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

 Yun Joong Kim  ;  Chul Hyoung Lyoo  ;  Sangkyoon Hong  ;  Nan Young Kim  ;  Myung Sik Lee 
 Parkinsonism & Related Disorders, Vol.21(4) : 402-406, 2015 
Journal Title
 Parkinsonism & Related Disorders 
Issue Date
Adolescent ; Adult ; Exome ; Female ; Group VI Phospholipases A2/genetics* ; Heredodegenerative Disorders, Nervous System*/genetics ; Heredodegenerative Disorders, Nervous System*/metabolism ; Heredodegenerative Disorders, Nervous System*/pathology ; Heredodegenerative Disorders, Nervous System*/physiopathology ; Humans ; Male ; Phenotype ; Republic of Korea ; Siblings
Intrafamilial phenotypic variability ; NBIA ; PLA2G6 ; PLAN ; Whole exome sequencing
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 [18F]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 [18F]-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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1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
Yonsei Authors
Lyoo, Chul Hyoung(류철형) ORCID logo https://orcid.org/0000-0003-2231-672X
Lee, Myung Sik(이명식) ORCID logo https://orcid.org/0000-0002-8413-1854
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