The MAP3K6 variant may be a causative genetic factor involved in the development of a later-onset neurovascular disease that is 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 haemorrhage, tremor, dysautonomy, and slight cognitive decline. Up to 8 affected, 2 unaffected, and 5 family members with undetermined clinical status were included. The study researchers examined each family member clinically, radiologically, and histopathologically. They carried out a genetic work-up that included the sequencing of the entire exome (WES) and the sequencing of the entire genome (WGS) as well as intrafamilial cosegregation analyzes.
In the family members who carried the MAP3K6 variant, 3 had slight symmetrical 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, clinically silent lacunar ischemic lesions, and cognitive dysfunction. Affected study participants also had atactic gait disorders and / or tremors.
There were pathological changes in both small and large cerebral arteries according to a post-mortem examination of 1 affected person. In skin biopsies from 3 affected family members, the researchers observed extracellular amorphous deposits just below the epidermis. Accordingly, these findings indicated degenerate arterioles in these members.
No potentially disease-causing variants were found in known genes for cerebral small-vessel diseases or idiopathic basal ganglia calcification according to WES or WGS. However, the study researchers found 1 heterozygous variant known as NM_004672.4 MAP3K6 c.322G> A p. (Asp108Asn). This variant was cosegregated with the disease in the overall cohort. The study researchers found that MAP3K6 is involved in both angiogenesis and expression of vascular endothelial growth factor, all of which may be associated with cerebrovascular disease.
One limitation of this study was its focus on the causal role of MAP3K6 and the lack of functional data and families with the disease, all of which contained limited evidence of the pathogenicity of the variant.
Given the limitations of the study, the researchers determined that further experimental data and the “discovery of MAP3K6 variants in additional subjects or families with this condition” could help “firmly establish MAP3K6 as the causative gene for this disorder”.
Ilinca A., Englund E., Samuelsson S. et al. MAP3K6 mutations in neurovascular disease that cause stroke, cognitive impairment, and tremor. Neurol Genet. 2021; 7 (1): e548. doi: 10.1212 / NXG.0000000000000548