Clinical and neuropathological analysis of the most common CSF1R p.Ile794Thr mutation

This study aims to define the clinical and neuropathological features associated with the CSF1R c.2381T > C, p.Ile794Thr variant.

Colony-stimulating factor 1 receptor (CSF1R)-related disorder (CSF1R-RD) is a rare, fatal, autosomal dominant leukoencephalopathy caused by mutations in the CSF1R gene, primarily affecting microglial function. The CSF1R c.2381T > C, p.Ile794Thr variant in exon 18 is the most frequently reported pathogenic mutation worldwide. The clinical presentation of carriers of different CSF1R mutations may vary.

We analyzed medical records and neuropathology of seven patients from four families evaluated at Mayo Clinic Florida (MCF). We compared them with 74 previously reported p.Ile794Thr cases identified through a systematic literature search (PubMed, Embase, Web of Science, and Google Scholar) up to January 2026. Data on age of onset, clinical symptoms, survival, and imaging findings were analyzed. Haplotype analysis was performed to investigate potential founder effects.

Parkinsonism occurred significantly more frequently in the MCF cohort than in the p.Ile794Thr cases reported in the literature (85.7% vs. 40.0%; p = 0.04). Haplotype analysis indicated that the mutation likely arose independently in different lineages rather than from a common ancestor, including a confirmed de novo case. Neuropathological evaluation confirmed classic hallmarks of CSF1R-RD: white matter degeneration, axonal spheroids, and pigmented glia.

CSF1R-RD associated with the p.Ile794Thr variant presents a consistent clinical phenotype across cases reported globally, though the prevalence of parkinsonian features may vary by population. The high frequency of this variant across diverse haplotypes suggests a mutational hotspot in exon 18.