Main features of COL4A1-COL4A2 related cerebral microangiopathies

Abstract

<i>COL4A1</i> and <i>COL4A2</i> genes encode the alpha1 and the alpha2 chains of type IV collagen, a key component of basement membranes. Mutations located in the coding sequence of <i>COL4A1/COL4A2</i> genes are responsible for an autosomal dominant (AD) cerebral angiopathy that manifest in either adults, children or fetuses. The most typical among such mutations are missense glycine mutations in the triple helix. They increase the susceptibility to brain hemorrhage but can also promote the occurrence of multiple other types of systemic manifestations that can involve the eyes, kidneys or muscles. This condition is characterized by a very incomplete penetrance, and a wide phenotypic variability even among members of the same family. Recently, mutations in the <i>COL4A1</i> 3'UTR non-coding region that upregulate <i>COL4A1</i> expression, and <i>COL4A1/COL4A2</i> duplications, have been shown to cause AD forms of ischemic cerebral small vessel disease in adults. Herein, we summarize the genetic and pathophysiological aspects of these conditions, detail their clinical and imaging characteristics and discuss some principles in their clinical management.