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Journal of Neurology

, Volume 263, Issue 5, pp 961–972 | Cite as

Expanded phenotypic spectrum of the m.8344A>G “MERRF” mutation: data from the German mitoNET registry

  • Judith Altmann
  • Boriana Büchner
  • Aleksandra Nadaj-Pakleza
  • Jochen Schäfer
  • Sandra Jackson
  • Diana Lehmann
  • Marcus Deschauer
  • Robert Kopajtich
  • Ronald Lautenschläger
  • Klaus A. Kuhn
  • Kathrin Karle
  • Ludger Schöls
  • Jörg B. Schulz
  • Joachim Weis
  • Holger Prokisch
  • Cornelia Kornblum
  • Kristl G. ClaeysEmail author
  • Thomas Klopstock
Original Communication

Abstract

The m.8344A>G mutation in the MTTK gene, which encodes the mitochondrial transfer RNA for lysine, is traditionally associated with myoclonic epilepsy and ragged-red fibres (MERRF), a multisystemic mitochondrial disease that is characterised by myoclonus, seizures, cerebellar ataxia, and mitochondrial myopathy with ragged-red fibres. We studied the clinical and paraclinical phenotype of 34 patients with the m.8344A>G mutation, mainly derived from the nationwide mitoREGISTER, the multicentric registry of the German network for mitochondrial disorders (mitoNET). Mean age at symptom onset was 24.5 years ±10.9 (6–48 years) with adult onset in 75 % of the patients. In our cohort, the canonical features seizures, myoclonus, cerebellar ataxia and ragged-red fibres that are traditionally associated with MERRF, occurred in only 61, 59, 70, and 63 % of the patients, respectively. In contrast, other features such as hearing impairment were even more frequently present (72 %). Other common features in our cohort were migraine (52 %), psychiatric disorders (54 %), respiratory dysfunction (45 %), gastrointestinal symptoms (38 %), dysarthria (36 %), and dysphagia (35 %). Brain MRI revealed cerebral and/or cerebellar atrophy in 43 % of our patients. There was no correlation between the heteroplasmy level in blood and age at onset or clinical phenotype. Our findings further broaden the clinical spectrum of the m.8344A>G mutation, document the large clinical variability between carriers of the same mutation, even within families and indicate an overlap of the phenotype with other mitochondrial DNA-associated syndromes.

Keywords

Myoclonus Ataxia Epilepsy Ragged-red fibres Psychiatric Hearing impairment 

Notes

Acknowledgments

We are grateful to the participating patients and collaborating colleagues for collecting patients’ data and providing these within the German network for mitochondrial disorders (mitoNET). The study was funded by the German Bundesministerium für Bildung und Forschung (BMBF) through the German Network for mitochondrial disorders (mitoNET; 01GM1113A to B. B. and T. K. for the registry, 01GM1113C to H. P. for biobanking and molecular diagnostics). K. G. Claeys received research Grants unrelated to the current study from the Deutsche Gesellschaft für Muskelkranke e.V. (DGM).

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical standards

The study was performed according to the Declaration of Helsinki and approved by the ethical committee of the RWTH Aachen University and University Hospital München.

informed consent

Written informed consent was obtained from the participants.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Judith Altmann
    • 1
    • 2
  • Boriana Büchner
    • 3
  • Aleksandra Nadaj-Pakleza
    • 4
  • Jochen Schäfer
    • 5
  • Sandra Jackson
    • 5
  • Diana Lehmann
    • 6
  • Marcus Deschauer
    • 6
    • 7
  • Robert Kopajtich
    • 8
    • 9
  • Ronald Lautenschläger
    • 10
  • Klaus A. Kuhn
    • 10
  • Kathrin Karle
    • 11
  • Ludger Schöls
    • 11
  • Jörg B. Schulz
    • 1
    • 12
  • Joachim Weis
    • 2
  • Holger Prokisch
    • 8
    • 9
  • Cornelia Kornblum
    • 13
    • 14
  • Kristl G. Claeys
    • 1
    • 2
    • 15
    Email author
  • Thomas Klopstock
    • 3
    • 16
    • 17
  1. 1.Department of NeurologyRWTH Aachen UniversityAachenGermany
  2. 2.Institute of NeuropathologyRWTH Aachen UniversityAachenGermany
  3. 3.Department of Neurology, Friedrich-Baur-InstituteLudwig-Maximilians-UniversityMünchenGermany
  4. 4.Department of NeurologyUniversity Hospital of AngersAngersFrance
  5. 5.Department of NeurologyUniversity Hospital Carl Gustav CarusDresdenGermany
  6. 6.Department of NeurologyUniversity of Halle-WittenbergHalle/SaaleGermany
  7. 7.Department of NeurologyUniversity of Technology MünchenMünchenGermany
  8. 8.Institute of Human GeneticsHelmholtz Centre MünchenMünchenGermany
  9. 9.Institute of Human GeneticsTechnical University MünchenMünchenGermany
  10. 10.Institute for Medical Statistics and EpidemiologyUniversity of Technology MünchenMünchenGermany
  11. 11.Institute of Clinical NeurogeneticsDepartment of Neurology and Hertie Institute for Clinical Brain ResearchTübingenGermany
  12. 12.JARA - Translational Brain MedicineAachenGermany
  13. 13.Department of NeurologyUniversity Hospital of BonnBonnGermany
  14. 14.Center for Rare Diseases Bonn (ZSEB)University Hospital of BonnBonnGermany
  15. 15.Department of NeurologyUniversity Hospitals Leuven and University of Leuven (KU Leuven)LeuvenBelgium
  16. 16.German Center for Neurodegenerative Diseases (DZNE)MünchenGermany
  17. 17.Munich Cluster for Systems Neurology (SyNergy)MünchenGermany

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