Early onset cerebral infarction in three generations in one family suggest the role of genetic risk factors. There are 19 single gene mutations of the proband and affected siblings was demonstrated apparently compared with healthy individuals in this family. These results indicated that polygenetic effects are the major components in the pathogenesis of CI. Among the candidate genes, AKT2/FFAR2/ATP1A3/GRIN2D genes enriched in the cAMP signaling pathway by KEGG analysis. AKT2 was predicted the association with CI.
In this family, proband and his old brother all suffered from ischemic infarction in basal ganglia and they do not have obvious great vessel stenosis. Infarction of basal ganglia supplied by lateral lenticulostriate arteries (LSA), which originate from the middle cerebral artery. There is still no publication to report that special gene mutation contribution to the basal ganglia infarction due to LSA. Nevertheless, a total of 14 from 19 genes expressed in the basal ganglia.
Cyclic adenosine monophosphate (cAMP) exerts important biological roles in the pathophysiology of ischemic stroke14. In the early stage of CI, necrotic cells release a mass of cytokines and chemokines, which activate astrocytes and microglial to produce pro-inflammatory factors15. cAMP could regulate neuroinflammation after ischemic stroke to protect against neuron injury. Researches has shown that prostaglandin E2 and prostaglandin I2 can protect neurons and reduce neuronal death by increasing intracellular cAMP15.
In our research, AKT2/FFAR2/ATP1A3/GRIN2D gene mutations in four patients may be associated with the dysfunction of the cAMP pathway. Genetically predicted AKT serine/threonine kinase 2 (AKT2) was associated with infarction by Phenolyzer software. Some research has demonstrated that ischemic postconditioning exerts its neuroprotective effect through negatively regulating PI3K/Akt2 signaling pathway5. Free fatty acid receptor 2 (FFAR2), a receptor for acetate, involved in glucose homeostasis16. The upregulation of ATPase Na+/K + transporting subunit alpha 3 (ATP1A3) attenuates ischemic brain damage17. In addition, the downregulation of glutamate ionotropic receptor NMDA type subunit 2D (GRIN2D) enhanced rates of neuroprotection from ischemic strokes compared to wild-type mice18.
For the fourth generation, the Ⅳ-1 and Ⅳ-2 have different gene mutations. Compared with control group, there are 11 and 7 genes with same mutation in Ⅳ-2 and Ⅳ-1 individually in 19 mutated genes. Moreover, the gene mutations were completely different in two members of this family. In this family, CI onset was in male-only member and gene mutation might contribute to the pathogenesis of CI. The genetic susceptibility to stroke might differ depending on the gender of aging people19. Base on the findings, the member Ⅳ-1 was susceptible to have ischemic stroke, which need more evidence.
In summary, polygene mutations may modulate the other risk factors in the pathogenesis of CI. Further research into the genetic risk factors of stroke will strictly compliment ongoing national and international efforts to decrease the global burden of stroke.