The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions

摘要: There is increasing evidence that frontotemporal dementia and amyotrophic lateral sclerosis are part of a disease continuum. Recently, hexanucleotide repeat expansion in C9orf72 was identified as major cause both sporadic familial sclerosis. The aim this study to investigate clinical neuropathological characteristics expansions large cohort Dutch patients with dementia. Repeat were successfully determined 353 or without sclerosis, 522 neurologically normal controls. Immunohistochemistry performed series 10 brains from carrying expanded repeats using panel antibodies. In addition, the presence RNA containing GGGGCC paraffin-embedded sections post-mortem brain tissue investigated fluorescence situ hybridization locked nucleic acid probe targeting repeat. Hexanucleotide found 37 (28.7%) five (2.2%). mean age at onset 56.9 ± 8.3 years (range 39-76), duration 7.6 4.6 1-22). phenotype these varied between behavioural variant (n = 34) primary progressive aphasia 8), concomitant seven patients. Predominant temporal atrophy on neuroimaging present 13 32 Pathological examination revealed lobar degeneration neuronal transactive response DNA binding protein-positive inclusions variable type, size morphology all brains. Fluorescence analysis material expansion, microtubule-associated protein tau progranulin mutation, controls did not show RNA-positive specific for expansion. an important sometimes associated aphasia. Neuropathological hallmarks include glial inclusions, dystrophic neurites protein. Future studies needed explain wide variation presentation.