Carnitine deficiency is a rare metabolic condition that can result in fasting hypoglycemia. Carnitine deficiency could be primary or secondary to other conditions. Among secondary causes, antiepileptics such as valproic acid have been incriminated. Valproic acid is known to deplete carnitine stores and inhibit the process of β-oxidation. Herein we report the case of a 44-year-old female with epilepsy that presented with breakthrough seizures associated with hypoglycemia despite being on appropriate antiepileptic therapy. The patient was later found to have carnitine deficiency. Discontinuation of valproic acid and supplementation with l-carnitine resolved the patient\'s hypoglycemia and breakthrough seizures. With this case report, we hope to encourage clinicians to include carnitine deficiency in the differential diagnosis of unexplained hypoglycemia.

Non-invasive diagnostics are crucial for the timely detection of renal cell carcinoma (RCC), significantly improving survival rates. Despite advancements, specific lipid markers for RCC remain unidentified. We aimed to discover and validate potent plasma markers and their association with dietary fats. Using lipid metabolite quantification, machine-learning algorithms, and marker validation, we identified RCC diagnostic markers in studies involving 60 RCC and 167 healthy controls (HC), as well as 27 RCC and 74 HC, by analyzing their correlation with dietary fats. RCC was associated with altered metabolism in amino acids, glycerophospholipids, and glutathione. We validated seven markers (l-tryptophan, various lysophosphatidylcholines [LysoPCs], decanoylcarnitine, and l-glutamic acid), achieving a 96.9% AUC, effectively distinguishing RCC from HC. Decreased decanoylcarnitine, due to reduced carnitine palmitoyltransferase 1 (CPT1) activity, was identified as affecting RCC risk. High intake of polyunsaturated fatty acids (PUFAs) was negatively correlated with LysoPC (18:1) and LysoPC (18:2), influencing RCC risk. We validated seven potential markers for RCC diagnosis, highlighting the influence of high PUFA intake on LysoPC levels and its impact on RCC occurrence via CPT1 downregulation. These insights support the efficient and accurate diagnosis of RCC, thereby facilitating risk mitigation and improving patient outcomes.

OBJECTIVE: To investigate the associations of choline, betaine, dimethylglycine (DMG), L-carnitine, and Trimethylamine-N-oxide (TMAO) with the risk of Gestational diabetes mellitus (GDM) as well as the markers of glucose homeostasis.
METHODS: We performed a case-control study including 200 diagnosed GDM cases and 200 controls matched by maternal age (±2 years) and gestational age (±2 weeks). Concentrations of serum metabolites were measured by the high-performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS).
RESULTS: Compared to the control group, GDM group had significantly lower serum betaine concentration and betaine/choline ratio, and higher DMG concentration. Furthermore, decreased betaine concentration and betaine/choline ratio, increased DMG concentration showed significant association with the risk of GDM. In addition, serum betaine concentrations were negatively associated with blood glucose levels at 1-h post-glucose load (OGTT-1h), and both betaine and L-carnitine concentrations were positively associated with 1,5-anhydroglucitol levels. Betaine/choline ratio was negatively associated with OGTT-1h and blood glucose levels at 2-h post-glucose load (OGTT-2h) and serum choline concentrations were negatively associated with fasting blood glucose and positively associated with OGTT-2h.
CONCLUSIONS: Decreased serum betaine concentrations and betaine/choline ratio, and elevated DMG concentrations could be significant risk factors for GDM. Furthermore, betaine may be associated with blood glucose regulation and short-term glycemic fluctuations.

The relationship between gut microbiota products trimethylamine oxide (TMAO) and related metabolites including betaine, choline and L-carnitine and hypertensive disorders of pregnancy (HDP) is unclear. In order to examine whether plasma TMAO and related metabolites predict the risk of HDP, a nested case-control study was conducted in Chinese women based on a prospective cohort including 9447 participants. 387 pairs of pregnant women (n = 774) were matched and their plasma TMAO, betaine, choline, and L-carnitine at 16-20 gestational weeks were measured by liquid chromatography-mass spectrometry. Odds ratio (OR) and the 95% confidence interval (95% CI) were calculated using the conditional logistic regression, to examine the association between TMAO metabolites and HDP. The findings showed that higher plasma betaine (≥24.94 μmol/L) was associated with a decreased risk of HDP and its subtype gestational hypertension (GH), with adjusted ORs of 0.404 (95% CI: 0.226-0.721) and 0.293 (95% CI: 0.134-0.642), respectively. Higher betaine/choline ratio (>2.64) was associated with a lower risk of HDP and its subtype preeclampsia or chronic hypertension with superimposed preeclampsia (PE/CH-PE), with adjusted ORs of 0.554 (95% CI: 0.354-0.866) and 0.226 (95% CI: 0.080-0.634). Moreover, compared with traditional factors (TFs) model, the TMAO metabolites+ TFs model had a higher predictive ability for PE/CH-PE (all indexes P values < 0.0001). Therefore, it suggests that the detection of plasma betaine and choline in the early second trimester of pregnancy can better assess the risk of HDP.

The cases were a pair of siblings with a carnitine palmitoyltransferase (CPT2) deficiency detected by tandem mass spectrometry. Their C16 and C18:1 levels were both within the normal range, while C0 was low, and the (C16+C18:1)/C2 ratio was high. Following genetic testing, a novel CPT2 gene mutation was identified in both patients. The male patient had a normal growth rate during 5 years of follow-up after treatment. By contrast, the female patient did not take l-carnitine supplements and died after an infectious disease-associated illness when she was 1 year old. These data emphasize the need to raise awareness about CPT2 deficiency so as to correctly diagnose and accurately manage the disease.

A 25-year-old Japanese woman with a history of repeated episodes of rhabdomyolysis since the age of 12 presented with rhabdomyolysis caused by hyperemesis gravidarum. Blood tests showed an elevated serum CK level (11,755 ‍IU/l; normal: 30-180 ‍IU/l). Carnitine fractionation analysis revealed low levels of total carnitine (18.3 ‍μmol/l; normal: 45-91 ‍μmol/l), free carnitine (13.1 ‍μmol/l; normal: 36-74 ‍μmol/l), and acylcarnitine (5.2 ‍μmol/l; normal: 6-23 ‍μmol/l). Tandem mass spectrometry showed high levels of C14:1 acylcarnitine (0.84 ‍nmol/ml: normal: <0.4 ‍nmol/ml) and a high C14:1/C2 ratio of 0.253 (normal: <0.013), indicating a potential diagnosis of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Enzyme activity measurement in the patient\'s peripheral blood lymphocytes confirmed the diagnosis of VLCAD deficiency, with low palmitoyl-CoA dehydrogenase levels (6.5% of normal control value). With the patient\'s informed consent, acyl-CoA dehydrogenase very long-chain (ACADVL) gene analysis revealed compound heterozygous mutations of c.1332G>A in exon 13 and c.1349G>A (p.R450H) in exon 14. In Japan, neonatal mass screening is performed to detect congenital metabolic diseases. With the introduction of tandem mass screening in 2014, fatty acid metabolism disorders, including VLCAD deficiency, are being detected before the onset of symptoms. However, it is important to note that mass screening cannot detect all cases of this disease. For patients with recurrent rhabdomyolysis, it is essential to consider congenital diseases, including fatty acid metabolism disorders, as a potential diagnosis.

Parenteral nutrition (PN) deficient in mitochondrial substrates and thiamine may lead to acidosis. This, combined with fatigue seen in patients with intestinal failure (IF), may suggest suboptimal oxidative metabolism. We therefore studied oxygen utilisation in otherwise apparently well-nourished individuals with intestinal failure receiving long term PN.
This was a retrospective analysis conducted in a tertiary IF institution, from 2010 to 2019, comparing treadmill/bicycle cardiopulmonary exercise test (CPET) derived variables including peak oxygen consumption (VO2 peak), anaerobic threshold (AT) and ventilatory efficiency (minute ventilation (VE)/CO2 output (VCO2) of patients with IF (cases) to those without (controls), matched in a 1:2 ratio for age ( ± 3 years), gender, use of beta-blockers and physiology parameters of p-POSSUM score ( ± 5). All subjects were free of sepsis and metastatic malignancy. Mann-Whitney or Student\'s t-test for continuous and Fisher\'s exact or chi-squared test for categorical variables were used as appropriate. Data shown represent mean or median values.
Participants (31 cases, 62 controls) were comparable in age (65.4 vs. 65.3, p = 0.98); p-POSSUM parameters (18.0 vs. 17.0, p = 0.45); gender (p = 1.00); smoking status (p = 0.52); use of beta-blockers (p = 1.00) and ≤10 mg/day of oral steroids (p = 0.34). Participants had been on PN for 11.0 (6.0-24.0) months and were adequately nourished (requirements 27.6 kcal/kg/day, replacement 23.5 kcal/kg/day). No differences were found between VO2 peak (15.2 vs. 14.6 ml/kg/min, p = 0.96), AT (10.4 vs. 11.0 ml/kg/min, p = 0.44) and VE/VCO2 (33.0 vs. 33.0, p = 0.96) of the examined groups.
Patients with intestinal failure receiving PN who are apparently well-nourished also appear to have normal oxygen utilisation, suggesting alternative causes for fatigue. More studies will be required to determine whether CPET could reliably be used to assess perioperative risk in this group of patients.

Carnitine is essential for transporting long-chain fatty acids into mitochondria and promotes energy metabolism via β-oxidation of long-chain fatty acids. Although carnitine is also present in the peripheral blood, 98% of total carnitine is stored in muscle tissue. Neuromuscular diseases accompanied by muscle atrophy are likely to lead to secondary carnitine deficiency, owing to the reduced amount of total carnitine stored in the body.
An 8-y-old Japanese boy with Fukuyama-type congenital muscular dystrophy accompanied by severe psychomotor retardation had been constantly bedridden, suffered from dysphagia, and had been fed through a gastrostomy tube since the age of 1 y. Regular oral carnitine supplementation (5 mg/kg/d of levocarnitine) was initiated at the age of 7 y, which increased serum carnitine value to within the normal range (serum total carnitine concentration, 58.5-60.9 μmol/L; acylcarnitine concentration, 45.8-55.0 μmol/L; free carnitine concentration, 5.9-12.7 μmol/L). He developed a fever, vomiting, and gastrointestinal bleeding at the age of 8 y. He fell into a coma and visited an emergency room 12 h later. Hypoglycemia and hypocarnitinemia (serum total carnitine concentration, 3.7 μmol/L; acylcarnitine concentration, 2.9 μmol/L; free carnitine concentration, 0.8 μmol/L; acyl-to-free carnitine ratio, 3.6) were observed, and he was found to be negative for urinary ketone bodies.
Neuromuscular diseases accompanied by muscle atrophy may lead to acute carnitine deficiency, even if the serum carnitine concentration is within the normal range before onset. During sick days, it may be necessary to modify a patient\'s treatment, such as increasing both oral supplementation and intravenous administration of carnitine.

The mechanism(s) of immune checkpoint inhibitor (ICI)-induced myasthenia gravis (MG), an immune-related adverse event (irAE) that is fatal and limits subsequent ICI use, remain unexplored. Here, through comparative genomic analysis, we identified a pathogenic p.S467C germline variant in SLC22A5 in a thymoma case with ICI-induced MG, which was found to be associated with fatty acid oxidation through its regulation on L-carnitine levels. Remarkably, ICI rechallenge with L-carnitine pretreatment led to durable response without MG-related symptoms. Thus, we provide the first clinical evidence of genetic test-directed irAE management, which integrates individualized ICI treatment into the evolving paradigm of cancer management.

Valproic acid (VPA) is a common antiepileptic drug that is also used routinely for various psychiatric disorders. VPA toxicity typically manifests as central nervous system depression, while hyperammonemic encephalopathy and hepatotoxicity are potentially life-threatening complications.
We describe the case of a 56-year-old man who presented to the emergency department after an intentional VPA overdose, was found to have hyperammonemia, and was treated with L-carnitine exclusively. He was subsequently admitted to the hospital for monitoring and serial laboratory testing. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although VPA toxicity has conventionally been managed by gastric decontamination, L-carnitine, and, in severe and refractory cases, extracorporeal removal, recent literature supports the use of carbapenem antibiotics, particularly meropenem. Thus, we report the details of current treatment modalities for VPA toxicity by reviewing current literature.