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Riboflavin and CoQ Disorders

  • Rita HorvathEmail author
  • Anne Lombès
Chapter

Abstract

Riboflavin, or vitamin B2, is the precursor of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), which are essential cofactors of numerous dehydrogenases. The most common form of riboflavin disorder is its deficiency due to insufficient dietary intake. Riboflavin-responsive inborn errors of metabolism were shown to be due to the riboflavin chaperone-like function, which stabilises mutant FAD-containing dehydrogenases, most often ETFDH. Recessive mutations of SLC52A2 and SLC52A3 encoding the human riboflavin transporters RFVT2 and RFVT3 are cause Brown-Vialetto-Van Laere and Fazio-Londe syndromes, while haploinsufficiency of SLC52A1 has been proposed to cause persistent riboflavin deficiency.

Ubiquinone (coenzyme Q10, CoQ10) is a lipid-soluble component of the cell membranes, where it functions as a mobile electron and proton carrier but also participates in other cellular processes as a potent antioxidant and by influencing pyrimidine metabolism. Five major clinical phenotypes of CoQ10 deficiency have been described (encephalomyopathy, multisystem infantile variant, cerebellar form, Leigh syndrome, isolated myopathy) before the identification of disease genes. An increasing number of molecular defects in the CoQ10 biosynthetic pathways have been identified in different clinical variants (PDSS1, PDSS2, COQ2, COQ6, COQ9, CABC1/ADCK3). Despite this, the number of reported patients is still low, and the absence of clear genotype-phenotype correlations makes the genetic diagnosis challenging. In addition to primary CoQ10 deficiencies, where the mutation impairs a protein directly involved in CoQ10 biosynthesis, secondary CoQ10 deficiencies include disease not due to deficient synthesis of CoQ10 but associated with decreased CoQ10 levels, which may be contributing to the clinical symptoms.

Because of the beneficial effect of CoQ10 and riboflavin supplementation, early recognition of riboflavin and CoQ10 diseases is important.

Keywords

Flavin Adenine Dinucleotide Flavin Adenine Dinucleotide Leigh Syndrome Flavin Mononucleotide CoQ10 Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Aeby A, Sznajer Y, Cavé H, Rebuffat E, Van Coster R, Rigal O, Van Bogaert P (2007) Cardiofaciocutaneous (CFC) syndrome associated with muscular coenzyme Q10 deficiency. J Inherit Metab Dis 30:827PubMedCrossRefGoogle Scholar
  2. Auré K, Benoist JF, Ogier de Baulny H, Romero NB, Rigal O, Lombès A (2004) Progression despite replacement of a myopathic form of coenzyme Q10 defect. Neurology 63:727–729PubMedCrossRefGoogle Scholar
  3. Bentinger M, Dallner G, Chojnacki T, Swiezewska E (2003) Distribution and breakdown of labeled coenzyme Q10 in rat. Free Radic Biol Med 34:563–575PubMedCrossRefGoogle Scholar
  4. Bosch AM, Abeling NG, Ijlst L, Knoester H, van der Pol WL, Stroomer AE, Wanders RJ, Visser G, Wijburg FA, Duran M, Waterham HR (2010) Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment. J Inherit Metab Dis 34:159–164PubMedCentralPubMedCrossRefGoogle Scholar
  5. Capo-Chichi CD, Gueant JL, Feillet F, Namour F, Vidailhet M (2000) Analysis of riboflavin and riboflavin cofactor levels in plasma by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 739:219–224PubMedCrossRefGoogle Scholar
  6. Chiong MA, Sim KG, Carpenter K, Rhead W, Ho G, Olsen RK, Christodoulou J (2007) Transient multiple acyl-CoA dehydrogenation deficiency in a newborn female caused by maternal riboflavin deficiency. Mol Genet Metab 92:109–114PubMedCrossRefGoogle Scholar
  7. Diomedi-Camassei F, Di Giandomenico S, Santorelli FM, Caridi G, Piemonte F, Montini G, Ghiggeri GM, Murer L, Barisoni L, Pastore A, Muda AO, Valente ML, Bertini E, Emma F (2007) COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement. J Am Soc Nephrol 18:2773–2780PubMedCrossRefGoogle Scholar
  8. Dipti S, Childs AM, Livingston JH, Aggarwal AK, Miller M, Williams C, Crow YJ (2005) Brown-Vialetto-Van Laere syndrome; variability in age at onset and disease progression highlighting the phenotypic overlap with Fazio-Londe disease. Brain Dev 27:443–446PubMedCrossRefGoogle Scholar
  9. Duncan AJ, Bitner-Glindzicz M, Meunier B, Costello H, Hargreaves IP, López LC, Hirano M, Quinzii CM, Sadowski MI, Hardy J, Singleton A, Clayton PT, Rahman S (2009) A nonsense mutation in COQ9 causes autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency: a potentially treatable form of mitochondrial disease. Am J Hum Genet 84:558–566PubMedCentralPubMedCrossRefGoogle Scholar
  10. Gempel K, Topaloglu H, Talim B, Schneiderat P, Schoser BG, Hans VH, Pálmafy B, Kale G, Tokatli A, Quinzii C, Hirano M, Naini A, DiMauro S, Prokisch H, Lochmüller H, Horvath R (2007) The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene. Brain 130:2037–2044PubMedCrossRefGoogle Scholar
  11. Gerards M, van den Bosch B, Calis C, Schoonderwoerd K, van Engelen K, Tijssen M, de Coo R, van der Kooi A, Smeets H (2010) Nonsense mutations in CABC1/ADCK3 cause progressive cerebellar ataxia and atrophy. Mitochondrion 10:510–515PubMedCrossRefGoogle Scholar
  12. Gironi M, Lamperti C, Nemni R, Moggio M, Comi G, Guerini FR, Ferrante P, Canal N, Naini A, Bresolin N, DiMauro S (2004) Late-onset cerebellar ataxia with hypogonadism and muscle coenzyme Q10 deficiency. Neurology 62:818–820PubMedCrossRefGoogle Scholar
  13. Green P, Wiseman M, Crow YJ, Houlden H, Riphagen S, Lin JP, Raymond FL, Childs AM, Sheridan E, Edwards S, Josifova DJ (2010) Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in c20orf54. Am J Hum Genet 86:485–489PubMedCentralPubMedCrossRefGoogle Scholar
  14. Gregersen N (1985) Riboflavin-responsive defects of beta-oxidation. J Inherit Metab Dis 8:65–69PubMedCrossRefGoogle Scholar
  15. Heeringa SF, Chernin G, Chaki M, Zhou W, Sloan AJ, Ji Z, Xie LX, Salviati L, Hurd TW, Vega-Warner V, Killen PD, Raphael Y, Ashraf S, Ovunc B, Schoeb DS, McLaughlin HM, Airik R, Vlangos CN, Gbadegesin R, Hinkes B, Saisawat P, Trevisson E, Doimo M, Casarin A, Pertegato V, Giorgi G, Prokisch H, Rötig A, Nürnberg G, Becker C, Wang S, Ozaltin F, Topaloglu R, Bakkaloglu A, Bakkaloglu SA, Müller D, Beissert A, Mir S, Berdeli A, Varpizen S, Zenker M, Matejas V, Santos-Ocaña C, Navas P, Kusakabe T, Kispert A, Akman S, Soliman NA, Krick S, Mundel P, Reiser J, Nürnberg P, Clarke CF, Wiggins RC, Faul C, Hildebrandt F (2011) COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest 121:2013–2024PubMedCentralPubMedCrossRefGoogle Scholar
  16. Henriques BJ, Rodrigues JV, Olsen RK, Bross P, Gomes CM (2009) Role of flavinylation in a mild variant of multiple acyl-CoA dehydrogenation deficiency: a molecular rationale for the effects of riboflavin supplementation. J Biol Chem 284:4222–4229PubMedCrossRefGoogle Scholar
  17. Ho G, Yonezawa A, Masuda S, Inui K, Sim KG, Carpenter K, Olsen RK, Mitchell JJ, Rhead WJ, Peters G, Christodoulou J (2011) Maternal riboflavin deficiency, resulting in transient neonatal-onset glutaric aciduria type 2, is caused by a microdeletion in the riboflavin transporter gene GPR172B. Hum Mutat 32:1976–1984CrossRefGoogle Scholar
  18. Hoey L, McNulty H, Strain JJ (2009) Studies of biomarker responses to intervention with riboflavin: a systematic review. Am J Clin Nutr 89:1960–1980CrossRefGoogle Scholar
  19. Horvath R, Schneiderat P, Schoser BGH, Gempel K, Neuen-Jacob E, Plöger H, Müller-Höcker J, Pongratz DE, Naini A, DiMauro S, Lochmüller H (2006) Coenzyme Q10 deficiency may cause isolated myopathy. Neurology 66:253–255PubMedCrossRefGoogle Scholar
  20. Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, Atawan A, Chattopadhyay S, Schubert M, Garip A, Kernt M, Petraki D, Rummey C, Leinonen M, Metz G, Griffiths PG, Meier T, Chinnery PF (2011) A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain 134:2677–86PubMedCentralPubMedCrossRefGoogle Scholar
  21. Lagier-Tourenne C, Tazir M, López LC, Quinzii CM, Assoum M, Drouot N, Busso C, Makri S, Ali-Pacha L, Benhassine T, Anheim M, Lynch DR, Thibault C, Plewniak F, Bianchetti L, Tranchant C, Poch O, DiMauro S, Mandel JL, Barros MH, Hirano M, Koenig M (2008) ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency. Am J Hum Genet 82:661–672PubMedCentralPubMedCrossRefGoogle Scholar
  22. Lalani SR, Vladutiu GD, Plunkett K, Lotze TE, Adesina AM, Scaglia F (2005) Isolated mitochondrial myopathy associated with muscle coenzyme Q10 deficiency. Arch Neurol 62:317–320PubMedCrossRefGoogle Scholar
  23. Lamperti C, Naini A, Hirano M, De Vivo DC, Bertini E, Servidei S, Valeriani M, Lynch D, Banwell B, Berg M, Dubrovsky T, Chiriboga C, Angelini C, Pegoraro E, DiMauro S (2003) Cerebellar ataxia and coenzyme Q10 deficiency. Neurology 60:1206–1208PubMedCrossRefGoogle Scholar
  24. Le Ber I, Dubourg O, Benoist JF, Jardel C, Mochel F, Koenig M et al (2007) Muscle coenzyme Q10 deficiencies in ataxia with oculomotor apraxia 1. Neurology 68:295–297PubMedCrossRefGoogle Scholar
  25. López LC, Schuelke M, Quinzii CM, Kanki T, Rodenburg RJT, Naini A, Dimauro S, Hirano M (2006) Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. Am J Hum Genet 79:1125–1130PubMedCentralPubMedCrossRefGoogle Scholar
  26. López LC, Quinzii CM, Area E, Naini A, Rahman S, Schuelke M, Salviati L, Dimauro S, Hirano M (2010) Treatment of CoQ(10) deficient fibroblasts with ubiquinone, CoQ analogs, and vitamin C: time- and compound-dependent effects. PLoS One 5:e11897PubMedCentralPubMedCrossRefGoogle Scholar
  27. Maldergem LV, Trijbels F, DiMauro S, Sindelar PJ, Musumeci O, Janssen A, Delberghe X, Martin JJ, Gillerot Y (2002) Coenzyme Q-responsive Leigh’s encephalopathy in two sisters. Ann Neurol 52:750–754PubMedCrossRefGoogle Scholar
  28. Mollet J, Giurgea I, Schlemmer D, Dallner G, Chretien D, Delahodde A, Bacq D, de Lonlay P, Munnich A, Rötig A (2007) Prenyldiphosphate synthase, subunit 1 (PDSS1) and OH-benzoate polyprenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders. J Clin Invest 117:765–72PubMedCentralPubMedCrossRefGoogle Scholar
  29. Mollet J, Delahodde A, Serre V, Chretien D, Schlemmer D, Lombes A, Boddaert N, Desguerre I, de Lonlay P, de Baulny HO, Munnich A, Rötig A (2008) CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures. Am J Hum Genet 82:623–630PubMedCentralPubMedCrossRefGoogle Scholar
  30. Montero R, Sánchez-Alcázar JA, Briones P, Navarro-Sastre A, Gallardo E, Bornstein B, Herrero-Martín D, Rivera H, Martin MA, Marti R, García-Cazorla A, Montoya J, Navas P, Artuch R (2009) Coenzyme Q10 deficiency associated with a mitochondrial DNA depletion syndrome: a case report. Clin Biochem 42:742–745PubMedCrossRefGoogle Scholar
  31. Musumeci O, Naini A, Slonim AE, Skavin N, Hadjigeorgiou GL, Krawiecki N, Weissman BM, Tsao CY, Mendell JR, Shanske S, De Vivo DC, Hirano M, DiMauro S (2001) Familial cerebellar ataxia with muscle coenzyme Q10 deficiency. Neurology 56:849–855PubMedCrossRefGoogle Scholar
  32. Ogasahara S, Engel AG, Frens D, Mack D (1989) Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci 86:2379–2382PubMedCentralPubMedCrossRefGoogle Scholar
  33. Olsen RK, Olpin SE, Andresen BS, Miedzybrodzka ZH, Pourfarzam M, Merinero B, Frerman FE, Beresford MW, Dean JC, Cornelius N, Andersen O, Oldfors A, Holme E, Gregersen N, Turnbull DM, Morris AA (2007) ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain 130:2045–2054PubMedCrossRefGoogle Scholar
  34. Quinzii CM, Hirano M (2010) Coenzyme Q and mitochondrial disease. Dev Disabil Res Rev 16:183–188PubMedCentralPubMedCrossRefGoogle Scholar
  35. Quinzii CM, Kattah AG, Naini A, Akman HO, Mootha VK, DiMauro S, Hirano M (2005) Coenzyme Q deficiency and cerebellar ataxia associated with an aprataxin mutation. Neurology 64:539–541PubMedCrossRefGoogle Scholar
  36. Quinzii C, Naini A, Salviati L, Trevisson E, Navas P, Dimauro S, Hirano M (2006) A mutation in para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am J Hum Genet 78:345–349PubMedCentralPubMedCrossRefGoogle Scholar
  37. Rahman S, Clarke CF, Hirano M (2012) 176th ENMC International Workshop: diagnosis and treatment of coenzyme Q(10) deficiency. Neuromuscul Disord 22:76–86PubMedCentralPubMedCrossRefGoogle Scholar
  38. Rotig A, Appelkvist EL, Geromel V, Chretien D, Kadhom N, Edery P, Lebideau M, Dallner G, Munnich A, Ernster L, Rustin P (2000) Quinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency. Lancet 356:391–395PubMedCrossRefGoogle Scholar
  39. Sacconi S, Trevisson E, Salviati L, Ayme S, Rigal O, Redondo AG et al (2010) Coenzyme Q10 is frequently reduced in muscle of patients with mitochondrial myopathy. Neuromuscul Disord 20:44–48PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Institute of Genetic MedicineNewcastle UniversityNewcastle upon TyneUK
  2. 2.APHP, Biochimie MétaboliqueGH Pitié-Salpêtrière, Inserm UMRS 1016 Institut Cochin, CNRS UMR 8104, Université Paris DescartesParisFrance

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