Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a neurodegenerative disease presenting in midlife and associated with rapidly progressive cognitive, behavioral and motor symptoms. HDLS results from mutations in the CSF1R gene and is inherited in an autosomal dominant pattern. We describe the clinical and neuroimaging features of two cases of HDLS evaluated at our medical center.and compare them with previously reported cases. Both patients had clinical genetic testing done revealing mutations in CSF1R. Patient 1 is a 46 year old woman who initially presented with gait changes and dysarthria, with rapid progression of bulbar and cognitive symptoms over 18 months, and was found to have a mutation in exon 19, c.2519C>G (p.Ser840Cys). Patient 2 is a 56 year old man presenting with 3 years of depression and memory problems without significant motor symptoms in the context of a family history of early onset dementia syndrome in his mother and prior diagnosis of HDLS in his maternal aunt; he was also found to have a mutation in exon 19, c.2480T>A (p.Ile827Asn). Both patients demonstrated extensive white matter hyperintensities and thinning of the corpus callosum on their MRIs with Patient 1 having cavitary lesions. Both mutations are located in the tyrosine kinase domain of the protein at or near the location of previously described mutations. Both mutations are predicted to be probably damaging by Polyphen with a score of 1.0. To our knowledge, these are the first reported cases of HDLS associated with these mutations. As has been described in the literature, the female patient had a younger age of onset than the male. Clinicians should be aware of the diversity of clinical presentations of HDLS and consider genetic testing for atypical dementia syndromes associated with significant white matter changes.