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Ann Clin Transl Neurol. 2016 Nov 16;4(1):4-14. doi: 10.1002/acn3.361. eCollection 2017 Jan.

POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism.

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Centre de génétique humaine Université de Franche-Comté Besançon France; Metabolic Unit Centre of Human Genetics University Hospital Liège Belgium.
Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas.
Department of Pediatrics Division of Child Neurology & Metabolism Ghent University Hospital Belgium.
Wellcome Trust Centre for Mitochondrial Research Institute of Neuroscience Newcastle University Newcastle upon Tyne United Kingdom.
Mitochondrial DNA Replication Group National Institute of Environmental Health Sciences Durham North Carolina.
Centre de génétique humaine Université de Franche-Comté Besançon France.
Department of Neurology Sambre and Meuse Regional Hospital Namur Belgium.
Metabolic Unit Centre of Human Genetics University Hospital Liège Belgium.
Born-Bunge Foundation University of Antwerp Belgium.
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.
Université catholique de Louvain CHU UCL Namur Department of Neurology B5530 Yvoir Belgium; UCL Institute of Neuroscience (IoNS) B1200 Brussels Belgium.



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 cytochrome c oxidase deficiency, and multiple mtDNA deletions. We identified a splice acceptor variant in POLG2, 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 include POLG2 sequencing 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-dominant POLG2 variant 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.

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