Singhal Sumeet, Bevan Steve, Barrick Tom, Rich Philip, Markus Hugh S
Clinical Neuroscience, St George's Hospital Medical School, London, UK.
Brain. 2004 Sep;127(Pt 9):2031-8. doi: 10.1093/brain/awh223. Epub 2004 Jun 30.
The clinical phenotype in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), an autosomal dominant cerebral arteriopathy, is variable, but the reasons for this remain uncertain. Possible factors include the mutation site and the influence of additional modulating factors, which could include both epistatic interactions and interactions with cardiovascular risk factors known to cause sporadic small vessel disease. In a large prospectively recruited cohort of CADASIL subjects we determined relationships between phenotype and mutation site, the apoE genotype and cardiovascular risk factors. In addition to clinical features, disease severity was assessed by MRI lesion volume, measured both semiquantitatively (Scheltens scale) and quantitatively. One hundred and twenty-seven CADASIL cases from 65 families with 17 different mutations were studied. Site of mutation was not associated with the presence or age of onset of stroke, migraine, dementia, dependency or MRI lesion load. There was no evidence of intrafamilial clustering of particular phenotypes. Amongst subjects with stroke/transient ischaemic attack, smoking at the time of the event was independently associated with earlier age of onset (P = 0.01). There were no associations between age of onset or presence of stroke and other cardiovascular risk factors, including homocysteine. Homocysteine levels were higher in migraineurs [mean (SD) 12.8 (5.6) versus 9.8 (3.4) micromol/l, P = 0.02)] and elevated homocysteine was independently associated with an earlier age of onset of migraine (P = 0.01). No relationship was found between MRI lesion volume and risk factors, or between apoE genotype and phenotype. Our results show no notch 3 genotype-phenotype correlations. This implies that modulating factors influence phenotype. Smoking appears to increase the risk of stroke, while high homocysteine levels are associated with an increased risk of migraine.
伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）是一种常染色体显性遗传性脑动脉病，其临床表型具有多样性，但其原因尚不确定。可能的因素包括突变位点以及其他调节因素的影响，这些调节因素可能包括上位相互作用以及与已知会导致散发性小血管疾病的心血管危险因素的相互作用。在一个前瞻性招募的大型CADASIL受试者队列中，我们确定了表型与突变位点、载脂蛋白E基因型和心血管危险因素之间的关系。除临床特征外，还通过MRI病变体积评估疾病严重程度，分别采用半定量（斯海尔托亨斯量表）和定量测量。对来自65个家庭的127例CADASIL病例进行了研究，这些病例有17种不同的突变。突变位点与中风、偏头痛、痴呆、失能或MRI病变负荷的存在或发病年龄无关。没有证据表明特定表型存在家族内聚集现象。在患有中风/短暂性脑缺血发作的受试者中，发病时吸烟与发病年龄较早独立相关（P = 0.01）。发病年龄或中风的存在与其他心血管危险因素（包括同型半胱氨酸）之间没有关联。偏头痛患者的同型半胱氨酸水平较高[平均值（标准差）为12.8（5.6）与9.8（3.4）微摩尔/升，P = 0.02]，而同型半胱氨酸升高与偏头痛发病年龄较早独立相关（P = 0.01）。未发现MRI病变体积与危险因素之间、载脂蛋白E基因型与表型之间存在关联。我们的结果显示不存在Notch 3基因型与表型的相关性。这意味着调节因素会影响表型。吸烟似乎会增加中风风险，而同型半胱氨酸水平升高与偏头痛风险增加有关。
