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Distal myopathy with cachexia: an unrecognised phenotype caused by dominantly-inherited mitochondrial polymerase γ mutations
  1. Robert D S Pitceathly1,
  2. Susan E Tomlinson1,2,
  3. Iain Hargreaves3,
  4. Nisha Bhardwaj4,
  5. Janice L Holton1,5,
  6. Jasper M Morrow1,
  7. Julie Evans6,
  8. Conrad Smith6,
  9. Carl Fratter6,
  10. Cathy E Woodward7,
  11. Mary G Sweeney7,
  12. Shamima Rahman1,8,
  13. Michael G Hanna1,5
  1. 1MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK
  2. 2Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
  3. 3Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK
  4. 4Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK
  5. 5Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
  6. 6Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Trust, Oxford, UK
  7. 7Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK
  8. 8Mitochondrial Research Group, UCL Institute of Child Health, London, UK
  1. Correspondence to Dr Shamima Rahman, MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, 8-11 Queen Square, London WC1N 3BG, UK; shamima.rahman{at}


Background The myopathy associated with mutations in the nuclear-encoded mitochondrial DNA maintenance gene POLG, coding for the catalytic subunit of DNA polymerase, is typically proximal with early ophthalmoplegia.

Results We report two unrelated patients in whom a distal, mainly upper limb, myopathy was the predominant and early clinical feature. One patient also suffered with marked cachexia. DNA genomic sequence analysis identified novel dominant heterozygous missense POLG mutations (Leu896Arg and Tyr951His) located within the conserved catalytic polymerase domain of the protein in both cases.

Conclusions Distal upper limb myopathy/cachexia is not previously described with dominant POLG mutations and our observations further highlight the diverse clinical spectrum of POLG-related mitochondrial disorders. These data indicate that dominant POLG mutations should be considered in the differential diagnosis of distal upper limb predominant myopathy.

  • Mitochondrial disease
  • polymerase gamma
  • multiple mtDNA deletions
  • distal myopathy
  • neuromuscular
  • mitochondrial disorders
  • neurogenetics
  • cerebellar ataxia
  • epilepsy
  • neurophysiology
  • muscle disease
  • neuropathy
  • MRI
  • paediatric
  • metabolic disease

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  • Funding RDSP is funded by MRC grant number G0800674. SR is supported by Great Ormond Street Hospital Children's Charity. MGH and JMM receive funding from an MRC Centre grant (G0601943). JH and MGH are supported by The Myositis Support Group. This study was supported by the UK NHS Specialised Service for Rare Mitochondrial Diseases of Adults and Children and the NIHR UCLH/UCL Comprehensive Biomedical Research Centre and undertaken at the University College London Hospitals/University College London, which received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme.

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.