P3-283: Familial Early-Onset Lewy Body Dementia: Clinical, Pathological and Genetic Dissection

Familial ocurrence of early-onset Lewy-body dementia is very infrequent and only a few families have been reported. We describe the clinical, pathological and genetic findings of four individuals from a two-generation family with early-onset autosonal dominant Lewy-body dementia. Mutation screening was performed for alpha- and beta-sinuclein, presenilin 1 and 2, amyloid precursor protein (APP) and MAPT using direct sequencing. Genome wide single nucleotide polymorphism typing using Ilumina's Human Hap550 Genotyping BeadChip was also performed. Three siblings presented with a clinical picture of cognitive impairment, parkinsonism and visual hallucinations with an age at onset between 26 and 29 years. Neuropathological examination disclosed abundant Lewy bodies and Lewy neurites in basal ganglia and the neocortex reactive for both alpha-sinuclein and tau. No amyloid plaques were detected. The father developed cognitive impairment, with early spontaneous parkinsonism at the age of 77. DAT scan showed low dopamine transporter uptake in the gasal ganglia. Genetic analysis showed no mutations in the alpha- or beta-synuclein, MAPT, APP, presenilin 1 or 2 genes. No structural genomic alterations (deletions and duplications) were found except for some described polymorphic copy number variations of the human genome. We report a family with pathological-confirmed early-onset Lewy-body dementia with coexistence of both tau and synuclein in the same inclusions. The absence of structural mutations in the genome and the lack of point mutations in genes known to cause LBD suggests that a novel locus or loci are involved in this neurodegenerative disease.