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CSF1R-Related Leukoencephalopathy

Summary

  • Rare genetic disorder affecting white matter of the brain
  • Caused by mutations in the CSF1R gene
  • Characterised by progressive cognitive decline, motor dysfunction, and psychiatric symptoms1

Pathophysiology

  • CSF1R gene mutations lead to dysfunction of microglia, the brain's primary immune cells
  • Impaired microglial function results in:
    • Reduced myelin maintenance and repair
    • Accumulation of axonal spheroids
    • Neuroinflammation and neurodegeneration
  • Autosomal dominant inheritance pattern

Demographics

  • Typically presents in adulthood (30-60 years)
  • No significant gender predilection
  • Rare disorder, exact prevalence unknown
  • Reported cases predominantly in Caucasian populations, but may affect all ethnicities

Diagnosis

  • Clinical presentation:
    • Progressive cognitive decline
    • Personality changes and psychiatric symptoms
    • Motor dysfunction (e.g., gait disturbances, parkinsonism)
    • Seizures (in some cases)
  • Genetic testing:
    • Identification of pathogenic variants in CSF1R gene
  • Family history assessment
  • Exclusion of other leukoencephalopathies

Imaging

  • MRI findings:
    • Bilateral, symmetrical white matter hyperintensities on T2-weighted and FLAIR sequences
    • Predominant involvement of frontal and parietal lobes
    • Corpus callosum atrophy
    • Diffusion restriction in active lesions
    • Calcifications in basal ganglia (in some cases)
  • CT scan:
    • May show hypodensities in affected white matter regions
    • Calcifications in basal ganglia (if present)

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  • A 50-year-old patient presented with behavioural change and low mood.
  • MRI showed diffuse white matter hyperintensity, mainly in the frontal lobes, loss of white matter volume.
  • Most characteristically, focal diffusion restriction persisted between the two scans that were 1 year apart.

Treatment

  • Largely supportive; haematopoietic stem cell transplantation is under investigation
  • The persistent (months-long) foci of restricted diffusion are a useful distinguishing feature

Differential diagnosis

Differential Diagnosis Distinguishing Feature
Multiple Sclerosis Periventricular and juxtacortical lesions with Dawson fingers; ovoid morphology; lacks corpus callosum thinning
CADASIL Temporal pole and external capsule involvement; subcortical lacunar infarcts
Cerebral vasculitis Multifocal infarcts in multiple vascular territories; vessel wall enhancement on high-resolution MRI

  1. Konno et al. CSF1R-related leukoencephalopathy: A major player in primary microgliopathies. 2018. Neurology - Open in new tab. ↩