In this study, we report a first 226leucine (Leu) mutation to phenylalanine (Phe) in (PSEN1, CTC>TTC, L226F) in Asia from a Korean early-onset Alzheimer's disease (EOAD) patient. Polymerase chain reaction (PCR)-single strand conformation polymorphism, sequencing, and in silico predictions were performed. Previously, L226F was reported in EOAD patients by Zekanowski et al and Gómez-Tortosa et al. Disease phenotypes appeared in their thirties, and family history was positive in both cases. In our patient, age of onset was similar (37 years of age), but the mutation seemed to be de novo, since no affected family member was found. This leucine to phenylalanine substitution may cause additional stresses inside the transmembrane region due to large aromatic side chain and increased hydrophobic interactions with hydrocarbon chains in the membrane and its binding partners. Clinical phenotype of the mutation was aggressive progression into neurodegeneration, resulting in rapid cognitive decline. One of the patients was initially diagnosed with frontotemporal dementia, but the diagnosis was revised to AD upon postmortem studies in which Aβ plaques were seen. A second mutation, L226R, was found for the L226 residue. Similar to L226F, the patient with L226R also developed the first symptoms in his 30s, but EOAD was diagnosed in his 40s. These findings suggested that L226 might be an important residue in PSEN1, since mutations could result in neurodegenerative disease phenotypes at relatively young ages. There are mutations, such as L226F, which may not present clear clinical symptoms for the definitive diagnosis between frontotemporal dementia and AD. In addition, the similarities in the phenotypes could also be possible between AD and frontotemporal dementia, suggesting difficulties in differential diagnosis of various neurodegenerative diseases.
Keywords: Alzheimer’s disease; PSEN1 mutation; frontotemporal dementia; sequencing.