Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study.
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.
Luoma
Petri
P
Department of Neurology and Programme of Neurosciences, Biomedicum-Helsinki, Helsinki University, and Helsinki University Central Hospital, Helsinki, Finland.
Melberg
Atle
A
Rinne
Juha O
JO
Kaukonen
Jyrki A
JA
Nupponen
Nina N
NN
Chalmers
Richard M
RM
Oldfors
Anders
A
Rautakorpi
Ilkka
I
Peltonen
Leena
L
Majamaa
Kari
K
Somer
Hannu
H
Suomalainen
Anu
A
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
D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human