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

Lookup NU author(s): Dr Emma Watson, Dr Langping He, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Objective: 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. Methods: 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. Results: 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. Interpretation: 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.

Publication metadata

Author(s): Van Maldergem L, Besse A, De Paepe B, Blakely EL, Appadurai V, Humble MM, Piard J, Craig K, He LP, Hella P, Debray FG, Martin JJ, Gaussen M, Laloux P, Stevanin G, Van Coster R, Taylor RW, Copeland WC, Mormont E, Bonnen PE

Publication type: Article

Publication status: Published

Journal: Annals of Clinical and Translational Neurology

Year: 2017

Volume: 4

Issue: 1

Pages: 4-14

Print publication date: 01/01/2017

Online publication date: 16/11/2016

Acceptance date: 12/08/2016

Date deposited: 23/03/2017

ISSN (print): 2328-9503

Publisher: Wiley-Blackwell Publishing Ltd.


DOI: 10.1002/acn3.361


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Funder referenceFunder name
Verum Foundation
French National Agency for Research (SPATAX-QUEST project)
Lily Foundation
UK NHS Highly Specialised "Rare Mitochondrial Disorders of Adults and Children" Service
096919Z/11/ZWellcome Trust Strategic Award
ANR-10-IAIHU-06Investissements d'Avenir program
E12009DDEuropean community
ES065078Intramural Research Program of the NIH, National Institute of Environmental Health Sciences
G0601943Medical Research Council (UK) Centre for Translational Muscle Disease Research
R01NS08372National Institute of Neurological Disorders and Stroke of the National Institutes of Health
U54HG006542NIH National Human Genome Research Institute