Tuominen S, Juvonen V, Amberla K, Jolma T, Rinne J O, Tuisku S, Kurki T, Marttila R, Pöyhönen M, Savontaus M L, Viitanen M, Kalimo H
Department of Neurology, Turku University Hospital and University of Turku, Finland.
Stroke. 2001 Aug;32(8):1767-74. doi: 10.1161/01.str.32.8.1767.
CADASIL is an autosomal dominant arteriopathy, characterized by multiple brain infarcts, cognitive decline, and finally dementia, which is caused by mutations in Notch3 gene encoding a Notch3 receptor protein. We describe the clinical, neuropsychological, imaging, genetic, and skin biopsy findings in a CADASIL patient homozygous for the C475T mutation resulting in R133C amino acid substitution, in comparison to 9 age-matched heterozygous patients with the same mutation.
The patients were examined clinically and neuropsychologically and with MRI and positron emission tomography for assessment of cerebral blood flow. The gene defect was analyzed by sequencing the products of polymerase chain reaction of exons 3 and 4 of the Notch3 gene. Dermal arteries were analyzed electron microscopically.
The homozygous patient had his first-ever stroke at age 28 years. This is markedly earlier than the average, but the patient's heterozygous son had his first transient ischemic attack-like episode at the same age and another heterozygous patient had his first-ever stroke when only 2 years older. He was neuropsychologically more severely deteriorated than all but 1 of the heterozygous patients. These 2 patients had the most severe (confluent grade D) white matter MRI changes. Positron emission tomography showed markedly reduced cerebral blood flow. Skin biopsy revealed profuse deposits of granular osmiophilic material. The progression of disease in the homozygous case was, however, slower than in the most severely affected heterozygous patient.
Our homozygous patient's phenotype is within the clinical spectrum of CADASIL, although at its severe end. Thus, CADASIL may follow the classic definition of a dominant disease, according to which the heterozygous and homozygous patients are clinically indistinguishable.
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动脉病，其特征为多发性脑梗死、认知功能减退并最终发展为痴呆，由编码Notch3受体蛋白的Notch3基因突变所致。我们描述了一名C475T突变纯合子CADASIL患者的临床、神经心理学、影像学、遗传学及皮肤活检结果，该突变导致R133C氨基酸替代，并与9名年龄匹配的携带相同突变的杂合子患者进行了比较。
对患者进行临床和神经心理学检查，并采用磁共振成像（MRI）和正电子发射断层扫描（PET）评估脑血流量。通过对Notch3基因第3和第4外显子的聚合酶链反应产物进行测序分析基因缺陷。对真皮动脉进行电子显微镜检查。
该纯合子患者在28岁时首次发生卒中。这明显早于平均发病年龄，但该患者的杂合子儿子在同一年龄首次出现短暂性脑缺血发作样发作，另一名杂合子患者在仅大2岁时首次发生卒中。在神经心理学方面，他的病情恶化程度比除1名杂合子患者外的所有患者都更严重。这2名患者的白质MRI改变最为严重（融合性D级）。PET显示脑血流量明显减少。皮肤活检显示有大量嗜锇颗粒物质沉积。然而，纯合子病例的疾病进展比受影响最严重的杂合子患者要慢。
我们的纯合子患者表型处于CADASIL的临床谱范围内，尽管处于严重端。因此，CADASIL可能遵循显性疾病的经典定义，根据该定义，杂合子和纯合子患者在临床上无法区分。
