CSF1R mutations in an Italian population of early-onset dementia: a case series

The diagnostic approach to subjects with early-onset dementia (EOD) is often challenging due to the broader range of possible etiologies as compared to late-onset dementia cases. Pathogenic variants in CSF1R gene have been increasingly reported in subjects with EOD, mostly clinically mimicking behavioral variant of frontotemporal dementia (bvFTD). Here we screened for variants in CSF1R gene in a large cohort of dementia patients consecutively referred for genetic analysis to an Italian tertiary center between 2005 and 2024 (n = 2163). Sequence of CSF1R gene was determined with next-generation sequencing through either a dedicated panel or whole-exome sequencing. Pathogenic variants or variants of uncertain significance with higher evidence of pathogenicity were found in four participants (one female); three of these were not previously reported. Clinical data were collected, including brain magnetic resonance imaging and neuropsychological assessment. Cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) protein were measured. A family history of dementia was present in one subject. Mean age at onset was 51.5. Seizures were the presenting symptom in two cases and later appeared in other two. Two subjects presented with behavioral disturbances, resembling early bvFTD. Neuropsychological assessment revealed executive and language impairment in most cases. Anterior-predominant atrophy, symmetric white-matter involvement, and serpentine calcifications were the most common imaging abnormalities. High CSF NfL levels were found in all cases, with two of them showing markedly elevated values. CSF1R-related disease should be considered in EOD subjects, especially those presenting with executive/language deficits, seizures, white matter involvement, and markedly elevated CSF NfL levels.