To describe a rare presentation of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and present evidence supporting pathogenicity of a previously uncertain variant.

Adult-onset leukodystrophies are rare genetic disorders with heterogeneous presentations affecting cerebral white matter. HDLS is one such disorder caused by autosomal dominant mutations in the CSF1R gene. CSF1R encodes a tyrosine kinase receptor that necessary for microglial development. Clinical presentations vary but include neuropsychiatric symptoms such as behavioral change and dementia, and motor findings of gait ataxia, bradykinesia and rigidity. Diagnosis is often delayed due to intrafamilial phenotypic-genetic variability. We report a case of HDLS in a patient with a mutation previously reported as variant of uncertain significance (VUS) in the CSF1R gene.

Case Presentation:

A 45-year-old female developed progressive cognitive, behavioral, and motor decline over one year including disorientation, hallucinations, speech changes and shuffling gait. She was admitted to an outside institution where a workup for infectious causes was unrevealing, and she was treated with pulse dosed corticosteroids to no avail prompting referral to our clinic.

Examination revealed paucity of speech, poor command following, diffuse bilateral hyperreflexia, appendicular ataxia with stooped shuffling gait. MRI showed progressive confluent symmetric subcortical T2 hyperintensities in bilateral frontal and parietal lobes. Vessel-wall MRI and CSF analysis was unrevealing for autoimmune or infectious etiology. Whole-genome sequencing identified a heterozygous CSF1R p.Ser759Pro variant confirming HDLS.

Genetic and phenotypic variability in HDLS complicates diagnosis but recognition is essential in adults with rapid onset cognitive, neuropsychiatric and motor decline. Early recognition and screening for other at-risk family members permits opportunity for treatment with hematopoietic stem cell transplantation (HSCT). This case expands the presentation of HDLS and supports reclassification of the CSF1R  p.Ser759Pro variant as likely pathogenic, consistent with prior reports in similarly affected twins.