Type 2 diabetes is a highly prevalent chronic metabolic disorder characterized by hyperglycemia and associated with several complications such as retinopathy, hyperlipidemia and polyneuropathy. The dysregulated fatty acid metabolism along with tissue lipid accumulation is generally assumed to be associated in the development of insulin resistance and T2D. Moreover, several studies suggest a central role for oxidative stress in the pathogenesis of the disease. Since L-carnitine (LC) has an indispensable role in lipid metabolism via its involvement in the β-oxidation of long-chain fatty acids and it has antioxidant properties as well, carnitine supplementation may prove to be an effective tool in the management of the clinical course of T2D. In this review we summarize the results from animal and clinical studies demonstrating the effects of supplementation with LC or LC derivatives (acetyl-LC, propionyl-LC) on various metabolic and clinical parameters associated with T2D.

Purpose: After a golden age of classic carnitine research three decades ago, the spread of mass spectrometry opened new perspectives and a much better understanding of the carnitine system is available nowadays. In the classic period, several human and animal studies were focused on various distinct physiological functions of this molecule and these revealed different aspects of carnitine homeostasis in normal and pathological conditions. Initially, the laboratory analyses were based on the classic or radioenzymatic assays, enabling only the determination of free and total carnitine levels and calculation of total carnitine esters’ amount without any information on the composition of the acyl groups. The introduction of mass spectrometry allowed the measurement of free carnitine along with the specific and sensitive determination of different carnitine esters. Beyond basic research, mass spectrometry study of carnitine esters was introduced into the newborn screening program because of being capable to detect more than 30 metabolic disorders simultaneously. Furthermore, mass spectrometry measurements were performed to investigate different disease states affecting carnitine homeostasis, such as diabetes, chronic renal failure, celiac disease, cardiovascular diseases, autism spectrum disorder or inflammatory bowel diseases.Results: This article will review the recent advances in the field of carnitine research with respect to mass spectrometric analyses of acyl-carnitines in normal and various pathological states.Conclusion: The growing number of publications using mass spectrometry as a tool to investigate normal physiological conditions or reveal potential biomarkers of primary and secondary carnitine deficiencies shows that this tool brought a new perspective to carnitine research.

L-carnitine-mediated beta-oxidation of fatty acids has a well established role in energy supply of oocytes and embryos. Disturbed carnitine metabolism may impair the reproductive potential in IVF and can serve as a biomarker of pregnancy outcome. Our study was performed between March 24, 2011 and May 9, 2011. We performed 44 unselected IVF cycles, (aged 23–40 years (mean: 32.3+/−5.1 years) and had BMI of 17.3-34.7 (mean: 23.80+/−4.9). Samples were also obtained from 18 healthy women of similar age admitted for minor elective surgery to serve as control for plasma carnitine profile. Serum and follicular fluid (FF) free carnitine (FC) and 20 major acylcarnitines (ACs) were measured by ESI/MS/MS method. Serum FC and AC levels in IVF patients were comparable to those in healthy control women. In FF FC and short-chain AC concentrations were similar to those in maternal serum, however, the levels of medium-chain, and long-chain AC esters were markedly reduced (p<0.05). The serum to FF ratio of individual carnitine compounds increased progressively with increasing carbon chain length of AC esters (p9 and/or with embryo number of >6 as compared to the respective values of <9 and/or <6 (p<0.05). In IVF patients with better reproductive potential the carnitine/AC pathway appears to be upregulated that may result in excess carintine consumption and relative depletion of carnitine pool. Consequently, IVF patients may benefit from carnitine supplementation.

Tuberous sclerosis complex (TSC) is a multisystem disorder characterized by seizures, neuropsychiatric disorders, and tumors of the heart, brain, skin, lungs, and kidneys. We present a three-year follow-up of a patient with TSC-associated rhabdomyoma detected in utero. Genetic examination of the fetus and the parents revealed a de novo variant in the TSC2 gene (c.3037delG, p.Asp1013IlefsTer3). Oral everolimus was initiated in the pregnant mother to regress the fetal tumor, which was successful. To the best of our knowledge, there is very little information regarding the use of everolimus therapy during pregnancy. West-syndrome was diagnosed when the proband was four months old. The symptoms were well-manageable, however temporarily. Therapy-resistant focal seizures were frequent. The patient had good vitals and was under regular cardiological control, showed a balanced circulation, and did not require any medication. Subependymal giant cell astrocytoma (SEGA) identified by regular neuroimaging examinations remained unchanged, which may be a consequence of early intrauterine treatment. Early detection of the pathogenic TSC2 variant, followed by in utero administration of everolimus and early vigabatrin therapy, allowed the detection of a milder developmental delay of the proband. Our study emphasizes how early genetic testing and management of epilepsy are pivotal for proper neurodevelopmental impacts and therapeutic strategies.

Neurofibromatosis type 1 is a tumor predisposition syndrome inherited in autosomal dominant manner. Besides the intragenic loss-of-function mutations in NF1 gene, large deletions encompassing the NF1 gene and its flanking regions are responsible for the development of the variable clinical phenotype. These large deletions titled as NF1 microdeletions lead to a more severe clinical phenotype than those observed in patients with intragenic NF1 mutations. Around 5-10% of the cases harbor large deletion and four major types of NF1 microdeletions (type 1, 2, 3 and atypical) have been identified so far. They are distinguishable in term of their size and the location of the breakpoints, by the frequency of somatic mosaicism with normal cells not harboring the deletion and by the number of the affected genes within the deleted region. In our study genotype-phenotype analyses have been performed in 17 mostly pediatric patients with NF1 microdeletion syndrome identified by multiplex ligation-dependent probe amplification after systematic sequencing of the NF1 gene. Confirmation and classification of the NF1 large deletions were performed using array comparative genomic hybridization, where it was feasible. In our patient cohort 70% of the patients possess type-1 deletion, one patient harbors type-2 deletion and 23% of our cases have atypical NF1 deletion. All the atypical deletions identified in this study proved to be novel. One patient with atypical deletion displayed mosaicism. In our study NF1 microdeletion patients presented dysmorphic facial features, macrocephaly, large hands and feet, delayed cognitive development and/or learning difficulties, speech difficulties, overgrowth more often than patients with intragenic NF1 mutations. Moreover, neurobehavior problems, macrocephaly and overgrowth were less frequent in atypical cases compared to type-1 deletion. Proper diagnosis is challenging in certain patients since several clinical manifestations show age-dependency. Large tumor load exhibited more frequently in this type of disorder, therefore better understanding of genotype-phenotype correlations and progress of the disease is essential for individuals suffering from neurofibromatosis to improve the quality of their life. Our study presented additional clinical data related to NF1 microdeletion patients especially for pediatric cases and it contributes to the better understanding of this type of disorder.

Accumulating evidence has suggested that miR-137 and its target genes, CACNA1C, and TCF4, are amongst the most robustly implicated genes in psychiatric disorders. This preliminary study is aimed at investigating the effects of genetic variations in miR-137 (rs1625579A/C), TCF4 (rs1261084C/T), and CACNA1C (rs10774053A/G and rs10466907G/T) on BD susceptibility. We recruited 252 BD patients and 213 healthy subjects as the control group. Genotyping was performed using PCR-RFLP and ARMS-PCR methods. Enhanced risk of BD was found under the codominant homozygous, dominant, and allelic models of TCF4 rs1261084C/T, codominant homozygous and allelic models of CACNA1C rs10466907G/T polymorphisms, as well as codominant homozygous, dominant, recessive, and allelic models of the CACNA1C rs10774053A/G. Moreover, both TT/AG/GT/AA and TT/GG/GT/AC genotype combinations strongly increased the risk of BD in the participants. The bioinformatics analyses revealed that rs1261084C/T and rs10466907G/T created and disrupted binding sites of some miRNAs in the 3-untranslated region of TCF4 and CACNA1C genes. In contrast, the rs10774053A/G created a new binding site for a major splicing factor and might have an effective role in the function of the CACNA1C protein. We have found that all the studied SNPs are positively associated with BD susceptibility. Replicated studies on different ethnicities are required to confirm these findings.