Page 68 - GPD-2-2

Gene & Protein in Disease Genetics of arteriovenous malformations

with a thorough analysis of emerging treatment options for
bAVM, based on its genetic profile.
2. Etiology and pathogenesis of AVM

2.1. Etiology and epidemiology
bAVM is twisted networks of blood vessels derived from
abnormal capillary network development which leads to
direct connections between cerebral arteries and veins .
[11]
They can be characterized by one or more arterial pedicles
feeding into a vascular nidus creating early drainage into
a venous outflow channel (Figure 1) . bAVM is rare
[12]
anomalies but generally are not present at birth and take
time to develop . Although bAVM is originally thought
[13]
to be congenital, continued research and increasing
Figure 1. Clinical consequences of AVM rupture. AVM is defined as evidence may indicate that bAVM is acquired and likely
vascular shunts connecting arteries and veins. Common consequences involves environmental and genetic influences. Some
of AVM rupture in the brain include hypoxia, stroke, ICH, and abscess. studies have shown that neurogenic locus notch homolog 4
Abbreviations: AVM: Arteriovenous malformations, ICH: Intracranial single nucleotide polymorphisms (SNPs) could potentially
hemorrhage.
be a genetic risk factor involved in the development,
presentation, and pathogenesis of bAVM . Risk factors for
[14]
What is clear from the available evidence is that developing bAVM are largely unknown but inflammation
genetics play a key role in AVM development, and with has been linked to the progression of bAVM .
[15]
advances in technology and DNA sequencing techniques,
the genetic underpinnings of bAVM are now more than bAVM is estimated to be in approximately 0.05% of the
ever much more easily studied [6,8] . Mutations in genes population and is detected in about one in every 100,000
[16]
related to inflammation or angiogenesis, for example, people . bAVM can be asymptomatic but commonly
[11,12,17]
have been identified for associations with bAVM and ICH. present with ICH or seizure . bAVM is the leading
[18]
These candidate genes are diverse, affecting pathways like cause of ICH in children and young adults . Over half of
. Of
those detected will first present with hemorrhage
[13,16]
interleukin (IL)-6 signaling and endothelial remodeling. those that do have symptoms presentation usually appears
Overexpression of vascular endothelial growth factor between the second and third decade of life. These findings
(VEGF), for instance, has been linked to increased are particularly of value because previous hemorrhage is the
hemorrhaging in bAVM . In addition to this, another most important indicator for subsequent hemorrhage .
[9]
[19]
focus of study has been examining already characterized Hemorrhage and recurrence of hemorrhage make bAVM
genetic syndromes that present with bAVM, like hereditary a serious condition for younger adults especially. bAVM
hemorrhagic telangiectasia (HHT), which often comprises can be associated with concurrent aneurysms, further
most familial cases of the condition . The hope is that increasing the risk of hemorrhage [20,21] . Specific aneurysms
[10]
by understanding these Mendelian diseases, we will gain linked to an increased risk of hemorrhage are feeding artery
insight into the pathogenesis of bAVM. and intranidal aneurysms . In a univariate analysis, it was
[21]
Clearly, we have advanced and will continue to indicated that feeding arterial aneurysms are independent
advance in our understanding of the genetics of bAVM. determinants for an increased risk of hemorrhage (hazard
However, while there is much in the literature in the way ratio [HR] = 1.78, 95% confidence interval [CI] = 0.91–
[22]
of specific gene associations and syndromes, there is a 3.46) . Other symptoms of bAVM may include focal
lack of comprehensive reviews overviewing the genetic neurologic deficits and headaches [11,12] . Large midline
underpinnings of the condition. Such an overview would AVM that drain into the vein of Galen can form but are not
allow for a better understanding of bAVM and its genetic considered true AVM and are classified as vein of Galen
[17]
associations. Thus, in the following paper, we aim to malformations . These malformations exclusively occur
remedy that gap, highlighting the etiology of bAVM, with a in children, and typically present with hydrocephalus,
[17]
special focus on preclinical and clinical studies examining congestive heart failure, and prominent forehead veins .
its genetic basis. We also generally review candidate genes The causes of bAVM are mostly unknown, but
thought to be involved in bAVM pathology and consider recent studies have shown that abnormal expression of
relevant syndromes and diseases. We end our discussion angiogenic and inflammatory proteins associated with

Volume 2 Issue 2 (2023) 2 https://doi.org/10.36922/gpd.0312