Genetic considerations relevant to intracranial hemorrhage and brain arteriovenous malformations

Abstract

SUMMARYBrain arteriovenous malformations (AVM) cause intracranial hemorrhage (ICH), especially in young adults. Molecular characterization of lesional tissue provides evidence for involvement of both angiogenic and inflammatory pathways, but the pathogenesis remain obscure and medical therapy is lacking. Abnormal expression patterns have been observed for proteins related to angiogenesis (e.g., VEGF, Angiopoietin-2, MMP-9), and inflammation (e.g., IL-6 and MPO). Macrophage and neutrophil invasion has also been observed in the absence of prior ICH. Candidate gene association studies have identified a number of germline variants associated with clinical ICH course and AVM susceptibility. A single nucleotide polymorphism (SNP) in ALK-1 is associated with AVM susceptibility, and SNPs in IL-6, TNF-α and APOE are associated with AVM rupture. These observations suggest that even without a complete understanding of the determinants of AVM development, the recent discoveries of downstream derangements in vascular function and integrity may offer potential targets for therapy development. Further, biomarkers can now be established for assessing ICH risk. Finally, these data will generate hypotheses that can be tested mechanistically in model systems, including surrogate phenotypes, such as vascular dysplasia and/or models recapitulating the clinical syndrome of recurrent spontaneous ICH. Keywords angiogenesis; inflammation; vascular malformationsBrain arteriovenous malformations (AVM) represent a relatively infrequent but important source of neurological morbidity in relatively young adults [4]. Brain AVMs have a population prevalence of 10-18 per 100,000 adults [3,7], and a new detection rate of ~1.3 per 100,000 person-years [58]. The basic morphology is of a vascular mass, called the nidus, that directly shunts blood between the arterial and venous circulations without a true capillary bed. There is usually high flow through the feeding arteries, nidus and draining veins. The nidus is a

Are parenchymal AVMs congenital lesions?

“…However, the exact mechanism of AVM formation has yet to be elucidated, and it may involve an interaction between genetic susceptibility and environmental (acquired) factors. Several studies of patients with hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease that includes AVMs in multiple sites (brain included) as part of its clinical spectrum, 18 have improved our understanding of these vascular lesions. Loss-of-function mutations have been identified in the 2 main subtypes of the disease.…”

Pathogenesis of Arteriovenous Malformations in the Absence of Endoglin

“…1,2 The factors leading to AVM formation are unknown, but a number of inherited diseases leading to vascular malformations have now been identified and the causal mutations mapped. 3 Of these familial disorders, hereditary hemorrhagic telangiectasia (HHT) patients have a strikingly high frequency of AVMs.…”

Central Nervous System Vascular Malformations

“…Although an initiating event has yet to be defined, possible candidates include trauma, tissue hypoxia, venous hypertension, infection, inflammation, irradiation, or compression [14,15]. The primary vascular defect may be the development of a simple arteriovenous fistula [16], with altered hemodynamic stresses occurring in the affected vessels.…”

“…Polymorphisms in the IL-6, IL-1β, TNF-α, and apolipoprotein-E (ApoE) genes have been associated with increased risk of hemorrhage [36][37][38][39], and SNPs in ALK-1 are associated with a susceptibility for AVM formation [15].…”