Phenotypic variability and neuropsychological findings associated with C9orf72 repeat expansions in a Bulgarian dementia cohort

BACKGROUND: The GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in several European populations. The objective of this study was to determine the frequency of C9orf72 repeat expansions in a Bulgarian dementia cohort and to delineate the associated clinical features. METHODS AND FINDINGS: PCR-based assessments of the C9orf72 hexanucleotide repeat expansion in all study samples (including 82 FTD, 37 Alzheimer’s disease (AD), and 16 other neurodegenerative/dementia disorder cases) were performed. We report the clinical, neuropsychological, and neuroimaging findings obtained for the C9orf72 repeat expansion carriers. Of the 135 cases screened, 3/82 (3.7%) of all FTD cases and 1/37 (2.7%) of all clinical AD cases had a C9orf72 repeat expansion. In this cohort, the C9orf72 pathological expansion was found in clinical diagnoses bridging the FTD, parkinsonism, ALS and AD spectrum. Interestingly, we showed early writing errors without aphasia in two subjects with C9orf72 expansions. CONCLUSIONS: This study represents the first genetic screening for C9orf72 repeat expansions in a Bulgarian dementia cohort. The C9orf72 repeat expansion does not appear to be a common cause of FTD and related disorders. This report confirms the notion that C9orf72 repeat expansions underlie a broad spectrum of neurodegenerative phenotypes. Relatively isolated agraphia in two cases with C9orf72 repeat expansions is a strong motivation to provide detailed and sophisticated oral and written language assessments that can be used to more precisely characterize early cognitive deficits in these heterogeneous conditions.