Skip to main content
SpringerLink
Log in

The Clinical Spectrum of Nuclear DNA-Related Mitochondrial Disorders

  • Chapter
  • First Online:
Mitochondrial Disorders Caused by Nuclear Genes

Abstract

We review the clinical presentations of nuclear DNA-related mitochondrial diseases, including those due to mutations in genes encoding subunits of the respiratory chain (RC) (“direct hits”), those involving ancillary factors needed for the assembly or stability of the RC (“indirect hits”), those affecting the intergenomic cross-talk, and those due to alterations in the protein milieu of the RC.

This field is already vast and is getting rapidly larger with the application of homozygosity mapping and MitoExome sequencing. The clinical spectrum is also predictably vast, but more homogeneous than that of mitochondrial DNA (mtDNA)-related disorders. In general, nuclear DNA (nDNA)-related diseases have infantile or early childhood onset, rapidly downhill course with rare survival into adolescence, and are dominated by encephalopathy (most commonly Leigh syndrome), hypertrophic cardiomyopathy, hepatocerebral syndrome, and nephropathy (often nephrotic syndrome).

Exceptions to these generalizations are seen especially in disorders due to mtDNA multiple deletions and mtDNA depletion, where the rules of Mendelian genetics and mitochondrial genetics overlap.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Holt IJ, Harding AE, Morgan Hughes JA (1988) Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331:717–719

    Article  PubMed  CAS  Google Scholar 

  2. Wallace DC, Singh G, Lott MT et al (1988) Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 242:1427–1430

    Article  PubMed  CAS  Google Scholar 

  3. DiMauro S, Andreu AL (2000) Mutations in mtDNA: are we scraping the bottom of the barrel? Brain Pathol 10:431–441

    Article  PubMed  CAS  Google Scholar 

  4. Zeviani M, Servidei S, Gellera C et al (1989) An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region. Nature 339:309–311

    Article  PubMed  CAS  Google Scholar 

  5. Moraes CT, Shanske S, Tritschler HJ et al (1991) mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases. Am J Hum Genet 48:492–501

    PubMed  CAS  Google Scholar 

  6. Bourgeron T, Rustin P, Chretien D et al (1995) Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 11:144–149

    Article  PubMed  CAS  Google Scholar 

  7. Distelmaier F, Koopman WJH, van den Heuvel LP et al (2009) Mitochondrial complex I deficiency: from organelle dysfunction to clinical disease. Brain 132:833–842

    Article  PubMed  Google Scholar 

  8. Valsecchi F, Koopman WJH, Manjeri GR et al (2010) Complex I disorders: causes, mechanisms, and development of treatment strategies at the cellular level. Devel Disabil Res Rev 16:175–182

    Article  Google Scholar 

  9. Haut S, Brivet M, Touati G et al (2003) A deletion in the human QP-C gene causes a complex III deficiency resulting in hypoglycemia and lactic acidosis. Hum Genet 113:118–122

    PubMed  CAS  Google Scholar 

  10. Massa V, Fernandez-Vizarra E, Alshahwan S et al (2008) Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase. Am J Hum Genet 82:1281–1289

    Article  PubMed  CAS  Google Scholar 

  11. DiMauro S (2011) A history of mitochondrial diseases. J Inher Metab Dis 34:261–276

    Article  PubMed  CAS  Google Scholar 

  12. DiMauro S, Davidzon G (2005) Mitochondrial DNA and disease. Ann Med 37:222–232

    Article  PubMed  CAS  Google Scholar 

  13. Holt IJ, Harding AE, Petty RK, Morgan Hughes JA (1990) A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 46:428–433

    PubMed  CAS  Google Scholar 

  14. Tatuch Y, Christodoulou J, Feigenbaum A et al (1992) Heteroplasmic mtDNA mutation (T>G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet 50:852–858

    PubMed  CAS  Google Scholar 

  15. Larsson NG, Holme E, Kristiansson B et al (1990) Progressive increase of the mutated mitochondrial DNA fraction in Kearns-Sayre syndrome. Pediatr Res 28:131–136

    Article  PubMed  CAS  Google Scholar 

  16. McShane MA, Hammans SR, Sweeney M et al (1991) Pearson syndrome and mitochondrial encephalomyopathy in a patient with a deletion of mtDNA. Am J Hum Genet 48:39–42

    PubMed  CAS  Google Scholar 

  17. Suomalainen A, Isohanni P (2010) Mitochondrial DNA depletion syndromes—many genes, common mechanisms. Neuromuscul Disord 20:429–437

    Article  PubMed  Google Scholar 

  18. Carrozzo R, Hirano M, Fromenty B et al (1998) Multiple mitochondrial DNA deletions features in autosomal dominant and recessive diseases suggest distinct pathogeneses. Neurology 50:99–106

    Article  PubMed  CAS  Google Scholar 

  19. Rotig A, Poulton J (2009) Genetic causes of mitochondrial DNA depletion in humans. Biochim Biophys Acta 1792:1103–1108

    Article  PubMed  CAS  Google Scholar 

  20. Hirano M, Lagier-Tourenne C, Valentino ML et al (2005) Thymidine phosphorylase mutations cause instability of mitochondrial DNA. Gene 354:152–156

    Article  PubMed  CAS  Google Scholar 

  21. Tyynismaa H, Sun R, Ahola-Erkkila S et al (2012) Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions. Hum Mol Genet 21:66–75

    Article  PubMed  CAS  Google Scholar 

  22. Hakonen AH, Isohanni P, Paetau A et al (2007) Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion. Brain 130:3032–3040

    Article  PubMed  Google Scholar 

  23. Sarzi E, Goffart S, Serre V et al (2007) Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA depletion. Ann Neurol 62:579–587

    Article  PubMed  CAS  Google Scholar 

  24. Wong L-JC, Naviaux RK, Brunetti-Pierri N et al (2008) Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat 29:E150–E172

    Article  PubMed  Google Scholar 

  25. Chan SSL, Copeland WC (2009) DNA polymerase gamma and mitochondrial disease: understanding the consequence of POLG mutations. Biochim Biophys Acta 1787:312–319

    Article  PubMed  CAS  Google Scholar 

  26. Horvath R, Hudson G, Ferrari G et al (2006) Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain 129:1674–1684

    Article  PubMed  Google Scholar 

  27. DiMauro S, Davidzon G, Hirano M (2006) A polymorphic polymerase. Brain 126:1637–1639

    Article  Google Scholar 

  28. Naviaux RK, Nguyen KV (2004) POLG mutations associated with Alpers’ syndrome and mitochondrial DNA depletion. Ann Neurol 55:706–712

    Article  PubMed  CAS  Google Scholar 

  29. Davidzon G, Mancuso M, Ferraris S et al (2005) POLG mutations and Alpers syndrome. Ann Neurol 57:921–923

    Article  PubMed  CAS  Google Scholar 

  30. Van Goethem G, Dermaut B, Lofgren A et al (2001) Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet 28:211–212

    Article  PubMed  CAS  Google Scholar 

  31. Davidzon G, Greene P, Mancuso M et al (2006) Early-onset familial; parkinsonism due to POLG mutations. Ann Neurol 59:859–862

    Article  PubMed  CAS  Google Scholar 

  32. Eerola J, Luoma PT, Peuralinna T et al (2010) POLG1 polyglutamine tract variants associated with Parkinson’s disease. Neurosci Lett 477:1–5

    Article  PubMed  CAS  Google Scholar 

  33. Van Goethem G, Martin JJ, Dermaut B et al (2003) Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia. Neuromuscul Disord 13:133–142

    Article  PubMed  Google Scholar 

  34. Hakonen AH, Heiskanen S, Juvonen V et al (2005) Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet 77:430–441

    Article  PubMed  CAS  Google Scholar 

  35. Milone M, Brunetti-Pierri N, Tang L-Y et al (2008) Sensory ataxic neuropathy with ophthalmoparesis caused by POLG mutations. Neuromuscul Disord 18:626–632

    Article  PubMed  Google Scholar 

  36. Smeitink J, Sengers R, Trijbels F, van den Heuvel L (2001) Human NADH: ubiquinone oxidoreductase. J Bioenerg Biomembr 33:259–266

    Article  PubMed  CAS  Google Scholar 

  37. Janssen RJ, Nijtmans LG, van den Heuvel LP, Smeitink JAM (2006) Mitochondrial complex I: structure, function and pathology. J Inher Metab Dis 29:499–515

    Article  PubMed  CAS  Google Scholar 

  38. Bugiani M, Invernizzi F, Alberio S et al (2004) Clinical and molecular findings in children with complex I deficiency. Biochim Biophys Acta 1659:136–147

    Article  PubMed  CAS  Google Scholar 

  39. DiMauro S, Garone C (2011) Metabolic disorders of fetal life: glycogenoses and mitochondrial defects of the mitochondrial respiratory chain. Semin Fetal Neonatal Med 16:181–189

    Article  PubMed  CAS  Google Scholar 

  40. Lebre AS, Rio M, Faivre d’ Arcier L et al (2011) A common pattern of brain MRI imaging in mitochondrial diseases with complex I deficiency. J Med Genet 48:16–23

    Article  PubMed  CAS  Google Scholar 

  41. Fernandez-Moreira D, Ugalde C, Smeets R et al (2007) X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy. Ann Neurol 61:73–83

    Article  PubMed  CAS  Google Scholar 

  42. Rustin P, Rotig A (2002) Inborn errors of complex II—unusual human mitochondrial diseases. Biochim Biophys Acta 1553:117–122

    Article  PubMed  CAS  Google Scholar 

  43. Parfait B, Chretien D, Rotig A et al (2000) Compound heterozygous mutation in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome. Hum Genet 106:236–243

    Article  PubMed  CAS  Google Scholar 

  44. Horvath R, Abicht A, Holinski-Feder E et al (2006) Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA). J Neurol Neurosurg Psychiatry 77:74–76

    Article  PubMed  CAS  Google Scholar 

  45. Van Coster R, Seneca S, Smet J et al (2003) Homozygous Gly555Glu mutation in the nuclear-encoded 7-kDa flavoprotein gene causes instability of respiratory chain complex II. Am J Med Genet 120:13–18

    Article  Google Scholar 

  46. Bugiani M, Lamantea E, Invernizzi F et al (2006) Effects of riboflavin in children with complex II deficiency. Brain Dev 28:576–581

    Article  PubMed  Google Scholar 

  47. Birch-Machin MA, Taylor RW, Cochran B et al (2000) Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene. Ann Neurol 48:330–335

    Article  PubMed  CAS  Google Scholar 

  48. Quinzii CM, Hirano M (2010) Coenzyme Q and mitochondrial disease. Dev Disabil Res Rev 16:183–188

    Article  PubMed  Google Scholar 

  49. Trevisson E, DiMauro S, Navas P, Salviati L (2011) Coenzyme Q deficiency in muscle. Curr Opin Neurol 24:449–456

    Article  PubMed  CAS  Google Scholar 

  50. Ogasahara S, Engel AG, Frens D, Mack D (1989) Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci U S A 86:2379–2382

    Article  PubMed  CAS  Google Scholar 

  51. Sobreira C, Hirano M, Shanske S et al (1997) Mitochondrial encephalomyopathy with coenzyme Q10 deficiency. Neurology 48:1238–1243

    Article  PubMed  CAS  Google Scholar 

  52. Boitier E, Degoul F, Desguerre I et al (1998) A case of mitochondrial encephalomyopathy associated with a muscle coenzyme Q10 deficiency. J Neurol Sci 156:41–46

    Article  PubMed  CAS  Google Scholar 

  53. Di Giovanni S, Mirabella M, Spinazzola A et al (2001) Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency. Neurology 57:515–518

    Article  Google Scholar 

  54. Auré K, Benoist JF, Ogier de Baulny H et al (2004) Progression despite replacement of a myopathic form of coenzyme Q10 defect. Neurology 63:727–729

    Article  PubMed  Google Scholar 

  55. Musumeci O, Naini A, Slonim AE et al (2001) Familial cerebellar ataxia with muscle coenzyme Q10 deficiency. Neurology 56:849–855

    Article  PubMed  CAS  Google Scholar 

  56. Lamperti C, Naini A, Hirano M et al (2003) Cerebellar ataxia and coenzyme Q10 deficiency. Neurology 60:1206–1208

    Article  PubMed  CAS  Google Scholar 

  57. Gironi M, Lamperti C, Nemni R et al (2004) Late-onset cerebellar ataxia with hypogonadism and muscle coenzyme Q10 deficiency. Neurology 62:818–820

    Article  PubMed  CAS  Google Scholar 

  58. Artuch R, Brea-Calvo G, Briones P et al (2006) Cerebellar ataxia with coenzyme Q10 deficiency: diagnosis and follow-up after coenzyme Q10 supplementation. J Neurol Sci 246:153–158

    Article  PubMed  CAS  Google Scholar 

  59. Lagier-Tourenne C, Tazir M, Lopez LC et al (2008) ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency. Am J Hum Genet 82:661–672

    Article  PubMed  CAS  Google Scholar 

  60. Mollet J, Delahodde A, Serre V et al (2008) CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures. Am J Hum Genet 82:623–630

    Article  PubMed  CAS  Google Scholar 

  61. Rotig A, Appelkvist EL, Geromel V et al (2000) Quinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency. Lancet 356:391–395

    Article  PubMed  CAS  Google Scholar 

  62. Montini G, Malaventura C, Salviati L (2008) Early coenzyme Q10 supplementation in primary coenzyme Q10 deficiency. N Engl J Med 358:2849–2850

    Article  PubMed  CAS  Google Scholar 

  63. Mollet J, Giurgea I, Schlemmer D et al (2007) Prenyldiphosphate synthase (PDSS1) and OH-benzoate prenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders. J Clin Invest 117:765–772

    Article  PubMed  CAS  Google Scholar 

  64. Lopez LC, Schuelke M, Quinzii C et al (2006) Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. Am J Hum Genet 79:1125–1129

    Article  PubMed  CAS  Google Scholar 

  65. Diomedi-Camassei F, Di Giandomenico S, Santorelli F et al (2007) COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement. J Am Soc Nephrol 18:2773–2780

    Article  PubMed  CAS  Google Scholar 

  66. Heeringa SF, Chernin G, Chaki M et al (2011) COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest 121:2013–2024

    Article  PubMed  CAS  Google Scholar 

  67. Gempel K, Topaloglu H, Talim B et al (2007) The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene. Brain 130:2037–2044

    Article  PubMed  Google Scholar 

  68. Liang W-C, Ohkuma A, Hayashi YK et al (2009) ETFDH mutations, CoQ10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Neuromuscul Disord 19:212–216

    Article  PubMed  Google Scholar 

  69. Ohkuma A, Noguchi S, Sugie H et al (2009) Clinical and genetic analysis of lipid storage myopathies. Muscle Nerve 39:333–342

    Article  PubMed  Google Scholar 

  70. Barel O, Shorer Z, Flusser H et al (2008) Mitochondrial complex III deficiency associated with a homozygous mutation in UQCRQ. Am J Hum Genet 82:1211–1216

    Article  PubMed  CAS  Google Scholar 

  71. Mayr JA, Havlickova V, Zimmermann F et al (2010) Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1 epsilon subunit. Hum Mol Genet 19:3430–3439

    Article  PubMed  CAS  Google Scholar 

  72. Cizkova A, Stranecky V, Mayr JA et al (2008) TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalomyopathy. Nat Genet 40:1288–1290

    Article  PubMed  CAS  Google Scholar 

  73. Lazarou M, Thorburn DR, Ryan MT, McKenzie M (2009) Assembly of mitochondrial complex I and defects in disease. Biochim Biophys Acta 1793:78–88

    Article  PubMed  CAS  Google Scholar 

  74. Hoefs SJ, Dieteren CEJ, Distelmaier F et al (2008) NDUFA2 complex I mutation leads to Leigh disease. Am J Hum Genet 82:1306–1315

    Article  PubMed  CAS  Google Scholar 

  75. Saada A, Vogel RO, Hoefs SJ et al (2009) Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease. Am J Hum Genet 84:718–727

    Article  PubMed  CAS  Google Scholar 

  76. Hoefs SJG, Skjeldal OH, Rodenburg RJ et al (2010) Novel mutations in the NDUFS1 gene cause low residual activities in human complex I deficiencies. Mol Genet Metab 100:251–256

    Article  PubMed  CAS  Google Scholar 

  77. Fassone E, Taanman J-W, Hargreaves IP et al (2011) Mutations in the mitochondrial complex I assembly factor NDUFAF1 cause fatal infantilehypertrophic cardiomyopathy. J Med Genet 48:691–697

    Article  PubMed  CAS  Google Scholar 

  78. Ferreira M, Torraco A, Rizza T et al (2011) Progressive cavitating leukoencephalopathy associated with respiratory chain complex I deficiency and a novel mutation in NDUFS1. Neurogenetics 12:9–17

    Article  PubMed  CAS  Google Scholar 

  79. Berger I, Hershkovitz E, Shaag A et al (2008) Mitochondrial complex I deficiency caused by a deleterious NDUFA11 mutation. Ann Neurol 63:405–408

    Article  PubMed  CAS  Google Scholar 

  80. Ogilvie I, Kennaway NG, Shoubridge EA (2005) A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy. J Clin Invest 115:2784–2792

    Article  PubMed  CAS  Google Scholar 

  81. Sugiana C, Pagliarini DJ, McKenzie M et al (2008) Mutation of C20orf7 disrupts complex I assembly and causes lethal neonatal mitochondrial disease. Am J Hum Genet 83:468–478

    Article  PubMed  CAS  Google Scholar 

  82. Saada A, Edvardson S, Rapoport M et al (2008) C6ORF66 is an assembly factor of mitochondrial complex I. Am J Hum Genet 82:32–38

    Article  PubMed  CAS  Google Scholar 

  83. Dunning CJ, McKenzie M, Sugiana C et al (2007) Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease. EMBO J 26:3227–3237

    Article  PubMed  CAS  Google Scholar 

  84. Gerards M, van den Bosch BJC, Danhauser K et al (2011) Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene. Brain 134:210–219

    Article  PubMed  Google Scholar 

  85. Haack TB, Danhauser K, Haberberger B et al (2010) Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nat Genet 42:1131–1134

    Article  PubMed  CAS  Google Scholar 

  86. Saada A, Edvardson S, Shaag A et al (2012) Combined OXPHOS complex I and IV defect, due to mutated complex I assembly factor C20ORF7. J Inherit Metab Dis 35:125–131

    Article  PubMed  CAS  Google Scholar 

  87. Calvo SE, Tucker EJ, Compton A et al (2010) High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nat Genet 42:851–858

    Article  PubMed  CAS  Google Scholar 

  88. Pagliarini DJ, Calvo SE, Chang B et al (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112–123

    Article  PubMed  CAS  Google Scholar 

  89. Ghezzi D, Goffrini P, Uziel G et al. (2009) SDHAF1, encoding a LYR complex II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy. Nat Genet 41:654–656

    Article  PubMed  CAS  Google Scholar 

  90. Fernandez-Vizarra E, Bugiani M, Goffrini P et al (2007) Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalomyopathy. Hum Mol Genet 16:1241–1252

    Article  PubMed  CAS  Google Scholar 

  91. Visapaa I, Fellman V, Vesa J et al (2002) GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Am J Hum Genet 71:863–876

    Article  PubMed  Google Scholar 

  92. de Lonlay P, Valnot I, Barrientos A et al (2001) A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nat Genet 29:57–60

    Article  PubMed  CAS  Google Scholar 

  93. Blazquez A, Gil-Borlado MC, Moran M et al (2009) Infantile mitochondrial encephalomyopathy with unusual phenotype caused by a novel BCS1L mutation in an isolated complex III-deficient patient. Neuromuscul Disord 19:143–146

    Article  PubMed  Google Scholar 

  94. Hinson JT, Fantin VR, Schonberger J et al (2007) Missense mutations in the BCS1L gene as a cause of the Bjornstad syndrome. N Engl J Med 356:809–819

    Article  PubMed  CAS  Google Scholar 

  95. Ghezzi D, Arzuffi P, Zordan M et al (2011) Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in human and flies. Nat Genet 43:259–263

    Article  PubMed  CAS  Google Scholar 

  96. DiMauro S, Servidei S, Zeviani M et al (1987) Cytochrome c oxidase deficiency in Leigh syndrome. Ann Neurol 22:498–506

    Article  PubMed  CAS  Google Scholar 

  97. Van Coster R, Lombes A, DeVivo DC et al (1991) Cytochrome c oxidase-associated Leigh syndrome: phenotypic features and pathogenetic speculations. J Neurol Sci 104:97–111

    Article  PubMed  Google Scholar 

  98. Zhu Z, Yao J, Johns T et al (1998) SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet 20:337–343

    Article  PubMed  CAS  Google Scholar 

  99. Tiranti V, Hoertnagel K, Carrozzo R et al (1998) Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am J Hum Genet 63:1609–1621

    Article  PubMed  CAS  Google Scholar 

  100. Tiranti V, Jaksch M, Hofmann S et al (1999) Loss-of-function mutations of SURF-1 are specifically associated with Leigh syndrome with cytochrome c oxidase deficiency. Ann Neurol 46:161–166

    Article  PubMed  CAS  Google Scholar 

  101. Moslemi AR, Tulinius M, Darin N et al (2003) SURF1 gene mutations in three cases with Leigh syndrome and cytochrome c oxidase deficiency. Neurology 61:991–993

    Article  PubMed  CAS  Google Scholar 

  102. Coenen MJH, Smeitink JAM, Pots JM et al (2006) Sequence analysis of the structural nuclear encoded subunits and assembly genes of cytochrome c oxidase in a cohort of 10 isolated complex IV-deficient patients revealed five mutations. J Child Neurol 21:508–511

    PubMed  Google Scholar 

  103. Bohm M, Pronicka E, Karczmarewicz E et al (2006) Retrospective, multicentric study of 180 children with cytochrome c oxidase deficiency. Pediatr Res 59:21–26

    Article  PubMed  Google Scholar 

  104. Darin N, Moslemi AR, Lebon S et al (2003) Genotypes and clinical phenotypes in children with cytochrome c oxidase deficiency. Neuropediatrics 34:311–317

    Article  PubMed  CAS  Google Scholar 

  105. Sue CM, Karadimas C, Checcarelli N et al (2000) Differential features of patients with mutations in two COX assembly genes, SURF-1 and SCO2. Ann Neurol 47:589–595

    Article  PubMed  CAS  Google Scholar 

  106. Pequignot MO, Dey R, Zeviani M et al (2001) Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome c oxidase deficiency. Hum Mutat 17:374–381

    Article  PubMed  CAS  Google Scholar 

  107. Rossi A, Biancheri R, Bruno C et al (2003) Leigh syndrome with COX deficiency and SURF1 gene mutations: MR imaging findings. Am J Neuradiol 24:1188–1191

    Google Scholar 

  108. Rahman S, Brown RM, Chong WK et al (2001) A SURF1 gene mutation presenting as isolated leukodystrophy. Ann Neurol 49:797–800

    Article  PubMed  CAS  Google Scholar 

  109. Salviati L, Freehauf C, Sacconi S et al (2004) Novel SURF1 mutation in a child with subacute encephalopathy and without the radiological features of Leigh syndrome. Am J Med Genet 128A:195–198

    Article  PubMed  Google Scholar 

  110. Tay SKH, Sacconi S, Akman HO et al (2005) Unusual clinical presentation in four cases of Leigh disease, cytochrome c oxidase deficiency, and SURF1 gene mutations. J Child Neurol 20:670–674

    Article  PubMed  Google Scholar 

  111. Papadopoulou LC, Sue CM, Davidson MM et al (1999) Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nat Genet 23:333–337

    Article  PubMed  CAS  Google Scholar 

  112. Jaksch M, Ogilvie I, Yao J et al (2000) Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency. Hum Mol Genet 9:795–801

    Article  PubMed  CAS  Google Scholar 

  113. Vesela K, Hulkova H, Hansikova H et al (2008) Structural analysis of tissues affected by cytochrome c oxidase deficiency due to mutations in the SCO2 gene. APMIS 116:41–49

    Article  PubMed  Google Scholar 

  114. Knuf M, Faber J, Huth RG et al (2007) Identification of a novel compound heterozygote SCO2 mutation cytochrome c oxidase deficient fatal infantile cardioencephalomyopathy. Acta Paediatr 96:128–134

    Article  Google Scholar 

  115. Tay SKH, Shanske S, Kaplan P, DiMauro S (2004) Association of mutations in SCO2, a cytochrome c oxidase assembly gene, with early fetal lethality. Arch Neurol 61:950–952

    Article  PubMed  Google Scholar 

  116. Leary SC, Mattman A, Wai T et al (2006) A hemizygous SCO2 mutation in an early onset rapidly progressive, fatal cardiomyopathy. Mol Genet Metab 89:129–133

    Article  PubMed  CAS  Google Scholar 

  117. Jaksch M, Horvath R, Horn N et al (2001) Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy. Neurology 57:1440–1446

    Article  PubMed  CAS  Google Scholar 

  118. Jaksch M, Paret C, Stucka R et al (2001) Cytochrome c oxidase deficiency due to mutations in SCO2, encoding a mitochondrial copper-binding protein, is rescued by copper in human myoblasts. Hum Mol Genet 10:3025–3035

    Article  PubMed  CAS  Google Scholar 

  119. Salviati L, Hernandez-Rosa E, Walker WF et al (2002) Copper supplementation restores cytochrome c oxidase activity in cultured cells from patients with SCO2 mutations. Biochem J 363:321–327

    Article  PubMed  CAS  Google Scholar 

  120. Freisinger P, Horvath R, Macmillan C et al (2004) Reversion of hypertrophic cardiomyopathy in a patient with deficiency of the mitochondrial copper binding protein Sco2: is there a potential effect of copper? J Inherit Metab Dis 27:67–79

    Article  PubMed  CAS  Google Scholar 

  121. Tarnopolsky MA, Bourgeois JM, Fu MH et al (2004) Novel SCO2 mutation (G1521A) presenting as a spinal muscular atrophy type I phenotype. Am J Med Genet A 125A:310–314

    Article  PubMed  Google Scholar 

  122. Salviati L, Sacconi S, Rasalan MM et al (2002) Cytochrome c oxidase deficiency due to a novel SCO2 mutation mimics Werdnig-Hoffmann disease. Arch Neurol 59:862–865

    Article  PubMed  Google Scholar 

  123. Pronicki M, Kowalski P, Piekutowska-Abramczuk D et al (2010) A homozygous mutation in the SCO2 gene causes a spinal muscular atrophy like presentation with stridor and respiratory insufficiency. Eur J Paediatr Neurol 14:253–260

    Article  PubMed  Google Scholar 

  124. Oskoui M, Davidzon G, Pascual J et al (2006) Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene. Arch Neurol 63:1122–1126

    Article  PubMed  Google Scholar 

  125. Valnot I, Osmond S, Gigarel N et al (2000) Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. Am J Hum Genet 67:1104–1109

    PubMed  CAS  Google Scholar 

  126. Brosel S, Yang H, Tanji K et al (2010) Unexpected vascular enrichment of SCO1 over SCO2 in mammalian tissues. Am J Pathol 177:2541–2548

    Article  PubMed  CAS  Google Scholar 

  127. Horvath R, Lochmuller H, Stucka R et al (2000) Characterization of human SCO1 and COX17 genes in mitochondrial cytochrome-c-oxidase deficiency. Biochem Biophys Res Commun 276:530–533

    Article  PubMed  CAS  Google Scholar 

  128. Sacconi S, Salviati L, Sue CM et al (2003) Mutation screening in patients with isolated cytochrome c oxidase deficiency. Pediatr Res 53:224–230

    Article  PubMed  CAS  Google Scholar 

  129. Valnot I, von Kleist-Retzow JC, Barrientos A et al (2000) A mutation in the human heme-A: farnesyltransferase gene (COX 10) causes cytochrome c oxidase deficiency. Hum Mol Genet 9:1245–1249

    Article  PubMed  CAS  Google Scholar 

  130. Antonicka H, Leary SC, Guercin GH et al (2003) Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and acount for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. Hum Mol Genet 12:2693–2702

    Article  PubMed  CAS  Google Scholar 

  131. Kennaway NG, Carrero-Valenzuela RD, Ewart G et al (1990) Isoforms of mammalian cytochrome c oxidase: correlation with human cytochrome c oxidase deficiency. Pediatr Res 28:529–535

    Article  PubMed  CAS  Google Scholar 

  132. Antonicka H, Mattman A, Carlson CG et al (2003) Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy. Am J Hum Genet 72:101–114

    Article  PubMed  CAS  Google Scholar 

  133. Oquendo CE, Antonicka H, Shoubridge EA et al (2004) Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome. J Med Genet 41:540–544

    Article  PubMed  CAS  Google Scholar 

  134. Bugiani M, Tiranti V, Farina L et al (2005) Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency. J Med Genet 42:e28

    Article  PubMed  CAS  Google Scholar 

  135. Huigsloot M, Nijtmans LGJ, Szklarczyk R et al (2011) A mutation in C2orf64 causes impaired cytochrome c oxidase assembly and mitochondrial cardiomyopathy. Am J Hum Genet 88:488–493

    Article  PubMed  CAS  Google Scholar 

  136. Ghezzi D, Saada A, D’Adamo P et al (2008) FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency. Am J Hum Genet 83:415–423

    Article  PubMed  CAS  Google Scholar 

  137. Mootha VK, Lepage P, Miller K et al (2003) Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc Nat Acad Sci U S A 100:605–610

    Article  CAS  Google Scholar 

  138. Morin C, Mitchell G, Larochelle J et al (1993) Clinical, metabolic, and genetic aspects of cytochrome c oxidase deficiency in Saguenay-Lac-Saint-Jean. Am J Hum Genet 53:488–496

    PubMed  CAS  Google Scholar 

  139. Xu F, Morin C, Mitchell G et al (2004) The tole of LRPPRC (leucine-rich pentatricopeptide repeat cassette) gene in cytochrome oxidase assembly: mutation causes lowered levels of COX (cytochrome c oxidase) I and COX III mRNA. Biochem J 382:331–336

    Article  PubMed  CAS  Google Scholar 

  140. Weraarpachai W, Antonicka H, Sasarman F et al (2009) Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome. Nat Genet 41:833–837

    Article  PubMed  CAS  Google Scholar 

  141. Seeger J, Schrank B, Pyle A et al (2010) Clinical and neuropathological findings in patients with TACO1 mutations. Neuromuscul Disord 20:720–724

    Article  PubMed  Google Scholar 

  142. Tiranti V, D’Adamo P, Briem E et al (2004) Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein. Am J Hum Genet 74:239–252

    Article  PubMed  CAS  Google Scholar 

  143. Tiranti V, Viscomi C, Hildebrandt T et al (2009) Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat Med 15:200–205

    Article  PubMed  CAS  Google Scholar 

  144. Mineri R, Rimoldi M, Burlina AB et al (2008) Identification ofnew mutations in the ETHE1 gene in a cohort of 14 patients presenting with ethylmalonic encephalopathy. J Med Genet 45:473–478

    Article  PubMed  CAS  Google Scholar 

  145. De Meirleir L, Seneca S, Lissens W et al (2004) Respiratory chain complex V deficiency due to a mutation in the assembly gene ATP12. J Med Genet 41:120–124

    Article  PubMed  CAS  Google Scholar 

  146. Honzik T, Tesarova M, Mayr JA et al (2010) Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation. Arch Dis Child 95:296–301

    Article  PubMed  Google Scholar 

  147. Cameron JM, Levandovskiy V, MacKay N et al (2011) Complex V TMEM70 deficiency results in mitochondrial nucleoid disorganization. Mitochondrion 11:191–199

    Article  PubMed  CAS  Google Scholar 

  148. Shchelochkov OA, Li FY, Wang J et al (2010) Milder clinical course of type IV 3-methylglutaconic aciduria due to a novel mutation in TMEM70. Mol Genet Metab 101:282–285

    Article  PubMed  CAS  Google Scholar 

  149. Spiegel R, Khayat M, Shalev SA et al (2011) TMEM70 mutations are a common cause of nuclear encoded ATP synthase assembly defect: further delineation of a new syndrome. J Med Genet 48:177–182

    Article  PubMed  Google Scholar 

  150. Chrzanowska-Lightowlers ZMA, Horvath R, Lightowlers RN (2011) 175th ENMC International workshop: mitochondrial protein synthesis in health and disease, 25–27th June 2010, Naarden, The Netherlands. Neuromusc Dis 21:142–147

    Article  Google Scholar 

  151. Tucker EJ, Hershman SG, Kohrer C et al (2011) Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation. Cell Metab 14:428–434

    Article  PubMed  CAS  Google Scholar 

  152. Scheper GC, van der Klok T, van Andel RJ et al (2007) Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet 39:534–539

    Article  PubMed  CAS  Google Scholar 

  153. Synofzik M, Schicks J, Lindig T et al (2011) Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation. J Med Genet 48:713–715

    Article  PubMed  CAS  Google Scholar 

  154. Smits P, Antonicka H, van Hasselt PM et al (2011) Mutation in subdomain G1 is associated with combined OXPHOS deficiency in fibroblasts but not in muscle. Eur J Hum Genet 19:275–279

    Article  PubMed  CAS  Google Scholar 

  155. Smits P, Saada A, Wortmann SB et al (2011) Mutation in mitopchondrial ribosomal protein MRPS22 leads to Cornelia de Lange phenotype, brain abnormalities and hypertrophic cardiomyopathy. Eur J Hum Genet 19:394–399

    Article  PubMed  CAS  Google Scholar 

  156. Zeharia A, Shaag A, Pappo O et al (2009) Acute infantile liver failure due to mutations in the TRMU gene. Am J Hum Genet 85:401–407

    Article  PubMed  CAS  Google Scholar 

  157. Schara U, von Kleist-Retzow J-C, Lainka E et al (2011) Acute liver failure with subsequent cirrhosis as the primary manifestation of TRMU mutations. J Inherit Metab Dis 34:197–201

    Article  PubMed  Google Scholar 

  158. Uusimaa J, Jungbluth H, Fratter C et al (2011) Reversible infantile respiratory chain deficiency is a unique, genetically heterogeneous mitochondrial disease. J Med Genet 48:660–668

    Article  PubMed  CAS  Google Scholar 

  159. Claypool SM, Koehler CM (2012) The complexity of cardiolipin in health and disease. Trends Biochem Sci 37:32–41

    Article  PubMed  CAS  Google Scholar 

  160. Schlame M, Ren M (2006) Barth syndrome, a human disorder of cardiolipin metabolism. FEBS Lett 580:5450–5455

    Article  PubMed  CAS  Google Scholar 

  161. Mitsuhashi S, Ohkuma A, Talim B et al (2011) A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis. Am J Hum Genet 88:845–851

    Article  PubMed  CAS  Google Scholar 

  162. Gutierrez-Rios P, Kalra AA, Wilson JD et al (2012) Congenital megaconial myopathy due to a novel defect in the choline kinase beta (CHKB) gene. Arch Neurol 69(5):657–661

    Article  PubMed  Google Scholar 

  163. Mitsuhashi S, Hatakeyama H, Karahashi M et al (2011) Muscle choline kinase beta defect causes mitochondrial dysfunction and increased mitophagy. Hum Mol Genet 20:3841–3851

    Article  PubMed  CAS  Google Scholar 

  164. DiMauro S, Hirano M, Schon EA (2006) Approaches to the treatment of mitochondrial diseases. Muscle Nerve 34:265–283

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work has been supported by NICHD grant P01-H23062 and by the Marriott Mitochondrial Disorder Clinical Research Fund (MMDCRF).

Author information

Authors and Affiliations

  1. College of Physicians & Surgeons, 630 West 168th Street, 10032, New York, NY, USA

    Salvatore DiMauro M.D.

  2. Neurology Department, H. Houston Merritt Clinical Research Center, Columbia University Medical Center, New York, NY, USA

    Salvatore DiMauro M.D.

  3. Department of Neurology, Columbia University Medical Center, New York, NY, USA

    Valentina Emmanuele M.D.

Authors
  1. Salvatore DiMauro M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valentina Emmanuele M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Salvatore DiMauro M.D. .

Editor information

Editors and Affiliations

  1. , Dept. of Molecular and Human Genetics, Baylor College of Medicine, Baylor Plaza ONE, Houston, 77030, Texas, USA

    Lee-Jun C. Wong

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

DiMauro, S., Emmanuele, V. (2013). The Clinical Spectrum of Nuclear DNA-Related Mitochondrial Disorders. In: Wong, LJ. (eds) Mitochondrial Disorders Caused by Nuclear Genes. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3722-2_1

Download citation

Publish with us

Policies and ethics

Search

Navigation