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Neurobiol Aging. 2017 Jan;49:216.e7-216.e13. doi: 10.1016/j.neurobiolaging.2016.09.020. Epub 2016 Oct 3.

Clinical, imaging, pathological, and biochemical characterization of a novel presenilin 1 mutation (N135Y) causing Alzheimer's disease.

Author information

1
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.
2
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.
3
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.
4
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.
5
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.
6
Dominantly Inherited Alzheimer's Network, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
7
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.

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.

KEYWORDS:

Alzheimer's disease; Elecrtoencephalography; PET scan; Presenilin 1

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