Abstract 50: Evaluation of Candidate Polymorphisms for Association With Brain Arteriovenous Malformations and Intracranial Hemorrhage in Hereditary Hemorrhagic Telangiectasia

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Ludmila Pawlikowska ◽  
Jeffrey Nelson ◽  
Diana E Guo ◽  
Charles E McCulloch ◽  
Michael T Lawton ◽  
...  
Keyword(s):  
Intracranial Hemorrhage ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Nucleotide Polymorphisms ◽  
Genetic Modifiers ◽  
Association Analyses ◽  
Brain Arteriovenous Malformations ◽  
Significance Threshold ◽  
Common Genetic Variants ◽  
Brain Avm

Introduction: Brain arteriovenous malformations (AVM) are an important cause of intracranial hemorrhage (ICH) in young adults. Most are sporadic, but also occur in inherited diseases such as hereditary hemorrhagic telangiectasia (HHT). ICH presentation of brain AVM in both sporadic and HHT cases is a marker of high ICH risk. In order to investigate whether the same genetic modifiers influence sporadic and HHT brain AVM, we evaluated candidate genetic polymorphisms reported as associated with sporadic brain AVM, with ICH presentation or ICH during clinical course, in HHT patients. Methods: We genotyped 8 polymorphisms ( APOE E2/3/4 [rs7412, rs429358], ANGPTL rs116724, EPHB4 rs314308, IL6 -174G>C [rs1800795], IL1B -31T>C [rs1143627], ITGB8 rs10486391, TNF -238G>A[rs361525]) in 753 Caucasian HHT patients enrolled by the Brian Vascular Malformation Consortium (BVMC). Genotypes were collapsed into risk allele carriers vs. other for analysis, as published for sporadic AVM. APOE E2/3/4 haplotypes were assigned based on genotypes of the 2 APOE polymorphisms. Association of genotype with phenotype was evaluated by multivariable logistic regression adjusted for age, gender and accounting for family clustering. We used a nominal significance threshold of p=0.05, requiring the same direction of effect as in sporadic brain AVM (odds ratio for risk genotype [OR]>1). Results: Among 753 HHT patients, 155 (21%) had brain AVM, of whom 26 (17%) presented with ICH. Two additional brain AVM patients had ICH during follow-up. None of the 7 variants (6 single nucleotide polymorphisms and APOE haplotype) were significantly associated with brain AVM (OR=0.6-1.3), with ICH presentation of brain AVM (OR=0.4-1.9), or with any brain AVM ICH in HHT patients (OR=0.5-2.1). Conclusions: Common genetic variants previously reported to be associated with sporadic brain AVM were not associated with brain AVM nor with ICH in the BVMC HHT cohort, suggesting different genetic modifiers may influence sporadic and HHT brain AVM. However, the number of ICH cases in the cohort is small, so the confidence intervals are wide and we cannot rule out clinically important associations. The BVMC is enrolling additional HHT patients to expand the cohort and increase power for association analyses.

Abstract W P417: A Common Variant in a TGFβ Modifier Locus Is Associated with Intracranial Hemorrhage Presentation of Brain Arteriovenous Malformation in Hereditary Hemorrhagic Telangiectasia

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Ludmila Pawlikowska ◽  
Jeffrey Nelson ◽  
Diana E Guo ◽  
Charles E McCulloch ◽  
Michael T Lawton ◽  
...  
Keyword(s):  
Intracranial Hemorrhage ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Statistical Significance ◽  
Genetic Modifier ◽  
Common Variant ◽  
Genetic Modifiers ◽  
Modifier Locus ◽  
Common Genetic Variants ◽  
Brain Avm ◽  
Genetic And Environmental Factors

Introduction: Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in TGFβ/BMP9 pathway genes, most commonly ENG or ALK1. HHT patients have arteriovenous malformations (AVM) in brain, lung and liver, leading to severe complications including intracranial hemorrhage (ICH) from brain AVM. ICH presentation of brain AVM in HHT is a marker of high ICH risk. The clinical heterogeneity of HHT suggests a potential role for genetic modifier effects. Common genetic variants in loci that modify phenotype severity in Tgfb knockout mice have been reported to be associated with pulmonary AVM in HHT. We sought to replicate these associations and investigate whether these variants are also associated with brain AVM and ICH presentation of brain AVM in HHT patients. Methods: We genotyped 3 variants (PTPN14 rs2936018, USH2A rs700024 and ADAM17 rs10495565) in 665 Caucasian HHT patients enrolled by the Brian Vascular Malformation Consortium (BVMC). Association of genotype with pulmonary AVM, brain AVM and ICH presentation was evaluated by multivariate logistic regression adjusted for age, gender and family clustering, and also stratified by HHT mutation (ALK1 or ENG). Results: Of 665 Caucasian HHT patients analyzed, 51% had pulmonary AVM and 20% had brain AVM, of whom 17% presented with ICH. None of the 3 SNPs was significantly associated with pulmonary or brain AVM. Among 130 brain AVM patients, USH2A rs700024 was associated with ICH presentation (OR=3.34, 95% CI=1.22-9.15, p=0.019). The effect size was similar in HHT patients with ALK1 and ENG mutations, but only reached statistical significance among the latter (OR=6.77, p=0.014). Conclusions: A common variant in USH2A, rs700024, previously reported to be associated with pulmonary AVM in HHT, was associated with ICH presentation of brain AVM, but not with brain or pulmonary AVM, in the BVMC HHT cohort. Association of the same USH2A variant with different HHT severity phenotypes in different cohorts suggests that it may act as a genetic modifier of HHT phenotype severity in concert with other genetic and environmental factors. Once validated, such genetic modifiers may improve our understanding of the phenotypic heterogeneity of HHT and aid in ICH risk prediction in HHT brain AVM.

scholarly journals Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: a systematic review and meta-analysis

2017 ◽  
Vol 127 (2) ◽  
pp. 302-310 ◽  
Author(s):  
Waleed Brinjikji ◽  
Vivek N. Iyer ◽  
Christopher P. Wood ◽  
Giuseppe Lanzino
Keyword(s):  
Systematic Review ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Clinical Presentation ◽  
Meta Analysis ◽  
Prevalence Rates ◽  
Brain Avm ◽  
Martin Grade ◽  
Cerebral Avms ◽  
Brain Avms

OBJECTIVEPatients with hereditary hemorrhagic telangiectasia (HHT) are known to suffer from high rates of cerebral arteriovenous malformations (AVMs). The authors performed a systematic review and meta-analysis of the literature examining prevalence rates, characteristics, and clinical presentation of cerebral AVMs in the HHT population.METHODSTo identify studies on AVM prevalence and characteristics in the HHT population, 4 databases (MEDLINE, EMBASE, Scopus and Web of Science) were searched by a reference librarian with over 30 years experience in systematic reviews and meta-analysis. The search period was January 1, 1990–March 2016. The following search terms were used: hereditary hemorrhagic telangiectasia, Osler-Weber-Rendu syndrome, AVM, brain AVM, arteriovenous malformation, arteriovenous fistula, prevalence, and epidemiology. The authors identified studies that examined the prevalence rates, characteristics, and clinical presentation of cerebral AVMs in patients with HHT. They assessed overall AVM prevalence rates as well as prevalence rates by age, sex, HHT type, and country/region. They also systematically reviewed the characteristics of AVMs, including rupture status, location, clinical presentation, angioarchitecture, and Spetzler-Martin grade. Data were analyzed using a random-effects meta-analysis model.RESULTSThirty-nine studies were included in this meta-analysis. Thirty studies examined brain AVM prevalence rates in various HHT patient populations, and 18 studies examined AVM clinical and angiographic characteristics (9 studies examined both prevalence rates and AVM characteristics). The prevalence of brain AVMs in HHT patients was 10.4% (95% CI 7.9%–13.0%) with no significant difference between males (8.5%, 95% CI 4.9%–12.0%) and females (11.0%, 95% CI 5.9%–16.1%). Patients with HHT Type 1 (HHT1) had a significantly higher brain AVM prevalence (13.4%, 95% CI 9.5%–17.4%) compared with those with HHT Type 2 (HHT2) (2.4%, 95% CI 1.0%–3.8%) (p < 0.0001). In 55.2% (95% CI 38.3%–72.1%) of cases, the AVMs were symptomatic. Spetzler-Martin grade was 2 or less in 86.9% (95% CI 67.5%–95.2%) of patients.CONCLUSIONSThe prevalence of brain AVMs in the HHT population is about 10%. HHT1 patients are significantly more likely to have brain AVMs than HHT2 patients. Most AVMs in the HHT population are symptomatic. The Spetzler-Martin grade for these lesions is 2 or less in nearly 90% of patients.

scholarly journals Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: Gene-phenotype correlations

2012 ◽  
Vol 158A (11) ◽  
pp. 2829-2834 ◽  
Author(s):  
Takeo Nishida ◽  
Marie E. Faughnan ◽  
Timo Krings ◽  
Murali Chakinala ◽  
James R. Gossage ◽  
...  
Keyword(s):  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Brain Arteriovenous Malformations

scholarly journals EPHB4 Gene Polymorphisms and Risk of Intracranial Hemorrhage in Patients With Brain Arteriovenous Malformations

2009 ◽  
Vol 2 (5) ◽  
pp. 476-482 ◽  
Author(s):  
Shantel Weinsheimer ◽  
Helen Kim ◽  
Ludmila Pawlikowska ◽  
Yongmei Chen ◽  
Michael T. Lawton ◽  
...  
Keyword(s):  
Intracranial Hemorrhage ◽  
Gene Polymorphisms ◽  
Arteriovenous Malformations ◽  
Brain Arteriovenous Malformations

scholarly journals Pathogenesis of non-hereditary brain arteriovenous malformation and therapeutic implications

2020 ◽  
Vol 26 (3) ◽  
pp. 244-253 ◽  
Author(s):  
Takahiro Ota ◽  
Masaki Komiyama
Keyword(s):  
High Risk ◽  
Arteriovenous Malformation ◽  
Signaling Pathways ◽  
Intracranial Hemorrhage ◽  
Arteriovenous Malformations ◽  
Genetic Factors ◽  
Angiogenic Factors ◽  
Brain Arteriovenous Malformation ◽  
Therapeutic Implications ◽  
Brain Arteriovenous Malformations

Brain arteriovenous malformations have a high risk of intracranial hemorrhage, which is a substantial cause of morbidity and mortality in patients with brain arteriovenous malformations. Although a variety of genetic factors leading to hereditary brain arteriovenous malformations have been extensively investigated, their pathogenesis is still not well elucidated, especially in sporadic brain arteriovenous malformations. The authors have reviewed the updated data of not only the genetic aspects of sporadic brain arteriovenous malformations, but also the architecture of microvasculature, the roles of the angiogenic factors, and the signaling pathways. This knowledge may allow us to infer the pathogenesis of sporadic brain arteriovenous malformations and develop pre-emptive treatments for them.

Arterial spin labeling magnetic resonance imaging: toward noninvasive diagnosis and follow-up of pediatric brain arteriovenous malformations

2015 ◽  
Vol 15 (4) ◽  
pp. 451-458 ◽  
Author(s):  
Thomas Blauwblomme ◽  
Olivier Naggara ◽  
Francis Brunelle ◽  
David Grévent ◽  
Stéphanie Puget ◽  
...  
Keyword(s):  
Arterial Spin Labeling ◽  
Arteriovenous Malformations ◽  
Spin Labeling ◽  
Absolute Quantification ◽  
Vascular Abnormalities ◽  
Brain Arteriovenous Malformations ◽  
Brain Avm ◽  
Pediatric Brain ◽  
Normal Cortex

OBJECT Arterial spin labeling (ASL)-MRI is becoming a routinely used sequence for ischemic strokes, as it quantifies cerebral blood flow (CBF) without the need for contrast injection. As brain arteriovenous malformations (AVMs) are highflow vascular abnormalities, increased CBF can be identified inside the nidus or draining veins. The authors aimed to analyze the relevance of ASL-MRI in the diagnosis and follow-up of children with brain AVM. METHODS The authors performed a retrospective analysis of 21 patients who had undergone digital subtraction angiography (DSA) and pseudo-continuous ASL-MRI for the diagnosis or follow-up of brain AVM after radiosurgery or embolization. They compared the AVM nidus location between ASL-MRI and 3D contrast-enhanced T1 MRI, as well as the CBF values obtained in the nidus (CBFnidus) and the normal cortex (CBFcortex) before and after treatment. RESULTS The ASL-MRI correctly demonstrated the nidus location in all cases. Nidal perfusion (mean CBFnidus 137.7 ml/100 mg/min) was significantly higher than perfusion in the contralateral normal cortex (mean CBFcortex 58.6 ml/100 mg/min; p < 0.0001, Mann-Whitney test). Among 3 patients followed up after embolization, a reduction in both AVM size and CBF values was noted. Among 5 patients followed up after radiosurgery, a reduction in the nidus size was observed, whereas CBFnidus remained higher than CBFcortex. CONCLUSIONS In this study, ASL-MRI revealed nidus location and patency after treatment thanks to its ability to demonstrate focal increased CBF values. Absolute quantification of CBF values could be relevant in the follow-up of pediatric brain AVM after partial treatment, although this must be confirmed in larger prospective trials.

Novel experimental model of brain arteriovenous malformations using conditional Alk1 gene deletion in transgenic mice

2021 ◽  
pp. 1-12
Author(s):  
Chul Han ◽  
Michael J. Lang ◽  
Candice L. Nguyen ◽  
Ernesto Luna Melendez ◽  
Shwetal Mehta ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Prussian Blue ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Gene Deletion ◽  
Blue Staining ◽  
Prussian Blue Staining ◽  
Brain Arteriovenous Malformations ◽  
Group 3 ◽  
Brain Avms

OBJECTIVE Hereditary hemorrhagic telangiectasia is the only condition associated with multiple inherited brain arteriovenous malformations (AVMs). Therefore, a mouse model was developed with a genetics-based approach that conditionally deleted the causative activin receptor-like kinase 1 (Acvrl1 or Alk1) gene. Radiographic and histopathological findings were correlated, and AVM stability and hemorrhagic behavior over time were examined. METHODS Alk1-floxed mice were crossed with deleter mice to generate offspring in which both copies of the Alk1 gene were deleted by Tagln-Cre to form brain AVMs in the mice. AVMs were characterized using MRI, MRA, and DSA. Brain AVMs were characterized histopathologically with latex dye perfusion, immunofluorescence, and Prussian blue staining. RESULTS Brains of 55 Tagln-Cre+;Alk12f/2f mutant mice were categorized into three groups: no detectable vascular lesions (group 1; 23 of 55, 42%), arteriovenous fistulas (AVFs) with no nidus (group 2; 10 of 55, 18%), and nidal AVMs (group 3; 22 of 55, 40%). Microhemorrhage was observed on MRI or MRA in 11 AVMs (50%). AVMs had the angiographic hallmarks of early nidus opacification, a tangle of arteries and dilated draining veins, and rapid shunting of blood flow. Latex dye perfusion confirmed arteriovenous shunting in all AVMs and AVFs. Microhemorrhages were detected adjacent to AVFs and AVMs, visualized by iron deposition, Prussian blue staining, and macrophage infiltration using CD68 immunostaining. Brain AVMs were stable on serial MRI and MRA in group 3 mice (mean age at initial imaging 2.9 months; mean age at last imaging 9.5 months). CONCLUSIONS Approximately 40% of transgenic mice satisfied the requirements of a stable experimental AVM model by replicating nidal anatomy, arteriovenous hemodynamics, and microhemorrhagic behavior. Transgenic mice with AVFs had a recognizable phenotype of hereditary hemorrhagic telangiectasia but were less suitable for experimental modeling. AVM pathogenesis can be understood as the combination of conditional Alk1 gene deletion during embryogenesis and angiogenesis that is hyperactive in developing and newborn mice, which translates to a congenital origin in most patients but an acquired condition in patients with a confluence of genetic and angiogenic events later in life. This study offers a novel experimental brain AVM model for future studies of AVM pathophysiology, growth, rupture, and therapeutic regression.

scholarly journals Significant Hematochezia and Intracranial Bleeding in Neonatal Hereditary Hemorrhagic Telangiectasia

2019 ◽  
Vol 09 (01) ◽  
pp. e10-e14 ◽  
Author(s):  
Matthew Merves ◽  
Kimberly Parsons ◽  
Adina Alazraki ◽  
Jonathan Meisel ◽  
Cary Sauer ◽  
...  
Keyword(s):  
High Risk ◽  
Gastrointestinal Bleeding ◽  
Intracranial Hemorrhage ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Autosomal Dominant ◽  
Clinical Course ◽  
Vascular Dysplasia ◽  
Prenatal Imaging ◽  
Delivery Options

AbstractHereditary hemorrhagic telangiectasia (HHT) is an underreported autosomal dominant vascular dysplasia. Neonatal presentations of HHT are rare, as this disorder typically presents in adolescence or beyond with epistaxis. We report a female neonate with hematochezia on the 1st day of life secondary to multiple gastrointestinal arteriovenous malformations (AVMs) along with intracranial hemorrhage. We describe her clinical course and management, as well as her novel family mutation in ENG. This is the first reported HHT case with significant gastrointestinal bleeding in the newborn. We review neonatal HHT and raise the consideration for more directed prenatal imaging and delivery options for fetuses at high risk of HHT.

Sign in / Sign up

Export Citation Format

Share Document