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Neurology. 2014 Jan 14;82(2):139-48. doi: 10.1212/WNL.0000000000000046. Epub 2013 Dec 13.

Haploinsufficiency of CSF-1R and clinicopathologic characterization in patients with HDLS.

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From the Departments of Neurology (T.K., Masayoshi Tada, A. Koyama, H.N., M.A., A.I., M.N., T. Ikeuchi), Pathology (Mari Tada, K.O., H.T., A. Kakita), Molecular Neuroscience (O.O.), and Molecular Genetics, Brain Research Institute (T. Ikeuchi), Niigata University; Department of Neurology (Y.H.), Maebashi Red Cross Hospital; Department of Neurology (J.N.), Gyotoku General Hospital, Ichikawa; Department of Neurology (A.M., M.Y.), University of Fukui Hospital; Department of Neurology and Geriatrics (N.Y., T. Inuzuka), Gifu University Graduate School of Medicine; Department of Neurology (K. Ishihara, M.K.), Showa University School of Medicine, Tokyo; Department of Human Pathology (H.Y.), Gunma University Graduate School of Medicine, Maebashi; and the Department of Pathology and Applied Neurobiology (K. Itoh), Kyoto Prefectural University of Medicine, Japan.



To clarify the genetic, clinicopathologic, and neuroimaging characteristics of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) with the colony stimulating factor 1 receptor (CSF-1R) mutation.


We performed molecular genetic analysis of CSF-1R in patients with HDLS. Detailed clinical and neuroimaging findings were retrospectively investigated. Five patients were examined neuropathologically.


We found 6 different CSF-1R mutations in 7 index patients from unrelated Japanese families. The CSF-1R mutations included 3 novel mutations and 1 known missense mutation at evolutionarily conserved amino acids, and 1 novel splice-site mutation. We identified a novel frameshift mutation. Reverse transcription PCR analysis revealed that the frameshift mutation causes nonsense-mediated mRNA decay by generating a premature stop codon, suggesting that haploinsufficiency of CSF-1R is sufficient to cause HDLS. Western blot analysis revealed that the expression level of CSF-1R in the brain from the patients was lower than from control subjects. The characteristic MRI findings were the involvement of the white matter and thinning of the corpus callosum with signal alteration, and sequential analysis revealed that the white matter lesions and cerebral atrophy relentlessly progressed with disease duration. Spotty calcifications in the white matter were frequently observed by CT. Neuropathologic analysis revealed that microglia in the brains of the patients demonstrated distinct morphology and distribution.


These findings suggest that patients with HDLS, irrespective of mutation type in CSF-1R, show characteristic clinical and neuroimaging features, and that perturbation of CSF-1R signaling by haploinsufficiency may play a role in microglial dysfunction leading to the pathogenesis of HDLS.

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