Expanding the Tyrosine Kinase Domain of CSF1R? A Case Report From an Adult-Onset Leukoencephalopathy.

Abstract

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), also termed hereditary diffuse leukoencephalopathy with spheroids-1 (HDLS1), results from mutations in the CSF1R gene and leads to progressive leukoencephalopathy. This autosomal dominant condition typically manifests in the fourth or fifth decade of life with a combination of early-onset dementia, neuropsychiatric changes, and motor symptoms. CSF1R mutations are predominantly located within the tyrosine kinase domain (TKD) of the protein, crucial for its kinase activity. However, variants outside the TKD can also disrupt kinase function. Here, we report a 58-year-old man with early-onset dementia and a novel missense variant [c.1735C>G, p.(Arg579Gly)] just outside the TKD of CSF1R. Functional analysis showed impaired autophosphorylation of the mutant protein, supporting its pathogenicity. This case highlights the importance of functional validation in newly identified CSF1R variants, underscoring the need for comprehensive genetic and functional analysis in diagnosing and understanding this rare neurological disorder.