Elsevier

The Lancet

Volume 364, Issue 9437, 4–10 September 2004, Pages 875-882
The Lancet

Mechanisms of Disease
Parkinsonism, premature menopause, and mitochondrial DNA polymerase γ mutations: clinical and molecular genetic study

https://doi.org/10.1016/S0140-6736(04)16983-3Get rights and content

Summary

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.

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])

References (40)

  • MC de Rijk et al.

    Prevalence of Parkinson's disease in Europe: a collaborative study of population-based cohorts

    Neurology

    (2000)
  • M Guttman et al.

    Burden of parkinsonism: a population-based study

    Mov Disord

    (2003)
  • P Lestienne et al.

    Normal mitochondrial genome in brain from patients with Parkinson's disease and complex I defect

    J Neurochem

    (1990)
  • M Orth et al.

    Mitochondria and degenerative disorders

    Am J Med Genet

    (2001)
  • A Suomalainen et al.

    Diseases caused by nuclear genes affecting mtDNA stability

    Am J Med Genet

    (2001)
  • AR Moslemi et al.

    Autosomal dominant progressive external ophthalmoplegia: distribution of multiple mitochondrial DNA deletions

    Neurology

    (1999)
  • G Siciliano et al.

    Mitochondrial DNA rearrangements in young onset parkinsonism: two case reports

    J Neurol Neurosurg Psychiatry

    (2001)
  • C Casali et al.

    Mitochondrial myopathy, parkinsonism, and multiple mtDNA deletions in a Sephardic Jewish family

    Neurology

    (2001)
  • J Kaukonen et al.

    Role of adenine nucleotide translocator 1 in mtDNA maintenance

    Science

    (2000)
  • JN Spelbrink et al.

    Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria

    Nat Genet

    (2001)
  • Cited by (0)

    View full text