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Carnitine-acylcarnitine translocase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Mitochondrial oxidation of long-chain fatty acids provides an important source of energy for the heart, as well as for skeletal muscle during prolonged aerobic work and for hepatic ketogenesis during long-term fasting. The carnitine shuttle is responsible for transferring long-chain fatty acids across the barrier of the inner mitochondrial membrane to gain access to the enzymes of β-oxidation. The shuttle consists of three enzymes (carnitine palmitoyltransferase [CPT] 1, carnitine-acylcarnitine translocase [CACT], CPT 2) and a small, soluble molecule (carnitine) to transport fatty acids as their long-chain fatty acylcarnitine esters. Carnitine is provided in the diet (animal protein) and also synthesized at low rates from trimethyllysine residues generated during protein catabolism. Carnitine turnover rates (300–500 μmol/day) represent <1 percent of body stores; 98 percent of carnitine stores are intracellular (total carnitine levels are 40–50 μM in plasma versus 2–3 mM in tissue). Carnitine is removed by urinary excretion after reabsorption of 98 percent of the filtered load; the renal carnitine threshold determines plasma concentrations and total body carnitine stores [5].
The Effects of Preconceptional Nutraceuticals Intake on Foetus Development and Health
Published in Priyanka Bhatt, Maryam Sadat Miraghajani, Sarvadaman Pathak, Yashwant Pathak, Nutraceuticals for Prenatal, Maternal and Offspring’s Nutritional Health, 2019
Doxorubicin and cyclophosphamide, which are very effective anticancer agents, were administered to female Wistar rats in doses of 1.8 mg/kg and 2.7 mg/kg respectively, every third week for 10 weeks. Also, 10 mg/kg of quercetin in combination with these anticancer agents was administered to two other groups of rats separately. The female rats were then moved to cages with male rats for mating to take place. The foetal brains were subsequently removed from foetuses and examined. The study showed an increase in superoxide dismutase and malondialdehyde, accompanied by a decrease in carnitine acylcarnitine translocase and glutathione indicative of oxidative damage in both cyclophosphamide and doxorubicin treatment groups. Treatment with quercetin improved the antioxidant capacity of foetal brain tissue with a reduction of free radical damage caused by oxidative stress. Women of child-bearing age on anticancer treatment with doxorubicin and cyclophosphamide could be treated with nutraceuticals such as quercetin, if they became pregnant, to reduce the risk of foetal damage of brain tissue (Doğan et al., 2015).
Alterations in Myocardial Energy Metabolism in Streptozotocin Diabetes
Published in John H. McNeill, Experimental Models of Diabetes, 2018
William C. Stanley, Gary D. Lopaschuk, Krista M. Kivilo
Esterified fatty acids are transferred across the mitochondrial membrane into the mitochondrial matrix by three carnitine dependent enzymes. The first one in the sequence, carnitine-palmitoyl transferase I (CPT I), catalyzes the formation of long-chain acylcarnitine from long-chain acyl CoA in the compartment between the inner and outer mitochondrial membrane (see Figure 2.4). The second enzyme, carnitine: acylcarnitine translocase, transports long-chain acylcarnitine across the inner mitochondrial membrane, whereas the last one in the sequence, carnitine palmitoyl transferase II (CPT II), regenerates long-chain acyl CoA in the mitochondrial matrix. Of the three enzymes involved in the transmitochondrial membrane transport, CPT I serves as the key regulatory enzyme. CPT I activity is inhibited by malonyl CoA, which is formed from carboxylation of acetyl CoA by acetyl CoA carboxylase (ACC) (see Figure 2.4). In STZ diabetic rat hearts, the authors have demonstrated that control of malonyl CoA production can be markedly repressed in diabetes. ACC expression and mRNA levels are not altered in STZ diabetic rat or swine hearts;22,23,37 however, a significant depression of ACC activity has been observed.54 This decrease occurs even in the presence of saturating concentrations of acetyl CoA. The above observation contrasts with data obtained from hepatic and adipose tissue measurements, in which a dramatic decrease in ACC expression occurs in STZ diabetes. ACC regulation is attributed to the cAMP-activated protein kinase and the 5′-AMP-activated protein kinase (AMPK). Phosphorylation of ACC inhibits its activity. In diabetes this regulation is induced by the increased activity in AMPK that, in turn, is activated by phosphorylation via a specific AMPK. ACC phosphorylation and inhibition lead to lower levels of malonyl CoA and removes the inhibition upon CPT I. These changes result in the enhancement of mitochondrial fatty acid uptake and oxidation in the diabetic heart. Such an increase in fatty acid oxidation is paralleled by a decrease in carbohydrate oxidation.
Clinical utility of chromosomal microarray analysis and whole exome sequencing in foetuses with oligohydramnios
Published in Annals of Medicine, 2023
Xiaomei Shi, Hongke Ding, Chen Li, Ling Liu, LiHua Yu, Juan Zhu, Jing Wu
We also identified a homozygous point variation c.199-10T > G in the SLC25A20 gene in case 4. Mutation of SLC25A20 is causative for Carnitine-acylcarnitine translocase deficiency (CACTD). Case 5 presented with oligohydramnios, hyperechogenic kidneys and enlarged kidneys. WES revealed a compound heterozygous mutation in PKHD1, a gene associated with PKD4. Case 6 had bilateral renal dysplasia and hypoplastic nasal bone in addition to oligohydramnios. WES revealed a compound heterozygous mutation in FRAS1. Mutations in the FRAS1 gene may cause Fraser syndrome. Case 7 carried a heterozygous mutation of (c.1406_1413dup8) in the HNF1B gene. Mutations in this gene cause renal cysts and diabetes syndrome. Ultrasound of this foetus showed severe oligohydramnios, bilateral renal dysplasia and an enlarged heart.
Logistic role of carnitine shuttle system on radiation-induced L-carnitine and acylcarnitines alteration
Published in International Journal of Radiation Biology, 2022
L-carnitine (β-hydroxy-γ-trimethylammonium butyrate) as a carrier of the carnitine shuttle system which is comprised of the carnitine palmitoyltransferase 1 (CPT1) and 2 (CPT2), the carnitine-acylcarnitine translocase (CACT), and the carnitine acetyltransferase (CrAT) to transport long-chain fatty acids from the cytosol into mitochondria (Ramsay et al. 2001; Virmani et al. 2015; Houten et al. 2016). The carnitine shuttle system controls the flux of fatty acid β-oxidation (FAO). Long-chain (C14–C20) fatty acid acyl groups are transported exclusively as carnitine esters by the carnitine shuttle system. In contrast, the short- (C2–C5) and medium-chain fatty acids are transported into the mitochondrial matrix without any carnitine assistance in the process. In addition, most of the acylcarnitines, which are esters of L-carnitine and acyl groups, are derived from the intermediates of FAO. The alteration of the carnitine pool comprised free L-carnitine and various acylcarnitines in blood and urine might represent the changing flux of FAO.
Inherited hyperammonemias: a Contemporary view on pathogenesis and diagnosis
Published in Expert Opinion on Orphan Drugs, 2018
Evelina Maines, Giovanni Piccoli, Antonia Pascarella, Francesca Colucci, Alberto B. Burlina
The most common FAODs presenting with hyperammonemia are carnitine uptake deficiency (CUD, OMIM #212140), carnitine acylcarnitine translocase deficiency (CACTD, OMIM #212138), the neonatal and infantile forms of carnitine palmitoyltransferase II deficiency (CPT II deficiency, OMIM #608836, #600649), medium-chain acyl-CoA dehydrogenase deficiency (MCADD, OMIM #201450) and multiple acyl-CoA dehydrogenase deficiency (MADD, OMIM #231680) [80]. While there is the possibility that many patients died without being diagnosed or are symptomatic but undiagnosed, it is also very likely that many undiagnosed individuals with these disorders are asymptomatic. There is considerable evidence that many infants identified by NBS with MCADD remain asymptomatic. Early infancy treatment is not likely the reason. It is therefore probable that many, perhaps most, of the infants identified with MCADD by NBS have a mild and perhaps asymptomatic form of the disorder [81].