Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL
Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL
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DOI：
10.1093/brain/awl360
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发表时间：
2007-02-01
期刊：
影响因子：
14.5
通讯作者：
Kalaria, R. N.
中科院分区：
文献类型：
--
作者：
Low, W. C.;Junna, M.;Kalaria, R. N.
近年来，已有几种遗传性脑部小血管疾病(SVD)的报道。1977年，Sourander和Walinder描述了一个瑞典家庭的遗传性多发性梗死性痴呆(MID)。同年，史蒂文斯和他的同事报告了一个具有类似表型的英国家庭的慢性家族性血管脑病。这些疾病总是被认为是常染色体显性遗传性脑动脉病伴皮质下梗塞和白质脑病(CADASIL)，但它们的遗传特征尚不清楚。我们使用分子、放射学和神经病理学方法来描述这些疾病。DNA直接测序出人意料地证实，在CADASIL的NOTCH3基因诊断中，受影响的英国家庭成员携带R141C突变。然而，我们没有在NOTCH3的整个8091bp阅读框中检测到任何致病突变，也没有在瑞典DNA中发现明显的NOTCH3基因连锁的证据。这与瑞典受试者在磁共振成像上前颞极和外囊缺乏高信号是一致的。我们进一步发现，在瑞典家庭中受影响成员的皮肤活检或死后脑样本中没有证据表明存在颗粒状嗜欧物质。此外，与患有CADASIL的英国家系相比，瑞典遗传性中间受试者的脑微血管中明显缺乏NOTCH3 N末端片段。灰质和白质的动脉硬化改变在这些疾病之间也有一些不同之处。英国CADASIL样本的硬化指数、微血管内IV型胶原免疫反应密度和血管周围巨噬细胞数均高于瑞典样本。多种方法表明，疑似CADASIL的遗传性MID瑞典家系有一种不同的新疾病，具有不同的病理特征，属于越来越多的遗传性无特征性家族性SVD。
Several hereditary small vessel diseases (SVDs) of the brain have been reported in recent years. In 1977, Sourander and Walinder described hereditary multi-infarct dementia ( MID) in a Swedish family. In the same year, Stevens and colleagues reported chronic familial vascular encephalopathy in an English family bearing a similar phenotype. These disorders have invariably been suggested to be cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy ( CADASIL) but their genetic identities remain unknown. We used molecular, radiological and neuropathological methods to characterize these disorders. Direct DNA sequencing unexpectedly confirmed that affected members of the English family carried the R141C mutation in the NOTCH3 gene diagnostic of CADASIL. However, we did not detect any pathogenic mutations in the entire 8091 bp reading frame of NOTCH3 or find clear evidence for NOTCH3 gene linkage in the Swedish DNA. This was consistent with the lack of hyperintense signals in the anterior temporal pole and external capsule in Swedish subjects upon magnetic resonance imaging. We further found no evidence for granular osmiophilic material in skin biopsy or post-mortem brain samples of affected members in the Swedish family. In addition, there was distinct lack of NOTCH3 N-terminal fragments in the cerebral microvasculature of the Swedish hereditary MID subjects compared to the intense accumulation in the English family afflicted with CADASIL. Several differences in arteriosclerotic changes in both the grey and white matter were also noted between the disorders. The sclerotic index values, density of collagen IV immunoreactivity in the microvasculature and number of perivascular macrophages were greater in the English CADASIL samples compared to those from the Swedish brains. Multiple approaches suggest that the Swedish family with hereditary MID suspected to be CADASIL has a different novel disorder with dissimilar pathological features and belongs to the growing number of genetically uncharacterized familial SVDs.