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 [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.
  
  
  CONCLUSIONS
  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.
authors: ILSONG Institute of Life Science, Hallym University, Anyang, Republic of Korea; Department of Neurology, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea; Hallym Institute of Translational Genomics and Bioinformatics, Anyang, Republic of Korea. Electronic address: yunkim@hallym.ac.kr.
authors: Yun Joong
authors: YJ
authors: Kim
authors: Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Chul Hyoung
authors: CH
authors: Lyoo
authors: Hallym Institute of Translational Genomics and Bioinformatics, Anyang, Republic of Korea.
authors: Sangkyoon
authors: S
authors: Hong
authors: Hallym Institute of Translational Genomics and Bioinformatics, Anyang, Republic of Korea.
authors: Nan Young
authors: NY
authors: Kim
authors: Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: mslee@yuhs.ac.
authors: Myung Sik
authors: MS
authors: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D059472:Exome; D005260:Female; D054522:Group VI Phospholipases A2 / Q000235:genetics*; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D010641:Phenotype; D056910:Republic of Korea; D035781:Siblings
chemical_list: D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human
keywords: Intrafamilial phenotypic variability; NBIA; PLA2G6; PLAN; Whole exome sequencing