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

被引：106

作者：

Konno, Takuya ^{[1
]}

Tada, Masayoshi ^{[1
]}

Tada, Mari ^{[2
]}

Koyama, Akihide ^{[1
]}

Nozaki, Hiroaki ^{[1
]}

Harigaya, Yasuo ^{[5
]}

Nishimiya, Jin ^{[6
]}

Matsunaga, Akiko ^{[7
]}

Yoshikura, Nobuaki ^{[8
]}

Ishihara, Kenji ^{[9
]}

Arakawa, Musashi ^{[1
]}

Isami, Aiko ^{[1
]}

Okazaki, Kenichi ^{[2
]}

Yokoo, Hideaki ^{[10
]}

Itoh, Kyoko ^{[11
]}

Yoneda, Makoto ^{[7
]}

Kawamura, Mitsuru ^{[9
]}

Inuzuka, Takashi ^{[8
]}

Takahashi, Hitoshi ^{[2
]}

Nishizawa, Masatoyo ^{[1
]}

Onodera, Osamu ^{[3
]}

Kakita, Akiyoshi ^{[2
]}

Ikeuchi, Takeshi ^{[1
,4
]}

机构：

[1] Niigata Univ, Dept Neurol, Niigata 95021, Japan

[2] Niigata Univ, Dept Pathol, Niigata 95021, Japan

[3] Niigata Univ, Dept Mol Neurosci, Niigata 95021, Japan

[4] Niigata Univ, Dept Mol Genet, Brain Res Inst, Niigata 95021, Japan

[5] Maebashi Red Cross Hosp, Dept Neurol, Maebashi, Gunma, Japan

[6] Gyotoku Gen Hosp, Dept Neurol, Ichikawa, Japan

[7] Univ Fukui Hosp, Dept Neurol, Fukui, Japan

[8] Gifu Univ, Grad Sch Med, Dept Neurol & Geriatr, Gifu, Japan

[9] Showa Univ, Sch Med, Dept Neurol, Tokyo 142, Japan

[10] Gunma Univ, Grad Sch Med, Dept Human Pathol, Maebashi, Gunma 371, Japan

[11] Kyoto Prefectural Univ Med, Dept Pathol & Appl Neurobiol, Kyoto 602, Japan

来源：

NEUROLOGY | 2014年 / 82卷 / 02期

关键词：

HEREDITARY DIFFUSE LEUKOENCEPHALOPATHY; ADULT-ONSET LEUKODYSTROPHY; AXONAL SPHEROIDS; NEUROAXONAL SPHEROIDS; PIGMENTARY TYPE; EXPRESSION; MICROGLIA; CELLS; MACROPHAGES; DEFICIENCY;

D O I：

10.1212/WNL.0000000000000046

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective: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.Methods: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.Results: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.Conclusions: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.

引用

页码：139 / 148

页数：10

共 33 条

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