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John C. Janssen, MRCP; Peter L. Lantos, MD, PhD, DSc, FRCPath; Nicholas C. Fox, MRCP; Richard J. Harvey, MD, MRCPsych; Jonathan Beck, BSc; Andrew Dickinson, BSc; Tracey A. Campbell, BSc; John Collinge, MD, FRCP, FRCPath; Diane P. Hanger, PhD; Lisa Cipolotti, PhD; John M. Stevens, FRCR; Martin N. Rossor, MD, FRCP

Arch Neurol. 2001;58:953-958.

Background  Three affected individuals are described from a small English kindred with early-onset autosomal dominant familial Alzheimer disease (FAD) caused by a leucine-to-valine change at codon 153 (L153V) of the presenilin 1 (PSEN1) gene.

Methods  Clinical information on the pedigree was collected directly from family members and from hospital records. Samples of DNA were screened by means of direct sequencing of all coding exons of PSEN1. One patient underwent neuropathological examination.

Results  Mean age at onset of symptoms was 35.3 years (95% confidence interval [CI], 34.6-36.0 years); at death, 44.0 years (95% CI, 39.1-48.9 years). Mean duration of illness was 8.3 years (95% CI, 4.7-11.9 years). Myoclonus was a late feature in 1 patient; seizures were not reported in any subjects. Spastic paraparesis and extrapyramidal signs were absent. The neuropsychometric profile of 1 patient showed relatively preserved naming skills in the setting of global cognitive deficits. Results of neuropathological examination demonstrated the signature lesions of Alzheimer disease and the presence of occasional cortical Lewy bodies.

Conclusions  The PSEN1 L153V mutation lies in the main mutation cluster of PSEN1 in the second transmembrane domain. It causes early-onset FAD with clinical features similar to those of other reported FAD pedigrees.

From the Dementia Research Group, Institute of Neurology (Drs Janssen, Fox, Harvey, and Rossor), the Departments of Neuropathology (Dr Lantos) and Neuroscience (Dr Hanger), Institute of Psychiatry, the Medical Research Council Prion Unit, Department of Neurogenetics, Imperial College School of Medicine (Messrs Beck and Dickinson, Ms Campbell, and Dr Collinge), and the Departments of Clinical Neuropsychology (Dr Cipolotti) and Neuroradiology (Dr Stevens), National Hospital for Neurology and Neurosurgery, London, England.

Corresponding author and reprints: M. N. Rossor, Dementia Research Group, Institute of Neurology, Queen Square, London WC1N 3BG, England (e-mail: m.rossor{at}dementia.ion.ucl.ac.uk).

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