Autopsy-confirmed familial early-onset Alzheimer disease caused by the L153V presenilin 1 mutation

Background: Three affected individuals are described from a small English k indred with early-onset autosomal dominant familial Alzheimer disease (FAD) caused by a leucine-to-valine change at codon 153 (L153V) of the presenili n 1 (PSEN1) gene. Methods: Clinical information on the pedigree was collected directly from f amily members and from hospital records. Samples of DNA were screened by me ans of direct sequencing of all coding exons of PSEN1. One patient underwen t 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 (9 5% 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 relati vely 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 cl inical features similar to those of other reported FAD pedigrees.