Sporadic hereditary diffuse leukoencephalopathy with axonal spheroids showing numerous lesions with restricted diffusivity caused by a novel splice site mutation in the CSF1R gene

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disease characterized by cerebral white matter degeneration with axonal spheroids. The disease is caused by mutations in the protein tyrosine kinase domain of colony-stimulating factor 1 receptor (CSF1R), encoded by the CSF1R gene on chromosome 5q34. Because of a preferential involvement of the frontal white matter, HDLS usually presents as presenile dementia. Here, we report an atypical case of HDLS mimicking primary progressive multiple sclerosis (PPMS). A 22-year-old woman had difficulty moving her left leg and hand in April 2011 and January 2012, respectively. These symptoms worsened, resulting in spastic quadriplegia and dysarthria. At first admission to Kyushu University hospital, Fukuoka, Japan, in January 2013, she had forced laughter, dysarthria, and rigidospasticity and hyperreflexia in all four limbs, and bilateral extensor plantar response, whereas her Mini-Mental State Examination score was 26 out of 30. Blood and cerebrospinal fluid tests were all normal, except for an elevated myelin basic protein level (294 pg/mL). Brain T2/fluid-attenuated inversion recovery-weighted magnetic resonance imaging showed bilateral high-signal intensity lesions in the parietal and posterior frontal deep white matter. Remarkably, numerous magnetic resonance imaging lesions showed restricted diffusion. Biopsied specimens from the right cerebral deep white matter showed decreased myelin, severe loss of axons with axonal spheroid,s and infiltration of CD68+ macrophages and CD45+ lymphocytes. She had a heterozygous mutation, c.2,442+1G>A in CSF1R. The present case emphasizes that diagnosis of HDLS should be considered as part of the differential diagnosis of PPMS. The presence of periventricular lesions with restricted diffusivity might favor a diagnosis of HDLS.