Mechanisms of DiseaseParkinsonism, premature menopause, and mitochondrial DNA polymerase γ mutations: clinical and molecular genetic study
Introduction
Parkinson's disease is the second most frequent neurodegenerative disease, with a prevalence of 0·4−2·2% in Europe and North America.1, 2 The morphological characteristic of this disease—degeneration of dopaminergic neurons in substantia nigra—is probably the end result of various genetic and environmental pathogenetic pathways. Researchers have argued about the role of mitochondrial DNA (mtDNA) defects in the pathogenesis of Parkinson's disease;3, 4, 5 however, no one mtDNA mutation has been shown to invariably lead to this disorder, leaving the causative role of mtDNA mutations in Parkinson's disease unproven.
Autosomal dominant or recessive progressive external ophthalmoplegia is a mitochondrial disease characterised by weakness of the ocular muscles and exercise intolerance; additional symptoms differ between families, and include, for example, polyneuropathy, hypogonadism, and cataracts.6 In anecdotal reports, families have been described with cosegregation of progressive external ophthalmoplegia, deletions of mtDNA, and parkinsonism,7, 8, 9, 10, 11 but the causal association of this disorder with parkinsonism has remained unproven because of the few cases reported.
Progressive external ophthalmoplegia is genetically heterogeneous: mutations have been recorded in genes encoding adenine nucleotide translocase 1 (ANT1; HUGO-approved gene name SLC25A4),12 TWINKLE, a mitochondrial helicase (PEO1),13 and mitochondrial DNA polymerase γ (POLG).14 All these proteins affect mtDNA maintenance, and their defects result in secondary accumulation of mtDNA deletions of variable sizes, mostly in the patient's brain, skeletal muscle, and heart.8, 15, 16 We aimed to analyse the sequence of POLG in families with progressive external ophthalmoplegia.
Section snippets
Participants
We included seven families with progressive external ophthalmoplegia; figure 1 shows their pedigrees. Clinical manifestations and mtDNA analyses of the British family C and the Swedish family S have been previously described.7, 17, 18 The two Finnish families V and L showed recessive and dominant inheritance, respectively, and the pattern was dominant in Swedish families S and E. The inheritance of Swedish family N was not known since the patient's father was not affected and data for the
Results
Table 1 summarises clinical findings of patients. Individuals with progressive external ophthalmoplegia developed signs of parkinsonism at various ages (age 36−46 years in families V and L and age 50−75 years in S, K, and C), typically starting with hemiparkinsonism, with rigidity and resting tremor of the limbs. Patients were hypomimic, generally with weakness of facial muscles. Patients V/II-6 and L/II-6 developed typical parkinsonian gait. These symptoms and signs responded to levodopa
Discussion
We have shown that parkinsonism and premature menopause cosegregate with POLG defects. We recorded three new and one previously described POLG mutation in seven pedigrees of progressive external ophthalmoplegia. In our total data (some unpublished) for 33 families,12, 13, 24 parkinsonism has been exclusively recorded in individuals with POLG mutations. Previously, parkinsonism and progressive external ophthalmoplegia with multiple mtDNA deletions has been described in six families,7, 8, 10, 11
Glossary
- Cosegregation
- Familial transmission of two or more genetic factors or traits together.
- Helicase
- A protein that uncoils DNA so that it can be replicated or repaired. RNA helicases also exist.
- Mitochondrial DNA polymerase γ (POLG)
- Enzyme that synthesises the new mitochondrial DNA strand in replication (polymerase domain [pol]) and that controls the quality of synthesis and corrects errors made (exonuclease domain [exo])
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