Abstract
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.
Glossary
- 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
Footnotes
Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.
↵* These authors contributed equally.
The Article Processing Charge was funded by the authors.
- Received June 15, 2020.
- Accepted in final form November 9, 2020.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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