Carnitine-acylcarnitine Translocase Research Articles

EPA and DHA Enhance CACT Promoter Activity by GABP/NRF2.

Carnitine-acylcarnitine translocase (CACT) is a nuclear-encoded mitochondrial carrier that catalyzes the transfer of long-chain fatty acids across the inner mitochondrial membrane for β-oxidation. In this study, we conducted a structural and functional characterization of the CACT promoter to investigate the molecular mechanism underlying the transcriptional regulation of the CACT gene by n-3 PUFA, EPA and DHA. In hepatic BRL3A cells, EPA and DHA stimulate CACT mRNA and protein expression. Deletion promoter analysis using a luciferase reporter gene assay identified a n-3 PUFA response region extending from -202 to -29 bp. This region did not contain a response element for PPARα, a well-known PUFA-responsive nuclear receptor. Instead, bioinformatic analysis revealed two highly conserved GABP responsive elements within this region. Overexpression of GABPα and GABPβ subunits, but not PPARα, increased CACT promoter activity, more remarkably upon treatment with EPA and DHA. ChIP assays showed that n3-PUFA enhanced the binding of GABPα to the -202/-29 bp sequence. Furthermore, both EPA and DHA induced nuclear accumulation of GABPα. In conclusion, our findings indicate that the upregulation of CACT by n3-PUFA in hepatic cells is independent from PPARα and could be mediated by GABP activation.

Maternal Serum Metabolomics in Mid-Pregnancy Identifies Lipid Pathways as a Key Link to Offspring Obesity in Early Childhood.

Maternal metabolism during pregnancy shapes offspring health via in utero programming. In the Healthy Start study, we identified five subgroups of pregnant women based on conventional metabolic biomarkers: Reference (n = 360); High HDL-C (n = 289); Dyslipidemic-High TG (n = 149); Dyslipidemic-High FFA (n = 180); Insulin Resistant (IR)-Hyperglycemic (n = 87). These subgroups not only captured metabolic heterogeneity among pregnant participants but were also associated with offspring obesity in early childhood, even among women without obesity or diabetes. Here, we utilize metabolomics data to enrich characterization of the metabolic subgroups and identify key compounds driving between-group differences. We analyzed fasting blood samples from 1065 pregnant women at 18 gestational weeks using untargeted metabolomics. We used weighted gene correlation network analysis (WGCNA) to derive a global network based on the Reference subgroup and characterized distinct metabolite modules representative of the different metabolomic profiles. We used the mummichog algorithm for pathway enrichment and identified key compounds that differed across the subgroups. Eight metabolite modules representing pathways such as the carnitine-acylcarnitine translocase system, fatty acid biosynthesis and activation, and glycerophospholipid metabolism were identified. A module that included 189 compounds related to DHA peroxidation, oxidative stress, and sex hormone biosynthesis was elevated in the Insulin Resistant-Hyperglycemic vs. the Reference subgroup. This module was positively correlated with total cholesterol (R:0.10; p-value < 0.0001) and free fatty acids (R:0.07; p-value < 0.05). Oxidative stress and inflammatory pathways may underlie insulin resistance during pregnancy, even below clinical diabetes thresholds. These findings highlight potential therapeutic targets and strategies for pregnancy risk stratification and reveal mechanisms underlying the developmental origins of metabolic disease risk.

Sex-Dependent Increases of Hepatic Acylcarnitines by Myocardial Infarction

Many different diseases and environmental stressors can lead to an increase in oxidative stress. Urban air pollution leads to inhalation of airborne particulate matter in high traffc environments. This has been linked to chronic oxidative stress and increased risk or severity of myocardial infarction (MI). MI is one cause of acute oxidative stress. A key player for cellular defense against oxidative stress is activation of Nrf2, a transcription factor that controls the expression of key antioxidant and cytoprotective genes. Although Nrf2 has been reported to regulate genes for anabolic or lipid metabolism, little is known about the impact of Nrf2 or MI on the biochemical metabolism in the liver. Because the liver is a center for metabolism, metabolomic landscapes were determined in a model of chronic oxidative stress by Nrf2 knockout or acute oxidative stress by induction of MI via left anterior descending coronary artery ligation. 1353 compounds were detected with a quality control coeffcient variation value &lt;20% using LC-MS/MS based non-targeted metabolomics. Differences in the baseline metabolic profiles of male versus female lead to comparison of Nrf2 knockout or MI in a sex specific manner. In male wild type mice, the liver responded to MI by elevating several carnitine derivatives, including linoleoyl carnitine, palmitoyl carnitine, and (11Z, 14Z)-eicosadienoyl carnitine. However, none of these changes were observed in female wild type mice. Either male or female Nrf2 knockout mice failed to respond to MI by elevating carnitines. These acylcarnitine increases were confirmed with a non-targeted lipidomics analysis. The elevated acylcarnitine levels correlate with an increase in carnitine palmitoyl transferase 1, CPT1, the enzyme responsible for the conjugation of carnitine and long-chain fatty acids. After this conjugation, acylcarnitines are transported into the mitochondria via carnitine-acylcarnitine translocase. Once inside the mitochondria, the carnitine moiety is removed via CPT2 and the long-chain fatty acid can be used for beta-oxidation to produce ATP. This data suggest that male mice are responding to MI by altering energy metabolism and increasing carnitines to compensate for energy production. Nrf2 appears to play a role in such metabolic reprogramming. The research programs under the direction of Dr. Qin M. Chen have been supported by NIH R01 GM125212, R01 GM126165, Holsclaw Endowment, the University of Arizona College of Pharmacy start-up fund, and NIEHS T32 ES007091. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Clinical and genetic analysis of two pedigrees affected with Carnitine-acylcarnitine translocase deficiency due to variant of SLC25A20 gene

To analyze the clinical phenotype and genotypes of two children with Carnitine-acylcarnitine translocase deficiency (CACTD). Two children diagnosed with CACTD at the Gansu Provincial Maternal and Child Health Care Hospital respectively on January 3 and November 19, 2018 were selected as the study subjects. Trio-whole exome sequencing (trio-WES) was carried out, and candidate variants were validated through Sanger sequencing and pathogenicity analysis. Both children were males and had manifested mainly with hypoglycemia. Trio-WES and Sanger sequencing showed that child 1 had harbored compound heterozygous variants of the SLC25A20 gene, namely c.49G>C (p.Gly17Arg) and c.106-2A>G, which were inherited from his father and mother, respectively. Child 2 had harbored homozygous c.199-10T>G variants of the SLC25A20 gene, which were inherited from both of his parents. Among these, the c.106-2A>G and c.49G>C variants were unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.49G>C (p.Gly17Arg), c.106-2A>G, and c.199-10T>G variants were classified as likely pathogenic (PM2_supporting+PP3+PM3_strong+PP4), pathogenic (PVS1+PM2_supporting+PM5+PP3), and pathogenic (PVS1+PM2_supporting+PP3+PP5), respectively. Combined with their clinical phenotype and genetic analysis, both children were diagnosed with CACTD. Above finding has provided a basis for their treatment as well as genetic counseling and prenatal diagnosis for their families.

The significance of acylcarnitine ratio indices in diagnosing carnitine-acylcarnitine translocase deficiency.

The significance of acylcarnitine ratio indices in diagnosing carnitine-acylcarnitine translocase deficiency.

Acylcarnitine ratio indices in diagnosing carnitine-acylcarnitine translocase deficiency in newborns.

Acylcarnitine ratio indices in diagnosing carnitine-acylcarnitine translocase deficiency in newborns.

Acylcarnitines’ Level in the Dried Blood Spot Samples of Healthy Newborns in Serbia-The Pilot Study

Abstract Analysis of the acylcarnitines’ (ACs) is the mainstay for screening for fatty acid oxidation disorders (FAOD). Data about the ACs profile in the dried blood spot samples of healthy newborns in Serbia are not at disposal. Therefore, we determined the ACs levels and established the cut-offs. Between August 2018 and August 2019 a total of 1771 samples had been analysed. Cut-offs, established using a non-parametric approach, were verified in comparison with the worldwide target ranges and the data for several Caucasian populations. The majority of ACs had comparable distribution in Serbian and the worldwide population. In case of discrepancy, the individual alterations had a frequency of less than 10%. Seventeen out of 25 established cutoffs were in the worldwide target range. Reliability of the cut-offs positioning out of the target ranges is not jeopardized, since alterations are negligible or similar findings were reported for other Caucasian populations. The established and verified set of cut-offs can be used in the future screening for carnitine uptake/transport defect, medium-chain acyl-CoA dehydrogenase deficiency, very long-chain acyl-CoA dehydrogenase deficiency, long-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency, trifunctional protein deficiency, carnitine palmitoyltransferase deficiency Ia and II, as well as carnitine:acylcarnitine translocase deficiency.

Novel targets of β-TrCP cooperatively accelerate carbohydrate and fatty acid consumption.

Cellular energy is primarily produced from glucose and fat through glycolysis and fatty acid oxidation (FAO) followed by the tricarboxylic acid cycle in mitochondria; energy homeostasis is carefully maintained via numerous feedback pathways. In this report, we uncovered a new master regulator of carbohydrate and lipid metabolism. When ubiquitin E3 ligase β-TrCP2 was inducibly knocked out in β-TrCP1 knockout adult mice, the resulting double knockout mice (DKO) lost fat mass rapidly. Biochemical analyses of the tissues and cells from β-TrCP2 KO and DKO mice revealed that glycolysis, FAO, and lipolysis were dramatically upregulated. The absence of β-TrCP2 increased the protein stability of metabolic rate-limiting enzymes including 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase 1A (CPT1A), and carnitine/acylcarnitine translocase (CACT). Our data suggest that β-TrCP is a potential regulator for total energy homeostasis by simultaneously controlling glucose and fatty acid metabolism and that targeting β-TrCP could be an effective strategy to treat obesity and other metabolic disorders.

Increased acylcarnitine ratio indices in newborn screening for carnitine-acylcarnitine translocase deficiency shows increased sensitivity and reduced false-positivity.

Carnitine-acylcarnitine translocase (CACT) deficiency is a rare autosomal recessive metabolic disorder of mitochondrial long-chain fatty acid oxidation. Newborn screening via tandem mass spectrometry (MS/MS) technology enables early diagnosis. However, previous analyses of MS/MS data of patients showed that some results were misdiagnosed because they did not show typical acylcarnitine profiles of CACT deficiency. This study aimed to identify additional indices to assist the diagnosis of CACT deficiency. To evaluate the acylcarnitine profile and the acylcarnitine ratios of individuals with CACT deficiency, the MS/MS data of 15 patients diagnosed via genetic testing were retrospectively analysed. The sensitivity and false-positive rates of primary acylcarnitine markers and ratio indices were validated using the data from 28,261 newborns and 53 false-positive cases. Additionally, the MS/MS data of 20 newborns carrying the c.199-10T>G mutation in SLC25A20 and 40 normal controls were compared to verify whether the carriers had abnormal acylcarnitine concentrations. The acylcarnitine profiles from 15 patients were classified into three categories using C12, C14, C16, C18, C16:1, C18:1, and C18:2 as the primary diagnostic markers. The first category represented a typical profile (P1-P6). The second category for patients P7 and P8 showed a significant decrease in the C0 level and a normal concentration of long-chain acylcarnitines. The third category for patients P9-P15 showed the presence of interfering acylcarnitines. The second and third categories may have been misdiagnosed. An acylcarnitine ratio analysis showed that C14/C3, C16/C2, C16/C3, C18/C3, C16:1/C3, and C16:1-OH/C3 were significantly increased in all 15 patients. The verification of 28,261 newborn screening results showed that the false-positive rate of ratios, except for (C16 + C18)/C0, was lower than that of acylcarnitine indices (0.02-0.08% vs. 0.16-0.88%). None of the single long-chain acylcarnitines could separate patients from the false-positive cases; however, all ratios produced good discrimination between the two groups. Based on the primary acylcarnitine markers alone, CACT deficiency can be misdiagnosed in newborn screening. The ratios of the primary markers (C16 + C18:1)/C2, C16/C2, C16:1/C3, and C16:1-OH/C3 can facilitate the diagnosis of CACT deficiency, thereby increasing sensitivity and reducing false-positivity.

Altered acylcarnitine metabolism and inflexible mitochondrial fuel utilization characterize the loss of neonatal myocardial regeneration capacity

Myocardial regeneration capacity declines during the first week after birth, and this decline is linked to adaptation to oxidative metabolism. Utilizing this regenerative window, we characterized the metabolic changes in myocardial injury in 1-day-old regeneration-competent and 7-day-old regeneration-compromised mice. The mice were either sham-operated or received left anterior descending coronary artery ligation to induce myocardial infarction (MI) and acute ischemic heart failure. Myocardial samples were collected 21 days after operations for metabolomic, transcriptomic and proteomic analyses. Phenotypic characterizations were carried out using echocardiography, histology and mitochondrial structural and functional assessments. In both groups, MI induced an early decline in cardiac function that persisted in the regeneration-compromised mice over time. By integrating the findings from metabolomic, transcriptomic and proteomic examinations, we linked regeneration failure to the accumulation of long-chain acylcarnitines and insufficient metabolic capacity for fatty acid beta-oxidation. Decreased expression of the redox-sensitive mitochondrial Slc25a20 carnitine-acylcarnitine translocase together with a decreased reduced:oxidized glutathione ratio in the myocardium in the regeneration-compromised mice pointed to a defect in the redox-sensitive acylcarnitine transport to the mitochondrial matrix. Rather than a forced shift from the preferred adult myocardial oxidative fuel source, our results suggest the facilitation of mitochondrial fatty acid transport and improvement of the beta-oxidation pathway as a means to overcome the metabolic barrier for repair and regeneration in adult mammals after MI and heart failure.

Design of a nanobiosystem with remote photothermal gene silencing in Chlamydomonas reinhardtii to increase lipid accumulation and production

Research development in the precise control of gene expression in plant cells is an emerging necessity that would lead to the elucidation of gene function in these biological systems. Conventional gene-interfering techniques, such as micro-RNA and short interfering RNA, have limitations in their ability to downregulate gene expression in plants within short time periods. However, nanotechnology provides a promising new avenue with new tools to overcome these challenges. Here, we show that functionalized gold nanoparticles, decorated with sense and antisense oligonucleotides (FANSAO), can serve as a remote-control optical switch for gene interference in photosynthetic plant cells. We demonstrate the potential of employing LEDs as optimal light sources to photothermally dehybridize the oligonucleotides on the surface of metallic nanostructures, consequently inducing regulation of gene expression in plant cells. We show the efficiency of metallic nanoparticles in absorbing light from an LED source and converting it to thermal energy, resulting in a local temperature increase on the surface of the gold nanoparticles. The antisense oligonucleotides are then released due to the opto-thermal heating of the nanobiosystem composed of the metallic nanoparticles and the sense-antisense oligonucleotides. By applying this approach, we silenced the Carnitine Acyl Carnitine Translocase genes at 90.7%, resulting in the accumulation of lipid bodies in microalgae cells. These results exhibit the feasibility of using functionalized gold nanoparticles with sense and antisense oligonucleotides to enhance nucleic acid delivery efficiency and, most importantly, allow for temporal control of gene silencing in plant cells. These nanobiosystems have broad applications in the development and biosynthesis of biofuels, pharmaceuticals, and specialized chemicals.

In Silico Analysis of the Structural Dynamics and Substrate Recognition Determinants of the Human Mitochondrial Carnitine/Acylcarnitine SLC25A20 Transporter.

The Carnitine-Acylcarnitine Carrier is a member of the mitochondrial Solute Carrier Family 25 (SLC25), known as SLC25A20, involved in the electroneutral exchange of acylcarnitine and carnitine across the inner mitochondrial membrane. It acts as a master regulator of fatty acids β-oxidation and is known to be involved in neonatal pathologies and cancer. The transport mechanism, also known as "alternating access", involves a conformational transition in which the binding site is accessible from one side of the membrane or the other. In this study, through a combination of state-of-the-art modelling techniques, molecular dynamics, and molecular docking, the structural dynamics of SLC25A20 and the early substrates recognition step have been analyzed. The results obtained demonstrated a significant asymmetry in the conformational changes leading to the transition from the c- to the m-state, confirming previous observations on other homologous transporters. Moreover, analysis of the MD simulations' trajectories of the apo-protein in the two conformational states allowed for a better understanding of the role of SLC25A20 Asp231His and Ala281Val pathogenic mutations, which are at the basis of Carnitine-Acylcarnitine Translocase Deficiency. Finally, molecular docking coupled to molecular dynamics simulations lend support to the multi-step substrates recognition and translocation mechanism already hypothesized for the ADP/ATP carrier.

Successful Management by Selective Embryo in the Carnitine-Acylcarnitine Translocase Deficiency with SLC25A20 C.199-10T&gt;G Variation: The First Case Report from Vietnam and Literature Review

Successful Management by Selective Embryo in the Carnitine-Acylcarnitine Translocase Deficiency with SLC25A20 C.199-10T&gt;G Variation: The First Case Report from Vietnam and Literature Review

Determination of Metabolomics Profiling in BPA-Induced Impaired Metabolism.

Exposure to bisphenol A (BPA) is unavoidable and it has far-reaching negative effects on living systems. This study aimed to explore the toxic effects of BPA in an experimental animal model through a metabolomics approach that is useful in measuring small molecule perturbations. Beside this, we also examined the ameliorative effects of resveratrol (RSV) against BPA-induced disturbances in experimental mice. This study was conducted for 28 days, and the results showed that BPA indeed induced an impairment in amino acid metabolism, taking place in the mitochondria by significantly (p &lt; 0.05) decreasing the levels of certain amino acids, i.e., taurine, threonine, asparagine, leucine, norleucine, and glutamic acid in the mice plasma. However, the administration of RSV did prove effective against the BPA-induced intoxication and significantly (p &lt; 0.05) restored the level of free amino acids. Lipid metabolites, L-carnitine, sphinganine, phytosphingosine, and lysophosphatidylcholine were also determined in the mice serum. A significant (p &lt; 0.05) decline in glutathione peroxidase (GPx), superoxide dismutase (SOD,) glutathione, and catalase levels and an elevation in malondialdehyde level in the BPA group confirmed the generation of oxidative stress and lipid peroxidation in experimental mice exposed to BPA. The expression of Carnitine palmitoyltransferase I (CPT-I), carnitine palmitoyltransferase II (CPT-II), lecithin-cholesterol acyltransferase (LCAT), carnitine O-octanoyltransferase (CROT), carnitine-acylcarnitine translocase (CACT), and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) genes was significantly upregulated in the liver tissue homogenates of experimental mice exposed to BPA, although RSV regulated the expression of these genes when compared with BPA treated experimental mice. CPT-I, CPT-II, and CACT genes are located in the mitochondria and are involved in the metabolism and transportation of carnitine. Hence, this study confirms that BPA exposure induced oxidative stress, upregulated gene expression, and impaired lipid and amino acid metabolism in experimental mice.

One potential hotspot SLC25A20 gene variants in Chinese patients with carnitine-acylcarnitine translocase deficiency.

Carnitine-acylcarnitine translocase deficiency (CACT deficiency) is a rare and life-threatening autosomal recessive disorder of mitochondrial fatty acid oxidation caused by variant of SLC25A20 gene. The most prevalent missense variant in the SLC25A20 gene in Asia was c.199-10T > G. Due to the c.199-10T > G variant, CACT deficiency is a severe phenotype. Herein, we present a neonatal case with c.199-10T > G variant in China and analyze the clinical, biochemical, and genetic aspects of 78 patients previously identified with CACT deficiency. The patient presented with a series of severe metabolic crises that rapidly deteriorated and eventually died 3 days after delivery. The sequencing of the patient's genome indicated that he was homozygous for the c.199-10T > G variant. 30 patients were found to have the c.199-10T > G mutation, of which 23 were Chinese and 22 were afflicted by the c.199-10T > G splicing variation. In China, c.199-10T > G allele frequency was 82.6%. In CACT deficiency, prompt recognition and treatment are critical. Our data suggested that c.199-10T > G may be a potential hotspot SLC25A20 gene mutation in the Chinese population. Detection of single nucleotide polymorphism is possible for high-risk patients and parents in China.

Fatty acid oxidation: a neglected factor in understanding the adjustment of mitochondrial function to cold temperatures.

For ectothermic species, adaptation to thermal changes is of critical importance. Mitochondrial oxidative phosphorylation (OXPHOS), which leverages multiple electron pathways to produce energy needed for survival, is among the crucial metabolic processes impacted by temperature. Our aim in this study was to identify how changes in temperature affect the less-studied electron transferring flavoprotein pathway, fed by fatty acid substrates. We used the planarian Dugesia tigrina, acclimated for 4weeks at 10°C (cold acclimated) or 20°C (normothermic). Respirometry experiments were conducted at an assay temperature of either 10 or 20°C to study specific states of the OXPHOS process using the fatty acid substrates palmitoylcarnitine (long chain), octanoylcarnitine (medium chain) or acetylcarnitine (short chain). Following cold acclimation, octanoylcarnitine exhibited increases in both the OXPHOS and electron transfer (ET, non-coupled) states, indicating that the pathway involved in medium-chain length fatty acids adjusts to cold temperatures. Acetylcarnitine only showed an increase in the OXPHOS state as a result of cold acclimation, but not in the ET state, indicative of a change in phosphorylation system capacity rather than fatty acid β-oxidation. Palmitoylcarnitine oxidation was unaffected. Our results show that cold acclimation in D. tigrina caused a specific adjustment in the capacity to metabolize medium-chain fatty acids rather than an adjustment in the activity of the enzymes carnitine-acylcarnitine translocase, carnitine acyltransferase and carnitine palmitoyltransferase-2. Here, we provide novel evidence of the alterations in fatty acid β-oxidation during cold acclimation in D. tigrina.

Rare Cause of Arrhythmia and Seizures in a Late-Preterm Newborn

Rare Cause of Arrhythmia and Seizures in a Late-Preterm Newborn

Hepatic Transcriptome Analysis Provides New Insight into the Lipid-Reducing Effect of Dietary Taurine in High-Fat Fed Groupers (Epinephelus coioides).

A transcriptome analysis was conducted to provide the first detailed overview of dietary taurine intervention on liver lipid accumulation caused by high–fat in groupers. After an eight-week feeding, the fish fed 15% fat diet (High–fat diet) had higher liver lipid contents vs. fish fed 10% fat diet (Control diet). 15% fat diet with 1% taurine (Taurine diet) improved weight gain and feed utilization, and decreased hepatosomatic index and liver lipid contents vs. the High–fat diet. In the comparison of the Control vs. High–fat groups, a total of 160 differentially expressed genes (DEGs) were identified, of which up- and down-regulated genes were 72 and 88, respectively. There were 49 identified DEGs with 26 and 23 of up- and down-regulated in the comparison to High–fat vs. Taurine. Several key genes, such as cysteine dioxygenase (CDO1), ADP–ribosylation factor 1/2 (ARF1_2), sodium/potassium–transporting ATPase subunit alpha (ATP1A), carnitine/acylcarnitine translocase (CACT), and calcium/calmodulin–dependent protein kinase II (CAMK) were obtained by enrichment for the above DEGs. These genes were enriched in taurine and hypotaurine metabolism, bile secretion, insulin secretion, phospholipase D signaling pathway, and thermogenesis pathways, respectively. The present study will also provide a new insight into the nutritional physiological function of taurine in farmed fish.

Low carnitine palmitoyltransferase 1 activity is a risk factor for narcolepsy type 1 and other hypersomnia.

Narcolepsy type 1 (NT1) is associated with metabolic abnormalities but their etiology remains largely unknown. The gene for carnitine palmitoyltransferase 1B (CPT1B) and abnormally low serum acylcarnitine levels have been linked to NT1. To elucidate the details of altered fatty acid metabolism, we determined levels of individual acylcarnitines and evaluated CPT1 activity in patients with NT1 and other hypersomnia. Blood samples from 57 NT1, 51 other hypersomnia patients, and 61 healthy controls were analyzed. The levels of 25 major individual acylcarnitines were determined and the C0/(t[C16] + t[C18]) ratio was used as a CPT1 activity marker. We further performed transcriptome analysis using independent blood samples from 42 NT1 and 42 healthy controls to study the relevance of fatty acid metabolism. NT1-specific changes in CPT1 activity and in expression of related genes were investigated. CPT1 activity was lower in patients with NT1 (p = 0.00064) and other hypersomnia (p = 0.0014) than in controls. Regression analysis revealed that CPT1 activity was an independent risk factor for NT1 (OR: 1.68; p = 0.0031) and for other hypersomnia (OR: 1.64; p = 0.0042). There was a significant interaction between obesity (BMI <25, ≥25) and the SNP rs5770917 status such that nonobese NT1 patients without risk allele had better CPT1 activity (p = 0.0089). The expression levels of carnitine-acylcarnitine translocase (CACT) and CPT2 in carnitine shuttle were lower in NT1 (p = 0.000051 and p = 0.00014, respectively). These results provide evidences that abnormal fatty acid metabolism is involved in the pathophysiology of NT1 and other hypersomnia.

Neonatal sudden death caused by a novel heterozygous mutation in SLC25A20 gene: A case report and brief literature review

Carnitine-acylcarnitine translocase deficiency (CACTD) is a rare and life-threatening autosomal recessive disorder of fatty acid β-oxidation (FAO). Most patients with CACTD develop severe metabolic decompensation which deteriorates progressively and rapidly, causing death in infancy or childhood. As CACTD in some patients is asymptomatic or only with some nonspecific symptoms, the diagnosis is easy to be ignored, resulting in sudden death, which often triggers medical disputes. Herein, we report a case of neonatal sudden death with CACTD. The neonate showed a series of severe metabolic crisis, deteriorated rapidly and eventually died 3 days after delivery. Tandem mass spectrometry (MS-MS) screening of dry blood spots before death showed that the level of long-chain acylcarnitines, especially C12-C18 acylcarnitine, was increased significantly, and therefore a diagnosis of inherited metabolic disease (IMD) was suspected. Autopsy and histopathological results demonstrated that there were diffuse vacuoles in the heart and liver of the deceased. Mutation analysis revealed that the patient was a compound heterozygote with c.199–10 T > G and a novel c.1A > T mutation in the SLC25A20 gene. Pathological changes such as heart failure, arrhythmia and cardiac arrest related to mitochondrial FAO disorders are the direct cause of death, while gene mutation is the underlying cause of death.