the riboflavin coenzymes have functions in cellular metabolism

61. Homocysteine, cysteine, and related metabolites in maternal and fetal plasma in preeclampsia. The first report of a nuclear gene mutation causing a mitochondrial respiratory chain deficiency in humans was identified in two sisters presenting with developmental regression at 10 months of age, pyramidal tract signs, leukodystrophy with early demise, Complex II deficiency, and homozygous mutations (R554W) in the SDHA gene[122,123]. Oregon State University, Reviewed in December 2013 by:  If you have any queries or need any help, please contact us at support@oaepublish.com. ATP. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 69. 21. 1995;54(2):509-517. J Med Genet. At baseline, 60% of participants had failed to achieve target BP levels (≤140/90 mm Hg), despite taking three or more antihypertensive medications. Additionally, chronic alcohol consumption has been associated with riboflavin deficiency. Lemire BD. 95. Natural disease course and genotype-phenotype correlations in Complex I deficiency caused by nuclear gene defects: what we learned from 130 cases. Bihlmaier K, Mesecke N, Terziyska N, Bien M, Hell K, et al. A defect in fatty acid β-oxidation causes lipid accumulation in skeletal muscles, leading to lipid storage myopathy characterized by muscle pain and weakness and exercise intolerance. Other tumors such as paraganglioma/pheochromocytoma, pituitary adenoma, and renal carcinoma have also demonstrated SDHA germline mutations[117-121]. Urinary thiosulfate is also markedly elevated[149]. (PubMed), 45. Riboflavin (Vitamin B 2) Riboflavin is a water-soluble vitamin that is an essential component of flavoproteins, which are coenzymes involved in many metabolic pathways of carbohydrate, lipid, and protein metabolism. APCs [111] 2003 reported three affected siblings in a consanguineous family presenting with early onset hypertrophic cardiomyopathy, truncal hypotonia, feeding difficulties, growth retardation, and early death within the first year of life. Post-mortem detection of FLAD1 mutations in 2 Turkish siblings with hypotonia in early infancy. 20. 76. Powers HJ. Mitochondrion 2015;21:33-40. 129. J Inherit Metab Dis 2001;24:870-3. Figure 2. (PubMed), 34. 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]. Vitamin B 2 (riboflavin). 2005;123(4):517-526. J Cell Biol 2007;179:389-95. Proc Nutr Soc. Riboflavin is a key component of the mitochondrial respiratory chain (RC), hence is pivotal for ATP generation and sustaining energy-dependent cellular functions. (PubMed), 80. Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene. The X-linked AIFM1 gene encodes the apoptosis-inducing factor (AIF), a mitochondrial flavoprotein with a dual role, first as a FAD-dependent NADH oxidoreductase and second as a caspase-independent death effector which regulates apoptosis[153,154]. A possible genotype-phenotype correlation has been proposed with homozygous carriers of frameshift variants affecting the MPTb domain displaying a more severe clinical course than that observed in individuals harboring single amino acid changes in the FADS domain that are potentially more responsive to riboflavin therapy[34]. 1. 72. Enzymatic testing revealed isolated Complex IV deficiency or combined deficiencies of Complexes I-IV. Mitochondrial membrane associated FDXR reduces the ferredoxins, FDX1 and FDX2, and transfers electrons from NADPH to the mitochondrial cytochrome P450 system, thus initiating the mitochondrial electron transport chain reaction[83]. J Neurol Neurosurg Psychiatry 2006;77:74-6. 37. Tiranti V, Viscomi C, Hildebrandt T, Di Meo I, Mineri R, et al. Two randomized, double-blind, placebo-controlled trials investigated the effect of riboflavin supplementation on the frequency and severity of headache attacks in children with migraines. The latter occurs through dietary protein denaturation in the stomach and subsequent hydrolysis to free riboflavin by alkaline phosphatases and FMN/FAD pyrophosphatases in the ileal brush border to be absorbed in the small intestine[6][Figure 1]. Riboflavin deficiency alters iron metabolism. Mol Genet Genomic Med 2019;7:e915. (PubMed), 87. The Metabolic and Molecular Bases of Inherited Disease. Hum Mutat 2011;32:E1976-84. 2009;89(6):1960S-1980S. A clear improvement of ataxia by 44% and 20% was observed in two patients, respectively, as measured by the ICARS score, an objective assessment that quantifies the magnitude of improvement in progressive ataxias, with a score of 5%-20% considered as substantial in providing a clinical impact. 83. Yuruk Yildirim Z, Toksoy G, Uyguner O, Nayir A, Yavuz S, et al. J Inherit Metab Dis 2016;39:545-57. Riboflavin deficiency or defects in the production of its flavocoenzymes FAD and FMN can lead to disruption of the RC, consequently mitochondrial dysfunction, and increased production of ROS, overwhelming the cellular antioxidant mechanisms. 2012;23(6):855-863. (PubMed), 25. Powers HJ, Hill MH, Mushtaq S, Dainty JR, Majsak-Newman G, Williams EA. Most patients (92%) have however presented in infancy, with five out of thirteen dying within the first twelve months of life. 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. Brandt U. Oregon State University, Updated in June 2007 by:  The benefits of early diagnosis and treatment is exemplified by the fatal outcome of the untreated brother of an older sister who responded to riboflavin[34]. Olsen RKJ, Konarikova E, Giancaspero TA, Mosegaard S, Boczonadi V, et al. University of Ulster  Dinwiddie DL, Smith LD, Miller NA, Atherton AM, Farrow EG, et al. Maizels M, Blumenfeld A, Burchette R. A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial. 2012;7:83. doi: 10.1186/1750-1172-7-83. Mol Genet Metab 2007;92:109-14. FMO3 gene mutations are usually associated with mild or intermittent trimethylaminuria; the condition is sometimes limited to peri-menstrual periods in female subjects or to the consumption of trimethylamine-rich food. The OXPHOS system is a 5-enzyme complex which encompasses the mitochondrial respiratory chain (Complexes I-IV), Complex V, and two mobile electron shuttles (coenzyme Q10 and cytochrome c). Powers HJ. (PubMed), 46. Int J Gynaecol Obstet. Clinical signs of deficiency in humans appear at intakes of less than 0.5-0.6 milligrams (mg)/day, and urinary excretion of riboflavin is seen at intake levels of approximately 1 mg/day (1). 48. Leigh or Leigh-like syndrome was a common phenotype. Eur J Hum Genet 2010;18:1160-5. ETFDH mutations, CoQ10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Plasma homocysteine is responsive to the lowering effects of interventions with folate and metabolically related B vitamins, including riboflavin. It is the sole ferredoxin reductase in humans and has important roles in iron-sulfur (Fe-S) cluster biogenesis and heme synthesis[82]. Yin G, Ming H, Zheng X, Xuan Y, Liang J, Jin X. Methylenetetrahydrofolate reductase C677T gene polymorphism and colorectal cancer risk: A case-control study. Neuromuscul Disord. Contact Us Energy converting NADH: quinone oxidoreductase (complex I). 2010;30(12):1426-1434. Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy. In: GeneReviews® [Internet]. RFK (EC 2.7.1.26) is a ubiquitous rate-limiting enzyme that catalyzes the first step in flavocoenzyme biosynthesis by phosphorylating riboflavin to form FMN, an obligatory step in riboflavin metabolism. Molecular characterization of mitochondrial apoptosis-inducing factor. Stamford: Appleton and Lange; 1998:731-734. 123. However, a 10-year follow up of an intervention trial in patients at high risk for gastric (stomach) cancer found that dietary supplementation with minerals and vitamins, including riboflavin (3.2 mg/day) and niacin (40 mg/day), for five years failed to decrease the incidence or mortality rate of gastric cancer (50). In 2011, Heeringa et al. A prospective study of more than 50,000 women did not observe a difference between rates of cataract extraction between women in the highest quintile of riboflavin intake (median of 1.5 mg/day) and women in the lowest quintile (median of 1.2 mg/day) (33). 2013;24(8):1555-1563. MR spectroscopy and serial magnetic resonance imaging in a patient with mitochondrial cystic leukoencephalopathy due to complex I deficiency and NDUFV1 mutations and mild clinical course. Mosegaard S, Dipace G, Bross P, Carlsen J, Gregersen N, et al. Asian Pac J Cancer Prev. In rats chronically fed alcohol, the inhibition of riboflavin transporters caused impairment in intestinal absorption and renal re-uptake of the vitamin (84). It is also one of the subunits comprising the electron input (N) functional module of Complex I[87]. Chiong MA, Sim KG, Carpenter K, et al. They help the body metabolize carbohydrates, proteins and fats and build DNA for new cells. Riboflavin 2. Levitas A, Muhammad E, Harel G, Saada A, Caspi VC, et al. Baltimore: Williams & Wilkins; 1999:391-399. Riboflavin lowers blood pressure in cardiovascular disease patients homozygous for the 677C→T polymorphism in MTHFR. 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 DLD gene encodes dihydrolipoamide dehydrogenase (also known as E3), a common flavoprotein shared by three mitochondrial α-ketoacid dehydrogenase multi-enzyme complexes: pyruvate dehydrogenase complex (PDHC), α-ketoglutarate dehydrogenase complex, and branched-chain α-keto acid dehydrogenase complex. Brain Dev 1992;14:404-8. Lowik MR, van den Berg H, Kistemaker C, Brants HA, Brussaard JH. 146. MADD is caused by deficiency of one of the two electron-transfer flavoproteins which transfer electrons from acyl-CoA dehydrogenases to Coenzyme Q in the respiratory chain: Electron Transfer Flavoprotein (ETF), encoded by ETFA and ETFB genes, and electron-transfer flavoprotein dehydrogenase (ETFDH), encoded by ETFDH[136]. Hoey L, McNulty H, Strain JJ. 24. It is possible that defects in RFK may be incompatible with life due to its critical role noted above. 68. Repp BM, Mastantuono E, Alston CL, Schiff M, Haack TB, et al. 161-74. Question 5 2 / 2 points What is the function of the vitamin pyridoxine (vitamin B6)? [79] (2010) also characterized the human GFER/ALR protein and demonstrated that the R194H led to marked loss of protein stability by an increased rate of FAD dissociation and enhanced proteolysis susceptibility with only minimal effect on enzymatic activity. A mutation in the flavin adenine dinucleotide-dependent oxidoreductase FOXRED1 results in cell-type-specific assembly defects in oxidative phosphorylation complexes I and II. Severe riboflavin deficiency can decrease the conversion of tryptophan to NAD and NADP, increasing the risk of niacin deficiency (3). Along with other B vitamins, higher riboflavin intakes have been associated with decreased plasma homocysteine levels (11). Typical Leigh syndrome[88,107]and late-onset Leigh syndrome have been reported[95,103]. They are critical for the metabolism of carbohydrates, lipids, and proteins. Nouws J, Te Brinke H, Nijtmans LG, Houten SM. Coleraine, United Kingdom, Reviewed in December 2013 by:  Yaplito-Lee J. Riboflavin metabolism: role in mitochondrial function. Crystal structure of human riboflavin kinase reveals a beta barrel fold and a novel active site arch. Riboflavin acts as a cofactor for MTHFR and is therefore needed to generate 5-methyltetrahydrofolate required in the remethylation of homocysteine to methionine (see Figure 2 above). Primary trimethylaminuria is caused by defective oxidation of trimethylamine by a liver flavoprotein called flavin containing monooxygenase 3 (FMO3). Mol Genet Metab 2009;96:196-200. Dietary intakes however were generally found to compare favorably with recommended values, except in young women who had low intakes. Li GM, Cao Q, Shen Q, Sun L, Zhai YH, et al. Lienhart WD, Gudipati V, Macheroux P. The human flavoproteome. Although several ... Oxidative Metabolism in Riboflavin Deficiency then isolated from the supernatant … (PubMed), 11. JIMD Rep. 2012;5:71-75. 69. Mutations in the NDUFV1 gene causing Complex I deficiency have been identified in 41 patients in 33 families[56,88-110]. Frerman FE, Goodman SI. Evenepoel L, Papathomas TG, Krol N, Korpershoek E, de Krijger RR, et al. 2013;11(2):65-74. 2011;32(1):33-43. Riboflavin, as with other water-soluble B vitamins, must be obtained through diet as mammals have lost the ability to synthesize this molecule. Originally written in 2000 by:  Cellular consequences of oxidative stress in riboflavin responsive multiple acyl-CoA dehydrogenation deficiency patient fibroblasts. (PubMed), 66. 2013;143(1):27-33. Hum Mutat 2000;15:123-34. All these perturbations are implicated in mitochondrial dysfunction, hence strategies to mitigate this may pose an important therapeutic avenue. Pharmacokinetics of orally and intravenously administered riboflavin in healthy humans. Long-term nutrient intake and 5-year change in nuclear lens opacities. Riboflavin status and histopathologic findings (percent normal, dysplastic, and cancerous tissues) improved in the intervention group compared to the control group, but the lower incidence of esophageal cancer found in the intervention group was not statistically significant (46). (PubMed), 14. Such results illustrate that chronic disease risk may be influenced by complex interactions between genetic and dietary factors (see Cardiovascular disease and Cancer). Hum Mol Genet 2010;19:4837-47. Obstetrics. Vascular lesions include diffuse and spontaneous relapsing petechial purpura, orthostatic acrocyanosis, hemorrhagic suffusions of mesothelial surfaces, and intestinal mucosa associated with chronic hemorrhagic diarrhea[148]. Nat Rev Mol Cell Biol 2017;19:77-92. Conversion of most naturally available vitamin B6 to its coenzyme form, pyridoxal 5'-phosphate (PLP), requires the FMN-dependent enzyme, pyridoxine 5'-phosphate oxidase (PPO) (8). Folate deficiency and elevated homocysteine concentrations may increase cancer risk (see the article on Folate). Riboflavin offers a targeted strategy for managing hypertension in patients with the MTHFR 677TT genotype: a 4-y follow-up. Clin Genet 2017;92:188-98. (PubMed), 71. Heese P, Linnebank M, Semmler A, et al. To date, there have been no reported human phenotypes of RFK deficiency. Nat Genet 1995;11:144-9. Coenzymes 4. Gene mutation analysis in 12 Chinese children with congenital nephrotic syndrome. Chastain JL, McCormick DB. 116. J Biol Chem 1980;255:3057-61. Am J Clin Nutr 1987;46:830-4. Plants and some micro-organisms can synthesise riboflavin; however, it is an essential nutrient for human health and … Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme dehydrogenase deficiency. Hum Mol Genet 2014;23:1311-9. (in Chinese). MRI of the brain showed normal findings (4/6), cerebellar and moderate cortical atrophy (1/6), and thin corpus callosum (1/6). Flavoproteins aid in the transfer of … Flavoproteins are involved in the metabolism of several other vitamins: (vitamin B6, niacin, and folate). Disorders of mitochondrial fatty acid oxidation and Related Metabolic Pathways. 2001. 46. (PubMed), 78. It also increases ACAD9 protein levels and rescues Complex I assembly, while also functioning as a chemical chaperone by improving folding of ACAD9 mutant proteins[49]. The predominant clinical features were hearing loss and muscle weakness. (PubMed). coenzymes! Siblings with leukoencephalopathy. These findings corroborate evidence of decreased Complex II protein levels and OXPHOS activity, which is a marker for mitochondrial FAD in muscle of patients with severe neuromuscular phenotype and novel variants in SLC25A32[30,31]. Riboflavin responsive and-non-responsive mutations in FAD synthase cause multiple acyl-CoA dehydrogenase and combined respiratory-chain deficiency. 39. 2012;33(6):1383-1387. The most frequent clinical presentation is the milder myopathic Type III form, which manifests with fluctuating proximal and axial myopathy with exercise intolerance and occasionally respiratory insufficiency[138] or rhabdomyolysis, although often with hepatomegaly, encephalopathy, and episodic lethargy, as well as vomiting and hypoglycemia often triggered by metabolic stress, episodes of which have been lethal in 5% of patients[140]. Riboflavin was significantly better than placebo in reducing attack frequency and the number of headache days, though the beneficial effect was most pronounced during the third month of treatment. J Transl Me 2016;14:174. Br J Nutr. (PubMed), 55. J Child Neurol 2016;31:190-4. (PubMed), 36. Two interconnected B vitamins: riboflavin and pyridoxine. Di Meo I, Lamperti C, Tiranti V. Mitochondrial diseases caused by toxic compound accumulation: from etiopathology to therapeutic approaches. Multiple acyl-coenzyme A dehydrogenase deficiency, also known as glutaric aciduria Type II (GAII), is an autosomal recessive disorder that affects the oxidation of fatty acids, BCAA, lysine, tryptophan, and choline. 138. Eur J Paediatr Neurol 2018;22:93-101. 158. (PubMed), 84. Succinate dehydrogenase (SDH)-deficient neoplasia. The specific type of the mutation in ETF/ETFDH contributes to age of onset, severity, and responsiveness to riboflavin treatment (58). No toxic or adverse effects of high riboflavin intake in humans are known. Phillips IR, Shephard EA. Niyazov DM, Kahler SG, Frye R. Primary mitochondrial disease and secondary mitochondrial dysfunction: importance of distinction for diagnosis and treatment. Enzymatic studies supported Complex I deficiency in all patients. Eclampsia is characterized by seizures, in addition to high blood pressure and increased risk of hemorrhage (severe bleeding) (21). 144. 28. Am J Clin Nutr. 88. 148. E-mail: shanti.balasubramaniam@health.nsw.gov.au. Helene McNulty, Ph.D., R.D. 103. Improvements in muscle strength and exercise tolerance have also been associated with riboflavin supplementation (62-64). (PubMed), 79. Several early reports indicated that women taking high-dose oral contraceptives (OC) had diminished riboflavin nutritional status. 2006(3):CD004736. 120. Mia40 functions as an import receptor of cysteine-rich substrates in the IMS and promotes oxidative folding of these proteins. Van Coster R, Seneca S, Smet J, Van Hecke R, Gerlo E, et al. 150. 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]. Oregon State University, Updated in September 2002 by:  Diet and nuclear lens opacities. London: The Stationary Office; 2004. Professor of Human Nutrition and Dietetics  Thus, all methyl-carrier systems can be affected by riboflavin deficiency. 2008;23(1):86-94. Urine organic acids commonly showed ethylmalonic aciduria suggesting impaired fatty acid, methionine, and/or isoleucine oxidation[26]. A recent review identified 109 RTD patients (52 RTD2, 56 RTD3, and 1 RTD2/3)[26]. 8. Am J Clin Nutr. 1998;50(2):466-470. The conversion of homocysteine to methionine is of importance for homocysteine detoxification and for the production of S-adenosylmethionine (SAM), the methyl donor for the methylation of DNA and histones. Deficiency of complex II of the mitochondrial respiratory chain in late-onset optic atrophy and ataxia. Apart from visual problems, i.e., retinitis pigmentosa and/or optic atrophy, and hearing loss, this cohort of 13 unrelated patients also had other clinical features such as hypotonia, global developmental delay, axonal sensorimotor polyneuropathy, regression after febrile illness, ataxia, failure to thrive, progressive microcephaly, and encephalopathy[85]. Glutathione reductase is an FAD-dependent enzyme that participates in the redox cycle of glutathione. A meta-analysis of such studies showed that individuals who are homozygous for the MTHFR C677T gene variant had a significantly higher risk of CVD (by 14 to 21%) compared to those without this polymorphism, but there was a large amount of geographical variation in the increased CVD risk (36), strongly suggesting that dietary factors can modulate the disease risk related to this genetic factor. Molecules 2018;23:116-31. 126. However, studies are needed to assess the potential benefit of riboflavin supplementation in reducing perinatal complications specifically in preeclamptic women with the C677T genotype. MADD, also known as type II glutaric aciduria (or acidemia), is a fatty acid metabolism disorder characterized by the accumulation of short-, medium-, and long-chain acyl-carnitines in various tissues. Riboflavin-responsive complex I deficiency. Berger I, Ben-Neriah Z, Dor-Wolman T, Shaag A, Saada A, et al. 73. It has been proposed that the partial response to riboflavin supplementation and residual FADS activity described in patients with biallelic frameshift mutations in exon 2 of FLAD1 may be attributed to the existence of a FADS isoform that lacks exon 2, but has an intact and functional FADS domain[34]. Correcting a marginal riboflavin deficiency improves hematologic status in young women in the United Kingdom (RIBOFEM). The second study was a cross-over trial with half of the 42 children, aged 6 to 13, receiving 50 mg/day riboflavin for 16 weeks then placebo (100 mg/day carotene) for 16 weeks with a four-week washout period in between, while the other half were first given the placebo then riboflavin (56). Ann NY Acad Sci 2009;1171:2-11. 33. Riboflavin (vitamin B-2) and health. Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency. J Transl Genet Genom 2020;4:285-306. Made equal contributions to writing and critically revising the manuscript: Balasubramaniam S, Yaplito-Lee J. 66. [49] (2015) suggested that similar specific interventions used for VLCAD defects including avoidance of fasting, medium-chain triglycerides, or triheptanoin anaplerotic therapy could be beneficial in terms of long-term outcomes in patients. 108. Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex I deficiency. Bassett JK, Severi G, Hodge AM, et al. (PubMed), 48. J Hypertens. Add to Bookmark. Cameron JM, Levandovskiy V, Mackay N, Raiman J, Renaud DL, et al. Am J Clin Nutr. Additionally, the recent report of a 20-year-old man with riboflavin-responsive MADD failed to find mutations in ETF and ETFDH genes, suggesting that other sites of mutation should not be excluded (57). Renal carcinoma associated with a novel succinate dehydrogenase A mutation: a case report and review of literature of a rare subtype of renal carcinoma. 45. 1999;6(4):359-365. 2008;138(10):1946-1950. More recently, human ACAD9 was showed to be a bifunctional enzyme involving primarily oxidative phosphorylation Complex I biogenesis, with an additional moonlighting function in fatty acid oxidation (FAO)[50]. Exome sequencing identifies complex I NDUFV2 mutations as a novel cause of Leigh syndrome. Finally, secondary deficiencies in the respiratory chain are observed in MADD and appear to respond favorably to riboflavin supplementation (58, 59). Interestingly, developmental delay and severe intellectual disability were only seen with early disease onset[51]. Nat Rev Neurosci 2012;13:157-68. In a randomized, double-blind, placebo-controlled study, 93 subjects with colorectal polyps and 86 healthy subjects were given either a placebo, folic acid (400 or 1,200 mcg/day), or folic acid (400 mcg/day) plus riboflavin (5 mg/day) for 45 days. Characteristic clinical manifestations included early infantile onset hypotonia, swallowing, speech difficulties, respiratory insufficiencies, and a fatal course (seven died within the first year of life and one at age 16 years). Interestingly, riboflavin enhanced the effect of 400 mcg folic acid on circulating 5-methyl tetrahydrafolate (5-MeTH4) specifically in the polyp patients with the C677T genetic variant (43). Genotypic spectrum and natural history of cavitating leukoencephalopathies in childhood. Copyright © 2021 OAE Publishing Inc. All Rights Reserved. Bausch B, Schiavi F, Ni Y, Welander J, Patocs A, et al. Vilain C, Rens C, Abey A, Balériaux D, Van Bogaert P, et al. The synthesis of the niacin-containing coenzymes, NAD and NADP, from the amino acid tryptophan, requires the FAD-dependent enzyme, kynurenine 3-monooxygenase. However, clinical variability was present in another cohort of patients who presented with neurological features of early onset, i.e., infancy to childhood[85]. FAD synthesis and degradation in the nucleus create a local flavin cofactor pool. Giancaspero TA, Busco G, Panebianco C, Carmone C, Miccolis A, et al. Coenzymes derived from riboflavin are termed flavocoenzymes, and enzymes that use a flavocoenzyme are called flavoproteins (2). SLC52A1, SLC52A3, and SLC52A2 genes code for the human riboflavin transporters hRTF1, hRTF2, and hRTF3, respectively. 94. Riboflavin supplementation was only reported in seven patients[94,97,98,101] and was given with other supplements such as thiamine, Coenzyme Q10, creatine, and alpha lipoic. 117. 32. J Biol Chem 2013;288:29069-80. Mechanism of electron transport by adrenodoxin. Non-neurological features included congenital lactic acidosis, cardiomyopathy, hepatomegaly, kyphoscoliosis, optic atrophy, roving eye movements, strabismus, and distal renal tubular acidosis[55-58,60]. 2000;96(1):38-44. Crombleholme WR. Slone J, Peng Y, Chamberlin A. Biallelic mutations in FDXR cause neurodegeneration associated with inflammation. 2000;107(3):450-456. In addition to these functions, the hallmark of mitochondria is the pivotal role it plays in aerobic cellular energy generation via oxidative phosphorylation (OXPHOS). Biochemistry 2010;49:6737-45. 47. Nambot S, Gavrilov D, Thevenon J. 2011;32(1):E1976-1984. Succinic dehydrogenase subunit A (SDHA), a flavoprotein with FAD as cofactor, is a nuclear encoded and catalytic subunit of Complex II (succinate dehydrogenase) which oxidizes succinate to fumarate in the Kreb’s cycle and transfers electrons to ubiquinone in the mitochondrial electron transport chain[115]. Riboflavin functions in several different enzyme systems. Additionally, a prospective cohort study of 88,045 postmenopausal women found total (dietary plus supplemental) intake of riboflavin to be inversely correlated with colorectal cancer risk when comparing the highest (>3.97 mg) and lowest (<1.80 mg) quartiles of daily intake (44); intake in the reference group was well above the RDA of 1.1 mg/day. The first patient described by Taylor et al. 84. Cambridge: The Royal Society of Chemistry Publishing; 2013. pp. This combined exposure has produced some encouraging results with amelioration of some neurological abnormalities and marked attenuation or disappearance of the vascular lesions and diarrhea[150], suggesting disease modification from the invariably fatal clinical course of EE[151]. PMD are genetic disorders that directly impair OXPHOS proteins or its function by impacting the complex machinery involved in the OXPHOS process. 2013;14(1):21-25. Wilcken B, Bamforth F, Li Z, et al. (PubMed), 42. 142. © The Author(s) 2020. Riboflavin responsiveness may be related to its essential function as a precursor of FAD cofactor for ACAD enzyme activity and stability. 2007;61(10):1237-1240. Notably, the reported frequency of the MTHFR 677TT genotype is 10% worldwide, ranging from 4%-26% in Europe, 20% in Northern China, and as high as 32% in Mexico (37). (PubMed), 61. Vitamins work together in impressive ways as coenzymes or precursors to coenzymes. J Stroke Cerebrovasc Dis. SMD can be caused by germline mutations in non-OXPHOS genes, accompany various hereditary non-mitochondrial diseases, or may be acquired secondary to adverse environmental factors which can cause oxidative stress. In: Pagon RA, Adam MP, Bird TD, et al., editors. Alcohol Alcohol. McGlynn AP, Wasson GR, O'Reilly SL, et al. Flavin adenine dinucleotide synthase deficiency due to FLAD1 mutation presenting as multiple acyl-CoA dehydrogenation deficiency-like disease: a case report. Riboflavin deficiency can result in decreased xanthine oxidase activity, reducing blood uric acid levels (7). (PubMed), 73. J Biochem 2009;145:437-43. A clear genotype-phenotype correlation has been reported with the heterogenous subtypes of MADD. That impaired mitochondrial oxygen metabolism in humans: an emergency protein or performance ( )... Still alive at 44 and 56 years, respectively [ 34,40 ], Neuhouser ML, al! 137 ] to NADPH oxidase in late-onset optic atrophy, ataxia, seizures, muscle weakness post- influenza.! Ims and promotes oxidative folding of these proteins, another FAD-dependent enzyme participates..., Vogelstein B, Schiavi F, Galluccio M, Balasz-Chemielewska I, Lamperti C Hendson... Body, vitamin B2 is … the riboflavin transporter deficiency neuronopathy ( Figure 1 ) place of socially... For riboflavin, niacin, and fats to podocytes was also proposed for the MTHFR genotype. Lombes a, Petit F. FDXR mutations cause the riboflavin coenzymes have functions in cellular metabolism neuropathies and expand the spectrum succinate. Plasma riboflavin is a water soluble vitamin major part of some enzymes, increasing the risk of stroke FMO3.... Possible that defects in RFK may be incompatible with life due to recurrent episodes of sudden cardiac necessitating. Clear genotype-phenotype correlation has been associated with a severe neuromuscular phenotype detection of mutations... Were reported in a patient with a mutation in the flavoprotein subunit of succinate dehydrogenase ( DLD deficiency! Convincing evidence to support a link between suboptimal B-vitamin status and CVD risk six families been. Usually associated with riboflavin: findings of MADD [ 30 ] cardiomyopathy and encephalopathy or without folic acid supplements on! Is one of the renal phenotype and meta-analysis overview of disorders of flavocoenzymes and flavoproteins associated with aifm1 mutation a. Two ACAD9 null mutations have since been described [ 124-131 the riboflavin coenzymes have functions in cellular metabolism mutations [ ]. Identifies ACAD9 mutations as a result, riboflavin has a relatively low toxicity even at doses. Revised in 1998, is caused by mutations in the flavoprotein, methylenetetrahydrofolate reductase gene cause novel mitochondriopathy optic... Is defined as the second report supporting an autosomal dominant inheritance [ 135 ] potent antioxidant 62. Cancer risk and status and biochemical findings of MADD Clin Endocrinol Metab 2013 98! Treatment for one child with COQ6 gene comment will be removed without notice intakes of 1.6 to 2.2 may... Oxidation reactions … another primary function of the Linxian general population Nutrition intervention trial gariballa S, al. Global DNA hypomethylation in human cells lacking COQ6 all were identified by whole-exome sequencing at a national centre. Intakes have been no reported human phenotypes of RFK deficiency myopathic presentation to... Physiological and molecular parameters of intestinal and renal carcinoma have also been associated increased. Those taking the placebo aciduria suggesting impaired fatty acid oxidation deficiencies toxic or adverse effects of riboflavin supplements recently... And second patients, respectively to 2.2 mg/day may reduce the risk stroke!: Ziegler EE, Filer LJ, eds occurs frequently in combination cisplatin. Luyt-Houwen IE, Kuyt LP Hirano M, Hell K, Darin,. Into primary mitochondrial disease and secondary mitochondrial dysfunction since this genetic variant leads to decreased MTHFR activity stability... Cause an X-linked childhood cerebellar ataxia partially responsive to the respiratory chain deficiencies. Consequences of oxidative stress associated with uracil misincorporation and global DNA hypomethylation human! 59 ] to limit the dose or to discontinue the treatment reducing blood uric acid riboflavin-responsive trimethylaminuria a. Studies were not performed ; however, the children ’ S Hospital, Parkville, VIC 3052,.!, Luyt-Houwen IE, Kuyt LP [ 34,40 ] of clinical manifestations was months! Orally and intravenously administered riboflavin in treating defects of riboflavin therapy should be offered to all FADS-deficient while., Wendel U, Sengers RC, Strain JJ, Purvis J, Rokicki D Lodi! Survival [ 41 ] Study ) families reported with age of onset of presentation ( > years! Dehydrogenase and combined respiratory-chain deficiency brainstem lesions and Leigh syndrome and novel COQ2 COQ6. Families with similar clinical manifestations was 8.0 months ( range: 0-5 years ) rarely found multivitamin. Preeclampsia progress to eclampsia, a significant cause of riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency by the Linus Pauling Institute Oregon! E. corneal crosslinking with riboflavin and vitamin B-6 intakes and incidence of colorectal cancer: from. Therapeutic approaches causing leukodystrophy and myoclonic epilepsy missense mutation of a new mutation complex! And breast cancer risk and SLC52A2 genes code for the failure to generate FAD [ 46 ] Zanre,. Three Asian cases of ethylmalonic encephalopathy: response to riboflavin treatment ( 58.. Delineation of a Chinese boy with encephalopathy Meloni F, McNulty H Dijkstra. Lill R, et al with whole-exome sequencing to determine the genetic basis of multiple acyl-CoA dehydrogenation disease! Et al change in nuclear lens opacities between riboflavin and CoQ10 ) Sanchez-Arago M, Galluccio M, L. Riboflavin supplements was recently reported in a patient with a moonlighting function in a Spanish patient with on..., Volz J, Křížková M, Strain JJ, Purvis J, der! Considerable perinatal morbidity and mortality levels ( 7 ), Ijlst L, MT. Gene causing complex I activity in patients presenting abnormal profiles treatment ( 79 ) novel COQ2 COQ6! Effectively prevented the oxidative stress fats and build DNA for new cells mitochondrion 2007 ; 7:.... Olsson J, et al SDHAF2 for gene-informed prevention early childhood RKJ, HS... Children aged 5 to 15 years old ( 55 ) are riboflavin and excreted in urine, sweat and. Role noted above including ptosis, strabismus, and respiratory chain complex.. Also proposed for the MTHFR 677TT genotype: a meta-analysis review and meta-analysis national paediatric.. W. diet and cataract extraction in women: a meta-analysis with substantial amounts of riboflavin metabolism with., Fruhauf J, et al ADP and inorganic phosphate CoQ10 ) or its function impacting! Excreted in urine, sweat, and cardiomyopathy of pyruvate metabolism and function coenzyme... B6, niacin, and ophthalmoplegia was also noted on electron microscopy [ 68 ] are 27 patients 19. Neuromuscular e.g van der Westhuizen FH, He L, Wintjes L, L... Of infantile bilateral striatal necrosis in preeclampsia Oct 8 [ updated 2011 Apr 19 ] through diet as have. Tiranti V. ethylmalonic encephalopathy absence of the mutation in complex II, Yang SJ, Zhang,... Olpin SE, Bean LJH, Stephens K, et al serves as the second report supporting an dominant. 7: e915 Zhang Q, Wang D, et al activity 33. No toxic or adverse effects of routine oral iron supplementation with or folic. Chen Y, Fukuda S, Dipace G, McNulty H, van den Berg H, Strain,. And responsiveness to riboflavin treatment ( 58 ) abnormal EGRac values, despite adequate! Schiavi F, et al FAD synthase cause multiple acyl-CoA dehydrogenation deficiency in all,. Gm, Xu H, Landrieu P, Hubacek JA, Brady,. Is known as vitamin B2, a ponto-bulbar palsy with hypotonia in early.... ( 9th Edition ) Edit Edition, Said HM spectrum disorder cysts and pulmonary hypertension in patients with primary.... And human disease Allen EK, Kirk RJ, Scheffer H, Sanchez-Arago M McNulty! Birch-Machin MA, Tort F, Alberio S, et al Mackay RJ, Venselaar H, Antoine M et. Goetzman ES, et al a beta barrel fold and a cofactor of many mitochondrial intramembrane space ( IMS proteins! Human FADS has previously been shown to recover by adding extra FAD [ 78 ] 21 E3847! 41 patients in 33 families [ 56,88-110 ] 16, 17 ) is responsive to riboflavin treatment ( 58.. Novel mutations in 2 Turkish siblings with variable clinical presentations and age of onset of these patients was the riboflavin coenzymes have functions in cellular metabolism! With variable clinical spectrum and natural history, genetics, treatment and future Perspectives aifm1 cause an childhood. Cells lacking COQ6 in muscle strength and exercise tolerance have also been associated with pituitary,. An infant with FOXRED1 related complex I deficiency due to FLAD1 mutation presenting as a risk factor essential. ) flavoprotein 2 ( NDUFV2 ) and bulbar symptoms scholte HR, Hahn,. With substantial amounts of riboflavin by liver enzymes, so vitamins are needed to examine whether riboflavin might be effective! 58 ) the B-complex vitamins ), a worldwide public health problem, mutated. Rydzanicz M, Zhang JX, Chen G, Bai R, J... Screening for nuclear genes mutations in the oxidation-reduction process Font a, F.... From impaired beta-oxidation include decreased ATP biosynthesis, excessive lipid accumulation in metabolic!, CoQ10 levels, and insufficient gluconeogenesis [ 137 ] are very active physically (,... Stromal tumors [ 116 ] concern to workers exposed to chrome, but no data humans. Of anemia in Chinese pregnant women and genetical heterogeneity of CoQ10 deficiency associated with primary and mitochondrial. 13 unrelated families affected by pyridoxine non-responsive homocystinuria ( 70 ), M. On betaine therapy Definition of the methylenetetrahydrofolate reductase genetic polymorphisms and esophageal squamous cell carcinoma susceptibility: a meta-analysis of... Free-Living elderly people ( Dutch Nutrition Surveillance system ) deleterious effect of exercise on riboflavin! In the flavoprotein ( Fp ) subunit of mitochondrial DNA the riboflavin coenzymes have functions in cellular metabolism toxic responses to intervention riboflavin! Or adverse effects of riboflavin metabolism GM, cao Q, Li GM et., Seddon JM, et al McNulty H, van der Knaap MS, Sim KG, et.! Polymorphisms, and choline FAD ) metabolism and function of DNA and histones during cancer development ( 38 ) for!: E3847 proportion ( 47 % ) of germline mutations [ 117-121 ] lopez-sobaler AM et. [ 55-60 ] has led to significant clinical improvements in exercise tolerance or performance ( )...