COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy

Abstract

Type IV collagen α1 and α2 chains form heterotrimers that constitute an essential component of basement membranes. Mutations in COL4A1, encoding the α1 chain, cause a multisystem disease with prominent cerebrovascular manifestations, including porencephaly, bleeding-prone cerebral small vessel disease, and intracranial aneurysms. Mutations in COL4A2 have only been reported in a few porencephaly families so far. Herein, we report on a young adult patient with recurrent intracerebral hemorrhage, leukoencephalopathy, intracranial aneurysms, nephropathy, and myopathy associated with a novel COL4A2 mutation. We extensively investigated a 29-year-old male patient with recurrent deep intracerebral hemorrhages causing mild motor and sensory hemisyndromes. Brain MRI showed deep intracerebral hemorrhages of different age, diffuse leukoencephalopathy, multiple cerebral microbleeds and small aneurysms of the carotid siphon bilaterally. Laboratory work-up revealed significant microscopic hematuria and elevation of creatine-kinase. Genetic testing found a de novo glycine mutation within the COL4A2 triple helical domain. The presented case completes the spectrum of cerebral and systemic manifestations of COL4A2 mutations that appears to be very similar to that in COL4A1 mutations. Therefore, we emphasize the importance of screening both COL4A1 and COL4A2 in patients showing recurrent intracerebral hemorrhage of unknown etiology, particularly if associated with leukoencephalopathy.

Periodontal Ehlers–Danlos syndrome is associated with leukoencephalopathy

“…Most common risk factors for leukoencephalopathies caused by small vessel disease are hypertension, hypercholesterolemia, diabetes mellitus, and age [17, 18]. Genetic vascular leukoencephalopathies, including CADASIL [19], CARASIL [20], CARASAL [21], and COL4A1- or COL4A2- related disorders in adults [22, 23], cause a similar MRI pattern. With the anterior temporal white matter abnormalities and involvement of the external and extreme capsules, the MRI pattern of our EDS patients is in fact very similar to that of CADASIL [20].…”

Monogenic causes of stroke: now and the future

“…Collagen also has roles in maintaining vascular tone and endothelial cell function [29]. COL4A1 and COL4A2-related arteriopathy is caused by missense mutations, often resulting in the substitution of a highly conserved hydrophobic glycine residue within the collagen molecule [61]. This alters the three-dimensional conformation of the chain, inhibiting the formation and deposition of a collagen heterotrimer in the vascular basement membrane, resulting in increased vessel wall fragility [29].…”

Cyclic Mechanical Stretch Induced Smooth Muscle Cell Changes in Cerebral Aneurysm Progress by Reducing Collagen Type IV and Collagen Type VI Levels

“…Collagen dysfunction in arterial walls has been reported to cause familial aneurysms [18-20]. Changes in the collagen type 4 alpha 1 and alpha 2 subunits (COL4A1 and COL4A2) are also related to cerebral vascular disease [21, 22]. The distribution of collagen type IV around SMCs depends on the SMC population and density.…”