RT Journal Article SR Electronic T1 MAP3K6 Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor JF Neurology Genetics JO Neurol Genet FD Lippincott Williams & Wilkins SP e548 DO 10.1212/NXG.0000000000000548 VO 7 IS 1 A1 Ilinca, Andreea A1 Englund, Elisabet A1 Samuelsson, Sofie A1 Truvé, Katarina A1 Kafantari, Efthymia A1 Martinez-Majander, Nicolas A1 Putaala, Jukka A1 Håkansson, Claes A1 Lindgren, Arne G. A1 Puschmann, Andreas YR 2021 UL http://ng.neurology.org/content/7/1/e548.abstract AB Objective To describe a possible novel genetic mechanism for cerebral small vessel disease (cSVD) and stroke.Methods 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.Results 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 MAP3K6 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.Conclusions Our data strongly suggest the MAP3K6 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 MAP3K6 mutations still limit the formal evidence for the variant's pathogenicity.ASK2=apoptosis signal-regulating kinase; cSVD=cerebral small vessel disease; HE=hematoxylin and eosin; JNK=c-Jun N-terminal kinase; MAP2K6=mitogen-activated protein kinase; VEGF=vascular endothelial growth factor; WES=whole-exome sequencing; WGS=whole-genome sequencing; WMHs=white matter hyperintensity