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BMJ (Clinical Research Ed.) Nov 2023
Topics: Humans; Vitamin B 12; Vitamin B 12 Deficiency; Vitamins
PubMed: 37984968
DOI: 10.1136/bmj-2022-071725 -
Annual Review of Nutrition Aug 2023Riboflavin, in its cofactor forms flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), plays fundamental roles in energy metabolism, cellular antioxidant... (Review)
Review
Riboflavin, in its cofactor forms flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), plays fundamental roles in energy metabolism, cellular antioxidant potential, and metabolic interactions with other micronutrients, including iron, vitamin B, and folate. Severe riboflavin deficiency, largely confined to low-income countries, clinically manifests as cheilosis, angular stomatitis, glossitis, seborrheic dermatitis, and severe anemia with erythroid hypoplasia. Subclinical deficiency may be much more widespread, including in high-income countries, but typically goes undetected because riboflavin biomarkers are rarely measured in human studies. There are adverse health consequences of low and deficient riboflavin status throughout the life cycle, including anemia and hypertension, that could contribute substantially to the global burden of disease. This review considers the available evidence on causes, detection, and consequences of riboflavin deficiency, ranging from clinical deficiency signs to manifestations associated with less severe deficiency, and the related research, public health, and policy priorities.
Topics: Humans; Riboflavin Deficiency; Riboflavin; Causality; Antioxidants; Bone Marrow Failure Disorders; Disease Progression; Lip Diseases
PubMed: 37603429
DOI: 10.1146/annurev-nutr-061121-084407 -
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 -
Genes Jul 2023Riboflavin transporter 1 (RFVT1) deficiency is an ultrarare metabolic disorder due to autosomal dominant pathogenic variants in . The RFVT1 protein is mainly expressed...
Riboflavin transporter 1 (RFVT1) deficiency is an ultrarare metabolic disorder due to autosomal dominant pathogenic variants in . The RFVT1 protein is mainly expressed in the placenta and intestine. To our knowledge, only five cases of RFVT1 deficiency from three families have been reported so far. While newborns and infants with variants mainly showed a multiple acyl-CoA dehydrogenase deficiency-like presentation, individuals identified in adulthood were usually clinically asymptomatic. We report two patients with novel heterozygous variants. Patient 1 presented at the age of 62 with mild hyperammonemia following gastroenteritis. An acylcarnitine analysis in dried blood spots was abnormal with a multiple acyl-CoA dehydrogenase deficiency-like pattern, and genetic analysis confirmed a heterozygous variant, c.68C > A, p. Ser23Tyr. Patient 2 presented with recurrent seizures and hypsarrhythmia at the age of 7 months. Metabolic investigations yielded unremarkable results. However, whole exome sequencing revealed a heterozygous start loss variant, c.3G > A, p. Met1Ile in These two cases expand the clinical spectrum of riboflavin transporter 1 deficiency and demonstrate that symptomatic presentation in adulthood is possible.
Topics: Female; Humans; Infant; Infant, Newborn; Pregnancy; Heterozygote; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Receptors, G-Protein-Coupled; Riboflavin; Membrane Transport Proteins
PubMed: 37510312
DOI: 10.3390/genes14071408 -
PLoS Medicine Dec 2023Maternal vitamin status preconception and during pregnancy has important consequences for pregnancy outcome and offspring development. Changes in vitamin status from... (Randomized Controlled Trial)
Randomized Controlled Trial
Maternal B-vitamin and vitamin D status before, during, and after pregnancy and the influence of supplementation preconception and during pregnancy: Prespecified secondary analysis of the NiPPeR double-blind randomized controlled trial.
BACKGROUND
Maternal vitamin status preconception and during pregnancy has important consequences for pregnancy outcome and offspring development. Changes in vitamin status from preconception through early and late pregnancy and postpartum have been inferred from cross-sectional data, but longitudinal data on vitamin status from preconception throughout pregnancy and postdelivery are sparse. As such, the influence of vitamin supplementation on vitamin status during pregnancy remains uncertain. This study presents one prespecified outcome from the randomized controlled NiPPeR trial, aiming to identify longitudinal patterns of maternal vitamin status from preconception, through early and late pregnancy, to 6 months postdelivery, and determine the influence of vitamin supplementation.
METHODS AND FINDINGS
In the NiPPeR trial, 1,729 women (from the United Kingdom, Singapore, and New Zealand) aged 18 to 38 years and planning conception were randomized to receive a standard vitamin supplement (control; n = 859) or an enhanced vitamin supplement (intervention; n = 870) starting in preconception and continued throughout pregnancy, with blinding of participants and research staff. Supplement components common to both treatment groups included folic acid, β-carotene, iron, calcium, and iodine; components additionally included in the intervention group were riboflavin, vitamins B6, B12, and D (in amounts available in over-the-counter supplements), myo-inositol, probiotics, and zinc. The primary outcome of the study was glucose tolerance at 28 weeks' gestation, measured by oral glucose tolerance test. The secondary outcome reported in this study was the reduction in maternal micronutrient insufficiency in riboflavin, vitamin B6, vitamin B12, and vitamin D, before and during pregnancy. We measured maternal plasma concentrations of B-vitamins, vitamin D, and markers of insufficiency/deficiency (homocysteine, hydroxykynurenine-ratio, methylmalonic acid) at recruitment, 1 month after commencing intervention preconception, in early pregnancy (7 to 11 weeks' gestation) and late pregnancy (around 28 weeks' gestation), and postdelivery (6 months after supplement discontinuation). We derived standard deviation scores (SDS) to characterize longitudinal changes among participants in the control group and measured differences between the 2 groups. At recruitment, the proportion of patients with marginal or low plasma status was 29.2% for folate (<13.6 nmol/L), 7.5% and 82.0% for riboflavin (<5 nmol/L and ≤26.5 nmol/L, respectively), 9.1% for vitamin B12 (<221 pmol/L), and 48.7% for vitamin D (<50 nmol/L); these proportions were balanced between the groups. Over 90% of all participants had low or marginal status for one or more of these vitamins at recruitment. Among participants in the control group, plasma concentrations of riboflavin declined through early and late pregnancy, whereas concentrations of 25-hydroxyvitamin D were unchanged in early pregnancy, and concentrations of vitamin B6 and B12 declined throughout pregnancy, becoming >1 SDS lower than baseline by 28 weeks gestation. In the control group, 54.2% of participants developed low late-pregnancy vitamin B6 concentrations (pyridoxal 5-phosphate <20 nmol/L). After 1 month of supplementation, plasma concentrations of supplement components were substantially higher among participants in the intervention group than those in the control group: riboflavin by 0.77 SDS (95% CI 0.68 to 0.87, p < 0.0001), vitamin B6 by 1.07 SDS (0.99 to 1.14, p < 0.0001), vitamin B12 by 0.55 SDS (0.46 to 0.64, p < 0.0001), and vitamin D by 0.51 SDS (0.43 to 0.60, p < 0.0001), with higher levels in the intervention group maintained during pregnancy. Markers of vitamin insufficiency/deficiency were reduced in the intervention group, and the proportion of participants with vitamin D insufficiency (<50 nmol/L) during late pregnancy was lower in the intervention group (35.1% versus 8.5%; p < 0.0001). Plasma vitamin B12 remained higher in the intervention group than in the control group 6 months postdelivery (by 0.30 SDS (0.14, 0.46), p = 0.0003). The main limitation is that generalizability to the global population is limited by the high-resource settings and the lack of African and Amerindian women in particular.
CONCLUSIONS
Over 90% of the trial participants had marginal or low concentrations of one or more of folate, riboflavin, vitamin B12, or vitamin D during preconception, and many developed markers of vitamin B6 deficiency in late pregnancy. Preconception/pregnancy supplementation in amounts available in over-the-counter supplements substantially reduces the prevalence of vitamin deficiency and depletion markers before and during pregnancy, with higher maternal plasma vitamin B12 maintained during the recommended lactational period.
TRIAL REGISTRATION
ClinicalTrials.gov NCT02509988; U1111-1171-8056.
Topics: Female; Humans; Pregnancy; Cross-Sectional Studies; Dietary Supplements; Folic Acid; Pregnancy Outcome; Riboflavin; Vitamin B 12; Vitamin B 6; Vitamin B Complex; Vitamin D; Adolescent; Young Adult; Adult
PubMed: 38051700
DOI: 10.1371/journal.pmed.1004260 -
International Journal of Molecular... Nov 2023Many inherited metabolic disorders (IMDs), including disorders of amino acid, fatty acid, and carbohydrate metabolism, are treated with a dietary reduction or exclusion... (Review)
Review
Many inherited metabolic disorders (IMDs), including disorders of amino acid, fatty acid, and carbohydrate metabolism, are treated with a dietary reduction or exclusion of certain macronutrients, putting one at risk of a reduced intake of micronutrients. In this review, we aim to provide available evidence on the most common micronutrient deficits related to specific dietary approaches and on the management of their deficiency, in the meanwhile discussing the main critical points of each nutritional supplementation. The emerging concepts are that a great heterogeneity in clinical practice exists, as well as no univocal evidence on the most common micronutrient abnormalities. In phenylketonuria, for example, micronutrients are recommended to be supplemented through protein substitutes; however, not all formulas are equally supplemented and some of them are not added with micronutrients. Data on pyridoxine and riboflavin status in these patients are particularly scarce. In long-chain fatty acid oxidation disorders, no specific recommendations on micronutrient supplementation are available. Regarding carbohydrate metabolism disorders, the difficult-to-ascertain sugar content in supplementation formulas is still a matter of concern. A ketogenic diet may predispose one to both oligoelement deficits and their overload, and therefore deserves specific formulations. In conclusion, our overview points out the lack of unanimous approaches to micronutrient deficiencies, the need for specific formulations for IMDs, and the necessity of high-quality studies, particularly for some under-investigated deficits.
Topics: Humans; Diet; Dietary Supplements; Micronutrients; Trace Elements; Metabolic Diseases; Fatty Acids
PubMed: 38069347
DOI: 10.3390/ijms242317024 -
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