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Oxidative Medicine and Cellular... 2020Riboflavin transporter deficiency (RTD) is a childhood-onset neurodegenerative disorder characterized by progressive pontobulbar palsy, sensory and motor neuron...
Riboflavin transporter deficiency (RTD) is a childhood-onset neurodegenerative disorder characterized by progressive pontobulbar palsy, sensory and motor neuron degeneration, sensorineural hearing loss, and optic atrophy. As riboflavin (RF) is the precursor of FAD and FMN, we hypothesize that both mitochondrial and peroxisomal energy metabolism pathways involving flavoproteins could be directly affected in RTD, thus impacting cellular redox status. In the present work, we used induced pluripotent stem cells (iPSCs) from RTD patients to investigate morphofunctional features, focusing on mitochondrial and peroxisomal compartments. Using this model, we document the following RTD-associated alterations: (i) abnormal colony-forming ability and loss of cell-cell contacts, revealed by light, electron, and confocal microscopy, using tight junction marker ZO-1; (ii) mitochondrial ultrastructural abnormalities, involving shape, number, and intracellular distribution of the organelles, as assessed by focused ion beam/scanning electron microscopy (FIB/SEM); (iii) redox imbalance, with high levels of superoxide anion, as assessed by MitoSOX assay accompanied by abnormal mitochondrial polarization state, evaluated by JC-1 staining; (iv) altered immunofluorescence expression of antioxidant systems, namely, glutathione, superoxide dismutase 1 and 2, and catalase, as assessed by quantitatively evaluated confocal microscopy; and (v) peroxisomal downregulation, as demonstrated by levels and distribution of fatty acyl -oxidation enzymes. RF supplementation results in amelioration of cell phenotype and rescue of redox status, which was associated to improved ultrastructural features of mitochondria, thus strongly supporting patient treatment with RF, to restore mitochondrial- and peroxisomal-related aspects of energy dysmetabolism and oxidative stress in RTD syndrome.
Topics: Antioxidants; Base Sequence; Benzimidazoles; Biological Transport; Carbocyanines; Cell Shape; Child; Child, Preschool; Energy Metabolism; Humans; Induced Pluripotent Stem Cells; Mitochondria; Oxidation-Reduction; Peroxisomes; Receptors, G-Protein-Coupled; Riboflavin
PubMed: 32855765
DOI: 10.1155/2020/6821247 -
Neuromolecular Medicine Dec 2023AIFM1 is a mitochondrial flavoprotein involved in caspase-independent cell death and regulation of respiratory chain complex biogenesis. Mutations in the AIFM1 gene have...
AIFM1 is a mitochondrial flavoprotein involved in caspase-independent cell death and regulation of respiratory chain complex biogenesis. Mutations in the AIFM1 gene have been associated with multiple clinical phenotypes, but the effectiveness of riboflavin treatment remains controversial. Furthermore, few studies explored the reasons underlying this controversy. We reported a 7-year-old boy with ataxia, sensorimotor neuropathy and muscle weakness. Genetic and histopathological analyses were conducted, along with assessments of mitochondrial function and apoptosis level induced by staurosporine. Riboflavin deficiency and supplementation experiments were performed using fibroblasts. A missense c.1019T > C (p. Met340Thr) variant of AIFM1 was detected in the proband, which caused reduced expression of AIFM1 protein and mitochondrial dysfunction as evidenced by downregulation of mitochondrial complex subunits, respiratory deficiency and collapse of ΔΨm. The proportion of apoptotic cells in mutant fibroblasts was lower than controls after induction of apoptosis. Riboflavin deficiency resulted in decreased AIFM1 protein levels, while supplementation with high concentrations of riboflavin partially increased AIFM1 protein levels in variant fibroblasts. In addition, mitochondrial respiratory function of mutant fibroblasts was partly improved after riboflavin supplementation. Our study elucidated the pathogenicity of the AIFM1 c.1019T > C variant and revealed mutant fibroblasts was intolerant to riboflavin deficiency. Riboflavin supplementation is helpful in maintaining the level of AIFM1 protein and mitochondrial respiratory function. Early riboflavin treatment may serve as a valuable attempt for patients with AIFM1 variant.
Topics: Male; Humans; Child; Riboflavin Deficiency; Riboflavin; Mutation, Missense; Mitochondria; Mitochondrial Diseases; Apoptosis Inducing Factor
PubMed: 37603145
DOI: 10.1007/s12017-023-08750-5 -
European Journal of Neurology Nov 2020Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a hereditary disorder of mitochondrial long-chain fatty acid oxidation that has variable presentations,...
BACKGROUND AND PURPOSE
Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a hereditary disorder of mitochondrial long-chain fatty acid oxidation that has variable presentations, including exercise intolerance, cardiomyopathy and liver disease. The aim of this study was to describe the clinical and genetic manifestations of six patients with adult-onset VLCADD.
METHODS
In this study, the clinical, pathological and genetic findings of six adult patients (four from Iran and two from Serbia) with VLCADD and their response to treatment are described.
RESULTS
The median (range) age of patients at first visit was 31 (27-38) years, and the median (range) age of onset was 26.5 (19-33) years. Parental consanguinity was present for four patients. Four patients had a history of rhabdomyolysis, and the recorded CK level ranged between 67 and 90 000 IU/l. Three patients had a history of exertional myalgia, and one patient had a non-fluctuating weakness. Through next-generation sequencing analysis, we identified six cases with variants in the ACADVL gene and a confirmed diagnosis of VLCADD. Of the total six variants identified, five were missense, and one was a novel frameshift mutation identified in two unrelated individuals. Two variants were novel, and three were previously reported. We treated the patients with a combination of L-carnitine, Coenzyme Q10 and riboflavin. Three patients responded favorably to the treatment.
CONCLUSION
Adult-onset VLCADD is a rare entity with various presentations. Patients may respond favorably to a cocktail of L-carnitine, Coenzyme Q10, and riboflavin.
Topics: Acyl-CoA Dehydrogenase, Long-Chain; Adult; Congenital Bone Marrow Failure Syndromes; Female; Humans; Lipid Metabolism, Inborn Errors; Male; Mitochondrial Diseases; Muscular Diseases; Young Adult
PubMed: 32558070
DOI: 10.1111/ene.14402 -
Current Developments in Nutrition Apr 2021Nutrition surveys suggest that <10% of Canadian adults have inadequate riboflavin intakes. However, biochemical riboflavin deficiency [erythrocyte glutathione reductase...
BACKGROUND
Nutrition surveys suggest that <10% of Canadian adults have inadequate riboflavin intakes. However, biochemical riboflavin deficiency [erythrocyte glutathione reductase activity coefficient (EGRac) ≥1.40] has been reported in 41% of young adult women living in Metro Vancouver. Canadian Chinese ethnicity comprise >25% of Vancouver's population and are postulated to have poorer riboflavin status than those of European ethnicity because they could be less likely to consume dairy products and fortified wheat.
OBJECTIVES
The objectives of this study were to determine dietary riboflavin intake and food sources, and to assess the association between riboflavin intake and status in young women of European (= 107) and Chinese (= 91) ethnicities living in Metro Vancouver, Canada.
METHODS
This was a cross-sectional study conducted in women (aged 19-45 y). Women were healthy, not pregnant or breastfeeding, of European or Chinese ethnicities, and not taking riboflavin-containing supplements for the past 4 mo. Dietary riboflavin intake was assessed using the past-year Diet History Questionnaire II, and riboflavin status (EGRac) was measured in fasting venous blood samples.
RESULTS
Only 7% of participants had dietary riboflavin intakes below the Estimated Average Requirement (0.9 mg/d), but 40% of women had biochemical riboflavin deficiency (EGRac ≥1.40). Although more Canadian women of European ethnicity than Chinese ethnicity had biochemical riboflavin deficiency (46% and 34%; < 0.001), median dietary riboflavin intake did not differ (1.73 and 1.82 mg/d; = 0.587). Dairy products and vegetables contributed the most to riboflavin intake. Energy-adjusted dietary riboflavin intake was inversely associated with EGRac (B = -0.04, 95% CI: -0.07, -0.01). However, after further adjustment the relation was not significant.
CONCLUSIONS
Overall, women of reproductive age living in Metro Vancouver, Canada, had a low prevalence of inadequate dietary riboflavin intake despite the high prevalence of apparent biochemical riboflavin deficiency.
PubMed: 33860148
DOI: 10.1093/cdn/nzab021 -
Pediatric Neurology Jul 2023Riboflavin transporter deficiency is a rare but severe neurometabolic disorder.
BACKGROUND
Riboflavin transporter deficiency is a rare but severe neurometabolic disorder.
METHODS
We report two siblings with pathogenic variants in SLC52A3 gene, resulting in riboflavin transporter 3 deficiency.
RESULTS
The first sibling was diagnosed at age 11 months with severe respiratory compromise and regression of developmental milestones. His symptoms significantly improved with riboflavin supplementation therapy. The younger sibling was diagnosed by antenatal genetic analysis; riboflavin supplementation was initiated in utero and continued from birth. Now at age two years, he remains clinically asymptomatic despite genetic confirmation of riboflavin transporter deficiency.
CONCLUSIONS
Antenatal riboflavin supplementation is a safe and effective treatment for the prevention of symptomatic manifestations of riboflavin transporter deficiency.
Topics: Pregnancy; Male; Humans; Female; Infant; Child, Preschool; Riboflavin; Bulbar Palsy, Progressive; Vitamins; Membrane Transport Proteins; Hearing Loss, Sensorineural
PubMed: 37116404
DOI: 10.1016/j.pediatrneurol.2023.04.004 -
The American Journal of Clinical... Dec 2022The generation of the active form of vitamin B-6, pyridoxal 5'-phosphate (PLP), in tissues is dependent upon riboflavin as flavin mononucleotide, but whether this... (Clinical Trial)
Clinical Trial
BACKGROUND
The generation of the active form of vitamin B-6, pyridoxal 5'-phosphate (PLP), in tissues is dependent upon riboflavin as flavin mononucleotide, but whether this interaction is important for maintaining vitamin B-6 status is unclear.
OBJECTIVE
To investigate vitamin B-6 and riboflavin status, their metabolic interaction, and relationship with methylenetetrahydrofolate reductase (MTHFR) genotype in adulthood.
METHODS
Data from 5612 adults aged 18-102 y were drawn from the Irish National Adult Nutrition Survey (NANS; population-based sample) and the Trinity-Ulster Department of Agriculture (TUDA) and Genovit cohorts (volunteer samples). Plasma PLP and erythrocyte glutathione reductase activation coefficient (EGRac), as a functional indicator of riboflavin, were determined.
RESULTS
Older (≥65 y) compared with younger (<65 y) adults had significantly lower PLP concentrations (P < 0.001). A stepwise decrease in plasma PLP was observed across riboflavin categories, from optimal (EGRac ≤1.26), to suboptimal (EGRac: 1.27-1.39), to deficient (EGRac ≥1.40) status, an effect most pronounced in older adults (mean ± SEM: 76.4 ± 0.9 vs 65.0 ± 1.1 vs 55.4 ± 1.2 nmol/L; P < 0.001). In individuals with the variant MTHFR 677TT genotype combined with riboflavin deficiency, compared with non-TT (CC/CT) genotype participants with sufficient riboflavin, we observed PLP concentrations of 52.1 ± 2.9 compared with 76.8 ±0.7 nmol/L (P < 0.001). In participants with available dietary data (i.e., NANS cohort, n = 936), PLP was associated with vitamin B-6 intake (nonstandardized regression coefficient β: 2.49; 95% CI 1.75, 3.24; P < 0.001), supplement use (β: 81.72; 95% CI: 66.01, 97.43; P < 0.001), fortified food (β: 12.49; 95% CI: 2.08, 22.91; P = 0.019), and EGRac (β: -65.81; 95% CI: -99.08, -32.54; P < 0.001), along with BMI (β: -1.81; 95% CI: -3.31, -0.30; P = 0.019).
CONCLUSIONS
These results are consistent with the known metabolic dependency of PLP on flavin mononucleotide (FMN) and suggest that riboflavin may be the limiting nutrient for maintaining vitamin B-6 status, particularly in individuals with the MTHFR 677TT genotype. Randomized trials are necessary to investigate the PLP response to riboflavin intervention within the dietary range. The TUDA study and the NANS are registered at www.ClinicalTrials.gov as NCT02664584 (27 January 2016) and NCT03374748 (15 December 2017), respectively.Clinical Trial Registry details: Trinity-Ulster-Department of Agriculture (TUDA) study, ClinicalTrials.gov no. NCT02664584 (January 27th 2016); National Adult Nutrition Survey (NANS), ClinicalTrials.gov no. NCT03374748 (December 15th 2017).
Topics: Adult; Aged; Humans; Flavin Mononucleotide; Genotype; Methylenetetrahydrofolate Reductase (NADPH2); Pyridoxal Phosphate; Riboflavin; Vitamin B 12; Vitamin B 6; Vitamins
PubMed: 36264281
DOI: 10.1093/ajcn/nqac240 -
Practical Neurology Aug 2019
Topics: Adult; Autoantibodies; Creatine Kinase; Electromyography; Female; Humans; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Muscle Weakness; Muscle, Skeletal; Riboflavin; Vitamin B Complex
PubMed: 30948559
DOI: 10.1136/practneurol-2019-002204 -
Human & Experimental Toxicology 2023Riboflavin deficiency produces severe peripheral neve demyelination in young, rapidly growing chickens. While this naturally-occurring vitamin B2 deficiency can cause a...
Riboflavin deficiency produces severe peripheral neve demyelination in young, rapidly growing chickens. While this naturally-occurring vitamin B2 deficiency can cause a debilitating peripheral neuropathy, and mortality, in poultry flocks, it can also be a useful experimental animal model to study the pathogenesis of reliably reproducible peripheral nerve demyelination. Moreover, restitution of normal riboflavin levels in deficient birds results in brisk remyelination. It is the only acquired, primary, demyelinating tomaculous neuropathy described to date in animals. The only other substance that causes peripheral nerve demyelination similar to avian riboflavin deficiency is tellurium and the pathologic features of the peripheral neuropathy produced by this developmental neurotoxin in weanling rats are also described.
Topics: Animals; Rats; Riboflavin Deficiency; Demyelinating Diseases; Remyelination; Chickens; Peripheral Nerves; Peripheral Nervous System Diseases; Dietary Supplements; Vitamins
PubMed: 37553751
DOI: 10.1177/09603271231188970 -
Biomedicines Jun 2022Riboflavin transporter deficiency (RTD) is a rare genetic disorder characterized by motor, sensory and cranial neuropathy. This childhood-onset neurodegenerative disease... (Review)
Review
Riboflavin transporter deficiency (RTD) is a rare genetic disorder characterized by motor, sensory and cranial neuropathy. This childhood-onset neurodegenerative disease is caused by biallelic pathogenic variants in either or genes, resulting in insufficient supply of riboflavin (vitamin B2) and consequent impairment of flavoprotein-dependent metabolic pathways. Current therapy, empirically based high-dose riboflavin supplementation, ameliorates the progression of the disease, even though response to treatment is variable and partial. Recent studies have highlighted concurrent pathogenic contribution of cellular energy dysmetabolism and cytoskeletal derangement. In this context, patient specific RTD models, based on induced pluripotent stem cell (iPSC) technology, have provided evidence of redox imbalance, involving mitochondrial and peroxisomal dysfunction. Such oxidative stress condition likely causes cytoskeletal perturbation, associated with impaired differentiation of RTD motor neurons. In this review, we discuss the most recent findings obtained using different RTD models. Relevantly, the integration of data from innovative iPSC-derived in vitro models and invertebrate in vivo models may provide essential information on RTD pathophysiology. Such novel insights are expected to suggest custom therapeutic strategies, especially for those patients unresponsive to high-dose riboflavin treatments.
PubMed: 35740351
DOI: 10.3390/biomedicines10061329