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

Area of Science:

• Neurogenetics
• Neurodegenerative Diseases
• Molecular Biology

Background:

• Monogenic Alzheimer's disease (AD) is rare, with presenilin 2 (PSEN2) gene mutations accounting for its rarest form.
• Investigating unusual clinical and neuroimaging presentations of PSEN2-AD contributes to understanding its pathophysiology and semiology.

Observation:

• Two female patients presented with early-onset dementia (ages 69 and 62) characterized by prominent behavioral and language dysfunction.
• Disease progression was rapid, leading to severe dementia within three years.
• Neuroimaging revealed significant frontal white matter hyperintensities (WMH) and frontotemporal atrophy/hypometabolism.

Findings:

• Genetic analysis identified two novel PSEN2 variants: c.772G>A (p.Ala258Thr) and c.1073-2_1073-1del.
• Cerebrospinal fluid (CSF) and experimental blood biomarkers supported an AD etiology.
• The clinical presentation mimicked frontotemporal dementia (FTD).

Implications:

• Behavioral and language dysfunction should be considered a potential clinical manifestation of PSEN2 mutations in Alzheimer's disease.
• Including PSEN2 in genetic panels for suspected frontotemporal dementia-like disorders (FTDL) is advisable.
• PSEN2 mutations may lead to pronounced WMH, possibly due to amyloid-induced myelin disruption.