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Alexander M. Nixon, Murat Gunel and Bauer E. Sumpio

Atherosclerosis and intracranial saccular aneurysms predictably localize in areas with complex arterial geometries such as bifurcations and curvatures. These sites are characterized by unique hemodynamic conditions that possibly influence the risk for these disorders. One hemodynamic parameter in particular has emerged as a key regulator of vascular biology—wall shear stress (WSS). Variations in geometry can change the distribution and magnitude of WSS, thus influencing the risk for vascular disorders. Computer simulations conducted using patient-specific data have suggested that departures from normal levels of WSS lead to aneurysm formation and progression. In addition, multiple studies indicate that disturbed flow and low WSS predispose patients to extracranial atherosclerosis, and particularly to carotid artery disease. Conversely, in the case of intracranial atherosclerosis, more studies are needed to provide a firm link between hemodynamics and atherogenesis. The recognition of WSS as an important factor in cerebral vascular disease may help to identify individuals at risk and guide treatment options.

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Puay-Yong Ng, Daniel Huddle, Murat Gunel and Issam A. Awad

Object. The endovascular procedure can provide proximal control, suction decompression, and prompt intraoperative angiography during microsurgical clipping of aneurysms of the paraclinoid segment of the internal carotid artery (ICA). The authors assess the safety and feasibility of this method in 24 consecutive cases.

Methods. Frontotemporal craniotomy and radical pterionectomy were performed with the patient's head immobilized in a radiolucent frame while femoral artery catheterizaton was achieved. Before dural opening, a balloon catheter with a coaxial lumen was positioned and tested in the ICA, after which microsurgical exposure was completed, including intradural clinoid drilling and optic canal decompression. Trapping of the lesion was achieved by inflating the balloon and placing a temporary clip beyond the aneurysm neck. The catheter was gently aspirated to achieve suction decompression and to facilitate clip application. Intraoperative digital subtraction angiography was then performed.

Twenty-two aneurysms were larger than 10 mm, and 11 of them were giant. Six patients presented with subarachnoid hemorrhage and nine with visual symptoms. Balloon occlusion and suction decompression were performed in 16 cases (67%), and proximal control alone in 1 case. Intraoperative angiography was performed in every case. Subsequent clip readjustment was necessary in seven cases, including three cases of residual aneurysm filling and four of ICA compromise. Complete aneurysm obliteration was achieved in 20 cases, and greater than 90% obliteration in 22. One major infarct likely related to catheter thromboembolism was found. There were no instances of visual deterioration or other complications attributable to the endovascular procedure.

Conclusions. The endovascular method allows safe and reliable proximal control, suction decompression, and intraoperative angiography in microsurgical treatment of large paraclinoid aneurysms.

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Baran Yılmaz, Zafer Orkun Toktaş, Akın Akakın, Semra Işık, Kaya Bilguvar, Türker Kılıç and Murat Günel

OBJECTIVE

Brain arteriovenous malformations (AVMs) can occur in patients with hereditary hemorrhagic telangiectasia (HHT). However, brain AVM without HHT has also been reported. Using whole exome sequencing, the authors performed comprehensive genomic characterization of a 6-person Turkish family with 3 cases of brain AVM without HHT.

METHODS

Three siblings with brain AVM, one of whom also had spinal AVM, were evaluated. The parents and the fourth sibling had no AVM on cranial MRI. The authors performed a whole exome capture and Illumina sequencing on blood samples from 2 siblings with AVM.

RESULTS

An ACVRL1 heterozygous mutation (p.Lys332Glu) was identified in 2 patients via whole exome sequencing. Variant segregation was confirmed using direct Sanger sequencing.

CONCLUSIONS

Study results suggested that whole exome sequencing analysis is particularly useful in cases of locus heterogeneity and uncertain diagnostic classification schemes in patients with hereditary brain AVM.

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Ozlem Guzeloglu-Kayisli, Umit A. Kayisli, Nduka M. Amankulor, Jennifer R. Voorhees, Ozgun Gokce, Michael L. Diluna, Maxwell S. H. Laurans, Guven Luleci and Murat Gunel

Object. Molecular genetic studies of cerebral cavernous malformation (CCM) have identified three loci, CCM1–3, that can lead to CCM when mutated. Examination of the CCM1 locus established KRIT1 (Krev1 Interaction Trapped gene 1) as the CCM1 gene. Despite the identification of KRIT1 as the gene mutated in CCM1, little has been learned regarding its function. The authors recently demonstrated specific KRIT1 expression in endothelial cells. Based on this result and the fact that the CCM phenotype features defects in microvasculature, we hypothesized that KRIT1 may take an active part in normal angiogenesis.

Methods. In this study, the authors investigated the spatial and temporal expression of KRIT1 during normal vessel development and maturation by examining KRIT1 protein in both in vitro and in vivo angiogenic systems with the use of postconfluent endothelial cell cultures along with placental tissues from different developmental stages.

Conclusions. The results demonstrate that KRIT1 is expressed during capillary-like tube formation in the early stages of angiogenesis in vitro. Histological examination of placental tissue, a well-established in vivo model of angiogenesis, shows KRIT1 expression in active angiogenic and vasculogenic areas of the immature placental villi. As the placenta matures, KRIT1 expression is restricted to microvascular and small arterial endothelial cells with little or no expression seen in the intima of large vessels. It can therefore be concluded that KRIT1 is expressed during early angiogenesis by endothelial cells and may play a key role in vessel formation and/or development.

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Cemaliye B. Akyerli, Şirin Yüksel, Özge Can, E. Zeynep Erson-Omay, Yavuz Oktay, Erdal Coşgun, Ege Ülgen, Yiğit Erdemgil, Aydın Sav, Andreas von Deimling, Murat Günel, M. Cengiz Yakıcıer, M. Necmettin Pamir and Koray Özduman

OBJECTIVE

Recent studies have established that hemispheric diffuse gliomas may be grouped into subsets on the basis of molecular markers; these subsets are loosely correlated with the histopathological diagnosis but are strong predictors of clinical tumor behavior. Based on an analysis of molecular and clinical parameters, the authors hypothesized that mutations of the telomerase promoter (TERTp-mut) mark separate oncogenic programs among isocitrate dehydrogenase 1 and/or 2 (IDH) mutant (IDH-mut) and IDH wild-type (IDH-wt) diffuse gliomas independent of histopathology or WHO grade.

METHODS

Four molecular subsets of the combined statuses of IDH and TERT-promoter mutations (double mutant, IDH only, TERT only, and double negative) were defined. Differences in age, anatomical location, molecular genetics, and survival rates in a surgical cohort of 299 patients with a total of 356 hemispheric diffuse gliomas (WHO Grade II, III, or IV) were analyzed.

RESULTS

TERTp-mut were present in 38.8% of IDH-mut and 70.2% of IDH-wt gliomas. The mutational status was stable in each patient at 57 recurrence events over a 2645-month cumulative follow-up period. Among patients with IDH-mut gliomas, those in the double-mutant subset had better survival and a lower incidence of malignant degeneration than those in the IDH-only subset. Of patients in the double-mutant subset, 96.3% were also positive for 1p/19q codeletions. All patients with 1p/19q codeletions had TERTp-mut. In patients with IDH-mut glioma, epidermal growth factor receptor or phosphatase and tensin homolog mutations were not observed, and copy-number variations were uncommon. Among IDH-wt gliomas, the TERT-only subset was associated with significantly higher age, higher Ki-67 labeling index, primary glioblastoma-specific oncogenic changes, and poor survival. The double-negative subset was genetically and biologically heterogeneous. Survival analyses (Kaplan-Meier, multivariate, and regression-tree analyses) confirmed that patients in the 4 molecular subsets had distinct prognoses.

CONCLUSIONS

Molecular subsets result in different tumor biology and clinical behaviors in hemispheric diffuse gliomas.

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Daniel Duran, Philipp Karschnia, Jonathan R. Gaillard, Jason K. Karimy, Mark W. Youngblood, Michael L. DiLuna, Charles C. Matouk, Beverly Aagaard-Kienitz, Edward R. Smith, Darren B. Orbach, Georges Rodesch, Alejandro Berenstein, Murat Gunel and Kristopher T. Kahle

Vein of Galen malformations (VOGMs) are rare developmental cerebrovascular lesions characterized by fistulas between the choroidal circulation and the median prosencephalic vein. Although the treatment of VOGMs has greatly benefited from advances in endovascular therapy, including technical innovation in interventional neuroradiology, many patients are recalcitrant to procedural intervention or lack accessibility to specialized care centers, highlighting the need for improved screening, diagnostics, and therapeutics. A fundamental obstacle to identifying novel targets is the limited understanding of VOGM molecular pathophysiology, including its human genetics, and the lack of an adequate VOGM animal model. Herein, the known human mutations associated with VOGMs are reviewed to provide a framework for future gene discovery. Gene mutations have been identified in 2 Mendelian syndromes of which VOGM is an infrequent but associated phenotype: capillary malformation–arteriovenous malformation syndrome (RASA1) and hereditary hemorrhagic telangiectasia (ENG and ACVRL1). However, these mutations probably represent only a small fraction of all VOGM cases. Traditional genetic approaches have been limited in their ability to identify additional causative genes for VOGM because kindreds are rare, limited in patient number, and/or seem to have sporadic inheritance patterns, attributable in part to incomplete penetrance and phenotypic variability. The authors hypothesize that the apparent sporadic occurrence of VOGM may frequently be attributable to de novo mutation or incomplete penetrance of rare transmitted variants. Collaboration among treating physicians, patients’ families, and investigators using next-generation sequencing could lead to the discovery of novel genes for VOGM. This could improve the understanding of normal vascular biology, elucidate the pathogenesis of VOGM and possibly other more common arteriovenous malformation subtypes, and pave the way for advances in the diagnosis and treatment of patients with VOGM.

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Kaya Bilguvar, Mohamad Bydon, Fatih Bayrakli, A. Gulhan Ercan-Sencicek, Yasar Bayri, Christopher Mason, Michael L. DiLuna, Margretta Seashore, Richard Bronen, Richard P. Lifton, Matthew State and Murat Gunel

Object

Greig cephalopolysyndactyly syndrome (GCPS) is one of a spectrum of overlapping clinical syndromes resulting from mutations in the gene GLI3 on chromosome 7p. Cerebral cavernous malformation (CCM) is caused by mutations in three distinct genes, including Malcavernin (CCM2), which also maps to chromosome 7p and is located 2.8 Mbp from GLI3. The authors describe a new syndrome that combines the vascular lesions characteristic of CCM with the hallmarks of GCPS, including polydactyly, hypertelorism, and developmental delay.

Methods

The authors used high-resolution array-based comparative genome hybridization (CGH) analysis to characterize the 3 million–bp deletion on chromosome 7 that accounts for this novel clinical presentation. A 4-year-old girl presented with polydactyly, hypertelorism, and developmental delay and was also found to have multiple CCMs after suffering a seizure.

Results

Genetic analysis using array-based CGH revealed a deletion affecting multiple genes in the 7p14-13 locus, the interval that includes both CCM2 and GLI3. Quantitative real-time polymerase chain reaction (RT-PCR) on genomic DNA confirmed this genomic lesion.

Conclusions

A novel syndrome, combining features of CCM and GCPS, can be added to the group of entities that result from deleterious genetic variants involving GLI3, including GCPS, acrocallosal syndrome, Pallister–Hall syndrome, and contiguous gene syndrome. The deletion responsible for this new entity can be easily detected using either array-based chromosomal analysis or quantitative RT-PCR.

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Maxwell S. H. Laurans, Michael L. DiLuna, Dana Shin, Faheem Niazi, Jennifer R. Voorhees, Carol Nelson-Williams, Eric W. Johnson, Adrian M. Siegel, Gary K. Steinberg, Michel J. Berg, R. Michael Scott, Gioacchino Tedeschi, T. Peter Enevoldson, John Anson, Guy A. Rouleau, Christopher Ogilvy, Issam A. Awad, Richard P. Lifton and Murat Gunel

Object. A gene contributing to the autosomal-dominant cerebral cavernous malformation (CCM) phenotype, KRIT1 (an acronym for Krev Interaction Trapped 1), has been identified through linkage analysis and mutation screening. The authors collected blood samples from 68 patients with familial CCM and 138 patients with apparently sporadic CCM as well as from their families, in an effort to characterize the prevalence and spectrum of disease-causing sequence variants in the KRIT1 gene.

Methods. The authors used single-strand conformational polymorphism analysis to identify genomic variants in KRIT1, which were sequenced to determine the specific mutation. Among 43 Hispanic-American kindreds who immigrated to the southwestern US from northern Mexico, 31 share an identical founder mutation. This Q455X mutation is found in 18 (86%) of 21 persons with a positive family history and in 13 (59%) of 22 persons with apparently sporadic CCM. This mutation was not found among 13 persons with CCM who were recruited from Mexico. These findings establish the key role of a recent founder mutation in Hispanic persons with CCM who live in the US.

Although nearly all Hispanic families in the US in which there are multiple CCM cases linked to the CCM1 locus, only 13 of 25 non-Hispanic CCM-carrying families have displayed evidence of linkage to the CCM1 locus. Among these 13 families, the authors identified eight independent mutations in nine kindreds. They identified four additional mutations among 22 familial CCM kindreds with no linkage information, bringing the total number of independent mutations to 12. Inherited KRIT1 mutations were not detected among 103 non-Hispanic persons in whom a family history of CCM was rigorously excluded.

Conclusions. All mutations were nonsense mutations, frame-shift mutations predicting premature termination, or splicesite mutations located throughout the KRIT1 gene, suggesting that these are genetic loss-of-function mutations. These genetic findings, in conjunction with the clinical phenotype, are consistent with a two-hit model for the occurrence of CCM.