A theory for polymicrogyria and brain arteriovenous malformations in HHT

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is generally considered a disorder of endothelial dysfunction, characterized by the development of multiple systemic arteriovenous malformations (AVMs), including within the brain. However, there have recently been a number of reports correlating HHT with malformations of cortical development, of which polymicrogyria is the most common type. Here we present 7 new cases demonstrating polymicrogyria in HHT, 6 of which demonstrate a brain AVM (bAVM) in close spatial proximity, with the aim of providing a common origin for the association. Upon reviewing patient genetics and imaging data and comparing with previously reported findings, we form 2 new conclusions: (1) polymicrogyria in HHT appears exclusively associated with a subset of mutations in the transmembrane protein endoglin that is involved with blood flow–related mechanotransduction signaling during angiogenesis and (2) the polymicrogyria is characteristically unilateral, typically focal, and correlates with vascular regions experiencing low fluid shear stress during corticogenesis in utero. Integrating these with findings in the literature from genetics and molecular biology experiments, we propose a theory suggesting haploinsufficient endoglin mutations, especially those that are dominant-negative, may predispose focal, aberrant hypersprouting angiogenesis during corticogenesis that leads to the production of polymicrogyria. This hypoxic insult may further serve as the revealing trigger for later development of a spatially coincident bAVM. This hypothesis suggests an essential role for endoglin-mediated hemodynamic mechanotransduction in normal corticogenesis.

Hereditary hemorrhagic telangiectasia associated with cortical development malformation due to a start loss mutation in ENG

“…The findings in our index patient add support for an association of polymicrogyria to variants in ENG [9]. In particular, the finding of cerebral AVMs in close proximity with polymicrogyria cortex (left frontal and temporal-insular lobes) fits with the hypothesis that altered neuronal migration and cortical organization leading to polymicrogyria is the consequence of focal hypoperfusion during corticogenesis due to functional impairment of endoglin.…”

“…Therefore, cDM prevalence in HHT is likely underestimated, particularly in subclinical forms. Neuroimaging findings suggest a clear prevalence of polymicrogyria in HHT patients with cDM [8,9].…”

“…Recently, Klostranec and colleagues disclosed the co-occurrence of polymicrogyria and cerebral AVMs in close spatial proximity in six HHT cases and suggested that functional impairment of endoglin might produce focal hypoperfusion during corticogenesis in utero, leading to impaired neuronal migration and cortical organization, resulting in polymicrogyria [ 9 ]. Hypoxia is also expected to prime the appearance of the second somatic mutation in endothelial cells of adjacent vessels, establishing the condition for the later appearance of cerebral AVMs whose morphology and dimension become radiologically evident by age.…”

Potential Second-Hits in Hereditary Hemorrhagic Telangiectasia

“…In addition, a subset of HHT patients present with polymicrogyria, a condition characterized by abnormal development of the brain with vascular regions experiencing low fluid shear stress during corticogenesis in utero, leading to a brain surface with many ridges or folds, called gyri. In HHT, polymicrogyria appears exclusively associated with a subset of pathogenic variants in endoglin that is involved in blood flow-related mechano-transduction [74]. Taken together, these findings suggest that the interplay between the BMP9/endoglin/ALK1 pathway and blood flow-induced mechano-transduction signals plays a critical role during development of HHT lesions [64][65][66]72,73].…”

Current Status of Clinical Diagnosis and Genetic Analysis of Hereditary Hemorrhagic Telangiectasia in South Korea: Multicenter Case Series and a Systematic Review

“…Malformations of cortical developments (MCDs), mostly polymicrogyria, are sometimes observed in association with HHT [18]. The exact pathogenetic mechanism for MCDs is not well established; however, it is postulated that decreased expression of ENG may result in focal hypersprouting angiogenesis during corticogenesis, leading to MCD [19]. All cases reported to date have been associated with HHT1, and the lesions are characteristically unilateral, focal, and correlate with arterial regions exposed to the lowest fluid shear stress in utero [19].…”