title: Clinical, imaging, pathological, and biochemical characterization of a novel presenilin 1 mutation (N135Y) causing Alzheimer's disease.
abstract: We present 2 cases of early-onset Alzheimer's disease due to a novel N135Y mutation in PSEN1. The proband presented with memory and other cognitive symptoms at age 32. Detailed clinical characterization revealed initial deficits in memory with associated dysarthria, progressing to involve executive dysfunction, spastic gait, and episodic confusion with polyspike discharges on long-term electroencephalography. Amyloid- and FDG-PET scans showed typical results of Alzheimer's disease. By history, the proband's father had developed cognitive symptoms at age 42 and died at age 48. Neuropathological evaluation confirmed Alzheimer's disease, with moderate to severe amyloid angiopathy. Skeletal muscle showed type 2 fiber-predominant atrophy with pale central clearing. Genetic testing of the proband revealed an N135Y missense mutation in PSEN1. This mutation was predicted to be pathogenic by in silico analysis. Biochemical analysis confirmed that the mutation caused an increased Aβ42/Aβ40 ratio, consistent with other PSEN1 mutations and with a loss of presenilin function.
authors: Alzheimer's Disease Center, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Neurology, Birmingham VA Medical Center, Birmingham, AL, USA.
authors: Marissa
authors: M
authors: Natelson Love
authors: Alzheimer's Disease Center, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Neurology, Birmingham VA Medical Center, Birmingham, AL, USA; Department of Neurology, Ralph H. Johnson VA Medical Center, Medical University of South Carolina, Charleston, SC, USA. Electronic address: clarkda@musc.edu.
authors: David G
authors: DG
authors: Clark
authors: Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA; Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: J Nicholas
authors: JN
authors: Cochran
authors: Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA; Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Kyle A
authors: KA
authors: Den Beste
authors: Alzheimer's Disease Center, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA; McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: David S
authors: DS
authors: Geldmacher
authors: Dominantly Inherited Alzheimer's Network, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Tammie L
authors: TL
authors: Benzinger
authors: Dominantly Inherited Alzheimer's Network, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Brian A
authors: BA
authors: Gordon
authors: Dominantly Inherited Alzheimer's Network, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
authors: John C
authors: JC
authors: Morris
authors: Dominantly Inherited Alzheimer's Network, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Randall J
authors: RJ
authors: Bateman
authors: Alzheimer's Disease Center, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA; Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA; McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Erik D
authors: ED
authors: Roberson
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D004569:Electroencephalography; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D059906:Neuroimaging; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D053764:Presenilin-1 / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; D053764:Presenilin-1
keywords: Alzheimer's disease; Elecrtoencephalography; PET scan; Presenilin 1