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.
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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
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 60:1354–1356
Alpers BJ (1931) Diffuse progressive degeneration of the gray matter of the cerebrum. Arch Neurol Psychiatry 25:469–505
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 153:133–135
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 57:921–924
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 22:498–499
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 128:723–731
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 59
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 63:107–111
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 11:770–776
Graziewicz MA, Longley MJ, Copeland WC (2006) DNA Polymerase γ in mitochondrial DNA replication and repair. Chem Rev 106:383–405
Haas R, Stumpf DA, Parks JK, Eguren L (1981) Inhibitory effects of sodium valproate on oxidative phosphorylation. Neurology 31:1473–1476
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 77:430–441
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 129:1674–1684
Janssen AJ, Smeitink JA, van den Heuvel LP (2003) Some practical aspects of providing a diagnostic service for respiratory chain defects. Ann Clin Biochem 40:3–8
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 52:211–219
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 56:454–455
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 15:123–134
Longley MJ, Graziewicz MA, Bienstock RJ, Copeland WC (2005) Consequences of mutations in human DNA polymerase γ. Gene 354:125–131
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 14:1907–1920
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 45:54–58
Naviaux RK, Nguyen KV (2004) POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. Ann Neurol 55:706–712
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 65:1493–1495
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 52:311–317
Smeitink J, Sengers R, Trijbels F, van den Heuvel L (2001) Human NADH: ubiquinone oxidoreductase. J Bioenerg Biomembr 33:259–266
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 376:56–59
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 61:1811–1813
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 11:547–549
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 13:133–142
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 63:1251–1257
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 64:1204–1208
Wolf NI, Smeitink JA (2002) Mitochondrial disorders: a proposal for consensus diagnostic criteria in infants and children. Neurology 59:1402–1405
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 339:309–311
Acknowledgements
Research at the NCMD is funded by the Radboud University Nijmegen Medical Centre, the Prinses Beatrix Fonds, the Dutch Scientific Organization and the European Union (EUMITOCOMBAT and MitoCircle grants).
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de Vries, M.C., Rodenburg, R.J., Morava, E. et al. Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations. Eur J Pediatr 166, 229–234 (2007). https://doi.org/10.1007/s00431-006-0234-9
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DOI: https://doi.org/10.1007/s00431-006-0234-9