title: POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism.
abstract: Mitochondrial dysfunction plays a key role in the pathophysiology of neurodegenerative disorders such as ataxia and Parkinson's disease. We describe an extended Belgian pedigree where seven individuals presented with adult-onset cerebellar ataxia, axonal peripheral ataxic neuropathy, and tremor, in variable combination with parkinsonism, seizures, cognitive decline, and ophthalmoplegia. We sought to identify the underlying molecular etiology and characterize the mitochondrial pathophysiology of this neurological syndrome.
  
  
  
  Clinical, neurophysiological, and neuroradiological evaluations were conducted. Patient muscle and cultured fibroblasts underwent extensive analyses to assess mitochondrial function. Genetic studies including genome-wide sequencing were conducted.
  
  
  
  Hallmarks of mitochondrial dysfunction were present in patients' tissues including ultrastructural anomalies of mitochondria, mosaic cytochromecoxidase deficiency, and multiple mtDNA deletions. We identified a splice acceptor variant inPOLG2,c.970-1G>C, segregating with disease in this family and associated with a concomitant decrease in levels of POLG2 protein in patient cells.
  
  
  
  This work extends the clinical spectrum of POLG2 deficiency to include an overwhelming, adult-onset neurological syndrome that includes cerebellar syndrome, peripheral neuropathy, tremor, and parkinsonism. We therefore suggest to includePOLG2sequencing in the evaluation of ataxia and sensory neuropathy in adults, especially when it is accompanied by tremor or parkinsonism with white matter disease. The demonstration that deletions of mtDNA resulting from autosomal-dominantPOLG2variant lead to a monogenic neurodegenerative multicomponent syndrome provides further evidence for a major role of mitochondrial dysfunction in the pathomechanism of nonsyndromic forms of the component neurodegenerative disorders.
authors.affiliation: Centre de génétique humaine Université de Franche-Comté Besançon France; Metabolic Unit Centre of Human Genetics University Hospital Liège Belgium.
authors.forename: Lionel
authors.initials: L
authors.lastname: Van Maldergem
authors.affiliation: Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Besse
authors.affiliation: Department of Pediatrics Division of Child Neurology & Metabolism Ghent University Hospital Belgium.
authors.forename: Boel
authors.initials: B
authors.lastname: De Paepe
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research Institute of Neuroscience Newcastle University Newcastle upon Tyne United Kingdom.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Blakely
authors.affiliation: Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas.
authors.forename: Vivek
authors.initials: V
authors.lastname: Appadurai
authors.affiliation: Mitochondrial DNA Replication Group National Institute of Environmental Health Sciences Durham North Carolina.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Humble
authors.affiliation: Centre de génétique humaine Université de Franche-Comté Besançon France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Piard
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research Institute of Neuroscience Newcastle University Newcastle upon Tyne United Kingdom.
authors.forename: Kate
authors.initials: K
authors.lastname: Craig
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research Institute of Neuroscience Newcastle University Newcastle upon Tyne United Kingdom.
authors.forename: Langping
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Neurology Sambre and Meuse Regional Hospital Namur Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hella
authors.affiliation: Metabolic Unit Centre of Human Genetics University Hospital Liège Belgium.
authors.forename: François-Guillaume
authors.initials: FG
authors.lastname: Debray
authors.affiliation: Born-Bunge Foundation University of Antwerp Belgium.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.affiliation: Inserm U1127 CNRS UMR 7225 Sorbonne Universités UPMC Paris France; Institut du Cerveau et de la Moelle épinière Hopital Pitié-Salpêtrière Paris France; Ecole Pratique des Hautes Etudes PSL Université Laboratoire de neurogénétique F-75013 Paris France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gaussen
authors.affiliation: Université catholique de Louvain CHU UCL Namur Department of Neurology B5530 Yvoir Belgium; UCL Institute of Neuroscience (IoNS) B1200 Brussels Belgium.
authors.forename: Patrice
authors.initials: P
authors.lastname: Laloux
authors.affiliation: Inserm U1127 CNRS UMR 7225 Sorbonne Universités UPMC Paris France; Institut du Cerveau et de la Moelle épinière Hopital Pitié-Salpêtrière Paris France; Ecole Pratique des Hautes Etudes PSL Université Laboratoire de neurogénétique F-75013 Paris France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.affiliation: Department of Pediatrics Division of Child Neurology & Metabolism Ghent University Hospital Belgium.
authors.forename: Rudy
authors.initials: R
authors.lastname: Van Coster
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research Institute of Neuroscience Newcastle University Newcastle upon Tyne United Kingdom.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Mitochondrial DNA Replication Group National Institute of Environmental Health Sciences Durham North Carolina.
authors.forename: William C
authors.initials: WC
authors.lastname: Copeland
authors.affiliation: Université catholique de Louvain CHU UCL Namur Department of Neurology B5530 Yvoir Belgium; UCL Institute of Neuroscience (IoNS) B1200 Brussels Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Mormont
authors.affiliation: Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas.
authors.forename: Penelope E
authors.initials: PE
authors.lastname: Bonnen