The MAP3K6 variant may be a causative genetic factor involved in the development of a later-onset neurovascular disease responsible for stroke, mild cognitive impairment, cerebellar signs, and dysautonomia, according to study results published in Neurology Genetics.
The study included 15 Swedish family members, including those who showed evidence of ischemic stroke and intracerebral hemorrhage, tremor, dysautonomia, and mild cognitive decline. Up to 8 affected, 2 unaffected, and 5 family members with undetermined clinical status were enrolled. Study researchers examined each family member clinically, radiologically, and by histopathology. They performed a genetic workup that included whole-exome sequencing (WES) and whole-genome sequencing (WGS) as well as intrafamilial cosegregation analyses.
In the family members who carried the MAP3K6 variant, 3 had mild symmetric calcifications in the basal ganglia and globi pallidi. A total of 12 affective family members had evidence of white matter hyperintensities and at least 1 stroke episode, clinically silent lacunar ischemic lesions, and cognitive dysfunction. Affected study participants also had atactic gait disturbance and/or tremor.
There were pathologic alterations in small and large brain arteries, according to a postmortem examination of 1 affected individual. In skin biopsies of 3 affected family members, the study researchers observed extracellular amorphous deposits immediately under the epidermis. According to them, these findings suggested degenerated arterioles in these members.
No potentially disease-causing variants were found in known genes for cerebral small vessel disease or idiopathic basal ganglia calcification upon WES or WGS; however, the study researchers found 1 heterozygous variant, known as NM_004672.4 MAP3K6 c.322G>A p.(Asp108Asn). This variant cosegregated with the disease in the overall cohort. The study researchers noted that MAP3K6 has been implicated in angiogenesis as well as expression of vascular endothelial growth factor, all of which may be associated with cerebrovascular disease.
A limitation of this study was the focus on the causative role of MAP3K6, and lack of functional data and families with this disease, all of which limited evidence regarding the pathogenicity of the variant.
Given the limitations of the study, the researchers noted that further experimental data as well as “discovery of MAP3K6 variants in additional probands or families with this clinical picture” may help “firmly establish MAP3K6 as a causative gene for this disorder.”
Ilinca A, Englund E, Samuelsson S, et al. MAP3K6 mutations in a neurovascular disease causing stroke, cognitive impairment, and tremor. Neurol Genet. 2021;7(1):e548. doi:10.1212/NXG.0000000000000548