A novel presenilin 2 mutation (V393M) in early‐onset dementia with profound language impairment

Background:  Mutations in the Presenilin 2 gene (PSEN2) are rare causes of Alzheimer’s disease (AD). Pathogenic mutations in the genes associated with autosomal dominant inherited AD have been shown to alter processing of the amyloid precursor protein (APP) resulting in a relative increase of the amount of Aβ42 peptide. Methods and results:  We present a patient with neuropathologically confirmed early-onset AD characterized by profound language impairment. The patient was heterozygous for a novel missense mutation in exon 11 of the PSEN2 gene leading to a predicted amino acid substitution from valine to methionine in position 393, a conserved residue. However, in vitro expression of PSEN2 V393M cDNA did not result in detectable increase of the secreted Aβ42/40 peptide ratio. The mutation was not found in 384 control individuals tested. Conclusions:  The possible pathogenic nature of the mutation is not clarified. We discuss the limitations of functional PSEN2 studies and the challenges associated with genetic counselling of family members at risk.