Early presentation of spastic paraparesis in individuals carrying PSEN1 mutations: a clinical and genetic analysis

Mutations in the presenilin 1 gene (PSEN1) are well-known causes of early-onset familial Alzheimer's disease, but they can also present with atypical phenotypes such as pure spastic paraparesis. This study aims to investigate the clinical and genetic features of PSEN1 variants in patients mainly manifested with hereditary spastic paraparesis (HSP)-like phenotypes.

Mutational analysis was performed in 242 unrelated Taiwanese patients with clinically suspected HSP using a targeted resequencing panel covering the entire coding regions of PSEN1, along with 76 genes associated with HSP and 55 genes linked to HSP-like phenotypes.

Two of the 242 patients (0.8%) were found to carry the pathogenic PSEN1 variants (p.P284S and p.F386S). In addition to the two probands, six affected family members were further identified to have the pathogenic PSEN1 variants. Six of these eight patients (75%) presented with spastic paraparesis as their initial symptom, one suffered from cognitive decline, and another manifested with personality change. The average age of symptom onset was 40.1 ± 4.8 years. Except for one patient, cognitive decline developed in all subjects before the last follow-up. For the patient carrying the PSEN1 p.P284S variant, amyloid deposition in bilateral lateral temporal, frontal, precuneus, and parietal regions was evident by amyloid PET, but no hippocampus atrophy was found on brain MRI. For the three patients carrying the PSEN1 p.F386S variant, brain atrophy with dilated ventricles were noted in the patient initially presented with personality changes, but normal MRI findings in the other two patients manifested with spastic paraparesis.

Spastic paraparesis can be the initial and isolated clinical presentation of PSEN1 mutations. We identified eight patients from two families carrying a pathogenic PSEN1 variant, all but one carriers have developed cognitive symptoms. PSEN1 related spastic paraparesis usually has a later age of onset compared to other common hereditary spastic paraparesis subtypes, and the family history of early onset dementia might be obscure. Our findings suggested that PSEN1 variants are a rare cause of spastic paraparesis but should be considered especially in those with a later age of onset.