Arteriovenous Malformations Of The Brain

A number sign (#) is used with this entry because of the occurrence of cerebral arteriovenous malformations in several genetic disorders including hereditary hemorrhagic telangiectasia (HHT; 187300) and hereditary neurocutaneous angioma (106070). A promoter polymorphism in the IL6 gene (147620) is associated with susceptibility to intracranial hemorrhage in brain arteriovenous malformations. Somatic activating mutations in the KRAS gene (190070) have been identified as a cause of arteriovenous malformations of the brain.

Clinical Features

Cerebral arteriovenous malformations are considered to be distinct from cerebral cavernous malformations (116860), which are venous and usually arteriographically 'silent' (Rigamonti, 1993).

Snead et al. (1979) reported cerebral arteriovenous malformations in 3 sibs with the same mother. Two were by one father and the third by another. HHT and von Hippel-Lindau disease were excluded. They found reports of 4 instances of familial aggregation. Aberfeld and Rao (1981) reported affected brother and sister. Yokoyama et al. (1991) described 6 cases in 3 families. These included a father-son pair, a mother-son pair, and male and female first cousins. They commented on the report by Boyd et al. (1985) of affected father and 3 sons and another father and daughter combination.

Biochemical Features

Chen et al. (2009) found increased levels of soluble endoglin (ENG; 131195) in vascular surgical specimens from 33 patients with arteriovenous malformations of the brain compared to similar specimens from 8 epileptic patients. However, there was no difference in expression of membrane-bound endoglin and no difference in plasma soluble endoglin between BAVM patients and controls. Transduction of soluble endoglin in mouse brain resulted in the formation of abnormal and dysplastic capillary structures, and was associated with increased levels of matrix metalloproteinase activity and oxidative radicals. Chen et al. (2009) suggested that soluble endoglin may play a role in the formation of sporadic BAVM by acting as a decoy receptor, resulting in inhibition of TGF-beta (TGFB1; 190180) signaling and functional haploinsufficiency of ENG, as observed in patients with hereditary hemorrhagic telangiectasia-1 (HHT1; 187300).

Molecular Genetics

Association with IL6 Promoter Polymorphism

Among 180 patients with brain arteriovenous malformations (BAVM), Pawlikowska et al. (2004) found an association between a promoter polymorphism in the IL6 gene (-174G/C; 147620.0001) and intracranial hemorrhage. Patients who were homozygous for the G allele had an increased risk intracranial bleed (odds ratio of 2.62) compared to carriers of the C allele. In brain tissue from patients with BAVM, Chen et al. (2006) found that the highest IL6 protein and mRNA levels were associated with the IL6 -174GG genotype compared to the GC and CC genotypes. IL6 protein levels were increased in BAVM tissue from patients with hemorrhagic presentation compared to those without hemorrhage. In vivo studies demonstrated that IL6 enhanced expression and activity of IL1B (147720), TNFA (191160), IL8 (146930), and several matrix metalloproteinases, MMP3 (185250), MMP9 (120361), and MMP12 (601046). IL6 also increased proliferation and migration of cultured human cerebral endothelial cells. Chen et al. (2006) suggested that IL6 expression may modulate downstream inflammatory and angiogenic targets that contribute to intracranial hemorrhage in BAVMs.

Somatic Mutation in KRAS

Nikolaev et al. (2018) analyzed tissue and blood samples from patients with BAVM to detect somatic mutations. They performed exome DNA sequencing of tissue samples of BAVM from 26 patients in the main study group and of paired blood samples from 17 of these patients, and confirmed their findings using droplet digital PCR analysis of tissue samples from 39 patients in the initial study group (21 of whom had matching blood samples) and from 33 patients in an independent validation group. Nikolaev et al. (2018) detected somatic activating KRAS mutations gly12 to asp (190070.0025) and gly12 to val (190070.0026) in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from BAVM, Nikolaev et al. (2018) detected KRAS mutations and observed that expression of mutant KRAS (KRAS G12V) in endothelial cells in vitro induced increased ERK activity, increased expression of genes related to angiogenesis and Notch (190198) signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK-ERK signaling (see 176872). Nikolaev et al. (2018) concluded that they identified activating KRAS mutations in the majority of BAVM tissue samples that were analyzed, and proposed that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain epithelial cells.

Animal Model

Murphy et al. (2008) found that mice with constitutively active Notch4 (164951) expression in endothelial cells from birth developed hallmarks of brain arteriovenous malformations by 3 weeks of age, including cerebral arteriovenous shunting and vessel enlargement. Most died by 5 weeks of age. Approximately 25% of the mutant mice showed signs of neurologic dysfunction, including ataxia and seizures. Imaging studies detected cerebral arteriovenous malformations. Repression of Notch4 resolved ataxia and reversed the disease progression, demonstrating that Notch4 is not only sufficient to induce but also required to sustain the disease. Postmortem examination showed hemorrhage and neuronal cell death within the cerebral cortex and cerebellum, as well as widespread enlargement of the cerebral microvasculature, which coincided with a reduction in capillary density. These findings suggested that vessel enlargement underlies the development of BAVM and linked this pathology to the known function of the NOTCH pathway as an inhibitor of vessel sprouting.