Bugiani Marianna, Kevelam Sietske H, Bakels Hannah S, Waisfisz Quinten, Ceuterick-de Groote Chantal, Niessen Hans W M, Abbink Truus E M, Lesnik Oberstein Saskia A M J, van der Knaap Marjo S
From the Departments of Child Neurology (M.B., S.H.K., H.S.B., T.E.M.A., M.S.v.d.K.) and Pathology (M.B., H.W.M.N.), Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam; Department of Clinical Genetics (Q.W.), VU University Medical Center, Amsterdam, the Netherlands; Laboratory for Ultrastructural Neuropathology (C.C.-d.G.), Institute Born-Bunge and University of Antwerp, Belgium; Department of Clinical genetics (S.A.M.J.L.O.), Leiden University Medical Center, Leiden; and Department of Functional Genomics (M.S.v.d.K.), Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands.
Neurology. 2016 Oct 25;87(17):1777-1786. doi: 10.1212/WNL.0000000000003251. Epub 2016 Sep 24.
To characterize the clinical and MRI features of 2 families with adult-onset dominant leukoencephalopathy and strokes and identify the underlying genetic cause.
We applied MRI pattern recognition, whole-exome sequencing, and neuropathology.
Based on brain imaging, 13 family members of 40 years or older from 2 families were diagnosed with the disease; in 11 family members of the same age, MRI was normal. In the affected family members, MRI showed a leukoencephalopathy that was disproportionately severe compared to the clinical disease. The clinical picture was dominated by ischemic and hemorrhagic strokes, slow and late cognitive deterioration, and therapy-resistant hypertension. With whole-exome sequencing, we identified one variant shared by both families and segregating with the disease: c.973C>T in CTSA. Haplotype analysis revealed a shared 1,145-kb interval encompassing the CTSA variant on chromosome 20q13.12, suggesting a common ancestor. Brain autopsy of 3 patients showed a leukoencephalopathy that was disproportionately extensive compared to the vascular abnormalities. CTSA encodes cathepsin A. Recessive CTSA mutations cause galactosialidosis. One of the numerous cathepsin A functions is to degrade endothelin-1. In the patients, striking endothelin-1 immunoreactivity was found in white matter astrocytes, correlating with increased numbers of premyelinating oligodendrocyte progenitors. This finding supports a role for endothelin-1 in the leukoencephalopathy through inhibition of oligodendrocyte progenitor maturation.
CARASAL (cathepsin A-related arteriopathy with strokes and leukoencephalopathy) is a novel hereditary adult-onset cerebral small vessel disease. It is of interest that, next to the cerebral vascular abnormalities, endothelin-1 may have a role in the pathogenesis of the extensive leukoencephalopathy.
描述2个患成年起病的显性白质脑病和中风的家系的临床及MRI特征，并确定潜在的遗传病因。
我们应用了MRI模式识别、全外显子组测序和神经病理学方法。
基于脑部影像学检查，来自2个家系的40岁及以上的13名家庭成员被诊断患有该病；在同一年龄段的11名家庭成员中，MRI检查结果正常。在患病家庭成员中，MRI显示白质脑病，与临床疾病相比严重程度不成比例。临床症状主要为缺血性和出血性中风、缓慢且晚期的认知功能衰退以及难治性高血压。通过全外显子组测序，我们在两个家系中均发现了一个与疾病共分离的变异：CTSA基因中的c.973C>T。单倍型分析显示在20号染色体q13.12上存在一个包含CTSA变异的1145kb共享区间，提示有共同的祖先。对3例患者进行的脑尸检显示，与血管异常相比，白质脑病范围广泛得不成比例。CTSA编码组织蛋白酶A。隐性CTSA突变会导致半乳糖唾液酸贮积症。组织蛋白酶A的众多功能之一是降解内皮素-１。在患者中，在白质星形胶质细胞中发现了显著的内皮素-1免疫反应性，并与未成熟少突胶质细胞祖细胞数量增加相关。这一发现支持内皮素-1通过抑制少突胶质细胞祖细胞成熟在白质脑病中发挥作用。
CARASAL（与中风和白质脑病相关的组织蛋白酶A动脉病）是一种新型的遗传性成年起病的脑小血管疾病。有趣的是，除脑血管异常外，内皮素-1可能在广泛的白质脑病发病机制中起作用。
