnitine in the diet. On the other hand, the content of carnitine in food of plant origin is low. In non-vegetarians, 75% of carnitine sources are obtained from diet, which provides 2–12 µmol of carnitine per kilogram per day (µmol/Kg/day), Molecules 2019, 24, 3251; doi:10.3390/molecules24183251 www.mdpi.com/journal/molecules Molecules 2019, 24, 3251 2 of 16 and the remaining 25% originates from endogenous production, which provides 1.2 µmol/Kg/day. In contrast, endogenous synthesis provides the majority (>90%) of total carnitine in strict vegetarians, in whom dietary intake provides less than 0.1 µmol/Kg/day of carnitine [9–11]. The vast majority (>99%) of body carnitine is situated in the intracellular compartment. Circulating carnitine represents only about 0.5% of body carnitine. Therefore, normal plasma free carnitine levels are low, ranging between 25–50 µmol/L[12]. Normal levels are variable based on age and gender. In one study of 80 healthy volunteers, mean serum-free carnitine levels in males were 41 µmol/L (range 26.4–53.4) whereas in females the mean was 39 µmol/L (range 19.2–44.5) [13]. The same study showed a positive correlation between carnitine levels (free and total) with age, although in males the correlation didn’t reach statistical significance [13]. Normal carnitine levels are maintained by balance between dietary intake, endogenous synthesis, and renal reabsorption. Based on carnitine content in food, bioavailability of dietary carnitine is about 54–86% [14]. In the kidney the majority of carnitine (90–99% of filtered load) is reabsorbed until saturation is reached. The renal threshold for carnitine excretion is around 50 µmol/L. The kidneys are very efficient in maintaining normal levels of plasma carnitine by modulating urinary carnitine excretion according to the intake from diet [14]. Carnitine inborn errors of metabolism (IEM) can be divided into disorders of carnitine biosynthesis, carnitine transport, and mitochondrial carnitine–acylcarnitine cycle. The presentation of these disorders is variable but common findings include hypoketotic hypoglycemia, cardio(myopathy), and liver disease. These manifestations occur due to energy deficiency and accumulation of fatty acids in affected organs. Secondary carnitine deficiency could develop in several IEM, as a side effect of some drugs, or due to increased excretion with tubular dysfunction or dialysis. 2. Carnitine Biosynthesis Disorders The precursors for carnitine biosynthesis are lysine and methionine which provide the carbon backbone and 4-N-methyl groups of carnitine, respectively. The substrate for carnitine biosynthesis is 6-N-trimethyllysine (TML) (Figure1a). Certain proteins, like cytochrome c, actin, myosin, and histones, contain N-methylated lysine residues that are produced by post-translational N-methylation modification. This process is catalyzed by methyltransferases which use S-adenosylmethionine as a methyl donor. Subsequently, TML is released by lysosomal or proteasomal degradation of these proteins. The first step of carnitine biosynthesis is hydroxylation of TML by TML dioxygenase (TMLD), producing 3-hydroxy-6-N-trimethyllysine (HTML). The latter undergoes cleavage by HTML aldolase (HTMLA), yielding 4-N-trimethylaminobutyraldehyde (TMABA) and glycine. TMABA is then dehydrogenated to 4-N-trimethylaminobutyrate (γ-butyrobetaine) through action of TMABA dehydrogenase (TMABADH). In the fourth and last reaction of carnitine biosynthesis, γ-butyrobetaine is hydroxylated by γ-butyrobetaine dioxygenase (BBD) to produce carnitine [3,15]. Recently, TMLD and BBD deficiencies have been reported. As mentioned earlier, in individuals eating a regular diet, most of carnitine is obtained from the diet whereas carnitine biosynthesis makes a small contribution. Therefore, carnitine deficiency is not observed with carnitine biosynthesis defects, provided dietary intake is normal. The underlying pathophysiologic mechanisms in these disorders then may include abnormal levels of intermediate metabolites in the carnitine biosynthetic pathway and carnitine deficiency early in life [16]. Given the rarity of these disorders, no strictly vegetarian individuals affected with carnitine biosynthesis disorders have been yet reported. However, it is possible that carnitine levels could be low in these circumstances. MoleculesMolecules 20192019, ,2424, ,x 3251 FOR PEER REVIEW 3 3of of 17 16 Figure 1. (a) Carnitine biosynthetic pathway. Only trimethyllysine dioxygenase (TMLD) and Figureγ-butyrobetaine 1. (a) Carnitine dioxygenase biosynthetic (BBD) deficienciespathway. Only have trimethyllysine been reported; bothdioxygenase are denoted (TMLD) with asterisks. and γ- butyrobetaine(b) Carnitine transportdioxygenase and (BBD) mitochondrial deficiencies carnitine–acylcarnitine have been reported; cycle.both are IMM: denoted inner with mitochondrial asterisks. (membrane;b) CarnitineOMM: transport outer and mitochondrial mitochondrial membrane; carnitine–acylcarnitine CPT I: carnitine cycle. palmitoyltransferase IMM: inner mitochondrial I; CACT: membrane;carnitine-acylcarnitine OMM: outer translocase; mitochondrial CPT membrane; II: carnitine CPT palmitoyltransferaseI: carnitine palmitoyltransferase II; OCTN2: I; organicCACT: carnitine-acylcarnitinecation/carnitine transporter translocase; novel type CPT 2. II: carnitine palmitoyltransferase II; OCTN2: organic cation/carnitine transporter novel type 2. 2.1. 6-N-Trimethyllysine Dioxygenase (TMLD) Deficiency 2.1. 6-N-TrimethyllysineTMLD is a mitochondrial Dioxygenase enzyme, (TMLD) encoded Deficiency by TMLHE on the X chromosome. Celestino-Soper et al. performedTMLD is a array mitochondrial CGH (comparative enzyme, genomicencoded hybridization)by TMLHE on inthe families X chromosome. with autism Celestino-Soper and identified etTMLHE al. performedexon 2 deletion array CGH in a male (comparative child with genomic autism, raising hybridization) the possibility in families of a link with between autism TMLD and identifieddeficiency
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