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

Abstract

ObjectiveMitochondrial 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.MethodsClinical, 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.ResultsHallmarks 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.InterpretationThis 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.

Targeted next generation sequencing with an extended gene panel does not impact variant detection in mitochondrial diseases

“…The second variant (c.390-2A > C) is supposed to have an effect on splicing by in silico analysis ( http://www.mutationtaster.org/ ). Mutations that affect splicing and POLG2 expression have previously been described in patients [ 15 , 16 ]. Thus the c.390-2A > C splice acceptor variant in POLG2 we identified is consistent with previous POLG2 pathogenic variants responsible for mtDNA deletions and late-onset mitochondrial disease.…”

Characterization of the human homozygous R182W POLG2 mutation in mitochondrial DNA depletion syndrome

“…The patient dermal fibroblasts exhibit a dramatic reduction in transcript levels for both p140 and p55, supporting the idea that R182W p55 is unstable. Recently, lowered p55 protein levels as a result of a heterozygous splice site mutation in the POLG2 gene was found responsible for adult onset syndromic sensory neuropathy, ataxia and parkinsonism and mtDNA deletions [ 47 ].…”

Nuclear Genes Associated with Mitochondrial DNA Processes as Contributors to Parkinson's Disease Risk

“…Additional mitochondrial disorders caused by POLG mutations such as sensory ataxic neuropathy dysarthria and ophtalmoparesis, as well as multiple system atrophy of the cerebellar subtype, have also been associated with a parkinsonism phenotype 54‐57 . In one family, a novel variant in POLG2 was identified as the cause of a neurological syndrome that included parkinsonism 58 …”

“…[54][55][56][57] In one family, a novel variant in POLG2 was identified as the cause of a neurological syndrome that included parkinsonism. 58 Instability of CAG-repeats in polyglutamine (poly-Q) tracts are a recognized cause of several neurodegenerative disorders 59 and have also been investigated in PD. Following the abovementioned reports associating POLG mutations with parkinsonism, a handful of studies investigated POLG poly-Q variants in PD risk produced conflicting results (Table 2); three [60][61][62] reported significant associations of POLG poly-Q repeats and three did not.…”