Cognitive impairment is not uncommon in patients with biallelic RFC1 AAGGG repeat expansion, but the expansion is rare in patients with cognitive disease.

INTRODUCTION: The biallelic repeat expansion (AAGGG)exp in RFC1 causes cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). Recently, cognitive impairment has been reported in patients with CANVAS and a broader neurodegenerative process associated with RFC1 has been suggested. Furthermore, rare cases of multiple system atrophy, Parkinson's disease, amyotrophic lateral sclerosis or CANVAS with features of dementia with Lewy bodies have been found. OBJECTIVE: We hypothesized that the biallelic (AAGGG)exp is associated with neurodegeneration manifested as cognitive symptoms and that atypical RFC1 disease may be found among patients with cognitive disorder. METHODS: Clinical data on nine patients with biallelic (AAGGG)exp were reviewed and 564 patients with Alzheimer's disease or frontotemporal dementia (FTD) were investigated for biallelic RFC1 (AAGGG)exp. RESULTS: Five patients with biallelic (AAGGG)exp were found with a cognitive impairment and in four of them the phenotype resembled FTD. However, biallelic (AAGGG)exp was not detected among patients with Alzheimer's disease or FTD. CONCLUSION: Cognitive impairment is a feature in patients with the biallelic (AAGGG)exp, but the pathogenic expansion seems to be rare in patients with dementia. Studies on patients with diverse phenotypes would be useful to further explore the involvement of RFC1 in neuronal degeneration and to identify atypical phenotypes, which should be taken into account in clinical practice.