A pedigree of early ⁃ onset familial Alzheimer's disease type 3 with spastic paraplegia as the primary manifestation

Objective To summarize the clinical and genetic mutation characteristics of a family of early ‑ onset familial Alzheimer's disease (EOFAD) type 3 with spastic paraplegia as the first symptom. Methods and Results A 29 ‑ year ‑ old male patient with spastic paraplegia as the first symptom was admitted to Xuanwu Hospital, Capital Medical University on March 30, 2021. Head MRI showed multiple ischemic foci in bilateral subfrontal cortex and bilateral temporal lobes. Thoracic MRI showed mild atrophic changes. Follow‑up medical history showed the first symptom of the his father were similar and progressed rapidly, including spastic paralysis, speech disorders, dementia, and mental and behavioral abnormalities. The duration from onset to death was 7 years, showing a relatively malignant course. Whole exome sequencing (WES) revealed a missense mutation of PSEN1 gene exon 7 c.668A > G (p.Gln223Arg) in the patient. The results of Sanger sequencing showed the mother and sister of the patient did not carry this mutation, and it was speculated the mutation came from the father of the patient. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the above mutation was classified as likely pathogenic (PS3 + PM2 + PS4_Moderate). The patient was diagnosed with spastic paraplegia, and the family was diagnosed with EOFAD3. Conclusions A missense mutation of PSEN1 gene exon 7 c.668A > G (p.Gln223Arg) was identified, which was the pathogenic variant of this family, resulting in a rare EOFAD3 with spastic paraplegia as the first symptom, detailed family investigation combined with WES would help improve the efficiency of early diagnosis.