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Novel Presenilin 1 Mutations Associated With Early Onset of Dementia in a Family With Both Early-Onset and Late-Onset Alzheimer Disease
Gayatria Devi, MD;
Alexandra Fotiou, MD;
Darlene Jyrinji, MA;
Benjamin Tycko, MD, PhD;
Steve DeArmand, MD;
Ekaterina Rogaeva, PhD;
You-Quiang Song, PhD;
Helena Medieros;
Yan Liang, MD;
Antonio Orlacchio, MD;
Jennifer Williamson;
Peter St George-Hyslop, MD, FRCPC;
Richard Mayeux, MD, MSc
Arch Neurol. 2000;57:1454-1457.
Two children of an adult with early-onset, autopsy-confirmed Alzheimer disease (AD) developed dementia in their late 20s and were subsequently found to have novel mutations in codon 434 of the presenilin 1 (PS1) gene on chromosome 14, a G-to-T substitution at nucleotide 1548 and a C-to-G substitution at nucleotide 1549. The younger of the 2 children had AD confirmed at postmortem examination. The disease course in these 3 individuals was characterized by cognitive and behavioral problems accompanied by myoclonus, seizures, and aphasia within 5 years after onset. Two grandparents had clinically diagnosed AD with stroke beginning at ages 78 and 66 years, but neither had a PS1 mutation. No other living family member was demented, nor did any other family member have the PS1 mutation. We conclude that the affected parent of the proband was a likely recent founder for these novel mutations in PS1. The family demonstrates the clinical and genetic heterogeneity of AD.
From the Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Drs Devi, Tycko, and Mayeux and Ms Williamson), the Gertrude H. Sergievsky Center and the Departments of Pathology (Dr Tycko), Neurology (Ms Williamson and Dr Mayeux), Psychiatry (Dr Mayeux), and College of Physicians and Surgeons, Columbia University, New York, NY; the Long Island Alzheimer's Disease Assistence Center, Stony Brook, NY (Dr Fotiou); the University of Rochester, Department of Psychiatry, Rochester, NY (Dr Jyrinji); the Department of Pathology, University of California, San Francisco (Dr DeArmand); and the Department of Medicine (Division of Neurology), Toronto Western Hospital, and the Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario (Drs Rogaeva, Song, Liang, Orlacchio, and St George-Hyslop and Ms Medieros). Dr Devi is with the New York Memory and Health Aging Services and the Departments of Medicine (Division of Neurology) and Psychiatry, Lenox Hill Hospital, New York, NY.
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