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Clinical and molecular features of mitochondrial DNA depletion syndromes

  • SSIEM Symposium 2008
  • Published:
Journal of Inherited Metabolic Disease

Summary

Mitochondrial DNA depletion syndromes (MDSs) form a group of autosomal recessive disorders characterized by profoundly decreased mitochondrial DNA copy numbers in affected tissues. Three main clinical presentations are known: myopathic, encephalomyopathic and hepatocerebral. The first is associated with mutations in thymidine kinase 2 (TK2) and p53-induced ribonucleotide reductase B subunit (RRM2B); the second with mutations in succinate synthase A (SUCLA2) and B (SUCLG1); the third with mutations in Twinkle (PEO1), pol-γA (POLG1), deoxyguanosine kinase (DGUOK) and MPV17 (MPV17). In this work, we review the MDS-associated phenotypes and present our own experience of 32 MDS patients, with the aim of defining the mutation frequency of the known genes, the clinical spectrum of the diseases, and the genotype–phenotype correlations. Five of our patients carried previously unreported mutations in one of the eight MDS genes.

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Abbreviations

CK:

creatine kinase

COX:

cytochrome-c oxidase

MDS:

mitochondrial DNA depletion syndrome

mtDNA:

mitochondrial DNA

NAA:

N-acetylaspartate

OXPHOS:

oxidative phosphorylation

RC:

respiratory chain

RRF:

ragged-red fibres

SANDO:

sensory ataxic neuropathy with dysarthria and ophthalmoplegia

SCAE:

spinocerebellar ataxia-epilepsy syndrome

SCS:

succinyl-CoA synthase

SDH:

succinate dehydrogenase

SMA:

spinal muscular atrophy

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Acknowledgments

We thank the patients and their families for the collaboration, understanding and support given to our work. This work was supported by the Pierfranco and Luisa Mariani Foundation, Fondazione Telethon-Italy grant no. GGP07019, Italian Ministry of University and Research (FIRB 2003 – project RBLA038RMA), the Italian Ministry of Health RF2006 ex 56/05/21, Marie Curie intra-European fellowship (FP6-2005-Mobility-5) no. 040140-MAD, MITOCIRCLE and EUMITOCOMBAT (LSHM-CT-2004–503116) network grants from the European Union framework program 6.

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Authors and Affiliations

  1. Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute ‘C. Besta’, Via Temolo, 4, 20126, Milan, Italy

    A. Spinazzola, F. Invernizzi, F. Carrara, E. Lamantea & M. Zeviani

  2. Metabolic and Muscular Unit, Clinic of Pediatric Neurology, AOU Meyer, Florence, Italy

    A. Donati

  3. Pediatric II, Institute ‘G. Gaslini’, Genoa, Italy

    M. DiRocco

  4. Department of Child and Adolescent Neuropsychiatry, Spedali Civili, Brescia, Italy

    I. Giordano

  5. Medical Faculty, Institute of Anatomy, University of Ljubljani, Ljubljana, Slovenia

    M. Meznaric-Petrusa

  6. Department of Genetics, Biology of Microrganisms, Anthropology and Evolution, University of Parma, Parma, Italy

    E. Baruffini & I. Ferrero

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  1. A. Spinazzola
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  2. F. Invernizzi
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  3. F. Carrara
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  4. E. Lamantea
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  5. A. Donati
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  6. M. DiRocco
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  7. I. Giordano
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  8. M. Meznaric-Petrusa
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  9. E. Baruffini
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  10. I. Ferrero
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  11. M. Zeviani
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Corresponding author

Correspondence to M. Zeviani.

Additional information

Communicating editor: Gary Brown

Competing interests: None declared

References to electronic databases: MDS myopathic form: OMIM #609560. MDS encephalomyopathic form: OMIM #612073. MDS, encephalomyopathic form, with renal tubulopathy: OMIM #612075. MDS hepatocerebral form: OMIM #251880.

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Spinazzola, A., Invernizzi, F., Carrara, F. et al. Clinical and molecular features of mitochondrial DNA depletion syndromes. J Inherit Metab Dis 32, 143–158 (2009). https://doi.org/10.1007/s10545-008-1038-z

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  • DOI: https://doi.org/10.1007/s10545-008-1038-z

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