伴皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病家系研究

A study of subcortical infarcts and leukoencephalopathy (CADASIL) in a family with autosomal cerebral dominant arteriopathy

目的 探讨伴皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病 (CADASIL)的临床特征、病理与基因改变及诊断方法。方法 调查先证者及其家族的发病情况及遗传方式 ,对其临床表现、影像学特征、病理学及分子遗传学等方面进行研究。结果 先证者中年起病 ,临床上主要表现为反复发作的缺血性卒中 ,波动渐进性记忆、认知功能减退 ,痴呆。磁共振显示皮层下多发腔隙性或小灶性梗死 ,脑深部白质广泛稀疏 ,呈现典型的O′Sullivin征。皮肤血管活检 :电镜下见小动脉基底膜增厚 ,其中存在嗜锇颗粒物质沉积 ;基因测序显示Notch 3基因第 4号外显子突变。全家系 5代 ,已有 4代 15人呈临床或亚临床发病 ,符合常染色体显性遗传。结论 该家系的临床、影像、病理及分子遗传学特征符合CADASIL诊断标准。该病凭皮肤活检和基因测序而不经脑组织活检 ,可以在生前确诊。

Objective To investigate the clinical features, hereditary pattern,neuroimaging characteristics and diagnostic method of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Methods A systematic study on the clinical manifestations, neuroimaging characteristics, pathology and molecular genetics was performed. An investigation on the onset and hereditary pattern of the family tree of the proband was also done. Results The main clinical features of the proband including history of recurrent ischemic stroke,poor memory /cognition or dementia were noted. Fifteen cases pertaining to 4 generations of the proband with clinical or subclinical onset and confirmed classical family history of autosomal dominant hereditary were studied. Neuroimaging examination showed subcortical multiinfarct lesions and leukoencephalopathy. Electron microscope examination of the skin. Biopsy indicated thickening of basement membrane and presence of granular osmiophilic material (GOM) in the arterioles. A mutation on the fourth exon of notch 3 gene was revealed. Migraine, hypertension, diabetes and risk factors of arteriosclerosis were not found. All the features mentioned above in this family are in conformity with the diagnostic standard of CADASIL. Conclusions It is prossible to define CADASIL clinically by way of studying the clinical features, hereditary pattern, neuroimaging characteristics, skin biopsy and sequencing of gene without resorting to brain biopsy.