Main features of COL4A1-COL4A2 related cerebral microangiopathies

Abstract

COL4A1 and COL4A2 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 COL4A1/COL4A2 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 COL4A1 3'UTR non-coding region that upregulate COL4A1 expression, and COL4A1/COL4A2 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.

Keywords: Autosomal dominant; Brain hemorrhage; COL4A1; COL4A2; Collagenopathy; hereditary cerebral small vessel disease.

Fig. 1

Cerebral MRI characteristics in patients with COL4A1 mutation involving a glycine of the triple-helix A: T1- weighted (left) and T2-weighted (right) axial sequences, showing a ventricle asymmetry due to porencephalic cysts in a one-month-old boy (left) and in a three-months-old girl (right) with a congenital hemiparesis. B: FLAIR sequence (left) and time-of-flight magnetic resonance angiography (right), showing a leukoencephalopathy (left) and a left intracranial internal carotid artery aneurysm (right) in a 70-year-old man (B1) and his 35-year-old daughter (B2) with a history of HANAC syndrome.

Fig. 2

Cerebral MRI characteristics in a patient with PADMAL T2-weighted axial sequences (A,B) and T1- weighted sagittal sequence (C), showing a diffuse leukopathy in centrum semi-ovale and periventricular white matter (A,B), and lacunes in pons (C, arrows) and subcortical white matter (A,B, arrows) in a 57 years-old man with history of transient focal deficits, progressive walking and cognitive disability.