Clinical and Molecular Findings in a Turkish Family Who Had a (c.869- 1G>A) Splicing Variant in PSEN1 Gene with A Rare Condition: The Variant Alzheimer's Disease with Spastic Paraparesis

Background: Early-onset Alzheimer's disease (EOAD) is commonly diagnosed with an onset age of earlier than 65 years and accounts for 5-10% of all Alzheimer's disease (AD) cases. To date, although only 10-15% of familial EOAD cases have been explained, the genetic cause of the vast proportion of cases has not been explained. The variant Alzheimer's disease with spastic paraparesis (var- AD) is defined as a rare clinical entity characterized by early-onset dementia, spasticity of the lower extremities, and gait disturbance. Although the disease was first associated with variants in exon 9 of the PSEN1 gene, it was later shown that variations in other exons were also responsible for the disease.

Objective: The current study aims to raise awareness of varAD, which occurs as a rare phenotype due to pathogenic variants in PSEN1. In addition, we aimed to evaluate the spectrum of mutations in varAD patients identified to date.

Methods: Detailed family histories and clinical data were recorded. Whole exome sequencing was performed and co-segregation analysis of the family was done by Sanger sequencing. Also, a review of the molecularly confirmed patients with (varAD) from the literature was evaluated.

Results: We identified a heterozygous splicing variant (c.869-1G>A) in the PSEN1 gene, in a family with two affected individuals who present with varAD. We reported the clinical and genetic findings from the affected individuals.

Conclusion: We present the detailed clinical and genetic profiles of a Turkish patient with the diagnosis of varAD together with subjects from the literature. Together, we think that the clinical characteristics and the effect of the (c.869-1G>A) variant will facilitate our understanding of the PSEN1 gene in AD pathogenesis.