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

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Abstract
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.
Keywords
MITOCHONDRIAL-DNA DELETIONS, POLYMERASE GAMMA-SUBUNITS, MUTATIONS, DISEASE, OPHTHALMOPLEGIA, MAINTENANCE, VARIANTS, DEMENTIA, PATIENT, TWINKLE

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MLA
Van Maldergem, Lionel, Arnaud Besse, Boel De Paepe, et al. “POLG2 Deficiency Causes Adult-onset Syndromic Sensory Neuropathy, Ataxia and Parkinsonism.” ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY 4.1 (2017): 4–14. Print.
APA
Van Maldergem, Lionel, Besse, A., De Paepe, B., Blakely, E. L., Appadurai, V., Humble, M. M., Piard, J., et al. (2017). POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism. ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, 4(1), 4–14.
Chicago author-date
Van Maldergem, Lionel, Arnaud Besse, Boel De Paepe, Emma L Blakely, Vivek Appadurai, Margaret M Humble, Juliette Piard, et al. 2017. “POLG2 Deficiency Causes Adult-onset Syndromic Sensory Neuropathy, Ataxia and Parkinsonism.” Annals of Clinical and Translational Neurology 4 (1): 4–14.
Chicago author-date (all authors)
Van Maldergem, Lionel, Arnaud Besse, Boel De Paepe, Emma L Blakely, Vivek Appadurai, Margaret M Humble, Juliette Piard, Kate Craig, Langping He, Pierre Hella, François-Guillaume Debray, Jean-Jacques Martin, Marion Gaussen, Patrice Laloux, Giovanni Stevanin, Rudy Van Coster, Robert W Taylor, William C Copeland, Eric Mormont, and Penelope E Bonnen. 2017. “POLG2 Deficiency Causes Adult-onset Syndromic Sensory Neuropathy, Ataxia and Parkinsonism.” Annals of Clinical and Translational Neurology 4 (1): 4–14.
Vancouver
1.
Van Maldergem L, Besse A, De Paepe B, Blakely EL, Appadurai V, Humble MM, et al. POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism. ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY. 2017;4(1):4–14.
IEEE
[1]
L. Van Maldergem et al., “POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism,” ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, vol. 4, no. 1, pp. 4–14, 2017.
@article{8173857,
  abstract     = {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.},
  author       = {Van Maldergem, Lionel and Besse, Arnaud and De Paepe, Boel and Blakely, Emma L and Appadurai, Vivek and Humble, Margaret M and Piard, Juliette and Craig, Kate and He, Langping and Hella, Pierre and Debray, François-Guillaume and Martin, Jean-Jacques and Gaussen, Marion and Laloux, Patrice and Stevanin, Giovanni and Van Coster, Rudy and Taylor, Robert W and Copeland, William C and Mormont, Eric and Bonnen, Penelope E},
  issn         = {2328-9503},
  journal      = {ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY},
  keywords     = {MITOCHONDRIAL-DNA DELETIONS,POLYMERASE GAMMA-SUBUNITS,MUTATIONS,DISEASE,OPHTHALMOPLEGIA,MAINTENANCE,VARIANTS,DEMENTIA,PATIENT,TWINKLE},
  language     = {eng},
  number       = {1},
  pages        = {4--14},
  title        = {POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism},
  url          = {http://dx.doi.org/10.1002/acn3.361},
  volume       = {4},
  year         = {2017},
}

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