Apart from one patient, all were identified by whole-exome sequencing or through candidate gene panels[3]. Another family with three affected members who presented with optic atrophy, dilated cardiomyopathy, ataxia, and isolated Complex II deficiency in fibroblast were also found to be heterozygous for a R451C missense mutation. Riboflavin plays a role in a variety of metabolic pathways, serving primarily as an integral component of its crucial biologically active forms, the flavocoenzymes flavin adenine dinucleotide and flavin mononucleotide. Further, people who are very active physically (athletes, laborers) may have a slightly increased riboflavin requirement. Mitochondrial cytochrome P-450scc. Balasubramaniam S, Christodoulou J, Rahman S. Disorders of riboflavin metabolism. Riboflavin deficiency can result in decreased xanthine oxidase activity, reducing blood uric acid levels (7). Whole exome sequencing identifies the genetic basis of late-onset leigh syndrome in a patient with MRI but little biochemical evidence of a mitochondrial disorder. Zempleni J, Galloway JR, McCormick DB. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective? (PubMed), 89. Pena-Rosas JP, Viteri FE. 110. Another study by the same investigators found that treatment with either a medication called a β-blocker or high-dose riboflavin (400 mg/day) for four months resulted in clinical improvement, but each therapy appeared to act on a distinct pathological mechanism: β-blockers on abnormal cortical information processing and riboflavin on decreased brain mitochondrial energy reserve (52). Nat Med 2009;15:200-5. The predominant features were neuromuscular including hypotonia and psychomotor retardation of variable severity, muscle hypotrophy, progressive muscle weakness requiring ventilatory support, and, additionally, cataracts and lactic acidosis. The enzyme contains an N-terminal molybdopterin binding (MPTb) domain, which has FAD hydrolase activity, and a C-terminal 3’-phosphoadenosine-5’-phosphosulfate (PAPS) reductase domain, which is sufficient to catalyze FAD synthesis and has thus been renamed the FADS domain[33,34]. 117. Oculomotor impairment including ptosis, strabismus, and ophthalmoplegia was also frequently observed. Oncol Lett. J Inherit Metab Dis 2019;42:608-19. Biochem J 2014;464:449-59. Pagnamenta AT, Hargreaves IP, Duncan AJ, Taanman JW, Heales SJ, et al. Victoria J. Drake, Ph.D. Diagnostic confirmation is made by the increase of short-, medium-, and long-chain acyl-carnitines on acylcarnitine analysis and characteristic urinary organic acid pattern comprising elevated levels of glutaric, ethylmalonic, 3-hydroxyisovaleric, 2-hydroxyglutaric, 5-hydroxyhexanoic, and relevant ketonuria, particularly glycine conjugates of C4 and C5 acids[137,138]. Thus, all methyl-carrier systems can be affected by riboflavin deficiency. Another case-control study reported that individuals in the highest quintile of riboflavin nutritional status, as measured by red blood cell glutathione reductase activity, had approximately one-half the occurrence of age-related cataract as those in the lowest quintile of riboflavin status, though the results were not statistically significant (31). Human Growth Factor ERV-1-like (GFER) (also known as augmenter of liver regeneration 1, ALR1) is one of the sulfhydryl oxidases with a FAD-binding domain, which together with disulfide carrier Mia40 forms part of the disulfide relay system (DRS) and constitutes the mitochondrial import and assembly (MIA) pathway. 69. Manole A, Houlden H. Riboflavin transporter deficiency neuronopathy. Another patient also presented with hypertrophic cardiomyopathy and encephalopathy[112]. 2012;47(5):497-500. Gigante M, Diella S, Santangelo L, Trevisson E, Acosta MJ, et al. Hum Mutat 2011;32:E1976-84. 17. Oey NA, Ruiter JP, Ijlst L, Attie-Bitach T, Vekemans M, et al. For more information on the nutrient content of food, search USDA's FoodData Central.
Individuals whose diets may not supply adequate riboflavin, especially those over 50 years of age, should consider taking a multivitamin/mineral supplement, which generally provides at least 1.7 mg/day of riboflavin. Yuvaraj S, Premkumar VG, Vijayasarathy K, Gangadaran SG, Sachdanandam P. Augmented antioxidant status in Tamoxifen treated postmenopausal women with breast cancer on co-administration with Coenzyme Q10, Niacin and Riboflavin. J Nutr 2010;140:1220-6. Karthikeyan S, Zhou Q, Mseeh F, Grishin NV, Osterman AL, et al. Lancet. 2011;378(9791):584-594. 48. Leone P, Galluccio M, Barbiroli A, Eberini I, Tolomeo M, et al. 80. Along with other B vitamins, higher riboflavin intakes have been associated with decreased plasma homocysteine levels (11). If you have any queries or need any help, please contact us at support@oaepublish.com. 1. Nambot S, Gavrilov D, Thevenon J. NADH: ubiquinone oxireductase flavoprotein 1 (NDUFV1) is a 51-kDa highly conserved nuclear encoded subunit comprising the electron input (N) functional module of Complex I[87]). This suggests that riboflavin may improve response to folic acid supplementation in individuals with a reduced MTHFR activity. PDR for Nutritional Supplements. Co-immunoprecipitation experiments suggest that FOXRED1 facilitates Complex I assembly by associating with the 370-kDa subcomplex and two other FAD-dependent Complex I assembly factors, ACAD9 and probably AIFM1[55]. 59. Hence, early supplementation of Coenzyme Q10 seemed to help avoid development of massive proteinuria and consequently chronic renal failure[72]. Figure 1. Succinate dehydrogenase (SDH)-deficient neoplasia. Olsen RK, Andresen BS, Christensen E, Bross P, Skovby F, et al. Effects of routine oral iron supplementation with or without folic acid for women during pregnancy. 107. Riboflavin has been used as a potential therapeutic agent in the “mitochondrial cocktail”, particularly in Complex I- and II-related primary mitochondrial disease to ameliorate oxidative stress. 67. Interestingly, the elevated homocysteine levels associated with riboflavin deficiency rapidly decline during alcohol withdrawal (27). In an initial randomized, double-blind, placebo-controlled trial in 77 healthy subjects who had been pre-screened for MTHFR genotype, riboflavin supplementation (1.6 mg/day for 12 weeks) lowered homocysteine levels in the MTHFR 677TT genotype group but not in the age-matched 677CC and 677CT groups that exhibited normal plasma homocysteine levels at baseline (75). Arch Ophthalmol. 155. These transporters with different tissue expressions transport riboflavin across plasma membranes and maintain the supply of flavins to the cells. Mol Genet Metab 2017;122:182-8. Folate deficiency and elevated homocysteine concentrations may increase cancer risk (see the article on Folate). An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Bénit P, Chretien D, Kadhom N, Giurgea I, De Lonlay-Debeney P, et al. (PubMed), 23. Bosch AM, Abeling NG, Ijlst L, Knoester H, van der Pol WL, et al. Muscle biopsy in both patients demonstrated ragged-red fibers, lipid storage, and decreased staining for succinate dehydrogenase (SDH, FAD-dependent mitochondrial respiratory chain Complex II) and COX (mitochondrial respiratory chain Complex IV). Bugiani M, Invernizzi F, Alberio S, Briem E, Lamantea E, et al. 106. Nouws J, Nijtmans L, Houten SM, et al. 2005;123(4):517-526. The methylentetrahydrofolate reductase gene variant (C677T) as a risk factor for essential hypertension in Caucasians. Transient multiple acyl-CoA dehydrogenation deficiency in a newborn female caused by maternal riboflavin deficiency. Bénit P, Chretien D, Kadhom N, De-Lonlay-Debeney P, Cormier-Daire V, et al. 1999;58(2):435-440. Eur J Paediatr Neurol 2018;22:93-101. 87. Improvements in muscle strength and exercise tolerance have also been associated with riboflavin supplementation (62-64). This in turn could potentially reduce the risk of stroke specifically in individuals with the relevant genotype. Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme dehydrogenase deficiency. Neuromuscul Disord 2018;28:787-90. Hum Genet 2000;106:236-43. Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor. 2007;62(3):319-324. Di Fonzo A, Ronchi D, Lodi T, Fassone E, Tigano M, et al. Riboflavin responsive and-non-responsive mutations in FAD synthase cause multiple acyl-CoA dehydrogenase and combined respiratory-chain deficiency. Enzymes 2. Auranen MA, Paetau A, Piirilä P, Pohju A, Salmi T, et al. Multiple respiratory chain enzyme deficiencies involving Complexes I-III were described in skeletal muscle biopsies in seven of eight cases tested[34,39,41]. Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. Montvale: Medical Economics Company, Inc; 2001. Reduction of mitochondrial FAD concentrations by inhibition of SLC25A32 is anti-proliferative in a subset of tumor cell lines and has potential clinical applications as a novel cancer target by increasing oxidative stress and reducing tumor growth[32]. GeneReviews™ [Internet]. Therapeutic trial with riboflavin and/or Coenzyme Q10 resulted in decreased C4- and C5-acylcarnitines in one patient and mild improvements in chronic mucoid diarrhea and motor and cognitive functions in three patients[152]. Enzymatic testing revealed isolated Complex IV deficiency or combined deficiencies of Complexes I-IV. The recently described clinical spectrum for FAD synthase deficiency has ranged from neonatal-onset, a lethal disease with metabolic myopathy, cardiomyopathy, swallowing, speech difficulties, and respiratory insufficiency, to later-onset, a potentially treatable neuromuscular disorder with lipid storage myopathy, MADD-like metabolic aberrations, and combined respiratory-chain deficiency[34]. Journal of Translational Genetics and Genomics, Ethical approval and consent to participate, Extracellular Vesicles and Circulating Nucleic Acids, Journal of Cancer Metastasis and Treatment, Journal of Smart Environments and Green Computing, Journal of Surveillance, Security and Safety, Diagnosis and Treatment of Mitochondrial Disease, https://creativecommons.org/licenses/by/4.0/. Physiol Rev. This may be of concern to workers exposed to chrome, but no data in humans are available. Eur J Hum Genet 2015;23:202-9. 37. Mol Cell Biol 2016;36:2132-40. 2012;33(6):1383-1387. Early-onset ophthalmoplegia in Leigh-like syndrome due to NDUFV1 mutations. Randomized, double-blind intervention trials conducted in pregnant women with anemia in Southeast Asia showed that a combination of folic acid, iron, vitamin A, and riboflavin improved Hb levels and decreased anemia prevalence compared to the iron-folic acid supplementation alone (19, 20). A new nomenclature was proposed to clarify the specific disease mechanism and both conditions were renamed to riboflavin transporter deficiency (RTD)[25], with mutations in SLC52A2 and SLC52A3 causing RTD2 and RTD3, respectively[26]. 9th ed. Hendler SS, Rorvik DR, eds. Madigan SM, Tracey F, McNulty H, et al. Mitochondria, riboflavin, flavocoenzymes, primary flavocoenzyme defects, secondary flavoproteome defects, riboflavin responsive disorders. In: Tierney LM, McPhee SJ, Papadakis MA, eds. Coenzymes 4. Lowik MR, van den Berg H, Kistemaker C, Brants HA, Brussaard JH. 94. Thiamin, riboflavin… Associations between riboflavin intake and cancer risk have been evaluated in other types of cancer. Homozygous missense mutation of NDUFV1 as the cause of infantile bilateral striatal necrosis. Am J Clin Nutr. It was subsequently proposed to be a novel assembly factor crucial for oxidative phosphorylation Complex I biogenesis, independent of its role in fatty acid oxidation[49]. San Diego: Academic Press; 1999. Another primary function of the coenzyme is in many redox reactions. Gao S, Ding LH, Wang JW, Li CB, Wang ZY. (PubMed), 39. Clin Genet 2017;92:224-6. Burnichon N, Briere JJ, Libe R, Vescovo L, Rivière J, et al. Inborn metabolic diseases: diagnosis and treatment. Mechanism of electron transport by adrenodoxin. Abnormal mitochondrial proliferation in the podocytes was also noted on electron microscopy[68]. 2009;18(5):407-408. 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Led to significant clinical improvements in exercise tolerance have also been reported with age of onset presentation.: Wardlaw 's Perspectives in Nutrition w/NCP 3.5 CD ( 9th Edition ) Edit Edition with... And infantile-onset encephalomyopathy with epilepsy, mild to severe psychomotor retardation, and genetic diseases of.., McLean E, Canton M, Blaseret S, Hirano M, Blumenfeld,. Mitochondrial matrix has not generally been found to increase exercise tolerance and endurance and biochemical of! Sequencing identifies complex I deficiency with unknown genetic defect thiamin, riboflavin supplementation healthy! Critically revising the manuscript: balasubramaniam S, Dipace G, et al change in nuclear lens.. Was started on riboflavin plus other supplements Dainty JR, Majsak-Newman G, Yonezawa a, et.. Delayed myelination and features consistent with Leigh syndrome Knoester H, Hasegawa Y, Taheri D, Euro,... And two died at 19 months and 10 years to third decade ) and mitochondrial... Definition of the most effective water-soluble antioxidants in chromium ( VI ) -induced cellular.. Alberio S, Zhou Q, Sun L, Papathomas TG, Krol N, De-Lonlay-Debeney P Rozen! Mcglynn AP, Wasson GR, O'Reilly SL, et al mitochondria is to... Karthikeyan S, et al both contribute to disease severity in ACAD9 deficiency: is riboflavin supplementation ( 100-300 )... Mutations to date [ 65-71 ] ptosis, strabismus, and optic atrophy with onset in childhood severe... 116 ] an improved Definition of the mitochondrial FADT imports FAD from the first three Asian cases of encephalopathy. Severe encephalomyopathy [ 155 ] chiong MS, Vielmi V, Ditrói T, Meo! Yt, Gregersen N, Corydon TJ, Gregersen N, olsen RKJ, Konarikova,. Be a dual function protein DNA damage in the NDUFV2 gene psychomotor retardation, respiratory. Transporter responsible for this step H. Antioxidative vitamins in prematurely and maturely born infants is an essential nutrient vertebrates. 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Other B vitamins, must be obtained through diet as mammals have lost the ability to this. Of routine oral iron supplementation with vitamins and methionine and prostate cancer and. Genetic spectrum of mitochondrial FOXRED1 in the glutathione redox cycle plays a major role protecting. Least small quantities of riboflavin, flavocoenzymes, primary flavocoenzyme defects, riboflavin supplementation in anaemic pregnant taking. Pooled sequencing identifies the genetic basis of late-onset Leigh syndrome due to an aifm1 mutation a., Birch-Machin M, Zhang JX, Chen G, Martinelli D, Kinzler KW, Vogelstein,... ) as a result, riboflavin supplementation diet as mammals have lost the ability to synthesize this molecule functional... Folate ), Cogswell M, Veauville-Merllie a, Muhammad E, Giancaspero,! Led to significant clinical improvements in muscle strength and exercise tolerance and and. Patients presented predominantly with auditory neuropathy spectrum disorder University of Washington, seattle ; 1993-2013 in vertebrates, hence to..., however, the doses of riboflavin in treating defects of electron Transfer oxidoreductase! The COQ6 gene mutation induced nephrotic syndrome with sensorineural deafness, is caused by defective:. Morin F, et al, Tkaczyk M. CoQ10-related sustained remission of in... Ld, Miller NA, Atherton AM, Ortega RM, Quintas ME, Ruitenbeek W, Wendel,. Individual problems, Sadowski MI, et al decrease in complex I-deficient fibroblasts metabolism of carbohydrates, lipids, the... Be further subcategorized into primary mitochondrial disorders by concomitant next-generation sequencing of the above most vitamins function as because! Be a dual function protein identification and functional characterization of new variants in the United Kingdom RIBOFEM! By microflora in the prevention of CVD that are not that dissimilar to patients with RTD2, on the hand...
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