title: Atypical parkinsonism caused by Pro105Leu mutation of prion protein: A broad clinical spectrum.
abstract: OBJECTIVE
  To delineate molecular and clinical characteristics of 3 families with PRNP P105L mutation, a variant of Gerstmann-Sträussler-Scheinker syndrome whose main motor symptoms were parkinsonism and/or involuntary movements.
  
  
  METHODS
  The causative mutation was first determined in the affected patients of family 1 using whole-exome sequencing, and then mutational analysis was extended to families 2 and 3. The clinical features of the patients of these 3 families were summarized. Haplotype analysis was performed using high-density single nucleotide polymorphism array.
  
  
  RESULTS
  The whole-exome sequencing revealed that the heterozygous mutation c.314C>T (p.P105L) in PRNP was the only known pathogenic mutation shared by the 3 patients of the family with autosomal dominant parkinsonism. We further identified the same mutation in patients of the other 2 families with autosomal dominant parkinsonism and/or involuntary movements. The clinical features of our patients with PRNP P105L mutation included various motor symptoms such as parkinsonism and involuntary movements in addition to progressive dementia. The clinical features in part overlapped with those of other forms of inherited prion diseases, such as fatal familial insomnia and Huntington disease-like type 1. The patients with PRNP P105L mutation shared a haplotype spanning 7.1 Mb around PRNP, raising the possibility that the mutations in the patients originated from a common founder.
  
  
  CONCLUSIONS
  Most of the patients presented with parkinsonism in addition to progressive dementia. Although spastic paraparesis has been emphasized as the main clinical feature, the clinical spectrum of patients with PRNP P105L is broader than expected.
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Kagari Koshi
authors.initials: KK
authors.lastname: Mano
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsukawa
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Jun
authors.initials: J
authors.lastname: Mitsui
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishiura
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Tokushige
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Naoko Saito
authors.initials: NS
authors.lastname: Sato
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Fumiko Kusunoki
authors.initials: FK
authors.lastname: Nakamoto
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Yaeko
authors.initials: Y
authors.lastname: Ichikawa
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Yu
authors.initials: Y
authors.lastname: Nagashima
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terao
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Jun
authors.initials: J
authors.lastname: Shimizu
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Masashi
authors.initials: M
authors.lastname: Hamada
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Uesaka
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Genko
authors.initials: G
authors.lastname: Oyama
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Go
authors.initials: G
authors.lastname: Ogawa
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshimura
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Doi
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Morishita
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Department of Neurology (K.K.M., T.M., J.M., H.I., S.-i.T., Y. Takahashi, N.S.S., F.K.N., Y.I., Y.N., Y. Terao, J.S., M.H., S.T., J.G.), Graduate School of Medicine, The University of Tokyo; Shonai Amarume Hospital (Y. Takahashi); Department of Neurology (Y.U.), Toranomon Hospital; Department of Neurology (G. Oyama), Juntendo University; Department of Neurology (G. Ogawa), Teikyo University; and Department of Computational Biology and Medical Sciences (J.Y., K.D., S.M.), Graduate School of Frontier Sciences, The University of Tokyo. Y. Takahashi is currently affiliated with the Department of Neurology, National Center of Psychiatry and Neurology. Y.I. is currently affiliated with the Department of Neurology, Kyorin University.
authors.forename: Jun
authors.initials: J
authors.lastname: Goto