Ectopic white matter neurons, a developmental abnormality that may be caused by the PSEN1 S169L mutation in a case of familial AD with myoclonus and seizures

We report clinical, neuropathologic and molecular genetic data from an indi vidual affected by a familial Alzheimer disease (AD) variant. The proband h ad an onset of dementia at age 29 followed by generalized seizures a year l ater. He died at age 40. Neuropathologically, he had severe brain atrophy a nd characteristic histopathologic lesions of AD. Three additional neuropath ologic features need to be emphasized: 1) severe deposition of AP in the fo rm of diffuse deposits in the cerebral and cerebellar cortices, 2) numerous AP deposits in the subcortical white matter and in the centrum. semiovale, and 3) numerous ectopic neurons, often containing tau-immunopositive neuro fibrillary tangles, in the white matter of the frontal and temporal lobes. A molecular genetic analysis of DNA extracted from brain tissue of the prob and revealed a S169L mutation in the Presenilin 1 (PSEN1) gene. The importa nce of this case lies in the presence of ectopic neurons in the white matte r, early-onset seizures, and a PSEN1 mutation. We hypothesize that the PSEN 1 mutation may have a causal relationship with an abnormality in neuronal d evelopment.