CSF1R mutations link POLD and HDLS as a single disease entity

Area of Science:

• Neurogenetics
• Molecular Neurology
• Rare Diseases

Background:

• Pigmented orthochromatic leukodystrophy (POLD) and hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) are rare neurodegenerative disorders with overlapping clinical and pathological features.
• Previously, mutations in the colony-stimulating factor 1 receptor (CSF1R) gene were identified as a cause of HDLS.
• The genetic basis and mechanistic link between POLD and HDLS remained unestablished.

Observation:

• CSF1R gene sequencing was performed on two pathologically confirmed POLD families.
• Brain samples from affected individuals were re-evaluated for HDLS features.
• In vitro functional characterization of wild-type and mutant CSF1R was conducted.

Findings:

• CSF1R mutations were identified in both POLD families studied.
• Immunohistochemical analysis of one family revealed characteristic HDLS findings.
• Functional studies demonstrated that identified CSF1R mutations impair receptor autophosphorylation, similar to previously observed HDLS mutations.

Implications:

• This study provides the first genetic and mechanistic evidence that POLD and HDLS are a single clinicopathologic entity.
• The findings suggest that CSF1R-related leukoencephalopathies represent a spectrum of disease.
• This discovery may impact diagnostic approaches and therapeutic strategies for these rare neurodegenerative disorders.