Yuta Ichinose1, Hiroyuki Ishiura2, Masaki Tanaka3, Jun Yoshimura4, Koichiro Doi4, Takako Umeda5, Hajime Yamauchi6, Mai Tsuchiya1, Kishin Koh1, Nobuo Yamashiro1, Jun Mitsui7, Jun Goto8, Hiroshi Onishi5, Toshihisa Ohtsuka6, Kazumasa Shindo1, Shinichi Morishita4, Shoji Tsuji9, Yoshihisa Takiyama10. 1. Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan. 2. Department of Neurology, The University of Tokyo, Tokyo, Japan. 3. Institute of Medical Genomics, International University of Health and Welfare, Chiba, Japan. 4. Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan. 5. Department of Radiology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan. 6. Department of Biochemistry, Graduate School of Medical Sciences, University Of Yamanashi, Yamanashi, Japan. 7. Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 8. Department of Neurology, Mita Hospital, International University of Health and Welfare, Tokyo, Japan. 9. Institute of Medical Genomics, International University of Health and Welfare, Chiba, Japan; Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 10. Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan. Electronic address: ytakiyama@yamanashi.ac.jp.
Abstract
INTRODUCTION: Glucocerebrosidase gene (GBA) variants are associated with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The molecular mechanisms underlying these diseases with GBA variants, however, are not well understood. In order to determine the effect of a deletion mutation in GBA, we performed a neuroimaging, genetic, and enzymatic study in a Japanese family with a gross deletion of exons 3 to 11 in GBA. METHODS: We performed [123I] FP-CIT SPECT and [123I] N-isopropyl-p-iodoamphetamine SPECT (IMP-SPECT), and determined GBA expression and glucocerebrosidase (GCase) activity in leukocytes in two GBA-associated PD patients and nine unaffected individuals (including four mutation carriers) in a Japanese family with a heterozygous gross deletion mutation in the GBA gene. RESULTS: The two PD patients and two of the four clinically unaffected carriers showed decreased [123I] FP-CIT uptake. IMP-SPECT showed a pattern like that in DLB in one patient. When we compared PD patients with GBA mutations with clinically unaffected carriers, there was a poor correlation between the development of PD and the expression level of GBA or GCase activity. CONCLUSION: We confirmed the gross deletion mutation in the GBA gene, which appeared to be associated with the PD or reduced [123I] FP-CIT in this family. However, since we cannot conclude whether a reduction of GCase activity is directly correlated with the pathogenesis of PD or not, longitudinal follow-up of this family is needed.
INTRODUCTION:Glucocerebrosidase gene (GBA) variants are associated with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The molecular mechanisms underlying these diseases with GBA variants, however, are not well understood. In order to determine the effect of a deletion mutation in GBA, we performed a neuroimaging, genetic, and enzymatic study in a Japanese family with a gross deletion of exons 3 to 11 in GBA. METHODS: We performed [123I] FP-CIT SPECT and [123I] N-isopropyl-p-iodoamphetamine SPECT (IMP-SPECT), and determined GBA expression and glucocerebrosidase (GCase) activity in leukocytes in two GBA-associated PDpatients and nine unaffected individuals (including four mutation carriers) in a Japanese family with a heterozygous gross deletion mutation in the GBA gene. RESULTS: The two PDpatients and two of the four clinically unaffected carriers showed decreased [123I] FP-CIT uptake. IMP-SPECT showed a pattern like that in DLB in one patient. When we compared PDpatients with GBA mutations with clinically unaffected carriers, there was a poor correlation between the development of PD and the expression level of GBA or GCase activity. CONCLUSION: We confirmed the gross deletion mutation in the GBA gene, which appeared to be associated with the PD or reduced [123I] FP-CIT in this family. However, since we cannot conclude whether a reduction of GCase activity is directly correlated with the pathogenesis of PD or not, longitudinal follow-up of this family is needed.