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JIMD Reports Sep 2023Contiguous / deletion syndrome (CADDS) is a rare deletion syndrome involving two contiguous genes on Xq28, and (formerly known as ). Only nine individuals with this...
Contiguous / deletion syndrome (CADDS) is a rare deletion syndrome involving two contiguous genes on Xq28, and (formerly known as ). Only nine individuals with this diagnosis have been reported in the medical literature to date. Intragenic loss-of-function variants in cause the deafness, dystonia, and cerebral hypomyelination syndrome (DDCH). Isolated pathogenic intragenic variants in are associated with the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), a single transporter deficiency, which in its more severe cerebral form is characterised by childhood-onset neurodegeneration and high levels of very-long-chain fatty acids (VLCFA). While increased VLCFA levels also feature in CADDS, the few patients described to date all presented as neonates with a severe phenotype. Here we report a tenth individual with CADDS, a male infant with dysmorphic facial features who was diagnosed through ultra-rapid whole genome sequencing (WGS) in the setting of persistent cholestatic liver disease, sensorineural hearing loss, hypotonia and growth failure and developmental delay. Biochemical studies showed elevated VLCFA and mildly reduced plasmalogens. He died at 7 months having developed pancreatic exocrine deficiency and interstitial lung disease, two features we propose to be possible extensions to the CADDS phenotype. We also review the genetic, phenotypic, and biochemical features in previously reported individuals with CADDS.
PubMed: 37701323
DOI: 10.1002/jmd2.12390 -
ACS Chemical Neuroscience Apr 2024Glutamate carboxypeptidase II (GCPII, also known as PSMA or FOLH1) is responsible for the cleavage of -acetyl-aspartyl-glutamate (NAAG) to -acetyl-aspartate and...
Glutamate carboxypeptidase II (GCPII, also known as PSMA or FOLH1) is responsible for the cleavage of -acetyl-aspartyl-glutamate (NAAG) to -acetyl-aspartate and glutamate in the central nervous system and facilitates the intestinal absorption of folate by processing dietary folyl-poly-γ-glutamate in the small intestine. The physiological function of GCPII in other organs like kidneys is still not known. GCPII inhibitors are neuroprotective in various conditions (e.g., ischemic brain injury) ; however, their utilization as potential drug candidates has not been investigated in regard to not yet known GCPII activities. To explore the GCPII role and possible side effects of GCPII inhibitors, we performed parallel metabolomic and lipidomic analysis of the cerebrospinal fluid (CSF), urine, plasma, and brain tissue of mice with varying degrees of GCPII deficiency (fully deficient in , -/-; one allele deficient in , +/-; and wild type, +/+). Multivariate analysis of metabolites showed no significant differences between wild-type and GCPII-deficient mice (except for NAAG), although changes were observed between the sex and age. NAAG levels were statistically significantly increased in the CSF, urine, and plasma of GCPII-deficient mice. However, no difference in NAAG concentrations was found in the whole brain lysate likely because GCPII, as an extracellular enzyme, can affect only extracellular and not intracellular NAAG concentrations. Regarding the lipidome, the most pronounced genotype-linked changes were found in the brain tissue. In brains of GCPII-deficient mice, we observed statistically significant enrichment in phosphatidylcholine-based lipids and reduction of sphingolipids and phosphatidylethanolamine plasmalogens. We hypothesize that the alteration of the NAA-NAAG axis by absent GCPII activity affected myelin composition. In summary, the absence of GCPII and thus similarly its inhibition do not have detrimental effects on metabolism, with just minor changes in the brain lipidome.
Topics: Animals; Mice; Brain; Dipeptides; Glutamate Carboxypeptidase II; Glutamic Acid; Lipidomics; Lipids; Metabolomics
PubMed: 38377674
DOI: 10.1021/acschemneuro.3c00494 -
The Journal of Physical Chemistry... May 2024Heart tissue can experience a progressive accumulation of transthyretin (TTR), a small four subunit protein that transports holoretinol binding protein and thyroxine....
Heart tissue can experience a progressive accumulation of transthyretin (TTR), a small four subunit protein that transports holoretinol binding protein and thyroxine. This severe pathology is known as transthyretin amyloid cardiomyopathy. Numerous experimental studies indicated that the aggregation rate and toxicity of TTR fibrils could be altered by the presence of lipids; however, the role of plasmalogens in this process remains unknown. In this study, we investigate the effect of choline plasmalogens (CPs) with different lengths and saturations of fatty acids (FAs) on TTR aggregation. We found that CPs with saturated and unsaturated FAs strongly suppressed TTR aggregation. We also found that CPs with saturated FAs did not change the morphology of TTR fibrils; however, much thicker fibrillar species were formed in the presence of CPs with unsaturated FAs. Finally, we found that CPs with C16:0, C18:0, and C18:1 FAs substantially lowered the cytotoxicity of TTR fibrils that were formed in their presence.
Topics: Prealbumin; Plasmalogens; Humans; Amyloid; Protein Aggregates; Fatty Acids
PubMed: 38661515
DOI: 10.1021/acs.jpclett.4c00868 -
Journal of Proteome Research Jun 2024The metabolites and microbiota in tongue coating display distinct characteristics in certain digestive disorders, yet their relationship with colorectal cancer (CRC)...
The metabolites and microbiota in tongue coating display distinct characteristics in certain digestive disorders, yet their relationship with colorectal cancer (CRC) remains unexplored. Here, we employed liquid chromatography coupled with tandem mass spectrometry to analyze the lipid composition of tongue coating using a nontargeted approach in 30 individuals with colorectal adenomas (CRA), 32 with CRC, and 30 healthy controls (HC). We identified 21 tongue coating lipids that effectively distinguished CRC from HC (AUC = 0.89), and 9 lipids that differentiated CRC from CRA (AUC = 0.9). Furthermore, we observed significant alterations in the tongue coating lipid composition in the CRC group compared to HC/CRA groups. As the adenoma-cancer sequence progressed, there was an increase in long-chain unsaturated triglycerides (TG) levels and a decrease in phosphatidylethanolamine plasmalogen (PE-P) levels. Furthermore, we noted a positive correlation between -acyl ornithine (NAOrn), sphingomyelin (SM), and ceramide phosphoethanolamine (PE-Cer), potentially produced by members of the phylum. The levels of inflammatory lipid metabolite 12-HETE showed a decreasing trend with colorectal tumor progression, indicating the potential involvement of tongue coating microbiota and tumor immune regulation in early CRC development. Our findings highlight the potential utility of tongue coating lipid analysis as a noninvasive tool for CRC diagnosis.
Topics: Humans; Colorectal Neoplasms; Lipidomics; Male; Female; Tongue; Middle Aged; Tandem Mass Spectrometry; Phosphatidylethanolamines; Aged; Chromatography, Liquid; Lipids; Triglycerides; Adenoma; Sphingomyelins; 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Plasmalogens; Case-Control Studies; Ethanolamines; Ceramides; Adult
PubMed: 38775738
DOI: 10.1021/acs.jproteome.4c00063 -
The Journal of Nutrition May 2024The intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been associated with health benefits. Blood levels of these fatty acids, measured by gas...
BACKGROUND
The intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been associated with health benefits. Blood levels of these fatty acids, measured by gas chromatography (GC), are associated with their dietary intake, but the relationships with lipidomic measurements are not well defined.
OBJECTIVES
This study aimed to determine the lipidomic biomarkers in whole blood that predict intakes of EPA + DHA and examine the relationship between lipidomic and GC-based n-3 polyunsaturated fatty acid (n-3 PUFA) biomarkers.
METHODS
Lipidomic and fatty acid analyses were completed on 120 whole blood samples collected from Danish participants. Dietary intakes were completed using a web-based 7-d food diary. Stepwise multiple linear regression was used to identify the fatty acid and lipidomic variables that predict intakes of EPA + DHA and to determine lipidomic species that predict commonly used fatty acid biomarkers.
RESULTS
Stepwise regression selected lipidomic variables with an R = 0.52 for predicting EPA + DHA intake compared to R = 0.40 for the selected fatty acid GC-based variables. More predictive models were generated when the lipidomic variables were selected for females only (R = 0.62, n = 68) and males only (R = 0.72, n = 52). Phosphatidylethanolamine plasmalogen species containing EPA or DHA tended to be the most predictive lipidomic variables. Stepwise regression also indicated that selected lipidomic variables can predict commonly used fatty acid GC-based n-3 PUFA biomarkers as the R values ranged from 0.84 to 0.91.
CONCLUSIONS
Both fatty acid and lipidomic data can be used to predict EPA + DHA intakes, and fatty acid GC-based biomarkers can be emulated by lipidomic species. Lipidomic-based biomarkers appear to be influenced by sex differences, probably in n-3 PUFA and lipoprotein metabolism. These results improve our ability to understand the relationship between novel lipidomic data and GC fatty acid data and will increase our ability to apply lipidomic methods to fatty acid and lipid nutritional research.
PubMed: 38710305
DOI: 10.1016/j.tjnut.2024.04.038 -
Frontiers in Endocrinology 2024Polycystic ovary syndrome with insulin resistance (PCOS-IR) is the most common endocrine and metabolic disease in women of reproductive age, and low fertility in PCOS...
High coverage of targeted lipidomics revealed lipid changes in the follicular fluid of patients with insulin-resistant polycystic ovary syndrome and a positive correlation between plasmalogens and oocyte quality.
BACKGROUND
Polycystic ovary syndrome with insulin resistance (PCOS-IR) is the most common endocrine and metabolic disease in women of reproductive age, and low fertility in PCOS patients may be associated with oocyte quality; however, the molecular mechanism through which PCOS-IR affects oocyte quality remains unknown.
METHODS
A total of 22 women with PCOS-IR and 23 women without polycystic ovary syndrome (control) who underwent fertilization and embryo transfer were recruited, and clinical information pertaining to oocyte quality was analyzed. Lipid components of follicular fluid (FF) were detected using high-coverage targeted lipidomics, which identified 344 lipid species belonging to 19 lipid classes. The exact lipid species associated with oocyte quality were identified.
RESULTS
The number (rate) of two pronuclear (2PN) zygotes, the number (rate) of 2PN cleaved embryos, and the number of high-quality embryos were significantly lower in the PCOS-IR group. A total of 19 individual lipid classes and 344 lipid species were identified and quantified. The concentrations of the 19 lipid species in the normal follicular fluid (control) ranged between 10 mol/L and 10 mol/L. In addition, 39 lipid species were significantly reduced in the PCOS-IR group, among which plasmalogens were positively correlated with oocyte quality.
CONCLUSIONS
This study measured the levels of various lipids in follicular fluid, identified a significantly altered lipid profile in the FF of PCOS-IR patients, and established a correlation between poor oocyte quality and plasmalogens in PCOS-IR patients. These findings have contributed to the development of plasmalogen replacement therapy to enhance oocyte quality and have improved culture medium formulations for oocyte maturation (IVM).
Topics: Humans; Female; Polycystic Ovary Syndrome; Follicular Fluid; Oocytes; Adult; Lipidomics; Insulin Resistance; Plasmalogens; Fertilization in Vitro; Lipids; Infertility, Female; Lipid Metabolism; Embryo Transfer; Case-Control Studies
PubMed: 38904043
DOI: 10.3389/fendo.2024.1414289 -
Genes Jun 2024Brain lipid homeostasis is an absolute requirement for proper functionality of nerve cells and neurological performance. Current evidence demonstrates that lipid...
Multifactor Analyses of Frontal Cortex Lipids in the APP/PS1 Model of Familial Alzheimer's Disease Reveal Anomalies in Responses to Dietary n-3 PUFA and Estrogenic Treatments.
Brain lipid homeostasis is an absolute requirement for proper functionality of nerve cells and neurological performance. Current evidence demonstrates that lipid alterations are linked to neurodegenerative diseases, especially Alzheimer's disease (AD). The complexity of the brain lipidome and its metabolic regulation has hampered the identification of critical processes associated with the onset and progression of AD. While most experimental studies have focused on the effects of known factors on the development of pathological hallmarks in AD, e.g., amyloid deposition, tau protein and neurofibrillary tangles, neuroinflammation, etc., studies addressing the causative effects of lipid alterations remain largely unexplored. In the present study, we have used a multifactor approach combining diets containing different amounts of polyunsaturated fatty acids (PUFAs), estrogen availabilities, and genetic backgrounds, i.e., wild type (WT) and APP/PS1 (FAD), to analyze the lipid phenotype of the frontal cortex in middle-aged female mice. First, we observed that severe n-3 PUFA deficiency impacts the brain n-3 long-chain PUFA (LCPUFA) composition, yet it was notably mitigated by hepatic de novo synthesis. n-6 LCPUFAs, ether-linked fatty acids, and saturates were also changed by the dietary condition, but the extent of changes was dependent on the genetic background and hormonal condition. Likewise, brain cortex phospholipids were mostly modified by the genotype (FAD>WT) with nuanced effects from dietary treatment. Cholesterol (but not sterol esters) was modified by the genotype (WT>FAD) and dietary condition (higher in DHA-free conditions, especially in WT mice). However, the effects of estrogen treatment were mostly observed in relation to phospholipid remodeling in a genotype-dependent manner. Analyses of lipid-derived variables indicate that nerve cell membrane biophysics were significantly affected by the three factors, with lower membrane microviscosity (higher fluidity) values obtained for FAD animals. In conclusion, our multifactor analyses revealed that the genotype, diet, and estrogen status modulate the lipid phenotype of the frontal cortex, both as independent factors and through their interactions. Altogether, the outcomes point to potential strategies based on dietary and hormonal interventions aimed at stabilizing the brain cortex lipid composition in Alzheimer's disease neuropathology.
Topics: Alzheimer Disease; Animals; Fatty Acids, Omega-3; Mice; Frontal Lobe; Female; Disease Models, Animal; Amyloid beta-Protein Precursor; Estrogens; Mice, Transgenic; Presenilin-1; Lipid Metabolism; Humans
PubMed: 38927745
DOI: 10.3390/genes15060810