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).
FINDINGS: 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.
INTERPRETATION: 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.
RELEVANCE TO PRACTICE: 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.