Abstract Details

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

Topic Aging and Dementia

Presentation(s) (-)

Poster/Presentation
Number 009

Objective

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.

Authors/Disclosures
Takuya Konno, MD, PhD (Horikawa Naika Shinkeinaika Iin) PRESENTER	No disclosure on file
Masayoshi Tada, MD, PhD (Brain Research Institute, Niigata University)	No disclosure on file
	No disclosure on file
Mari Tada, MD, PhD (Niigata University, Brain Research Institute)	Dr. Tada has nothing to disclose.
Akihiro Sugai, MD (Dept of Neurology, Clinical Neuroscience)	The institution of Dr. Sugai has received research support from Japan Society for the Promotion of Science. The institution of Dr. Sugai has received research support from SERIKA FUND. The institution of Dr. Sugai has received research support from Japan Agency for Medical Research and Development.
Hiroaki Nozaki, MD, PhD (Niigata City General Hospital)	No disclosure on file
Orhun H. Kantarci, MD	Dr. Kantarci has nothing to disclose.
	No disclosure on file
Yasuo Harigaya	No disclosure on file
	No disclosure on file
	No disclosure on file
Makoto Yoneda (Univ of Fukui)	No disclosure on file
	No disclosure on file
Hitoshi Takahashi	No disclosure on file
	No disclosure on file
Osamu Onodera, MD	Dr. Onodera has nothing to disclose.
Masatoyo Nishizawa, MD (Niigata University of Health and Welfare)	No disclosure on file
Takeshi Ikeuchi, MD (Brain Research Institute, Niigata University)	Dr. Ikeuchi has nothing to disclose.

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