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Chinese Medical Journal Jan 2016Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is the most common type of lipid storage myopathies in China. Most patients with late-onset MADD are well...
BACKGROUND
Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is the most common type of lipid storage myopathies in China. Most patients with late-onset MADD are well responsive to riboflavin. Up to now, these patients are often treated with glucocorticoids as the first-line drug because they are misdiagnosed as polymyositis without muscle biopsy or gene analysis. Although glucocorticoids seem to improve the fatty acid metabolism of late-onset MADD, the objective evaluation of their rationalization on this disorder and comparison with riboflavin treatment are unknown.
METHODS
We performed a historical cohort study on the efficacy of the two drugs among 45 patients with late-onset MADD, who were divided into glucocorticoids group and riboflavin group. Detailed clinical information of baseline and 1-month follow-up were collected.
RESULTS
After 1-month treatment, a dramatic improvement of muscle strength was found in riboflavin group (P < 0.05). There was no significant difference in muscle enzymes between the two groups. Significantly, the number of patients with full recovery in glucocorticoids group was less than the number in riboflavin group (P < 0.05). On the other hand, almost half of the patients in riboflavin group still presented high-level muscle enzymes and weak muscle strength after 1-month riboflavin treatment, meaning that 1-month treatment duration maybe insufficient and patients should keep on riboflavin supplement for a longer time.
CONCLUSIONS
Our results provide credible evidences that the overall efficacy of riboflavin is superior to glucocorticoids, and a longer duration of riboflavin treatment is necessary for patients with late-onset MADD.
Topics: Adolescent; Adult; Age of Onset; Child; Cohort Studies; Female; Glucocorticoids; Humans; Lipid Metabolism, Inborn Errors; Male; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Muscular Dystrophies; Riboflavin; Young Adult
PubMed: 26830983
DOI: 10.4103/0366-6999.173438 -
The Journal of Nutritional Biochemistry Apr 2006Eukaryotes convert riboflavin to flavin adenine dinucleotide, which serves as a coenzyme for glutathione reductase and other enzymes. Glutathione reductase mediates the...
Eukaryotes convert riboflavin to flavin adenine dinucleotide, which serves as a coenzyme for glutathione reductase and other enzymes. Glutathione reductase mediates the regeneration of reduced glutathione, which plays an important role in scavenging free radicals and reactive oxygen species. Here we tested the hypothesis that riboflavin deficiency decreases glutathione reductase activity in HepG2 liver cells, causing oxidative damage to proteins and DNA, and cell cycle arrest. As a secondary goal, we determined whether riboflavin deficiency is associated with gene expression patterns indicating cell stress. Cells were cultured in riboflavin-deficient and riboflavin-supplemented media for 4 days. Activity of glutathione reductase was not detectable in cells cultured in riboflavin-deficient medium. Riboflavin deficiency was associated with an increase in the abundance of damaged (carbonylated) proteins and with increased incidence of DNA strand breaks. Damage to proteins and DNA was paralleled by increased abundance of the stress-related transcription factor GADD153. Riboflavin-deficient cells arrested in G1 phase of the cell cycle. Moreover, oxidative stress caused by riboflavin deficiency was associated with increased expression of clusters of genes that play roles in cell stress and apoptosis. For example, the abundance of the pro-apoptotic pleiomorphic adenoma gene-like 1 gene was 183% greater in riboflavin-deficient cells compared with riboflavin-sufficient controls. We conclude that riboflavin deficiency is associated with oxidative damage to proteins and DNA in liver cells, leading to cell stress and G1 phase arrest.
Topics: Cell Line; DNA Damage; G1 Phase; Glutathione Reductase; Humans; Liver; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Protein Carbonylation; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Riboflavin Deficiency; Transcription Factor CHOP
PubMed: 16109485
DOI: 10.1016/j.jnutbio.2005.05.004 -
Scientific Reports Oct 2020Riboflavin transporter 3 (RFVT3), encoded by the SLC52A3 gene, is important for riboflavin homeostasis in the small intestine, kidney, and placenta. Our previous study...
Riboflavin transporter 3 (RFVT3), encoded by the SLC52A3 gene, is important for riboflavin homeostasis in the small intestine, kidney, and placenta. Our previous study demonstrated that Slc52a3 knockout (Slc52a3-/-) mice exhibited neonatal lethality and metabolic disorder due to riboflavin deficiency. Here, we investigated the influence of Slc52a3 gene disruption on brain development using Slc52a3-/- embryos. Slc52a3-/- mice at postnatal day 0 showed hypoplasia of the brain and reduced thickness of cortical layers. At embryonic day 13.5, the formation of Tuj1 neurons and Tbr2 intermediate neural progenitors was significantly decreased; no significant difference was observed in the total number and proliferative rate of Pax6 radial glia. Importantly, the hypoplastic phenotype was rescued upon riboflavin supplementation. Thus, it can be concluded that RFVT3 contributes to riboflavin homeostasis in embryos and that riboflavin itself is required during embryonic development of the cerebral cortex in mice.
Topics: Animals; Cerebral Cortex; Membrane Transport Proteins; Mice; Mice, Knockout; Neural Stem Cells; Neurons; Riboflavin Deficiency
PubMed: 33116204
DOI: 10.1038/s41598-020-75601-9 -
BMC Neurology Dec 2019Multiple acyl-CoA dehydrogenase deficiency (MADD) is a riboflavin-responsive lipid-storage myopathy caused by mutations in the EFTA, EFTB or ETFDH genes. We report a...
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a riboflavin-responsive lipid-storage myopathy caused by mutations in the EFTA, EFTB or ETFDH genes. We report a Chinese family of Southern Min origin with two affected siblings with late-onset riboflavin-responsive MADD due to a homozygous c.250G > A EFTDH mutation and review the genetic epidemiology of the c.250G > A mutation.
CASE PRESENTATION
Both siblings presented with exercise-induced myalgia, progressive proximal muscle weakness and high levels of serum muscle enzymes and were initially diagnosed as polymyositis after a muscle biopsy. A repeat biopsy in one sibling subsequently showed features of lipid storage myopathy and genetic analysis identified a homozygous mutation (c.250G > A) in the ETFDH gene in both siblings and carriage of the same mutation by both parents. Glucocorticoid therapy led to improvement in muscle enzyme levels, but little change in muscle symptoms, and only after treatment with riboflavin was there marked improvement in exercise tolerance and muscle strength. The frequency and geographic distribution of the c.250G > A mutation were determined from a literature search for all previously reported cases of MADD with documented mutations. Our study found the c.250G > A mutation is the most common EFTDH mutation in riboflavin-responsive MADD (RR-MADD) and is most prevalent in China and South-East Asia where its epidemiology correlates with the distribution and migration patterns of the southern Min population in Southern China and neighbouring countries.
CONCLUSIONS
Mutations in ETFDH should be screened for in individuals with lipid-storage myopathy to identify patients who are responsive to riboflavin. The c.250G > A mutation should be suspected particularly in individuals of southern Min Chinese background.
Topics: Adolescent; Asian People; China; Electron-Transferring Flavoproteins; Female; Genetic Testing; Homozygote; Humans; Iron-Sulfur Proteins; Male; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Mutation; Oxidoreductases Acting on CH-NH Group Donors; Young Adult
PubMed: 31852447
DOI: 10.1186/s12883-019-1562-5 -
Molecular Genetics and Metabolism... Jun 2021In infancy multiple acyl-CoA dehydrogenase deficiency (MADD) is commonly a severe inherited metabolic disease caused by genetic defects in electron transfer flavoprotein...
BACKGROUND
In infancy multiple acyl-CoA dehydrogenase deficiency (MADD) is commonly a severe inherited metabolic disease caused by genetic defects in electron transfer flavoprotein (ETF) or ETF ubiquinone oxidoreductase. Both enzymes require flavin adenine dinucleotide (FAD) as a cofactor. Riboflavin (vitamin B) is a precursor in the synthesis of FAD. MADD can be detected by newborn screening (NBS) based on elevation of multiple acylcarnitines.
METHODS
We present the results of two children whose NBS results and subsequent confirmatory testing resulted in a suspected diagnosis of MADD. In parallel in both children vitamin B deficiency was detected.
RESULTS
Biochemical profiles normalized rapidly in both children under supplementation with riboflavin. After extensive work-up of both cases including molecular genetic studies there was no indication of MADD. Vitamin B deficiency in both children was caused by maternal vitamin B deficiency and was rapidly corrected by oral supplementation with vitamin B or (partial) formula feeding. As both vitamin B and riboflavin have similar food sources we postulate that in these cases positive NBS for MADD was caused by combined maternal vitamin B deficiencies.
CONCLUSION
The differential diagnosis of maternally caused vitamin B deficiencies should be considered in children with abnormal NBS results for MADD, especially in the presence of normal molecular genetic analysis or in case of associated findings of other maternal vitamin B deficiencies like vitamin B or folic acid deficiency.
PubMed: 33732619
DOI: 10.1016/j.ymgmr.2021.100738 -
BMC Genomics Apr 2020Ashbya gossypii naturally overproduces riboflavin and has been utilized for industrial riboflavin production. To improve riboflavin production, various approaches have...
BACKGROUND
Ashbya gossypii naturally overproduces riboflavin and has been utilized for industrial riboflavin production. To improve riboflavin production, various approaches have been developed. In this study, to investigate the change in metabolism of a riboflavin-overproducing mutant, namely, the W122032 strain (MT strain) that was isolated by disparity mutagenesis, genomic analysis was carried out.
RESULTS
In the genomic analysis, 33 homozygous and 1377 heterozygous mutations in the coding sequences of the genome of MT strain were detected. Among these heterozygous mutations, the proportion of mutated reads in each gene was different, ranging from 21 to 75%. These results suggest that the MT strain may contain multiple nuclei containing different mutations. We tried to isolate haploid spores from the MT strain to prove its ploidy, but this strain did not sporulate under the conditions tested. Heterozygous mutations detected in genes which are important for sporulation likely contribute to the sporulation deficiency of the MT strain. Homozygous and heterozygous mutations were found in genes encoding enzymes involved in amino acid metabolism, the TCA cycle, purine and pyrimidine nucleotide metabolism and the DNA mismatch repair system. One homozygous mutation in AgILV2 gene encoding acetohydroxyacid synthase, which is also a flavoprotein in mitochondria, was found. Gene ontology (GO) enrichment analysis showed heterozygous mutations in all 22 DNA helicase genes and genes involved in oxidation-reduction process.
CONCLUSION
This study suggests that oxidative stress and the aging of cells were involved in the riboflavin over-production in A. gossypii riboflavin over-producing mutant and provides new insights into riboflavin production in A. gossypii and the usefulness of disparity mutagenesis for the creation of new types of mutants for metabolic engineering.
Topics: Acetolactate Synthase; Citric Acid Cycle; DNA Mismatch Repair; Eremothecium; Fungal Proteins; Genome, Fungal; Genomics; Genotype; Metabolic Engineering; Mutagenesis; Mutation; Riboflavin
PubMed: 32326906
DOI: 10.1186/s12864-020-6709-7 -
Neurology India 2008Treatment of the genetic metabolic myopathies remains generally unsatisfactory with the exception of a select few. Multiple Acyl Co-A Dehydrogenase Deficiency (Glutaric... (Review)
Review
Treatment of the genetic metabolic myopathies remains generally unsatisfactory with the exception of a select few. Multiple Acyl Co-A Dehydrogenase Deficiency (Glutaric Aciduria type II), in particular, has been shown to respond well to riboflavin supplementation. Recently, studies have also confirmed the effectiveness of recombinant enzyme replacement therapy for Acid Maltase Deficiency (Pompe's Disease). Accurate and early diagnosis of these diseases is vital to prevent serious complications and impaired recovery following delayed treatment.
Topics: Glycogen Storage Disease Type II; Humans; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Recombinant Proteins; Riboflavin; Vitamin B Complex; alpha-Glucosidases
PubMed: 18974560
DOI: 10.4103/0028-3886.43452 -
Nutrients May 2019Taiwanese women may practice traditional confinement after childbirth, and no study has investigated the nutritional status and the effects of postpartum depression on...
Taiwanese women may practice traditional confinement after childbirth, and no study has investigated the nutritional status and the effects of postpartum depression on such women. The aim of this study was to investigate the association between nutritional status and postpartum depression at 6-8 weeks postpartum. A cross-sectional study was conducted on postpartum women who returned to the obstetrics and gynecology clinic for routine examination from January 2016 to September 2017. A total of 344 women received assessments based on the Edinburgh Postnatal Depression Scale (EPDS). An EPDS score of ≥10 indicated the presence of postpartum depressive symptoms (PPDS). A total of 97 women without such symptoms and 23 with PPDS completed nutritional parameter analyses and questionnaires. The results showed that the prevalence of postpartum depression (PPD) was 8.4%. The proportion was 70% for those who practiced confinement at home, significantly higher than for those in the non-PPDS group (45%). The overall psychological stress score was significantly higher and the postpartum care satisfaction score was significantly lower in those with PPDS compared to those without. In terms of nutritional biomarkers, the plasma riboflavin levels in the PPDS group were significantly lower than those in their symptomless counterparts (13.9%). The vitamin D insufficiency and deficiency rates in the non-PPD and PPDS groups were 35%, 41%, 48%, 26%, respectively. However, compared with those in the non-PPDS group, those with PPDS had significantly higher ratios of Σn-6/Σn-3, C20:3n-6/C18:3n-6, and C20:4n-6/(C20:5n-3 + C22:6n-3) (by 8.2%, 79.7%, and 8.8%, respectively), whereas they had lower ratios of C22:6n-3/C22:5n-6 (by 15.5%). Higher plasma riboflavin and erythrocyte C16:1n-9, C24:1n-9, C18:3n-6, and C20:5n-3 levels and lower Σn-6 fatty acid and C22:5n-6 levels decreased the risk of PPD after type of confinement, overall mental stress scores, and postpartum care satisfaction scores were adjusted for the logistic regression analysis. In conclusion, the plasma riboflavin level and erythrocyte fatty acid composition are potentially major contributors to PPD development.
Topics: Adult; Affect; Biomarkers; Cross-Sectional Studies; Depression, Postpartum; Erythrocytes; Fatty Acids; Female; Humans; Maternal Nutritional Physiological Phenomena; Nutritional Status; Postpartum Period; Pregnancy; Prevalence; Riboflavin; Risk Factors; Taiwan
PubMed: 31141947
DOI: 10.3390/nu11061204 -
Journal of Plant Physiology Jul 2010Hyoscyamus albus hairy roots secrete riboflavin under Fe-deficient conditions. To determine whether this secretion was linked to an enhancement of respiration, both...
Hyoscyamus albus hairy roots secrete riboflavin under Fe-deficient conditions. To determine whether this secretion was linked to an enhancement of respiration, both riboflavin secretion and the reduction of 2,3,5-triphenyltetrazolium chloride (TTC), as a measure of respiration activity, were determined in hairy roots cultured under Fe-deficient and Fe-replete conditions, with or without aeration. Appreciable TTC-reducing activity was detected at the root tips, at the bases of lateral roots and in internal tissues, notably the vascular system. TTC-reducing activity increased under Fe deficiency and this increase occurred in concert with riboflavin secretion and was more apparent under aeration. Riboflavin secretion was not apparent under Fe-replete conditions. In order to examine which elements of the mitochondrial electron transport chain might be involved, the effects of the respiratory inhibitors, barbiturate, dicoumarol, malonic acid, antimycin, KCN and salicylhydroxamic acid (SHAM) were investigated. Under Fe-deficient conditions, malonic acid affected neither root growth, TTC-reducing activity nor riboflavin secretion, whereas barbiturate and SHAM inhibited only root growth and TTC-reducing activity, respectively, and the other compounds variously inhibited growth and TTC-reducing activity. Riboflavin secretion was decreased, in concert with TTC-reducing activity, by dicoumarol, antimycin and KCN, but not by SHAM. In Fe-replete roots, all inhibitors which reduced riboflavin secretion in Fe-deficient roots showed somewhat different effects: notably, antimycin and KCN did not significantly inhibit TTC-reducing activity and the inhibition by dicoumarol was much weaker in Fe-replete roots. Combined treatment with KCN and SHAM also revealed that Fe-deficient and Fe-replete roots reduced TTC in different ways. A decrease in the Fe content of mitochondria in Fe-deficient roots was confirmed. Overall, the results suggest that, under conditions of Fe deficiency in H. albus hairy roots, the alternative NAD(P)H dehydrogenases, complex III and complex IV, but not the alternative oxidase, are actively involved both in respiration and in riboflavin secretion.
Topics: Antimycin A; Barbiturates; Cyanates; Dicumarol; Electron Transport; Hyoscyamus; Iron Deficiencies; Malonates; Plant Roots; Riboflavin; Salicylamides
PubMed: 20181408
DOI: 10.1016/j.jplph.2010.01.011 -
BMJ Case Reports Jan 2022Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive inherited inborn error of metabolism, which presents with various severity depending...
Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive inherited inborn error of metabolism, which presents with various severity depending on the level of residual enzyme activity. In neonates, it can present with recurrent hypoventilation episodes, persistent encephalopathy with or without microcephaly. MTHFR deficiency also results in hyperhomocysteinemia, homocystinuria and hypomethionemia. We report a male neonate with severe MTHFR deficiency presenting to us on third week of life with progressive encephalopathy, microcephaly, seizures, central hypoventilation. There was similar history in the previous sibling. The patient's blood lactate, ammonia, tandem mass spectrometry for amino acids and acyl carnitine were normal. He remained encephalopathic with progressive increase in need of respiratory support in spite of supportive treatment and metabolic cocktail consisting of riboflavin, pyridoxine, coenzyme Q and carnitine. This neonate had novel homozygous mutation, which results in MTHFR deficiency. In newborn with hypoventilation or recurrent apnoea with encephalopathy and microcephaly, MTHFR deficiency should be considered as a differential diagnosis. Mutation study helps in confirming diagnosis; however, extended newborn metabolic screening with homocysteine level could help in early diagnosis of these cases.
Topics: Homocystinuria; Humans; Hypoventilation; Infant, Newborn; Male; Methylenetetrahydrofolate Reductase (NADPH2); Muscle Spasticity; Psychotic Disorders
PubMed: 34983810
DOI: 10.1136/bcr-2021-246431