Neuroimaging studies and whole exome sequencing of PLA2G6-associated neurodegeneration in a family with intrafamilial phenotypic heterogeneity

Yun Joong Kim, Chulhyoung Lyoo, Sangkyoon Hong, Nan Young Kim, Myung Sik Lee

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: PLA2G6-associated neurodegeneration (PLAN) encompasses infantile- or atypical neuroaxonal dystrophy, and adult-onset dystonia-parkinsonism. Examination of the intrafamilial phenotypic variability of PLAN by neuroimaging data and background genetic differences has not been reported. Methods: We report clinical, genetic (whole exome sequencing data), and neuroimaging findings from a Korean PLAN family showing intrafamilial phenotypic variability. Non-synonymous single nucleotide variants (SNVs) in Mendelian disorder genes related to parkinsonism, dystonia, ataxia, dementia or neurodegeneration with brain iron accumulation were compared between affected siblings. Results: The proband presented with adult-onset dystonia-parkinsonism, whereas the affected brother presented with childhood-onset atypical neuroaxonal dystrophy. In the proband, an [ 18 F]FP-CIT PET study showed markedly reduced uptake in the whole putamen, but fluid attenuated inversion recovery and gradient echo MRI studies revealed mild hypointensities in the substantia nigra and the putamen and severe hypointensities in the pallidum. On the other hand, in the affected brother, MRI scans showed severe hypointensities in the substantia nigra and the pallidum, and a [ 18 F]-FP-CIT PET scan was normal. Analysis of the non-synonymous SNVs that were not shared between the two family members revealed non-synonymous SNVs related to parkinsonism including a novel heterozygous mutation (p.T44N) in FBX07 (PARK15) only in the proband, and non-synonymous SNVs related to neurodegeneration with brain iron accumulation in the affected brother. Conclusion: Our data suggests that dopaminergic neuronal degeneration may not secondary to iron accumulation in PLAN. The burden of pathogenic SNVs may influence the intrafamilial phenotypic variability of PLAN.

Original languageEnglish
Pages (from-to)402-406
Number of pages5
JournalParkinsonism and Related Disorders
Volume21
Issue number4
DOIs
Publication statusPublished - 2015 Apr 1

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Neuroaxonal Dystrophies
Exome
Neuroimaging
Nucleotides
Siblings
Globus Pallidus
Putamen
Parkinsonian Disorders
Substantia Nigra
Dystonia
Ataxia
Positron-Emission Tomography
Dementia
Iron
Magnetic Resonance Imaging
Mutation

All Science Journal Classification (ASJC) codes

  • Neurology
  • Geriatrics and Gerontology
  • Clinical Neurology

Cite this

@article{22e0a496566b48c18527b792f5b5fa1c,
title = "Neuroimaging studies and whole exome sequencing of PLA2G6-associated neurodegeneration in a family with intrafamilial phenotypic heterogeneity",
abstract = "Background: PLA2G6-associated neurodegeneration (PLAN) encompasses infantile- or atypical neuroaxonal dystrophy, and adult-onset dystonia-parkinsonism. Examination of the intrafamilial phenotypic variability of PLAN by neuroimaging data and background genetic differences has not been reported. Methods: We report clinical, genetic (whole exome sequencing data), and neuroimaging findings from a Korean PLAN family showing intrafamilial phenotypic variability. Non-synonymous single nucleotide variants (SNVs) in Mendelian disorder genes related to parkinsonism, dystonia, ataxia, dementia or neurodegeneration with brain iron accumulation were compared between affected siblings. Results: The proband presented with adult-onset dystonia-parkinsonism, whereas the affected brother presented with childhood-onset atypical neuroaxonal dystrophy. In the proband, an [ 18 F]FP-CIT PET study showed markedly reduced uptake in the whole putamen, but fluid attenuated inversion recovery and gradient echo MRI studies revealed mild hypointensities in the substantia nigra and the putamen and severe hypointensities in the pallidum. On the other hand, in the affected brother, MRI scans showed severe hypointensities in the substantia nigra and the pallidum, and a [ 18 F]-FP-CIT PET scan was normal. Analysis of the non-synonymous SNVs that were not shared between the two family members revealed non-synonymous SNVs related to parkinsonism including a novel heterozygous mutation (p.T44N) in FBX07 (PARK15) only in the proband, and non-synonymous SNVs related to neurodegeneration with brain iron accumulation in the affected brother. Conclusion: Our data suggests that dopaminergic neuronal degeneration may not secondary to iron accumulation in PLAN. The burden of pathogenic SNVs may influence the intrafamilial phenotypic variability of PLAN.",
author = "Kim, {Yun Joong} and Chulhyoung Lyoo and Sangkyoon Hong and Kim, {Nan Young} and Lee, {Myung Sik}",
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Neuroimaging studies and whole exome sequencing of PLA2G6-associated neurodegeneration in a family with intrafamilial phenotypic heterogeneity. / Kim, Yun Joong; Lyoo, Chulhyoung; Hong, Sangkyoon; Kim, Nan Young; Lee, Myung Sik.

In: Parkinsonism and Related Disorders, Vol. 21, No. 4, 01.04.2015, p. 402-406.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Neuroimaging studies and whole exome sequencing of PLA2G6-associated neurodegeneration in a family with intrafamilial phenotypic heterogeneity

AU - Kim, Yun Joong

AU - Lyoo, Chulhyoung

AU - Hong, Sangkyoon

AU - Kim, Nan Young

AU - Lee, Myung Sik

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N2 - Background: PLA2G6-associated neurodegeneration (PLAN) encompasses infantile- or atypical neuroaxonal dystrophy, and adult-onset dystonia-parkinsonism. Examination of the intrafamilial phenotypic variability of PLAN by neuroimaging data and background genetic differences has not been reported. Methods: We report clinical, genetic (whole exome sequencing data), and neuroimaging findings from a Korean PLAN family showing intrafamilial phenotypic variability. Non-synonymous single nucleotide variants (SNVs) in Mendelian disorder genes related to parkinsonism, dystonia, ataxia, dementia or neurodegeneration with brain iron accumulation were compared between affected siblings. Results: The proband presented with adult-onset dystonia-parkinsonism, whereas the affected brother presented with childhood-onset atypical neuroaxonal dystrophy. In the proband, an [ 18 F]FP-CIT PET study showed markedly reduced uptake in the whole putamen, but fluid attenuated inversion recovery and gradient echo MRI studies revealed mild hypointensities in the substantia nigra and the putamen and severe hypointensities in the pallidum. On the other hand, in the affected brother, MRI scans showed severe hypointensities in the substantia nigra and the pallidum, and a [ 18 F]-FP-CIT PET scan was normal. Analysis of the non-synonymous SNVs that were not shared between the two family members revealed non-synonymous SNVs related to parkinsonism including a novel heterozygous mutation (p.T44N) in FBX07 (PARK15) only in the proband, and non-synonymous SNVs related to neurodegeneration with brain iron accumulation in the affected brother. Conclusion: Our data suggests that dopaminergic neuronal degeneration may not secondary to iron accumulation in PLAN. The burden of pathogenic SNVs may influence the intrafamilial phenotypic variability of PLAN.

AB - Background: PLA2G6-associated neurodegeneration (PLAN) encompasses infantile- or atypical neuroaxonal dystrophy, and adult-onset dystonia-parkinsonism. Examination of the intrafamilial phenotypic variability of PLAN by neuroimaging data and background genetic differences has not been reported. Methods: We report clinical, genetic (whole exome sequencing data), and neuroimaging findings from a Korean PLAN family showing intrafamilial phenotypic variability. Non-synonymous single nucleotide variants (SNVs) in Mendelian disorder genes related to parkinsonism, dystonia, ataxia, dementia or neurodegeneration with brain iron accumulation were compared between affected siblings. Results: The proband presented with adult-onset dystonia-parkinsonism, whereas the affected brother presented with childhood-onset atypical neuroaxonal dystrophy. In the proband, an [ 18 F]FP-CIT PET study showed markedly reduced uptake in the whole putamen, but fluid attenuated inversion recovery and gradient echo MRI studies revealed mild hypointensities in the substantia nigra and the putamen and severe hypointensities in the pallidum. On the other hand, in the affected brother, MRI scans showed severe hypointensities in the substantia nigra and the pallidum, and a [ 18 F]-FP-CIT PET scan was normal. Analysis of the non-synonymous SNVs that were not shared between the two family members revealed non-synonymous SNVs related to parkinsonism including a novel heterozygous mutation (p.T44N) in FBX07 (PARK15) only in the proband, and non-synonymous SNVs related to neurodegeneration with brain iron accumulation in the affected brother. Conclusion: Our data suggests that dopaminergic neuronal degeneration may not secondary to iron accumulation in PLAN. The burden of pathogenic SNVs may influence the intrafamilial phenotypic variability of PLAN.

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