Genetic determinants of juvenile stroke

Stroke is a heterogeneous multifactorial disorder. Although epidemiological data from twin and family studies provide substantial evidence for a genetic basis for stroke, the contribution of genetic factors identified so far is small. Large progress has been made in single-gene disorders associated with ischemic stroke, particularly at young age. The identification of NOTCH3 mutations in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) and of TREX1 mutations in retinal vasculopathy with cerebral leukodystrophy (RVCL) have led to new insights on lacunar stroke and small-vessel disease. Studies of sickle-cell disease have drawn attention to the importance of modifier genes and of gene-gene interactions in determining stroke risk, while there is now evidence that Fabry disease is an underdiagnosed cause of stroke. Furthermore, stroke is a well-known complication of several heritable connective tissue disorders, including Marfan's syndrome (FBN1 mutations) and Ehlers-Danlos syndrome type IV (COL3A1 mutations), which predispose to cervical artery dissection, the most frequent cause of cerebral ischemia at young age. By contrast, little is known about the genes associated with multifactorial stroke. The reported genome-wide association studies of ischemic stroke have shown that no single common genetic variant imparts major risk. Pharmacogenomic studies have uncovered genetic determinants of response to warfarin, statins and clopidogrel. Larger studies with samples numbering in the thousands are ongoing to identify common variants with smaller effects on risk. This approach will contribute to the identification of additional genes, novel pathways, and eventually novel therapeutic approaches to cerebrovascular disorders.