Chapter 16 - Monogenic causes of cerebral small vessel disease and stroke

Abstract

Cerebral small vessel disease (cSVDs) account for 25% of stroke and are a frequent cause of cognitive or motor disability in adults. In a small number of patients, cSVDs result from monogenic diseases, the most frequent being cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). An early disease onset, a suggestive family history, and a low vascular risk profile contrasting with a high load of cSVD imaging markers represent red flags that must trigger molecular screening. To date, a dozen of genes is involved in Mendelian cSVDs, most of them are responsible for autosomal dominant conditions of variable penetrance. Some of these mendelian cSVDs (CADASIL, HTRA1-related cSVD, pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), cathepsin-A related arteriopathy with strokes and leukoencephalopathy (CARASAL), and cSVD related to LAMB1 mutations) are causing ischemic stroke. Others (COL4A1/COL4A2-related angiopathy and hereditary cerebral amyloid angiopathy) preferentially lead to intracerebral hemorrhages. The clinical features of different Mendelian cSVDs can overlap. Therefore, the current approach is based on simultaneous screening of all genes involved in these conditions through a panel-targeted sequencing gene or exome sequencing. Nevertheless, a pathogenic variant is identified in less than 15% of patients with a suspected genetic cerebrovascular disease, suggesting that many additional genes remain to be identified.