Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS): Clinical Characteristics and Molecular Analyses of CSF-1R (PD5.009)

OBJECTIVE: To clarify phenotypic and molecular genetic characterization in Japanese patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS), we examined 5 patients from 5 families with colony stimulating factor 1 receptor (CSF-1R) mutations. BACKGROUND: HDLS is an adult-onset leukoencephalopathy, pathologically characterized by the white matter changes with axonal spheroids and macrophages infiltration. Recently, mutations in CSF-1R were indentified in patients with HDLS. DESIGN/METHODS: We performed mutational analysis of CSF-1R in Japanese patients with HDLS and characterized their clinical and MRI features. CSF-1R expression was biochemically analyzed using autopsied brain samples. Mutant CSF-1R was expressed in culture cells, and CSF-1 dependent signaling was investigated. RESULTS: We found 4 different mutations of CSF-1R from 5 unrelated families. All mutations were located in the tyrosine kinase domain; three are novel and one is previously reported mutations. The mean age at onset was 46 ± 7.9 years (range 37-55 years) with mean disease duration of 6 ± 4.8 years (range 1-14 years). All patients presented with progressive dementia and personality changes. Other clinical features included depression (2/5), parkinsonism (4/5), pyramidal signs (4/5), seizure (2/5) and frontal lobe signs (2/5). Brain MRI showed confluent and diffuse white matter signal changes with periventricular and fronto-parietal predominance. Cortical atrophy also appeared in patients with long disease course. Thinning of corpus callosum with signal intensity change was characteristically observed in all patients from the early stage. Western blot analysis revealed decreased expression of CSF-1R in a patient with the splice site mutation. Ligand-dependent autophosphorylation of CSF-1R was severely impaired when CSF-1R mutants were expressed in culture cells. CONCLUSIONS: Analyses of Japanese HDLS patients revealed characteristic clinical and neuroimaging features. CSF-1 dependent signaling pathway is inactivated in disease-causing mutant CSF-1R-expressing cells. Downstream effects of CSF-1R signaling abnormalities as the pathogenesis of HDLS warrant further investigation. Disclosure: Dr. Konno has nothing to disclose. Dr. Tada has nothing to disclose. Dr. Koyama has nothing to disclose. Dr. Tada has nothing to disclose. Dr. Sugai has nothing to disclose. Dr. Nozaki has nothing to disclose. Dr. Matsunaga has nothing to disclose. Dr. Harigaya has nothing to disclose. Dr. Nishimiya has nothing to disclose. Dr. Ishihara has nothing to disclose. Dr. Yoneda has nothing to disclose. Dr. Kakita has nothing to disclose. Dr. Takahashi has nothing to disclose. Dr. Kawamura has nothing to disclose. Dr. Onodera has nothing to disclose. Dr. Nishizawa has nothing to disclose. Dr. Ikeuchi has nothing to disclose.