POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism.
Ann Clin Transl Neurol. 2016-11-16; 4(1): 4-14
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1. Ann Clin Transl Neurol. 2016 Nov 16;4(1):4-14. doi: 10.1002/acn3.361. eCollection
POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and
Van Maldergem L(1), Besse A(2), De Paepe B(3), Blakely EL(4), Appadurai V(2),
Humble MM(5), Piard J(6), Craig K(4), He L(4), Hella P(7), Debray FG(8), Martin
JJ(9), Gaussen M(10), Laloux P(11), Stevanin G(10), Van Coster R(3), Taylor
RW(4), Copeland WC(5), Mormont E(11), Bonnen PE(2).
(1)Centre de génétique humaine Université de Franche-Comté Besançon France;
Metabolic Unit Centre of Human Genetics University Hospital Liège Belgium.
(2)Department of Molecular and Human Genetics Baylor College of Medicine Houston
(3)Department of Pediatrics Division of Child Neurology & Metabolism Ghent
University Hospital Belgium.
(4)Wellcome Trust Centre for Mitochondrial Research Institute of Neuroscience
Newcastle University Newcastle upon Tyne United Kingdom.
(5)Mitochondrial DNA Replication Group National Institute of Environmental Health
Sciences Durham North Carolina.
(6)Centre de génétique humaine Université de Franche-Comté Besançon France.
(7)Department of Neurology Sambre and Meuse Regional Hospital Namur Belgium.
(8)Metabolic Unit Centre of Human Genetics University Hospital Liège Belgium.
(9)Born-Bunge Foundation University of Antwerp Belgium.
(10)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
(11)Université catholique de Louvain CHU UCL Namur Department of Neurology B5530
Yvoir Belgium; UCL Institute of Neuroscience (IoNS) B1200 Brussels Belgium.
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.