title: Syndromic parkinsonism and dementia associated with OPA1 missense mutations.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Unit of Neurology, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.affiliation: Department of Neuroscience, University of Messina, Messina, Italy.
authors.forename: Olimpia
authors.initials: O
authors.lastname: Musumeci
authors.affiliation: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Caporali
authors.affiliation: Unit of Neurology, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Zanna
authors.affiliation: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Unit of Neurology, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: La Morgia
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Del Dotto
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Porcelli
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Rugolo
authors.affiliation: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Unit of Neurology, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Valentino
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Iommarini
authors.affiliation: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Unit of Neurology, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Maresca
authors.affiliation: Studio Oculistico, D'Azeglio, Bologna, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Barboni
authors.affiliation: Studio Oculistico, D'Azeglio, Bologna, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Carbonelli
authors.affiliation: Ophthalmology Clinic, University of Messina, Messina, Italy.
authors.forename: Costantino
authors.initials: C
authors.lastname: Trombetta
authors.affiliation: Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
authors.affiliation: Department of Morphology, Surgery, and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Patergnani
authors.affiliation: Department of Morphology, Surgery, and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Giorgi
authors.affiliation: Department of Morphology, Surgery, and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.affiliation: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Unit of Neurology, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Rizzo
authors.affiliation: Functional Magnetic Resonance Unit, St Orsola-Malpighi Polyclinic, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Tonon
authors.affiliation: Functional Magnetic Resonance Unit, St Orsola-Malpighi Polyclinic, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Lodi
authors.affiliation: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Unit of Neurology, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Avoni
authors.affiliation: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Unit of Neurology, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Liguori
authors.affiliation: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Unit of Neurology, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Baruzzi
authors.affiliation: Department of Neuroscience, University of Messina, Messina, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Toscano
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge, United Kingdom.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
mesh_terms: D000368:Aged; D003704:Dementia / Q000150:complications / Q000235:genetics*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007558:Italy; D008297:Male; D020125:Mutation, Missense; D017246:Ophthalmoplegia, Chronic Progressive External / Q000150:complications / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000150:complications / Q000235:genetics*; D010375:Pedigree
chemical_list: D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human
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