title: Genetic bases and clinical manifestations of coenzyme Q10 (CoQ 10) deficiency.
abstract: Coenzyme Q(10) is a remarkable lipid involved in many cellular processes such as energy production through the mitochondrial respiratory chain (RC), beta-oxidation of fatty acids, and pyrimidine biosynthesis, but it is also one of the main cellular antioxidants. Its biosynthesis is still incompletely characterized and requires at least 15 genes. Mutations in eight of them (PDSS1, PDSS2, COQ2, COQ4, COQ6, ADCK3, ADCK4, and COQ9) cause primary CoQ(10) deficiency, a heterogeneous group of disorders with variable age of onset (from birth to the seventh decade) and associated clinical phenotypes, ranging from a fatal multisystem disease to isolated steroid resistant nephrotic syndrome (SRNS) or isolated central nervous system disease. The pathogenesis is complex and related to the different functions of CoQ(10). It involves defective ATP production and oxidative stress, but also an impairment of pyrimidine biosynthesis and increased apoptosis. CoQ(10) deficiency can also be observed in patients with defects unrelated to CoQ(10) biosynthesis, such as RC defects, multiple acyl-CoA dehydrogenase deficiency, and ataxia and oculomotor apraxia.Patients with both primary and secondary deficiencies benefit from high-dose oral supplementation with CoQ(10). In primary forms treatment can stop the progression of both SRNS and encephalopathy, hence the critical importance of a prompt diagnosis. Treatment may be beneficial also for secondary forms, although with less striking results.In this review we will focus on CoQ(10) biosynthesis in humans, on the genetic defects and the specific clinical phenotypes associated with CoQ(10) deficiency, and on the diagnostic strategies for these conditions.
authors.affiliation: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Via Giustiniani 3, Padova, 35128, Italy.
authors.forename: Maria Andrea
authors.initials: MA
authors.lastname: Desbats
authors.forename: Giada
authors.initials: G
authors.lastname: Lunardi
authors.forename: Mara
authors.initials: M
authors.lastname: Doimo
authors.forename: Eva
authors.initials: E
authors.lastname: Trevisson
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001259:Ataxia / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D002493:Central Nervous System Diseases / Q000378:metabolism; D004195:Disease Models, Animal; D004579:Electron Transport; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D018908:Muscle Weakness / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D009404:Nephrotic Syndrome / Q000378:metabolism; D018384:Oxidative Stress; D010641:Phenotype; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics
chemical_list: D014451:Ubiquinone; D000255:Adenosine Triphosphate; C003741:ubiquinol
references.citation: N Engl J Med. 2014 Jul 3;371(1):80-1
references.pmid: 24988568
references.citation: Ochsner J. 2010 Spring;10(1):16-21
references.pmid: 21603349
references.citation: J Med Genet. 2012 Mar;49(3):187-91
references.pmid: 22368301
references.citation: Lancet. 2000 Jul 29;356(9227):391-5
references.pmid: 10972372
references.citation: J Biol Chem. 2010 Sep 3;285(36):27827-38
references.pmid: 20592037
references.citation: J Clin Invest. 2013 Dec;123(12):5179-89
references.pmid: 24270420
references.citation: FASEB J. 2010 Oct;24(10):3733-43
references.pmid: 20495179
references.citation: Am J Hum Genet. 2006 Feb;78(2):345-9
references.pmid: 16400613
references.citation: Orphanet J Rare Dis. 2012 Apr 19;7:21
references.pmid: 22515166
references.citation: Free Radic Res. 2002 Apr;36(4):437-43
references.pmid: 12069108
references.citation: Mitochondrion. 2010 Aug;10(5):510-5
references.pmid: 20580948
references.citation: Proc Natl Acad Sci U S A. 1989 Apr;86(7):2379-82
references.pmid: 2928337
references.citation: Biochim Biophys Acta. 1995 May 24;1271(1):195-204
references.pmid: 7599208
references.citation: Mol Syndromol. 2014 Jul;5(3-4):156-62
references.pmid: 25126048
references.citation: J Neurol Sci. 2013 Mar 15;326(1-2):24-8
references.pmid: 23343605
references.citation: EMBO Mol Med. 2011 Jul;3(7):410-27
references.pmid: 21567994
references.citation: Nutrition. 2010 Mar;26(3):250-4
references.pmid: 19932599
references.citation: Cell. 2013 Jan 31;152(3):504-18
references.pmid: 23374346
references.citation: N Engl J Med. 2014 Jul 3;371(1):80
references.pmid: 24988567
references.citation: J Biol Chem. 2005 May 27;280(21):20231-8
references.pmid: 15792955
references.citation: J Clin Invest. 2007 Mar;117(3):765-72
references.pmid: 17332895
references.citation: Mitochondrion. 2007 Jun;7 Suppl:S78-88
references.pmid: 17482886
references.citation: Mitochondrion. 2007 Jun;7 Suppl:S175-80
references.pmid: 17442628
references.citation: Cell Metab. 2008 Sep;8(3):249-56
references.pmid: 18762025
references.citation: Int J Nephrol. 2011;2011:609213
references.pmid: 21811680
references.citation: Liver. 1994 Jun;14(3):138-40
references.pmid: 8078393
references.citation: Biochim Biophys Acta. 2011 May;1811(5):348-60
references.pmid: 21296186
references.citation: N Engl J Med. 2014 Jul 3;371(1):81-2
references.pmid: 24988570
references.citation: Chem Biol. 2010 May 28;17(5):449-59
references.pmid: 20534343
references.citation: Neurology. 2005 Aug 23;65(4):606-8
references.pmid: 16116126
references.citation: J Am Soc Nephrol. 2007 Oct;18(10):2773-80
references.pmid: 17855635
references.citation: Neurobiol Dis. 2012 Jan;45(1):219-33
references.pmid: 21871565
references.citation: N Engl J Med. 2008 Jun 26;358(26):2849-50
references.pmid: 18579827
references.citation: Nature. 2000 Nov 30;408(6812):609-13
references.pmid: 11117751
references.citation: Biochim Biophys Acta. 2004 Jan 28;1660(1-2):171-99
references.pmid: 14757233
references.citation: Biochim Biophys Acta. 2014 Jul;1842(7):893-901
references.pmid: 24576561
references.citation: N Engl J Med. 2014 Jul 3;371(1):81
references.pmid: 24988569
references.citation: Curr Neurovasc Res. 2005 Dec;2(5):447-59
references.pmid: 16375724
references.citation: Clin Biochem. 2008 Jun;41(9):697-700
references.pmid: 18387363
references.citation: Free Radic Biol Med. 2010 Jun 15;48(12):1610-7
references.pmid: 20226852
references.citation: Neurology. 2005 Feb 8;64(3):539-41
references.pmid: 15699391
references.citation: Pediatr Neurol. 2006 Jul;35(1):30-7
references.pmid: 16814082
references.citation: J Inherit Metab Dis. 2009 Aug;32(4):570-5
references.pmid: 19504350
references.citation: Clin Chem. 2005 Dec;51(12):2380-2
references.pmid: 16306103
references.citation: Mol Aspects Med. 1997;18 Suppl:S1-6
references.pmid: 9266500
references.citation: J Inherit Metab Dis. 2014 Jan;37(1):53-62
references.pmid: 23774949
references.citation: J Clin Invest. 2011 May;121(5):2013-24
references.pmid: 21540551
references.citation: Eur J Paediatr Neurol. 2013 Nov;17(6):625-30
references.pmid: 23816342
references.citation: J Biol Chem. 1998 Oct 2;273(40):25734-40
references.pmid: 9748242
references.citation: Eur J Paediatr Neurol. 2012 May;16(3):248-56
references.pmid: 21873089
references.citation: JIMD Rep. 2014;12:103-7
references.pmid: 24048965
references.citation: Neuromuscul Disord. 2010 Jan;20(1):44-8
references.pmid: 19945282
references.citation: Neuromuscul Disord. 2012 Jan;22(1):76-86
references.pmid: 21723727
references.citation: Am J Hum Genet. 2008 Mar;82(3):623-30
references.pmid: 18319072
references.citation: J Biol Chem. 2005 Dec 30;280(52):42627-35
references.pmid: 16230336
references.citation: J Biol Chem. 2012 Jul 6;287(28):23571-81
references.pmid: 22593570
references.citation: Clin J Am Soc Nephrol. 2013 Apr;8(4):637-48
references.pmid: 23349334
references.citation: J Biol Chem. 2008 Sep 19;283(38):26217-27
references.pmid: 18635541
references.citation: BMJ Open. 2013 Mar 25;3(3):
references.pmid: 23533218
references.citation: Am J Physiol Renal Physiol. 2008 Nov;295(5):F1535-44
references.pmid: 18784258
references.citation: Hum Mol Genet. 2013 Mar 15;22(6):1233-48
references.pmid: 23255162
references.citation: PLoS Genet. 2008 Apr 25;4(4):e1000061
references.pmid: 18437205
references.citation: Neurogenetics. 2010 Feb;11(1):1-12
references.pmid: 19440741
references.citation: J Neurol Neurosurg Psychiatry. 2014 May;85(5):493-8
references.pmid: 24218524
references.citation: Genomics. 2013 Sep;102(3):148-56
references.pmid: 23631824
references.citation: J Inherit Metab Dis. 2007 Oct;30(5):827
references.pmid: 17703371
references.citation: Biochim Biophys Acta. 2014 Jan;1842(1):1-6
references.pmid: 24140869
references.citation: Biochem J. 2004 Sep 1;382(Pt 2):519-26
references.pmid: 15153069
references.citation: Am J Physiol Renal Physiol. 2013 Oct 15;305(8):F1228-38
references.pmid: 23926186
references.citation: Biochem Biophys Res Commun. 2008 Jul 18;372(1):35-9
references.pmid: 18474229
references.citation: Mitochondrion. 2013 Jul;13(4):337-41
references.pmid: 23583954
references.citation: Am J Hum Genet. 2008 Mar;82(3):661-72
references.pmid: 18319074
references.citation: Mitochondrion. 2007 Jun;7 Suppl:S62-71
references.pmid: 17482885
references.citation: Pediatr Nephrol. 2012 Apr;27(4):539-50
references.pmid: 21656172
references.citation: Hum Mol Genet. 2013 Oct 1;22(19):3819-27
references.pmid: 23727839
references.citation: Hum Mol Genet. 2007 May 1;16(9):1091-7
references.pmid: 17374725
references.citation: J Neurol Neurosurg Psychiatry. 2012 Feb;83(2):174-8
references.pmid: 22036850
references.citation: Biochim Biophys Acta. 2009 Jan;1791(1):69-75
references.pmid: 19022396
references.citation: PLoS One. 2010 Jul 30;5(7):e11897
references.pmid: 20689595
references.citation: Clin Biochem. 2009 May;42(7-8):732-5
references.pmid: 19133251
references.citation: J Pediatr. 2001 Sep;139(3):456-8
references.pmid: 11562630
references.citation: J Pediatr. 2011 Mar;158(3):458-62
references.pmid: 20884007
references.citation: Arch Neurol. 2012 Aug;69(8):978-83
references.pmid: 22490322
references.citation: Brain. 2007 Aug;130(Pt 8):2037-44
references.pmid: 17412732
references.citation: FASEB J. 2013 Feb;27(2):612-21
references.pmid: 23150520
references.citation: Am J Hum Genet. 2009 May;84(5):558-66
references.pmid: 19375058
references.citation: FASEB J. 2011 Aug;25(8):2669-87
references.pmid: 21551238
references.citation: Autophagy. 2009 Jan;5(1):19-32
references.pmid: 19115482
references.citation: Biofactors. 2008;32(1-4):113-8
references.pmid: 19096106
references.citation: Curr Opin Neurol. 2011 Oct;24(5):449-56
references.pmid: 21844807
references.citation: N Engl J Med. 2013 Jul 18;369(3):233-44
references.pmid: 23758206