title: Distal myopathy with cachexia: an unrecognised phenotype caused by dominantly-inherited mitochondrial polymerase γ mutations.
abstract: 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.
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Robert D S
authors.initials: RD
authors.lastname: Pitceathly
authors.forename: Susan E
authors.initials: SE
authors.lastname: Tomlinson
authors.forename: Iain
authors.initials: I
authors.lastname: Hargreaves
authors.forename: Nisha
authors.initials: N
authors.lastname: Bhardwaj
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.forename: Jasper M
authors.initials: JM
authors.lastname: Morrow
authors.forename: Julie
authors.initials: J
authors.lastname: Evans
authors.forename: Conrad
authors.initials: C
authors.lastname: Smith
authors.forename: Carl
authors.initials: C
authors.lastname: Fratter
authors.forename: Cathy E
authors.initials: CE
authors.lastname: Woodward
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sweeney
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
mesh_terms: D000328:Adult; D002100:Cachexia / Q000150:complications / Q000235:genetics*; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D049310:Distal Myopathies / Q000150:complications / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human