Early onset familial Alzheimer’s disease (EOFAD) can be caused by mutations in genes for amyloid precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2). There is considerable phenotypic variability in EOFAD, including some patients with spastic paraparesis. The objective is to describe clinical and neuropathologic features of a family with a PSEN1 mutation that has been reported previously, without autopsy confirmation, in a single Greek family whose affected members presented with memory loss in their thirties, as well as variable limb spasticity and seizures.
We prospectively evaluated two children (son and daughter) with EOFAD and reviewed medical records on their mother. Archival material from the autopsy of the mother was reviewed and postmortem studies were performed on the brain of the daughter.
All three individuals in this family had disease onset in their thirties, with cognitive deficits in multiple domains, including memory, language and attention, as well as less common features such as spastic dysarthria, limb spasticity and seizures. At autopsy both the mother and her daughter had pathologic findings of AD, as well as histological evidence of corticospinal tract degeneration. Genetic studies revealed a mutation in PSEN1 leading to an asparagine to serine substitution at amino acid residue 135 (N135S) in presenilin-1.
This is the first description of neuropathologic findings in EOFAD due to N135S PSEN1 mutation. The clinical phenotype was remarkable for spastic dysarthria, limb spasticity and seizures, in addition to more typical features of EOFAD.