title: [Familial progressive external opthalmoplegia, parkinsonism and polyneuropathy associated with POLG1 mutation].
abstract: Multiple mitochondrial DNA (mtDNA) deletions usually occur secondarily to a mutation in one of the enzymes involved in mtDNA maintenance, such as polymerase γ, which is encoded by the nuclear polymerase γ1 gene (POLG1) and POLG2. Patients with multiple mtDNA deletion disorders show clinical heterogeneity of symptoms, in addition to usually seen progressive external ophthalmoplegia (PEO). We conducted clinical, histological and genetic analyses of two affected sisters in a family with the autosomal dominant inheritance pattern of PEO. A 73-year-old woman (patient 1) with congenital hypogonadism and PEO developed L-dopa responsive parkinsonism about the age of 60. Neurological examination revealed mild proximal muscle weakness and polyneuropathy too. Her 69-year-old sister (patient 2) also showed PEO, parkinsonism and polyneuropathy. Histopathological studies of biopsied muscle specimens from patient 1 revealed numerous ragged red fibers as well as fibers with increased succinate dehydrogenase activity and decreased cytochrome c oxidase activity. Multiple mtDNA deletions were detected, both by Southern blot and long-range PCR assays of total DNA from the biopsied muscle specimens. A systemic mutational analysis in both sisters revealed a heterozygous p.Y955C (c.2864A>G) mutation in POLG1. This is the first Japanese family identified with this mutation. We reviewed cases with this mutation highlighting a wide phenotypic spectrum of this disorder.
authors.affiliation: Department of Neurology, Tokyo Metropolitan Neurological Hospital.
authors.forename: Masako
authors.initials: M
authors.lastname: Mukai
authors.forename: Keizo
authors.initials: K
authors.lastname: Sugaya
authors.forename: Shiro
authors.initials: S
authors.lastname: Matsubara
authors.forename: Huaying
authors.initials: H
authors.lastname: Cai
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yabe
authors.forename: Hidenao
authors.initials: H
authors.lastname: Sasaki
authors.forename: Imaharu
authors.initials: I
authors.lastname: Nakano
mesh_terms: D000368:Aged; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D005799:Genes, Dominant / Q000235:genetics*; D006801:Humans; D007980:Levodopa; D008297:Male; D008594:Menopause, Premature / Q000235:genetics; D028361:Mitochondrial Diseases / Q000235:genetics*; D009135:Muscular Diseases / Q000235:genetics; D009154:Mutation; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics*; D010375:Pedigree; D011115:Polyneuropathies / Q000235:genetics*; D013577:Syndrome
chemical_list: D004272:DNA, Mitochondrial; D007980:Levodopa; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human