European Journal of Pediatrics

, Volume 166, Issue 3, pp 229–234

Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations

  • Maaike C. de Vries
  • Richard J. Rodenburg
  • Eva Morava
  • Edwin P. M. van Kaauwen
  • Henk ter Laak
  • Reinier A. Mullaart
  • Irina N. Snoeck
  • Peter M. van Hasselt
  • Peter Harding
  • Lambert P. W. van den Heuvel
  • Jan A. M. Smeitink
Original Paper

Abstract

Failure to thrive, feeding difficulties, variable forms of infantile epilepsy or psychomotor developmental delay and hypotonia were the most frequent clinical disease presentations in eight children with combined oxidative phosphorylation enzyme complex deficiencies carrying mutations in the polymerase gamma (POLG1) gene. Five out of eight patients developed severe liver dysfunction during the course of the disease. Three of these patients fulfilled the disease criteria for Alpers syndrome. Most children showed deficiencies of respiratory chain enzyme complexes I and III, in combination with complex II, complex IV and/or PDHc in muscle, whereas in fibroblasts normal enzyme activities were measured. All children carried homozygous or compound heterozygous mutations in the POLG1 gene, including two novel mutations in association with mtDNA depletion. Conclusion We suggest performing POLG1 mutation analysis in children with combined oxidative phosphorylation deficiencies in muscle, even if the clinical picture is not Alpers syndrome.

Keywords

POLG1 Combined OXPHOS deficiencies Mitochondrial medicine 

Abbreviations

ATP

adenosine triphosphate

CSF

cerebrospinal fluid

ECG

electrocardiography

EEG

electroencephalography

MRI

magnetic resonance imaging

mtDNA

mitochondrial DNA

OXPHOS

oxidative phosphorylation system

PCR

polymerase chain reaction

PDHc

pyruvate dehydrogenase complex

PEO

progressive external ophthalmoplegia

POLG

polymerase gamma

References

  1. 1.
    Agostino A, Valetta L, Chinnery PF, Ferrari G, Carrara F, Taylor RW, Schaefer AM, Turnbull DM, Tiranti V, Zeviani M (2003) Mutations of SLC25A4, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO). Neurology 60:1354–1356PubMedGoogle Scholar
  2. 2.
    Alpers BJ (1931) Diffuse progressive degeneration of the gray matter of the cerebrum. Arch Neurol Psychiatry 25:469–505Google Scholar
  3. 3.
    Chabrol B, Mancini J, Chretien D, Rustin P, Munnich A, Pinsard N (1994) Valproate induced hepatic failure in a case of cytochrome c oxidase deficiency. Eur J Pediatr 153:133–135PubMedGoogle Scholar
  4. 4.
    Davidzon G, Mancuso M, Ferraris S, Quinzii C, Hirano M, Peters HL, Kirby D, Thorburn DR, DiMauro S (2005) POLG mutations and Alpers syndrome. Ann Neurol 57:921–924PubMedCrossRefGoogle Scholar
  5. 5.
    Di Fonzo A, Bordoni A, Crimi M, Sara G, Del Bo R, Bresolin N, Comi GP (2003) POLG mutations in sporadic mitochondrial disorders with multiple mtDNA deletions. Hum Mutat 22:498–499PubMedCrossRefGoogle Scholar
  6. 6.
    Ferrari G, Lamantea E, Donati A, Filosto M, Briem E, Carrara F, Parini R, Simonati A, Santer R, Zeviani M (2005) Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-γa. Brain 128:723–731PubMedCrossRefGoogle Scholar
  7. 7.
    Gonzalez E, Blázquez A, Bornstein B, Martin MG, Campos Y, Cabello A, Arenas J, Garesse R (2004) POLG and Twinkle mutations causing progressive external ophthalmoplegia and mitochondrial myopathy. Euromit Abstract Book, p 59Google Scholar
  8. 8.
    González-Vioque E, Blázquez A, Fernández-Moreira D, Bornstein B, Bautista J, Arpa J, Navarro C, Campos Y, Fernández-Moreno MA, Garesse R, Arenas J, Martin MG (2006) Association of novel POLG mutations and multiple mitochondrial DNA deletions with variable clinical phenotypes in a Spanish population. Arch Neurol 63:107–111PubMedCrossRefGoogle Scholar
  9. 9.
    Graziewicz MA, Longley MJ, Bienstock RJ, Zeviani M, Copeland WC (2004) Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia. Nat Struct Mol Biol 11:770–776PubMedCrossRefGoogle Scholar
  10. 10.
    Graziewicz MA, Longley MJ, Copeland WC (2006) DNA Polymerase γ in mitochondrial DNA replication and repair. Chem Rev 106:383–405PubMedCrossRefGoogle Scholar
  11. 11.
    Haas R, Stumpf DA, Parks JK, Eguren L (1981) Inhibitory effects of sodium valproate on oxidative phosphorylation. Neurology 31:1473–1476PubMedGoogle Scholar
  12. 12.
    Hakonen AH, Heiskanen S, Juvonen V, Lappalainen I, Luoma PT, Rantamaki M, Goethem GV, Lofgren A, Hackman P, Paetau A, Kaakkola S, Majamaa K, Varilo T, Udd B, Kaariainen H, Bindoff LA, Suomalainen A (2005) Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet 77:430–441PubMedCrossRefGoogle Scholar
  13. 13.
    Horvath R, Hudson G, Ferrari G, Fütterer N, Ahola S, Lamantea E, Prokisch H, Lochmüller H, McFarland R, Ramesh V, Klopstock T, Freisinger P, Slavi F, Mayr JA, Santer R, Tesarova M, Zeman J, Udd B, Taylor RW, Turnbull D, Suomalainen A, Zeviani M, Hanna M, Fialho D, Chinnery PF (2006) Phenotypic spectrum associated with mutations of the mitochondrial polymerase γ gene. Brain 129:1674–1684Google Scholar
  14. 14.
    Janssen AJ, Smeitink JA, van den Heuvel LP (2003) Some practical aspects of providing a diagnostic service for respiratory chain defects. Ann Clin Biochem 40:3–8PubMedCrossRefGoogle Scholar
  15. 15.
    Lamantea E, Tiranti V, Bordoni A, Toscano A, Bono F, Servidei S, Papadimitriou A, Spelbrink H, Silvestri L, Casari G, Comi GP, Zeviani M (2002) Mutations of mitochondrial DNA polymerase gamma A are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia. Ann Neurol 52:211–219PubMedCrossRefGoogle Scholar
  16. 16.
    Lamantea E, Zeviani M (2004) Sequence analysis of familial PEO shows additional mutations associated with the 752C→T and 3527C→T changes in the POLG1 gene. Ann Neurol 56:454–455PubMedCrossRefGoogle Scholar
  17. 17.
    Loeffen JL, Smeitink JAM, Trijbels JM, Janssen AJ, Triepels RH, Sengers RC, van den Heuvel LP (2000) Isolated complex I deficiency in children: clinical, biochemical and genetic aspects. Hum Mutat 15:123–134PubMedCrossRefGoogle Scholar
  18. 18.
    Longley MJ, Graziewicz MA, Bienstock RJ, Copeland WC (2005) Consequences of mutations in human DNA polymerase γ. Gene 354:125–131PubMedCrossRefGoogle Scholar
  19. 19.
    Luoma PT, Luo N, Loscher WN, Farr CL, Horvath R, Wanschitz J, Kiechl S, Kaguni LS, Suomalainen A (2005) Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome. Hum Mol Genet 14:1907–1920PubMedCrossRefGoogle Scholar
  20. 20.
    Naviaux RK, Nyhan WL, Barshop BA, Poulton J, Markusic D, Karpinski NC, Haas RH (1999) Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers syndrome. Ann Neurol 45:54–58PubMedCrossRefGoogle Scholar
  21. 21.
    Naviaux RK, Nguyen KV (2004) POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. Ann Neurol 55:706–712PubMedCrossRefGoogle Scholar
  22. 22.
    Nguyen KV, Ostergaard E, Ravn SH, Balslev T, Danielsen ER, Vardag A, McKiernan PJ, Gray G, Naviaux RK (2005) POLG mutations in Alpers syndrome. Neurology 65:1493–1495PubMedCrossRefGoogle Scholar
  23. 23.
    Salviati L, Sacconi S, Mancuso M, Otaegui D, Camaño P, Marina A, Rabinowitz S, Shiffman R, Thompson K, Wilson CM, Feigenbaum A, Naina AB, Hirano M, Bonilla E, DiMauro S, Vu TH (2002) Mitochondrial DNA depletion and dGK gene mutations. Ann Neurol 52:311–317PubMedCrossRefGoogle Scholar
  24. 24.
    Smeitink J, Sengers R, Trijbels F, van den Heuvel L (2001) Human NADH: ubiquinone oxidoreductase. J Bioenerg Biomembr 33:259–266PubMedCrossRefGoogle Scholar
  25. 25.
    Taanman JW, Schapira AH (2005) Analysis of the trinucleotide CAG repeat from the DNA polymerase gamma gene (POLG) in patients with Parkinson’s disease. Neurosci Lett 376:56–59PubMedCrossRefGoogle Scholar
  26. 26.
    Van Goethem G, Mercelis R, Lofgren A, Seneca S, Ceuterick C, Martin JJ, Van Broeckhoven C (2003) Patient homozygous for a recessive POLG mutation presents with features of MERRF. Neurology 61:1811–1813PubMedGoogle Scholar
  27. 27.
    Van Goethem G, Schwartz M, Lofgren A, Dermaut B, Van Broeckhoven C, Vissing J (2003) Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. Eur J Hum Genet 11:547–549PubMedCrossRefGoogle Scholar
  28. 28.
    Van Goethem G, Martin JJ, Dermaut B, Lofgren A, Wibail A, Ververken D, Tack P, Dehaene I, Van Zandijcke M, Moonen M, Ceuterick C, De Jonghe P, Van Broeckhoven C (2003) Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia. Neuromuscul Disord 13:133–142PubMedCrossRefGoogle Scholar
  29. 29.
    Van Goethem G, Luoma P, Rantamaki M, Al Memar A, Kaakkola S, Hackman P, Krahe R, Lofgren A, Martin JJ, De Jonghe P, Suomalainen A, Udd B, Van Broeckhoven C (2004) POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. Neurology 63:1251–1257PubMedGoogle Scholar
  30. 30.
    Winterthun S, Ferrari G, He L, Taylor RW, Zeviani M, Turnbull DM, Engelsen BA, Moen G, Bindoff LA (2005) Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations. Neurology 64:1204–1208PubMedGoogle Scholar
  31. 31.
    Wolf NI, Smeitink JA (2002) Mitochondrial disorders: a proposal for consensus diagnostic criteria in infants and children. Neurology 59:1402–1405PubMedGoogle Scholar
  32. 32.
    Zeviani M, Servidei S, Gellera C, Bertini E DiMauro S, DiDonato S (1989) An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region. Nature 339:309–311PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Maaike C. de Vries
    • 1
    • 6
  • Richard J. Rodenburg
    • 1
  • Eva Morava
    • 1
  • Edwin P. M. van Kaauwen
    • 1
  • Henk ter Laak
    • 1
  • Reinier A. Mullaart
    • 2
  • Irina N. Snoeck
    • 3
  • Peter M. van Hasselt
    • 4
  • Peter Harding
    • 5
  • Lambert P. W. van den Heuvel
    • 1
  • Jan A. M. Smeitink
    • 1
  1. 1.Nijmegen Centre for Mitochondrial Disorders, Departments of Pediatrics, Laboratory of Pediatrics and Neurology and Department of PathologyRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  2. 2.Department of Child NeurologyRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  3. 3.Department of NeurologyJuliana Children’s HospitalDen HaagThe Netherlands
  4. 4.Department of PediatricsAcademic Medical Centre UtrechtUtrechtThe Netherlands
  5. 5.Department of PediatricsKlinikum OldenburgOldenburgGermany
  6. 6.Department of PediatricsRadboud University Nijmegen Medical CentreNijmegenThe Netherlands

Personalised recommendations