Abstract Details

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant degenerative disease characterized by axonal loss and axonal spheroids within cerebral white matter. HDLS is caused by mutations in Colony Stimulating Factor 1 receptor (CSF1R) gene, which encodes for a cell-surface protein essential for microglial development.

A 35-year-old Chinese woman without significant past medical history presented with rapidly progressive dementia and parkinsonism. MRI showed bilateral frontal subcortical white matter lesions and frontal atrophy. Other reversible causes including vasculitis were excluded. Her mother had a similar dementia with age onset at 49 years old and passed away at age 55 years from an unknown cause.

Whole-genome sequencing revealed a novel heterozygous missense mutation in CSF1R (c.C1700T, p.T567M), but no other potentially pathogenic variants.   As T567M lies in the juxtamembrane domain instead of the tyrosine kinase domain (TKD), we performed functional analysis to determine its pathogenicity.

T567M expression was comparable to that of wild-type. However, we observed moderate impairment of autophosphorylation at Tyr546 of T567M, as compared to mutants located within the TKD. As CSF1R signaling requires receptor dimerization and autophosphorylation, mutations affecting autophosphorylation will inhibit CSF1R signaling. However, no detrimental effect was observed on cell survival of SHSY-5Y cells transfected with mutants. Additionally, we observed that cells expressing T567M mutation showed reduced tyrosine hydroxylase, a rate-limiting enzyme in the synthesis pathway of dopamine.

Overall, we identified a rare novel missense mutation in the CSF1R gene located outside the TKD in a patient with clinical features consistent with HDLS. Functional studies reveal loss of function with autophosphorylation impairment and reduced tyrosine hydroxylase. Functional studies using patient-derived cell lines is currently ongoing.