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Molecular Genetics and Metabolism... Mar 2024Riboflavin transporter deficiency (RTD) is a neurodegenerative disorder that presents from infancy to adulthood with a progressive axonal neuropathy characterized by a...
Riboflavin transporter deficiency (RTD) is a neurodegenerative disorder that presents from infancy to adulthood with a progressive axonal neuropathy characterized by a variety of neurologic symptoms including hearing loss, weakness, bulbar palsy, and respiratory insufficiency. Pathogenic variants in and are implicated in the pathogenesis of RTD type 2 and 3, respectively. Early identification of this disorder is critical, as it is treatable with riboflavin supplementation. We describe a 16-year-old female with a phenotype consistent with RTD3 found to have a novel heterozygous variant. Though RTD is typically considered an autosomal recessive condition, her heterozygous variant was thought to be disease causing after further genetic analysis and given her improvement in response to riboflavin supplementation. This case highlights the importance of reinterpretation of genetic testing, particularly when there is a high clinical suspicion for disease.
PubMed: 38469093
DOI: 10.1016/j.ymgmr.2024.101051 -
PLoS Pathogens Mar 2024The emergence of resistance against antimalarials and insecticides poses a significant threat to malaria elimination strategies. It is crucial to explore potential risk... (Review)
Review
The emergence of resistance against antimalarials and insecticides poses a significant threat to malaria elimination strategies. It is crucial to explore potential risk factors for malaria to identify new targets and alternative therapies. Malnutrition is a well-established risk factor for malaria. Deficiencies of micronutrients such as vitamin A, zinc, iron, folic acid, and phenotypic measures of malnutrition, such as stunting and wasting, have been studied extensively in the context of malaria. Vitamin B2, also known as riboflavin, is a micronutrient involved in maintaining cellular homeostasis. Riboflavin deficiency has been shown to have an inverse correlation with malarial parasitaemia. This article reviews the role of riboflavin in maintaining redox homeostasis and probes how riboflavin deficiency could alter malaria pathogenesis by disrupting the balance between oxidants and antioxidants. Though riboflavin analogues have been explored as antimalarials, new in vivo and patient-based research is required to target riboflavin-associated pathways for antimalarial therapy.
Topics: Humans; Riboflavin Deficiency; Antimalarials; Malaria; Folic Acid; Micronutrients; Riboflavin
PubMed: 38427625
DOI: 10.1371/journal.ppat.1011991 -
Journal of Clinical Medicine Feb 2024Obesity is a prevalent condition associated with various comorbidities, impacting mortality, fertility, and quality of life. Its relationship with type 2 diabetes...
Obesity is a prevalent condition associated with various comorbidities, impacting mortality, fertility, and quality of life. Its relationship with type 2 diabetes mellitus (DMII) is well established, with nearly 44% prevalence. Bariatric surgery has proven crucial for treating both obesity and DMII. The comparison between surgical techniques, such as sleeve gastrectomy (SG) and one anastomosis gastric bypass (OAGB), remains controversial in terms of glycemic control efficacy. This retrospective study aimed to assess DMII remission efficacy between SG and OAGB after 36 months. From January 2016 to September 2020, 201 patients who underwent SG and OAGB for morbid obesity associated with DMII were accurately followed-up with for 36 months, focusing on %HbA1c, DMII remission, anthropometric results, and nutrient deficiency. Although DMII remission did not exhibit statistical significance between the groups (82% vs. 93%, SG vs. OAGB, = 0.051), OAGB demonstrated a more robust association with glycemic control (Odds Ratio 0.51) throughout the entire follow-up and yielded superior anthropometric outcomes. Notably, nutrient deficiencies, excluding cholecalciferol, iron, and riboflavin, did not show significant intergroup differences. This study contributes valuable insights into the extended-term efficacy of SG and OAGB in DMII remission. The nuanced findings underscore the multifaceted nature of metabolic outcomes, suggesting that factors beyond weight loss influence diabetes resolution. Larger comparative studies are warranted to comprehensively address this issue.
PubMed: 38337593
DOI: 10.3390/jcm13030899 -
Frontiers in Microbiology 2023Insect-microbe endosymbiotic associations are omnipresent in nature, wherein the symbiotic microbes often play pivotal biological roles for their host insects. In...
Insect-microbe endosymbiotic associations are omnipresent in nature, wherein the symbiotic microbes often play pivotal biological roles for their host insects. In particular, insects utilizing nutritionally imbalanced food sources are dependent on specific microbial symbionts to compensate for the nutritional deficiency via provisioning of B vitamins in blood-feeding insects, such as tsetse flies, lice, and bedbugs. Bat flies of the family Nycteribiidae (Diptera) are blood-sucking ectoparasites of bats and shown to be associated with co-speciating bacterial endosymbiont " Aschnera chinzeii," although functional aspects of the microbial symbiosis have been totally unknown. In this study, we report the first complete genome sequence of from the bristled bat fly . The genome consisted of a 748,020 bp circular chromosome and a 18,747 bp circular plasmid. The chromosome encoded 603 protein coding genes (including 3 pseudogenes), 33 transfer RNAs, and 1 copy of 16S/23S/5S ribosomal RNA operon. The plasmid contained 10 protein coding genes, whose biological function was elusive. The genome size, 0.77 Mbp, was drastically reduced in comparison with 4-6 Mbp genomes of free-living γ-proteobacteria. Accordingly, the genome was devoid of many important functional genes, such as synthetic pathway genes for purines, pyrimidines, and essential amino acids. On the other hand, the genome retained complete or near-complete synthetic pathway genes for biotin (vitamin B7), tetrahydrofolate (vitamin B9), riboflavin (vitamin B2), and pyridoxal 5'-phosphate (vitamin B6), suggesting that provides these vitamins and cofactors that are deficient in the blood meal of the host bat fly. Similar retention patterns of the synthetic pathway genes for vitamins and cofactors were also observed in the endosymbiont genomes of other blood-sucking insects, such as of human lice, of louse flies, and of tsetse flies, which may be either due to convergent evolution in the blood-sucking host insects or reflecting the genomic architecture of -allied bacteria.
PubMed: 38318130
DOI: 10.3389/fmicb.2023.1336919 -
Cell Death Discovery Jan 2024Riboflavin Transporter Deficiency (RTD) is a rare genetic, childhood-onset disease. This pathology has a relevant neurological involvement, being characterized by motor...
Riboflavin Transporter Deficiency (RTD) is a rare genetic, childhood-onset disease. This pathology has a relevant neurological involvement, being characterized by motor symptoms, ponto-bulbar paralysis and sensorineural deafness. Such clinical presentation is associated with muscle weakness and motor neuron (MN) degeneration, so that RTD is considered part of the MN disease spectrum. Based on previous findings demonstrating energy dysmetabolism and mitochondrial impairment in RTD induced Pluripotent Stem cells (iPSCs) and iPSC-derived MNs, here we address the involvement of intrinsic apoptotic pathways in disease pathogenesis using these patient-specific in vitro models by combined ultrastructural and confocal analyses. We show impaired neuronal survival of RTD iPSCs and MNs. Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) documents severe alterations in patients' cells, including deranged mitochondrial ultrastructure, and altered plasma membrane and nuclear organization. Occurrence of aberrantly activated apoptosis is confirmed by immunofluorescence and TUNEL assays. Overall, our work provides evidence of a role played by mitochondrial dysfunction in RTD, and identifies neuronal apoptosis as a contributing event in disease pathogenesis, indicating intrinsic apoptosis pathways as possible relevant targets for more effective therapeutical approaches.
PubMed: 38278809
DOI: 10.1038/s41420-024-01812-y -
Journal of Pharmaceutical and... Apr 2024B vitamins are essential for human life and their disorders can cause a variety of diseases. Solid-phase extraction (SPE) coupled to LC-MS/MS is a preferred technique...
A novel automated multi-cycle magnetic solid-phase extraction coupled to LC-MS/MS to study the disorders of six functional B vitamins in patients with gastroenterology and hyperhomocysteinemia.
B vitamins are essential for human life and their disorders can cause a variety of diseases. Solid-phase extraction (SPE) coupled to LC-MS/MS is a preferred technique for determining multiple B vitamins, however, their complexity in real biological matrices makes it hard to achieve satisfactory recovery and accuracy when simultaneous detection. In this study, a novel automated multi-cycle magnetic SPE (MSPE) coupled to the LC-MS/MS method was established using a mixed-mode anion exchange magnetic adsorbent for the simultaneous extraction of six functional B vitamins, including methylmalonic acid, riboflavin, pantothenic acid, 4-pyridoxic acid, folic acid, and 5-methyltetrahydrofolate. After three consecutive MSPE cycles, the recoveries of all analytes were between 51.5% and 89.6%. The method exhibited excellent sensitivity and linearity, with a dynamic range of 200-fold (R > 0.99 for all analytes), exceptional accuracy (ranging between 95.4% and 105.6%) and precision (with RSDs ≤ 6.2%) without significant matrix effects or interferences. Compared to manual SPE method, the automated multi-cycle MSPE method has better feasibility and greater vitamin coverage. It shows a high correlation with the manual method for the detection of 5-methyltetrahydrofolate and folate (R > 0.99). A study of patients from the gastroenterology department showed that those undergoing surgery and those with malignancies may be at risk of folate deficiency. In addition, patients with hyperhomocystinemia had higher levels of methylmalonic acid and lower levels of 5-methyltetrahydrofolate, which correlated with homocysteine levels (R = 0.404 and -0.311, respectively) and showed dose-response relationships. This method is highly automated and cost-effective, with minimal systematic error, making it suitable for the analysis of clinical samples.
Topics: Humans; Chromatography, Liquid; Vitamin B Complex; Liquid Chromatography-Mass Spectrometry; Gastroenterology; Hyperhomocysteinemia; Methylmalonic Acid; Tandem Mass Spectrometry; Vitamin A; Folic Acid; Solid Phase Extraction; Magnetic Phenomena; Chromatography, High Pressure Liquid
PubMed: 38271858
DOI: 10.1016/j.jpba.2024.115989 -
Orphanet Journal of Rare Diseases Jan 2024Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder resulting from pathogenic variants in three distinct genes, with most of the...
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder resulting from pathogenic variants in three distinct genes, with most of the variants occurring in the electron transfer flavoprotein-ubiquinone oxidoreductase gene (ETFDH). Recent evidence of potential founder variants for MADD in the South African (SA) population, initiated this extensive investigation. As part of the International Centre for Genomic Medicine in Neuromuscular Diseases study, we recruited a cohort of patients diagnosed with MADD from academic medical centres across SA over a three-year period. The aim was to extensively profile the clinical, biochemical, and genomic characteristics of MADD in this understudied population.
METHODS
Clinical evaluations and whole exome sequencing were conducted on each patient. Metabolic profiling was performed before and after treatment, where possible. The recessive inheritance and phase of the variants were established via segregation analyses using Sanger sequencing. Lastly, the haplotype and allele frequencies were determined for the two main variants in the four largest SA populations.
RESULTS
Twelve unrelated families (ten of White SA and two of mixed ethnicity) with clinically heterogeneous presentations in 14 affected individuals were observed, and five pathogenic ETFDH variants were identified. Based on disease severity and treatment response, three distinct groups emerged. The most severe and fatal presentations were associated with the homozygous c.[1067G > A];c.[1067G > A] and compound heterozygous c.[976G > C];c.[1067G > A] genotypes, causing MADD types I and I/II, respectively. These, along with three less severe compound heterozygous genotypes (c.[1067G > A];c.[1448C > T], c.[740G > T];c.[1448C > T], and c.[287dupA*];c.[1448C > T]), resulting in MADD types II/III, presented before the age of five years, depending on the time and maintenance of intervention. By contrast, the homozygous c.[1448C > T];c.[1448C > T] genotype, which causes MADD type III, presented later in life. Except for the type I, I/II and II cases, urinary metabolic markers for MADD improved/normalised following treatment with riboflavin and L-carnitine. Furthermore, genetic analyses of the most frequent variants (c.[1067G > A] and c.[1448C > T]) revealed a shared haplotype in the region of ETFDH, with SA population-specific allele frequencies of < 0.00067-0.00084%.
CONCLUSIONS
This study reveals the first extensive genotype-phenotype profile of a MADD patient cohort from the diverse and understudied SA population. The pathogenic variants and associated variable phenotypes were characterised, which will enable early screening, genetic counselling, and patient-specific treatment of MADD in this population.
Topics: Humans; Child, Preschool; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Mutation; South Africa; Genotype; Riboflavin; Guanine Nucleotide Exchange Factors; Death Domain Receptor Signaling Adaptor Proteins
PubMed: 38221620
DOI: 10.1186/s13023-023-03014-8 -
Nutrition & Metabolism Jan 2024Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. Riboflavin, one of water soluble vitamins, plays a role in lipid...
BACKGROUND
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. Riboflavin, one of water soluble vitamins, plays a role in lipid metabolism and antioxidant function. However, the effects of riboflavin deficiency on NAFLD development have not yet to be fully explored.
METHODS
In the present study, an animal model of NAFLD was induced by high fat diet feeding in mice and a cellular model of NAFLD was developed in HepG2 cells by palmitic acid (PA) exposure. The effects of riboflavin deficiency on lipid metabolism and antioxidant function were investigated both in vivo and in vitro. In addition, the possible role of peroxisome proliferator-activated receptor gamma (PPARγ) was studied in HepG2 cells using gene silencing technique.
RESULTS
The results showed that riboflavin deficiency led to hepatic lipid accumulation in mice fed high fat diet. The expressions of fatty acid synthase (FAS) and carnitine palmitoyltransferase 1 (CPT1) were up-regulated, whereas that of adipose triglyceride lipase (ATGL) down-regulated. Similar changes in response to riboflavin deficiency were demonstrated in HepG2 cells treated with PA. Factorial analysis revealed a significant interaction between riboflavin deficiency and high dietary fat or PA load in the development of NAFLD. Hepatic PPARγ expression was significantly upregulated in mice fed riboflavin deficient and high fat diet or in HepG2 cells treated with riboflavin deficiency and PA load. Knockdown of PPARγ gene resulted in a significant reduction of lipid accumulation in HepG2 cells exposed to riboflavin deficiency and PA load.
CONCLUSIONS
There is a synergetic action between riboflavin deficiency and high dietary fat on the development of NAFLD, in which PPARγ may play an important role.
PubMed: 38169398
DOI: 10.1186/s12986-023-00775-8 -
International Journal of Food... Feb 2024Some lactic acid bacteria (LAB) have the ability to synthesize riboflavin, a trait linked to the presence of ribG, ribB, ribA and ribH genes located in the rib operon....
Some lactic acid bacteria (LAB) have the ability to synthesize riboflavin, a trait linked to the presence of ribG, ribB, ribA and ribH genes located in the rib operon. Previous screening of riboflavin producers identified several LAB strains belonging to different species with this ability, but none of them surpassed 0.25 mg/L production of the vitamin. In this study, we explored two strategies to obtain riboflavin-overproducing strains: by roseoflavin selection of mutants, and by the transformation of selected strains with plasmids pNZ:TuR.rib or pNZ:TuB.rib containing the genes ribG, ribB, ribA and ribH from Lactococcus cremoris MG1363. The resulting riboflavin-overproducing strains were able to produce yields between 0.5 and 6 mg/L in culture media and several of them were selected for the fermentation of soy beverages. Riboflavin in bio-enriched soy beverages was evaluated by direct fluorescence measurement and high-performance liquid chromatography-fluorescence analysis. Soy beverages fermented with the recombinant strains Lactococcus cremoris ESI 277 pNZ:TuB.rib and Lactococcus lactis INIA 12 pNZ:TuR.rib showed the highest riboflavin yields (>5 mg/L) after 24 h fermentation. On the other hand, roseoflavin-resistant mutant Limosilactobacillus fermentum INIA P143R2 was able to enrich fermented soy beverages with 1.5 mg/L riboflavin. Riboflavin-overproducing LAB strains constitute a good option for riboflavin enrichment of soy beverages by fermentation and the commercialization of such beverages could be very useful to prevent riboflavin deficiency.
Topics: Lactobacillales; Soy Milk; Riboflavin; Fermentation; Lactococcus lactis
PubMed: 38150774
DOI: 10.1016/j.ijfoodmicro.2023.110547