The Clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients

Authors

  • Dr. Masaki Ikeda MD,

    Corresponding author
    1. Centre for Research in Neurodegenerative Diseases, Department of Medicine Division of Neurology, University of Toronto, and Department of Medicine, Toronto Hospital, Toronto, Ontario, Canada
    2. Department of Neurology, Gunma University School of Medicinr, Marbashi
    • The Centre for Research in Neurodegenerative Diseases, Tanz Neuroscience Bldg, University of Toronto, 6, Queen's Park Crescent West, Toronto, Ontario, Canada M5S 3H2
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  • Vikram Sharma PhD,

    1. Departments of Medicine and Neurology, University of Washington Medical School
    2. Geriatrics Research Education and Clinical Center and Neurology Section, Veteans Affairs Puget Sound Health Care System, Scattle, WA
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  • S. Mark Sumi MD,

    1. Departments of Medicine and Neurology, University of Washington Medical School
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  • Ekaterina A. Rogaeva PhD,

    1. Centre for Research in Neurodegenerative Diseases, Department of Medicine Division of Neurology, University of Toronto, and Department of Medicine, Toronto Hospital, Toronto, Ontario, Canada
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  • Parvoneh Poorkaj PhD,

    1. Departments of Medicine and Neurology, University of Washington Medical School
    2. Geriatrics Research Education and Clinical Center and Neurology Section, Veteans Affairs Puget Sound Health Care System, Scattle, WA
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  • Robin Sherrington PhD,

    1. Centre for Research in Neurodegenerative Diseases, Department of Medicine Division of Neurology, University of Toronto, and Department of Medicine, Toronto Hospital, Toronto, Ontario, Canada
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  • Linda Nee MSW,

    1. Clinical Neuropharmacology Section, National Institure of Neurologic Disease and Stroke, Bethesda, MD
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  • Takehide Tsuda MD,

    1. Department of Neurology, Tohoku University School of Medicine, Sendai
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  • Nobuhito Oda MD,

    1. Division of Neurology and Neurosurgery, Ishii Hospital of Neurosurgery and Ophthalmology, Iwaki, Japan
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  • Mitsunori Watanabe MD,

    1. Department of Neurology, Gunma University School of Medicinr, Marbashi
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  • Masashi Aoki MD,

    1. Department of Neurology, Tohoku University School of Medicine, Sendai
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  • Mikio Shoji MD,

    1. Department of Neurology, Gunma University School of Medicinr, Marbashi
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  • Koji Abe MD,

    1. Department of Neurology, Tohoku University School of Medicine, Sendai
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  • Yasuto Itoymia MD,

    1. Department of Neurology, Tohoku University School of Medicine, Sendai
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  • Shurisaku Hirai MD,

    1. Department of Neurology, Gunma University School of Medicinr, Marbashi
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  • Gerard D. Schellenberg PhD,

    1. Departments of Medicine and Neurology, University of Washington Medical School
    2. Geriatrics Research Education and Clinical Center and Neurology Section, Veteans Affairs Puget Sound Health Care System, Scattle, WA
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  • Thomas D. Bird MD,

    1. Departments of Medicine and Neurology, University of Washington Medical School
    2. Geriatrics Research Education and Clinical Center and Neurology Section, Veteans Affairs Puget Sound Health Care System, Scattle, WA
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  • P. H. St George-Hyslop MD, FRCP(C)

    1. Centre for Research in Neurodegenerative Diseases, Department of Medicine Division of Neurology, University of Toronto, and Department of Medicine, Toronto Hospital, Toronto, Ontario, Canada
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Abstract

We report the clinical and neuropathologic phenotypes associated with two different missense mutations in the presenilin 1 (PS-1) gene in Japanese patients with early-onset familial Alzheimer's disease (FAD). In the Ah4/JPN1 pedigree a missense mutation (C→T) was found at nucleotide 1102, which is predicted to cause an alanine-to-valine missense substitution at codon 260. In this family, the disease had a mean age of onset of 40.3 years and an indolent course (range, 8–19 years). Neuropathologic studies in 3 members of this pedigree showed widespread senile plaques, neurofibrillary tangles, and neuronal loss, as well as abundant perivascular subpial amyloid deposits in the Virchow-Robin spaces and the presence of Pick-like intraneuronal inclusions in the dentate gyrus. In the second pedigree, transmitting a C→T nucleotide substitution at position 1027, leading to the missense mutation of alanine to valine at codon 285, the disease had a later onset (mean, 51 years) but a more rapid course. Comparison of the disease phenotypes associated with other missense mutations in exon 9 of PS-1 reveals no clinical or pathological phenotype, which uniquely distinguishes Alzheimer's disease associated with PS-1 mutations from other forms of early-onset FAD, implying that direct mutation screening is required to identify these cases.

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