Clinical and Pathological Features of CSF1R-Related Disorder Associated With the p.R777Q Pathogenic Variant

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Colony-stimulating factor-1 receptor (CSF1R)-related disorder (CSF1R-RD) is a rare, rapidly progressive neurodegenerative disease.
• Over 200 pathogenic variants in CSF1R have been identified, leading to diverse clinical presentations.
• The p.R777Q variant is a known deleterious mutation associated with CSF1R-RD.

Purpose of the Study:

• To characterize the clinical and pathological features of CSF1R-RD associated with the p.R777Q variant.
• To report a new family with the p.R777Q variant and compare disease progression and neuropathology.
• To investigate the aggressive nature of the p.R777Q variant in CSF1R-RD.

Main Methods:

• Clinical and imaging data from a new family with the p.R777Q variant were collected.
• Neuropathological examination of the index patient was performed.
• Literature review of 13 individuals with the p.R777Q variant was conducted and compared with a long-duration CSF1R-RD case.

Main Results:

• The p.R777Q variant was identified in a new family, with onset around 41 years and mean survival of 3.3 years.
• Neuropathology in the index patient (10-month duration) showed severe axonal and myelin pathology in the periventricular white matter.
• This pathology was less severe compared to a CSF1R-RD patient with an 11-year disease duration.

Conclusions:

• The p.R777Q variant is associated with an aggressive clinical course in CSF1R-RD.
• Milder neuropathological findings in the short-duration index case suggest variant-specific or rapid progression-related differences.
• Further research is needed to understand the specific mechanisms driving the aggressive nature of the p.R777Q variant.