ClinVar

In 3 brothers with early-onset Alzheimer disease with spastic paraparesis (see 607822) and unusually rapid progression, Dolzhanskaya et al. (2014) identified a heterozygous c.1141C-T transition in the PSEN1 gene, resulting in a leu381-to-phe (L381F) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database and segregated with the disorder in the family. The boys' father and paternal grandmother were reportedly similarly affected. The brothers had onset of progressive dementia and ataxia between ages 29 and 32 years; 2 died by age 32 and the other at age 36. The proband presented with memory deficits and ataxia, and later developed dysarthria, and spastic paraparesis. Electron microscopy of a skin biopsy showed lipofuscin-containing phagocytic cells and distinct curvilinear lysosomal inclusion bodies, suggestive of neuronal ceroid lipofuscinosis. Neuropathologic examination showed changes consistent with Alzheimer disease, including neuritic and amyloid-containing plaques and neurofibrillary tangles. Additional findings included Hirano bodies and granulovacuolar degeneration in the hippocampus. The proband was originally ascertained from a cohort of patients clinically thought to have autosomal dominant adult-onset neuronal ceroid lipofuscinosis (CLN4B; 162350) who were negative for mutations in the DNAJC5 gene (611203). Functional studies of the L381F variant were not performed.