Ilinca Andreea, Englund Elisabet, Samuelsson Sofie, Truvé Katarina, Kafantari Efthymia, Martinez-Majander Nicolas, Putaala Jukka, Håkansson Claes, Lindgren Arne G, Puschmann Andreas
Department of Clinical Sciences Lund, Neurology (A.I., E.K., A.G.L., A.P.), Lund University; Section of Neurology (A.I., E.K., A.G.L., A.P.), Skåne University Hospital, Lund; Department of Clinical Genetics and Pathology (E.E., S.S.), Laboratory Medicine, Region Skåne; Department of Clinical Sciences Lund (E.E.), Division of Pathology, Lund University; Bioinformatics Core Facility (K.T.), Sahlgrenska Academy at University of Gothenburg, Sweden; Neurology (N.M.-M., J.P.), University of Helsinki, and Helsinki University Hospital, Finland; Department of Imaging and Function (C.H.), Skånes University Hospital, Lund; and Department of Clinical Sciences, Diagnostic Radiology (C.H.), Lund University, Sweden.
Neurol Genet. 2021 Jan 21;7(1):e548. doi: 10.1212/NXG.0000000000000548. eCollection 2021 Feb.
To describe a possible novel genetic mechanism for cerebral small vessel disease (cSVD) and stroke.
We studied a Swedish kindred with ischemic stroke and intracerebral hemorrhage, tremor, dysautonomia, and mild cognitive decline. Members were examined clinically, radiologically, and by histopathology. Genetic workup included whole-exome sequencing (WES) and whole-genome sequencing (WGS) and intrafamilial cosegregation analyses.
Fifteen family members were examined clinically. Twelve affected individuals had white matter hyperintensities and 1 or more of (1) stroke episodes, (2) clinically silent lacunar ischemic lesions, and (3) cognitive dysfunction. All affected individuals had tremor and/or atactic gait disturbance. Mild symmetric basal ganglia calcifications were seen in 3 affected members. Postmortem examination of 1 affected member showed pathologic alterations in both small and large arteries the brain. Skin biopsies of 3 affected members showed extracellular amorphous deposits within the subepidermal zone, which may represent degenerated arterioles. WES or WGS did not reveal any potentially disease-causing variants in known genes for cSVDs or idiopathic basal ganglia calcification, but identified 1 heterozygous variant, NM_004672.4 c.322G>A p.(Asp108Asn), that cosegregated with the disease in this large family. MAP3K6 has known functions in angiogenesis and affects vascular endothelial growth factor expression, which may be implicated in cerebrovascular disease.
Our data strongly suggest the variant to be causative for this novel disease phenotype, but the absence of functional data and the present lack of additional families with this disease and mutations still limit the formal evidence for the variant's pathogenicity.
描述一种可能的脑小血管病（cSVD）和中风的新型遗传机制。
我们研究了一个患有缺血性中风、脑出血、震颤、自主神经功能障碍和轻度认知衰退的瑞典家族。对家族成员进行了临床、放射学和组织病理学检查。基因检测包括全外显子组测序（WES）、全基因组测序（WGS）以及家族内共分离分析。
对15名家族成员进行了临床检查。12名受累个体有白质高信号，以及以下一种或多种情况：（1）中风发作，（2）临床无症状的腔隙性缺血性病变，（3）认知功能障碍。所有受累个体都有震颤和/或共济失调步态障碍。3名受累成员可见轻度对称性基底节钙化。对1名受累成员进行尸检显示大脑中小动脉和大动脉均有病理改变。对3名受累成员进行皮肤活检，结果显示在表皮下区域有细胞外无定形沉积物，可能代表退化的小动脉。WES或WGS未在已知的cSVD或特发性基底节钙化相关基因中发现任何潜在的致病变异，但发现了1个杂合变异，NM_004672.4 c.322G>A p.(Asp108Asn)，该变异在这个大家族中与疾病共分离。丝裂原活化蛋白激酶激酶6（MAP3K6）在血管生成中具有已知功能，并影响血管内皮生长因子的表达，这可能与脑血管疾病有关。
我们的数据强烈提示该变异是这种新型疾病表型的病因，但缺乏功能数据以及目前仍缺乏患有这种疾病和该突变的其他家族，这仍然限制了该变异致病性的正式证据。
