De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS)

Area of Science:

• Neurogenetics
• Neuroimaging

Background:

• Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant disorder.
• It is caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene.
• HDLS leads to progressive cognitive and motor decline.

Observation:

• Genetic confirmation of HDLS in 6 of 25 patients with adult-onset leukoencephalopathy.
• Clinical presentation included dementia, apraxia, and extrapyramidal signs.
• Early white matter MRI changes were observed.

Findings:

• De novo CSF1R mutations were identified in one-third of patients.
• Reduced penetrance of CSF1R mutations was observed in one family.
• Family history was negative in most index patients.

Implications:

• Early clinical and MRI findings aid HDLS diagnosis.
• Consider HDLS even without a family history due to de novo mutations.
• Findings impact genetic counseling for asymptomatic carriers and suggest research into disease modifiers.