Altered arterial homeostasis and cerebral aneurysms: a review of the literature and justification for a search of molecular biomarkers.

DESPITE THE CATASTROPHIC consequence of ruptured intracranial aneurysms, very little is understood regarding their pathogenesis, and there are no reliable predictive markers for identifying at-risk individuals. Given that intracranial aneurysms have a strong but complex genetic component and well-characterized modifiable risk factors, it seems likely that the most valuable approach to developing minimally invasive diagnostic and prognostic tools will involve a multifactorial model that includes both genetic and environmental risk factors. Unfortunately, the genetic basis of intracranial aneurysms is poorly described, and reports describing the association of nonrandom deoxyribonucleic acid sequence variation with intracranial aneurysms have been limited to a handful of ad hoc studies that have focused on a variety of markers in small populations. One reason for this lack of coordinated analysis of the genetic basis of intracranial aneurysms is that the molecular pathogenesis and pathobiological characteristics of the disease are poorly described, so candidate marker selection has been problematic. Few studies have addressed the molecular pathological basis of intracranial aneurysms or the possible mechanisms of intracranial aneurysm formation. In this regard, candidate gene selection strategies have relied almost exclusively on limited knowledge of monogenic disorders such as Ehlers-Danlos syndrome and Marfan's syndrome, in which intracranial aneurysm is a feature of a spectrum of syndromic phenotypes. Without exception, these approaches have not affected the clinical identification and/or management of intracranial aneurysms significantly. Therefore, it is imperative that coordinated large-scale efforts in genetics, molecular biology, and genetic epidemiology are implemented to overcome these obstacles and drive developments in the field. In this review, we summarize the current screening modalities for intracranial aneurysms, review the current state of understanding relating to the genetic basis of intracranial aneurysms, and suggest a broader theory of aneurysm pathogenesis to form the foundation of a coordinated molecular search for biological markers that may be associated with aneurysm formation and rupture.