Dataset Information

Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation.

ABSTRACT: Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.

SUBMITTER: Duran D

PROVIDER: S-EPMC10292091 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation.

Duran Daniel D Zeng Xue X Jin Sheng Chih SC Choi Jungmin J Nelson-Williams Carol C Yatsula Bogdan B Gaillard Jonathan J Furey Charuta Gavankar CG Lu Qiongshi Q Timberlake Andrew T AT Dong Weilai W Sorscher Michelle A MA Loring Erin E Klein Jennifer J Allocco August A Hunt Ava A Conine Sierra S Karimy Jason K JK Youngblood Mark W MW Zhang Jinwei J DiLuna Michael L ML Matouk Charles C CC Mane Shrikant S Tikhonova Irina R IR Castaldi Christopher C López-Giráldez Francesc F Knight James J Haider Shozeb S Soban Mariya M Alper Seth L SL Komiyama Masaki M Ducruet Andrew F AF Zabramski Joseph M JM Dardik Alan A Walcott Brian P BP Stapleton Christopher J CJ Aagaard-Kienitz Beverly B Rodesch Georges G Jackson Eric E Smith Edward R ER Orbach Darren B DB Berenstein Alejandro A Bilguvar Kaya K Vikkula Miikka M Gunel Murat M Lifton Richard P RP Kahle Kristopher T KT

Neuron 20181218 3

Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play ...[more]

PMID: 30578106

Similar Datasets

Project description:ImportanceMajor neurological complications from the embolization of vein of Galen malformations (VOGMs) are poorly understood. We provide a detailed analysis of contributors to periprocedural neurological complications and lessons learned.ObjectiveTo assess the rate of major periprocedural neurological complications following VOGM embolization with major procedural and strategic contributors.Design, setting, and participantsThis retrospective cohort study was conducted at a quarternary referral pediatric hospital (Hospital for Sick Children; Toronto, Ontario, Canada) from January 1999 to December 2018 with a mean clinical follow-up of 44.7 months; all children with VOGM diagnosed and/or treated were eligible (n = 48). Thirty-three patients who underwent endovascular treatment were included.InterventionsEndovascular staged transarterial embolization performed in 33 patients over 91 sessions.Main outcomes and measuresThe primary outcome was the rate of periprocedural neurological complications (occurring within 1 week of embolization). The secondary outcomes were mortality, long-term neurological outcomes, and contributing anatomical and management factors to neurological complications.ResultsOf 33 patients who underwent embolization (31 boys [64.6%]; 17 girls [35.4%]; median age at first embolization, 4 months [range, 0-29 months]), 10 patients (30.3%) developed major periprocedural neurological complications. Five of these patients died. Univariate logistic regression analyses identified internal cerebral vein drainage to the main venous sac of the VOGM and use of a microcatheter with a distal outer diameter of more than 2.0F as significant predictors of poor neurological outcomes. Lessons learned from our experience include the need to assess the internal cerebral vein drainage pattern on preprocedural magnetic resonance venography, avoidance of excessive embolization into the venous sac, treatment of more distal fistulae before proximal fistulae to avoid a sump effect, and preferably use of smaller (<2.0F outer diameter) microcatheters in neonatal embolization procedures.Conclusions and relevanceIn this cohort, 10 patients with VOGM treated with embolization (30.3%) experienced major periprocedural neurological complications, half of whom died. While these outcomes are superior to historic conservative and surgical treatment results, ongoing improvements in treatment and pretreatment diagnostic approaches are needed. Awareness of the lessons learned from our experience can help to avoid similar complications in the future for this vulnerable population.

Project description:BackgroundVein of Galen aneurysmal malformation (VGAM) is a rare cerebral vascular malformation associated with significant morbidity and mortality. Newborns with VGAM without adequate treatment may develop rapidly deteriorating high output heart failure (HOHF) and are at risk for severe neurological outcomes.ObjectiveTo describe the clinical course and management of newborns with VGAM, and identify which echocardiographic and neuroradiologic factors may be associated with severe heart failure at birth and adverse short term outcomes.MethodsThis is a single center retrospective cohort study including all consecutive newborns with VGAM admitted to Gaslini Children's Hospital between 2009 and 2022. We reviewed clinical data, intensive care support, fetal and neonatal cardiologic and neuroradiologic findings and we studied the association with severe HOHF, endovascular complications and death.ResultsOut of 40 newborns, 17 (42.5%) developed severe HOHF requiring early endovascular procedures. Medical treatment was focused on the main components of HOHF by providing inotropic support and peripheral vasodilation. Pulmonary vasodilators were avoided to reduce the negative effects of pulmonary overflow and prevent vascular remodeling. Reduction of the obligatory left to right shunt through the VGAM was possible only through endovascular treatment. Fetal cardiothoracic ratio was significantly associated with severe HOHF at birth and death. Cardiologic parameters of right ventricular overload, pulmonary hypertension and systemic steal were the leading findings associated with haemodynamic compromise at birth. The mediolateral diameter of the straight or falcine sinus at its shortest section (SS-MD), and arterial pseudofeeders were significantly associated with severe HOHF at birth in prenatal and postnatal assessments. None of the postnatal echocardiographic and MRI variables, nor a higher inotropic support were associated with major periprocedural complications or death. Mortality was due to palliation for congenital severe brain damage (4/40, 10%), or major periprocedural complications (3/40, 7.5%). None of the patients died due to HOHF and multiorgan failure. Overall survival at discharge was 82.5% (33/40).ConclusionsThe complexity of neonatal VGAM pathophysiology requires a multidisciplinary approach, specialized intensive care management, and early endovascular treatment to reduce mortality and optimize clinical outcomes. Cardiologic and neuroradiologic parameters are key to define risk stratification and treatment strategies.

Project description:BackgroundOutcomes after endovascular embolization of vein of Galen malformations remain relatively poorly described.PurposeWe performed a systematic review of the literature to determine outcomes and predictors of good outcomes following endovascular treatment of vein of Galen malformations.Data sourcesWe used Ovid MEDLINE, Ovid Embase, and the Web of Science.Study selectionOur study consisted of all case series with ≥4 patients receiving endovascular treatment of vein of Galen malformations published through January 2017.Data analysisWe studied the following outcomes: complete/near-complete occlusion rates, technical complications, perioperative stroke, perioperative hemorrhage, technical mortality, all-cause mortality, poor neurologic outcomes, and good neurologic outcomes. Outcomes were stratified by age-group (neonate, infant, child). A random-effects meta-analysis was performed.Data synthesisA total of 27 series with 578 patients were included; 41.9% of patients were neonates, 45.0% of patients were infants, and 13.1% of patients were children. All-cause mortality was 14.0% (95% CI, 8.0%-22.0%). Overall good neurologic outcome rates were 62.0% (95% CI, 57.0%-67.0%). Overall poor neurologic outcome rates were 21.0% (95% CI, 17.0%-26.0%). Neonates were significantly less likely to have good neurologic outcomes than infants (48.0%; 95% CI, 35.0%-62.0% versus 77.0%; 95% CI, 70.0%-84.0%; P < .01). Treatment indications following the Bicêtre neonatal evaluation score resulted in significantly higher rates of good neurologic outcome (P = .04). Patients with congestive heart failure had significantly lower rates of good neurologic outcome (OR, 0.50; 95% CI, 0.28-0.88; P = .01).LimitationsLimitations were selection and publication biases.ConclusionsPatients receiving endovascular embolization of vein of Galen malformations experienced good long-term clinical outcomes in >60% of cases. Appropriate patient selection is key as treatment guided by the Bicêtre neonatal evaluation score was associated with improved neurologic outcomes.

Dataset Information

Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation.

Publications

Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets