CSF1R-Related Leukoencephalopathy Caused by CSF1R p.Arg777Trp and CSF1R p.Arg782Cys Mutations: A Report of Four Cases in Sweden

Abstract Background: Colony stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is a rare and devastating genetic disease caused by heterozygous mutations in the CSF1R gene. It is characterized by adult onset, rapidly progressive neurodegeneration and variable behavioral, cognitive, and motor disturbances and seizures. With only one affected family currently reported, the disease’s prevalence in Sweden is unknown. Objective: To describe four cases of CSF1R-related leukoencephalopathy from three families with two different pathogenic mutations in the tyrosine kinase domain of CSF1R and to develop an integrated presentation of inter-individual diversity of clinical presentations. Methods: This is an observational study of a case series. Patients diagnosed with CSF1R-encephalopathy were evaluated with standardized functional estimation scores and analysis of cerebrospinal fluid biomarkers. Brain computed tomography (CT) and magnetic resonance imaging (MRI) were systematically evaluated. We performed a functional phosphorylation assay to confirm the pathogenicity of the mutations. We performed neuropathologic examination on one deceased relative for diagnostic verification. Results: Two mutationsin CSF1R gene were identified, a missense variant c.2344C>T, p.Arg782Cys and a missense variant c.2329C>T, p.Arg777Trp. A phosphorylation assay in vitro showed markedly reduced autophosphorylation in cells expressing the CSF1R mutations p.Arg777Trp and p.Arg782Cys, confirming the pathogenicity of these mutations. A radiological investigation revealed typical white matter lesions in all cases. There was marked individual variation in the loss of frontal, motor neuronal and extrapyramidal functions, with a reciprocal relation to neurofilament light levels in the cerebrospinal fluid. Conclusions: Including the present cases, currently three CSF1R mutations are known in Sweden. We present a visualization tool to capture the degree of disability and clinical diversity, with a potential use for longitudinal follow-up for this and other leukoencephalopathies.Trial Registration: N/A (non-interventional study)