# PSEN2 Mutations May Mimic Frontotemporal Dementia: Two New Case Reports and a Review

## TL;DR

Two new cases show that PSEN2 gene mutations can mimic frontotemporal dementia with behavioral and language issues, suggesting a link to Alzheimer's disease.

## Contribution

Highlights under-recognized clinical features of PSEN2 mutations resembling frontotemporal dementia and suggests their inclusion in genetic testing.

## Key findings

- PSEN2 mutations presented with behavioral and language dysfunction similar to frontotemporal dementia.
- Neuroimaging showed frontal white matter hyperintensities and frontotemporal atrophy/hypometabolism.
- CSF and blood biomarkers confirmed Alzheimer's disease etiology in both cases.

## Abstract

Background: Monogenic Alzheimer’s disease (AD) has severe health and socioeconomic repercussions. Its rarest cause is presenilin 2 (PSEN2) gene mutations. We present two new cases with presumed PSEN2-AD with unusual clinical and neuroimaging findings in order to provide more information on the pathophysiology and semiology of these patients. Methods: Women aged 69 and 62 years at clinical onset, marked by prominent behavioral and language dysfunction, progressing to severe dementia within three years were included. The complete study is depicted. In addition, a systematic review of the PSEN2-AD was performed. Results: Neuroimaging revealed pronounced frontal white matter hyperintensities (WMH) and frontotemporal atrophy/hypometabolism. The genetic study unveiled PSEN2 variants: c.772G>A (p.Ala258Thr) and c.1073-2_1073-1del. Both cerebrospinal fluid (CSF) and experimental blood biomarkers shouldered AD etiology. Conclusions: Prominent behavioral and language dysfunction suggesting frontotemporal dementia (FTD) may be underestimated in the literature as a clinical picture in PSEN2 mutations. Thus, it may be reasonable to include PSEN2 in genetic panels when suspecting FTDL. PSEN2 mutations may cause striking WMH, arguably related to myelin disruption induced by amyloid accumulation.