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Ann Neurol. 2015 Jul;78(1):21-38. doi: 10.1002/ana.24410. Epub 2015 Jun 10.

Syndromic parkinsonism and dementia associated with OPA1 missense mutations.

Author information

1
IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.
2
Unit of Neurology, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
3
Department of Neuroscience, University of Messina, Messina, Italy.
4
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
5
Studio Oculistico, D'Azeglio, Bologna, Italy.
6
Ophthalmology Clinic, University of Messina, Messina, Italy.
7
Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
8
Department of Morphology, Surgery, and Experimental Medicine, University of Ferrara, Ferrara, Italy.
9
Functional Magnetic Resonance Unit, St Orsola-Malpighi Polyclinic, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
10
Mitochondrial Biology Unit, Medical Research Council, Cambridge, United Kingdom.

Abstract

OBJECTIVE:

Mounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.

METHODS:

Patients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements.

RESULTS:

Affected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase-negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy.

INTERPRETATION:

The association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism.

PMID:
25820230
PMCID:
PMC5008165
DOI:
10.1002/ana.24410
[Indexed for MEDLINE]
Free PMC Article

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