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.
Neurology. 2014 Jan 14;82(2):139-48. doi: 10.1212/WNL.0000000000000046. Epub 2013 Dec 13.
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.
阐明伴有集落刺激因子 1 受体（CSF-1R）突变的遗传性弥漫性脑白质病伴硬化（HDLS）患者的遗传、临床病理和神经影像学特征。
我们对 HDLS 患者的 CSF-1R 进行了分子遗传学分析。回顾性调查了详细的临床和神经影像学发现。对 5 名患者进行了神经病理学检查。
我们在来自 7 个无血缘关系的日本家庭的 7 名索引患者中发现了 6 种不同的 CSF-1R 突变。CSF-1R 突变包括 3 种新突变和 1 种进化上保守氨基酸的已知错义突变，以及 1 种新的剪接位点突变。我们发现了一种新的移码突变。逆转录 PCR 分析表明，移码突变通过产生过早的终止密码子导致无意义介导的 mRNA 衰变，表明 CSF-1R 的单倍不足足以引起 HDLS。Western blot 分析表明，患者大脑中的 CSF-1R 表达水平低于对照。特征性的 MRI 发现是白质受累和胼胝体变薄伴有信号改变，连续分析表明，白质病变和脑萎缩随着疾病持续时间的延长而无情地进展。CT 常观察到白质中的点状钙化。神经病理学分析表明，患者大脑中的小胶质细胞表现出明显的形态和分布。
这些发现表明，HDLS 患者无论 CSF-1R 突变类型如何，均表现出特征性的临床和神经影像学特征，CSF-1R 信号通路的单倍不足可能在小胶质细胞功能障碍中发挥作用，导致 HDLS 的发病机制。
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