A novel presenilin 1 mutation (L282F) in familial Alzheimer’s disease

Abstract

Sirs, Mutations in the genes of b-amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) have been identified as causative in familial Alzheimer’s disease (FAD) [9]. Mutations in PSEN1 are most common in FAD, and 168 pathogenic PSEN1 mutations have been reported to date [3]. We report a novel mutation of PSEN1 (L282F) in a patient with FAD. A 57-year-old woman consulted our hospital because of progressive memory loss. She had noticed forgetfulness since age 53 and had been treated with donepezil at a local clinic since age 55. She presented with impairment of recent memory and orientation for date and scored 24/30 on the mini-mental state examination without any other neurological deficits. Findings of routine blood tests were normal. Serum apolipoprotein E phenotype was E3/E4. Mild medial temporal atrophy was demonstrated on brain magnetic resonance imaging. Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) revealed glucose hypometabolism in the bilateral parietal cortices and posterior cingulate gyri. Her family history suggested FAD, but we could not determine the hereditary pattern of FAD (Fig. 1). After written consent was obtained from the patient and her family, all exons of APP, PSEN1 and PSEN2 were analyzed by direct cycle sequencing as described previously [5, 10]. The analysis of PSEN1 demonstrated a C ? T transversion at the first position of codon 282 in exon 8 (genomic accession number: g. 50029C[T), which predicted a L282F substitution (Fig. 2). There were no other mutations detected in the analyzed genes. We also searched for this mutation in 192 Japanese patients with Alzheimer’s disease (AD) or other forms of dementia, and none demonstrated this PSEN1 mutation. We diagnosed this patient as having probable AD according to the NINCDS-ADRDA criteria [6]. The pattern of brain hypometabolism on FDG-PET supported the diagnosis [2, 7]. Although this L282F mutation has not been described previously, two other mutations at the same