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Jill R. Murrell, PhD; Ann M. Hake, MD; Kimberly A. Quaid, PhD; Martin R. Farlow, MD; Bernardino Ghetti, MD

Arch Neurol. 2000;57:885-887.

Context  Alzheimer disease is the most common form of dementia. Mutations in the genes amyloid precursor protein (APP), presenilin 1(PS1) and presenilin 2(PS2) have been found in early-onset familial forms of Alzheimer disease

Objective  To determine the cause of dementia in a family with early-onset illness.

Design, Setting, and Participants  A family with a history of dementia was referred to the Indiana Alzheimer Disease Center, Indianapolis. All the research in this study was done in a university or university hospital. The proband and her 4 siblings took part in the study. The proband, who is still alive, showed symptoms of Alzheimer disease at 38 years of age. Genomic DNA was obtained from blood samples of 5 family members. The APP and PS1 genes of the proband were screened for mutations by amplification followed by direct sequencing.

Results  Sequence of exon 17 of the APP gene revealed a single nucleotide (guanine to cytosine) substitution in 1 allele, resulting in an amino acid change at codon 717 (valine to leucine). Each of the proband's siblings were tested for this mutation by direct sequencing. Two of the 4 were found to have the mutation; one of whom was recently clinically diagnosed at the age of 36 years.

Conclusions  A novel mutation in the APP gene (V717L) has been found in a family with a history of dementia, beginning in the mid to late 30s. The age of onset in this family is earlier than most of the other families with Alzheimer disease who also have APP mutations.

From the Departments of Pathology and Laboratory Medicine, Division of Neuropathology (Drs Murrell and Ghetti), Neurology (Drs Hake and Farlow), and Medical and Molecular Genetics (Dr Quaid), Indiana University School of Medicine, Indianapolis.

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