Clinical and genetic characteristics of CSF1R-related leukoencephalopathy: a retrospective analysis of three cases.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant neurodegenerative disorder caused by CSF1R variants, which lead to microglial dysfunction and progressive white matter degeneration. This study identified CSF1R variants in three unrelated Chinese patients with HDLS. We identified heterozygous CSF1R variants (NM_001288705.3) in three unrelated Chinese patients with HDLS: c.2522 A > C/p.(Tyr841Ser), c.2442 + 1G > A/p.?, and c.2546_2548del/p.(Phe849del). While the former two variants were categorized as likely pathogenic under the American College of Medical Genetics and Genomics framework, the latter (c.2546_2548del) was classified as a variant of uncertain significance due to insufficient evidence at the time of analysis. All patients exhibited cognitive decline, personality changes, and motor symptoms. Brain MRI showed characteristic diffuse white matter hyperintensities, restricted diffusion, corpus callosum atrophy, and brain atrophy. Symptoms progressed in Patient 1 (c.2522 A > C p.(Tyr841Ser)) and Patient 3 (c.2546_2548del p.(Phe849del)) despite standard symptomatic treatments. Clinical status remained relatively stable in Patient 2 (c.2442 + 1G > A/p.?) following allogeneic hematopoietic stem cell transplantation (HSCT). These findings expand the molecular and clinical spectrum of CSF1R in Chinese populations and highlight the diagnostic value of genetic sequencing in adult-onset leukoencephalopathies. Establishing a precise molecular diagnosis is crucial, as allogeneic HSCT remains a potentially disease-modifying therapy for patients with CSF1R-related leukoencephalopathy. Further longitudinal studies are warranted to evaluate the long-term efficacy of HSCT and to explore emerging targeted therapeutic strategies.