cqvip:Background Mutations in the gene encoding mitochondrial DNA polymerase γ.(POL G), the enzyme that synthesises mitochondrial DNA (mtDNA), have been associated with a mitochondrial disease autosomal dominant or recessive progressive extern al ophthalmoplegia and multiple deletions of mtDNA. Mitochondrial dysfunction is also suspected to participate in the pathogenesis of Parkinsons disease. Howe ver, no primary gene defects affecting mitochondrial proteins causing mendelian transmission of parkinsonism have been characterised. We aimed to analyse the ge ne sequence of POLG in patients with progressive external ophthalmoplegia and th eir healthy relatives. Methods In seven families of various ethnic origins we as sessed patients with progressive external ophthalmoplegia and unaffected individ uals by clinical, biochemical, morphological, and molecular genetic characterisa tion and positron emission tomography (PET). Findings We recorded mutations in P OLG in members of all seven families. Clinical assessment showed significant cos egregation of parkinsonism with POLG mutations (p < 0 0001), and PET findings w ere consistent with dopaminergic neuron loss. Post mortem examination in two in dividuals showed loss of pigmented neurons and pigment phagocytosis in substanti a nigra without Lewy bodies. Furthermore, most women with progressive external o phthalmoplegia had early menopause before age 35 years. The POLG gene defect r esulted in secondary accumulation of mtDNA deletions in patientstissues. Inter pretation Dysfunction of mitochondrial POLG causes a severe progressive multisys tem disorder including parkinsonism and premature menopause, which are not typic
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