This case presents a patient with cognitive decline and spasticity associated with a previously unidentified pathogenic variant of presinilin1 (PSEN1). 

Mutations in PSEN1 are the most common cause of familial Alzheimer’s Disease (AD). Mutations in PSEN1 are highly penetrant with autosomal dominant inheritance, presenting at a young age and often with unusual features including spastic paraplegia (SP). We report a novel mutation found in our patient that is suspected to be the cause of his AD with associated SP.

A male presented initially with cognitive concerns in his 40s followed by gait impairment within 5 years. Now in his 50s, he has marked dementia and requires the use of a wheelchair. His examination is notable for disorientation to place and time, palilalia, and inability to reliably follow commands or provide history. Motor exam reveals pyramidal weakness and spasticity limited to the lower extremities. His mother had a very similar presentation of dementia and SP and died in her 40s.

Serum labs were unremarkable. Cerebrospinal fluid studies revealed a reduced A-Beta 42 to Total Tau index, consistent with AD. MRI demonstrated diffuse atrophy and FDG-PET demonstrated temporoparietal hypometabolism as well as asymmetric hypometabolism in the posterior cingulate. Genetic testing revealed a previously undescribed mutation in PSEN1 (p.Met270dup). Notably, mutations at both amino acids 269 and 271 have previously been reported as pathogenic, with the latter resulting in abnormal splicing at exon 8 which includes a portion of the catalytic domain.

Although it is known that mutations in PSEN1 can be associated with AD with SP, we present a case with a novel mutation thought to be the cause of our patient’s presentation. This variant has not been reported in the literature, and our case helps to highlight the importance of this previously unidentified variant.