Parkinsonism, premature menopause, and mitochondrial DNA polymerase γ mutations: clinical and molecular genetic study
P Luoma, A Melberg, JO Rinne, JA Kaukonen… - The Lancet, 2004 - thelancet.com
P Luoma, A Melberg, JO Rinne, JA Kaukonen, NN Nupponen, RM Chalmers, A Oldfors…
The Lancet, 2004•thelancet.comBackground Mutations in the gene encoding mitochondrial DNA polymerase γ (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 …
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 …
Background
Mutations in the gene encoding mitochondrial DNA polymerase γ (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 POLGin 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 POLGmutations (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.
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