title: Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study.
abstract: BACKGROUND
  Mutations in the gene encoding mitochondrial DNA polymerase gamma (POLG), the enzyme that synthesises mitochondrial DNA (mtDNA), have been associated with a mitochondrial disease-autosomal dominant or recessive progressive external ophthalmoplegia-and multiple deletions of mtDNA. Mitochondrial dysfunction is also suspected to participate in the pathogenesis of Parkinson's disease. However, no primary gene defects affecting mitochondrial proteins causing mendelian transmission of parkinsonism have been characterised. We aimed to analyse the gene sequence of POLG in patients with progressive external ophthalmoplegia and their healthy relatives.
  
  
  METHODS
  In seven families of various ethnic origins we assessed patients with progressive external ophthalmoplegia and unaffected individuals by clinical, biochemical, morphological, and molecular genetic characterisation and positron emission tomography (PET).
  
  
  RESULTS
  We recorded mutations in POLG in members of all seven families. Clinical assessment showed significant cosegregation of parkinsonism with POLG mutations (p<0.0001), and PET findings were consistent with dopaminergic neuron loss. Post-mortem examination in two individuals showed loss of pigmented neurons and pigment phagocytosis in substantia nigra without Lewy bodies. Furthermore, most women with progressive external ophthalmoplegia had early menopause-before age 35 years. The POLG gene defect resulted in secondary accumulation of mtDNA deletions in patients' tissues.
  
  
  CONCLUSIONS
  Dysfunction of mitochondrial POLG causes a severe progressive multisystem disorder including parkinsonism and premature menopause, which are not typical of mitochondrial disease. Cosegregation of parkinsonism and POLG mutations in our families suggests that when defective, this gene can underlie mendelian transmission of parkinsonism.
  
  
  CONCLUSIONS
  Awareness that mitochondrial POLG mutations can underlie parkinsonism is important for clinicians working in diagnosis of movement disorders, as well as for studies of the genetics of Parkinson's disease. Further, progressive external ophthalmoplegia with muscle weakness and neuropathy can mask symptoms of parkinsonism, and clinicians should pay special attention to detect and treat parkinsonism in those individuals.
authors.affiliation: Department of Neurology and Programme of Neurosciences, Biomedicum-Helsinki, Helsinki University, and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Petri
authors.initials: P
authors.lastname: Luoma
authors.forename: Atle
authors.initials: A
authors.lastname: Melberg
authors.forename: Juha O
authors.initials: JO
authors.lastname: Rinne
authors.forename: Jyrki A
authors.initials: JA
authors.lastname: Kaukonen
authors.forename: Nina N
authors.initials: NN
authors.lastname: Nupponen
authors.forename: Richard M
authors.initials: RM
authors.lastname: Chalmers
authors.forename: Anders
authors.initials: A
authors.lastname: Oldfors
authors.forename: Ilkka
authors.initials: I
authors.lastname: Rautakorpi
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Kari
authors.initials: K
authors.lastname: Majamaa
authors.forename: Hannu
authors.initials: H
authors.lastname: Somer
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
mesh_terms: D000328:Adult; D017668:Age of Onset; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008594:Menopause, Premature / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D017246:Ophthalmoplegia, Chronic Progressive External / Q000150:complications / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D017422:Sequence Analysis, DNA; D014055:Tomography, Emission-Computed
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human