title: The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)-linked adPEO.
abstract: BACKGROUND
  Mutations in the Twinkle (PEO1) gene are a recognized cause of autosomal dominant progressive external ophthalmoplegia (adPEO), resulting in the accumulation of multiple mitochondrial DNA (mtDNA) deletions and cytochrome c oxidase (COX)-deficient fibers in skeletal muscle secondary to a disorder of mtDNA maintenance. Patients typically present with isolated extraocular muscle involvement, with little apparent evidence of the clinical heterogeneity documented in other mtDNA maintenance disorders, in particular POLG-related disease.
  
  
  METHODS
  We reviewed the clinical, histochemical, and molecular genetics analysis of 33 unreported patients from 26 families together with all previous cases described in the literature to define the clinical phenotype associated with PEO1 mutations.
  
  
  RESULTS
  Ptosis and ophthalmoparesis were almost universal clinical features among this cohort, with 52% (17/33) reporting fatigue and 33% (11/33) having mild proximal myopathy. Features consistent with CNS involvement were rarely described; however, in 24% (8/33) of the patients, cardiac abnormalities were reported. Mitochondrial histochemical changes observed in muscle showed remarkable variability, as did the secondary mtDNA deletions, which in some patients were only detected by PCR-based assays and not Southern blotting. Moreover, we report 7 novel PEO1 variants.
  
  
  CONCLUSIONS
  Our data suggest a shared clinical phenotype with variable mild multiorgan involvement, and that the contribution of PEO1 mutations as a cause of adPEO may well be underestimated. Direct sequencing of the PEO1 gene should be considered in adPEO patients prior to muscle biopsy.
authors.affiliation: Oxford Medical Genetics Laboratories, Churchill Hospital, Oxford, UK.
authors.forename: C
authors.initials: C
authors.lastname: Fratter
authors.forename: G S
authors.initials: GS
authors.lastname: Gorman
authors.forename: J D
authors.initials: JD
authors.lastname: Stewart
authors.forename: M
authors.initials: M
authors.lastname: Buddles
authors.forename: C
authors.initials: C
authors.lastname: Smith
authors.forename: J
authors.initials: J
authors.lastname: Evans
authors.forename: A
authors.initials: A
authors.lastname: Seller
authors.forename: J
authors.initials: J
authors.lastname: Poulton
authors.forename: M
authors.initials: M
authors.lastname: Roberts
authors.forename: M G
authors.initials: MG
authors.lastname: Hanna
authors.forename: S
authors.initials: S
authors.lastname: Rahman
authors.forename: S E
authors.initials: SE
authors.lastname: Omer
authors.forename: T
authors.initials: T
authors.lastname: Klopstock
authors.forename: B
authors.initials: B
authors.lastname: Schoser
authors.forename: C
authors.initials: C
authors.lastname: Kornblum
authors.forename: B
authors.initials: B
authors.lastname: Czermin
authors.forename: B
authors.initials: B
authors.lastname: Lecky
authors.forename: E L
authors.initials: EL
authors.lastname: Blakely
authors.forename: K
authors.initials: K
authors.lastname: Craig
authors.forename: P F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: D M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: R
authors.initials: R
authors.lastname: Horvath
authors.forename: R W
authors.initials: RW
authors.lastname: Taylor
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D004265:DNA Helicases / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000235:genetics* / Q000473:pathology; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009801:Oculomotor Muscles / Q000473:pathology; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics* / Q000473:pathology; D010641:Phenotype
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D004265:DNA Helicases; C431576:TWNK protein, human