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Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis

From the Departments of Neurology (Drs. Moretti and Foster, K.J. Kluin), Pathology (Dr. Lieberman), and Psychiatry (Drs. Wilde and Giordani) and Division of Nuclear Medicine (Drs. Koeppe, Minoshima, and Kuhl), University of Michigan, Ann Arbor; and Athena Diagnostics, Inc. (Dr. Seltzer), Worchester, MA.

Address correspondence and reprint requests to Dr. N.L. Foster, Department of Neurology, University of Michigan, 1920 Taubman, 1500 E. Medical Center Dr., Ann Arbor, MI 48109; e-mail: nlfoster{at}umich.edu

A four-generation pedigree exhibiting early-onset autosomal dominant Alzheimer disease (AD) with spastic paraplegia, dystonia, and dysarthria due to a novel 6-nucleotide insertional mutation in exon 3 of the presenilin 1 gene (PS1) is described. Serial examinations, PET scans, and autopsy revealed that the mutation in this highly conserved portion of PS1 causes an aggressive dementia that maintains the usual regional hierarchy of disease pathology while extending abnormalities into more widespread brain areas than typically seen in AD.

Received December 5, 2003. Accepted in final form January 21, 2004.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the May 25 issue to find the title link for this article.

Dr. Moretti’s current address is Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm. T836, Houston, TX 77030. Dr. Wilde’s current address is Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, 6560 Fannin St., Suite 1144, Box 67, Houston, TX 77030.

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