Deciphering impact of single nucleotide polymorphisms on cotranscriptional modification in CCM gene mRNAs.

Novel insights on regulation of gene expression mechanisms highlight the pivotal role of epitranscriptomic modifications on decision about transcript fate. These modifications include methylation of adenosine and cytosine in RNA molecules. Impairment of the normal epitranscriptome profile was observed in several pathological conditions, such as cancer and neurodegeneration. However, it is still unknown if alteration of this regulatory mechanism can be involved in cerebral cavernous malformation (CCM) development. CCM is a rare genetic condition affecting brain microvasculature, resulting from mutations in the three genes KRIT1, CCM2, and PDCD10. By data integration of association study, in silico prediction, and gene expression analysis, we evaluated role of single nucleotide polymorphisms (SNPs) highly recurrent in patients with CCM, on CCM gene expression regulation. Results showed that several of these SNPs lead to a drastic downexpression, in KRIT1 and CCM2 genes and this downregulation can be due to alteration of epitranscriptome profile, occurring these SNPs in gene regions that are subject to epitranscriptome modifications. These data suggest that this novel mechanism of gene expression regulation can be consider to further investigation on CCM pathogenesis.

Editome landscape of CCM-derived endothelial cells.

By regulating several phases of gene expression, RNA editing modifications contribute to maintaining physiological RNA expression levels. RNA editing dysregulation can affect RNA molecule half-life, coding/noncoding RNA interaction, alternative splicing, and circular RNA biogenesis. Impaired RNA editing has been observed in several pathological conditions, including cancer and Alzheimer's disease. No data has been published yet on the editome profile of endothelial cells (ECs) isolated from human cerebral cavernous malformation (CCM) lesions. Here, we describe a landscape of editome modifications in sporadic CCM-derived ECs (CCM-ECs) by comparing editing events with those observed in human brain microvascular endothelial cells (HBMECs). With a whole transcriptome-based variant calling pipeline, we identified differential edited genes in CCM-ECs that were enriched in pathways related to angiogenesis, apoptosis and cell survival, inflammation and, in particular, to thrombin signalling mediated by protease-activated receptors and non-canonical Wnt signalling. These pathways, not yet associated to CCM development, could be a novel field for further investigations on CCM molecular mechanisms. Moreover, enrichment analysis of differentially edited miRNAs suggested additional small noncoding transcripts to consider for development of targeted therapies.

Vis-à-vis: a focus on genetic features of cerebral cavernous malformations and brain arteriovenous malformations pathogenesis.

Cerebrovascular malformations include a wide range of blood vessel disorders affecting brain vasculature. Neuroimaging differential diagnosis can result unspecific due to similar phenotypes of lesions and their deep localization. Next-generation sequencing (NGS) platforms simultaneously analyze several hundreds of genes and can be applied for molecular distinction of different phenotypes within the same disorder's macro-area. We discuss about the main criticisms regarding molecular bases of cerebral cavernous malformations (CCM) and brain arteriovenous malformations (AVM), highlighting both common pathogenic aspects and genetic differences leading to lesion development. Many recent studies performed on human CCM and AVM tissues aim to detect genetic markers to better understand molecular bases and pathogenic mechanism, particularly for sporadic cases. Several genes involved in angiogenesis show different expression patterns between CCM and AVM, and these could represent a valid starting point to project a NGS panel to apply for differential cerebrovascular malformation diagnosis.

Introducing the concept of "CSF-shift edema" in traumatic brain injury.

Brain edema after severe traumatic brain injury (TBI) plays an important role in the outcome and survival of injured patients. It is also one of the main targets in the therapeutic approach in the current clinical practice. To date, the pathophysiology of traumatic brain swelling is complex and, being that it is thought to be mainly cytotoxic and vasogenic in origin, not yet entirely understood. However, based on new understandings of the hydrodynamic aspects of cerebrospinal fluid (CSF), an additional mechanism of brain swelling can be considered. An increase in pressure into the subarachnoid space, secondary to traumatic subarachnoid hemorrhage, would result in a rapid shift of CSF from the cisterns, through the paravascular spaces, into the brain, resulting in an increase of brain water content. This mechanism of brain swelling would be termed as "CSF-shift edema." This "CSF-shift," promoted by a pressure gradient, leads to increased pressure inside the paravascular spaces and the interstitium of the brain, disturbing the functions of the paravascular system, with implications of secondary brain injury. Cisternostomy, an emerging surgical treatment, would reverse the direction of the CSF-shift, allowing for a decrease in brain swelling. In addition, this technique would reduce the pressure in the paravascular spaces and interstitium, leading to a recovery of the functionality of the paravascular system.

A Novel Pathophysiological Mechanism Contributing to Trigeminal Neuralgia.

Trigeminal neuralgia (TN) is a form of neuropathic pain that affects the fifth cranial nerve, the most widely distributed nerve in the head. Although TN has been associated with a variety of pathological conditions, neurovascular compression on the trigeminal nerve, as it exits the brain stem, is the most frequent reported cause. This compression provides a progressive demyelination of the nerve and a subsequent aberrant neural transmission. Although several studies have clarified some physiopathological mechanisms underlying TN, the molecular basis remains vague. Very recently the substitution of methionine 136 by valine (MET126Val) in sodium channel Nav1.6 in a case study of typical TN has suggested a new possible mechanism for TN. The findings of this new mutation provide novel information that warrants further conclusive investigations.

Erythropoietin for the Treatment of Subarachnoid Hemorrhage: A Feasible Ingredient for a Successful Medical Recipe.

Subarachnoid hemorrhage (SAH) following aneurysm bleeding accounts for 6% to 8% of all cerebrovascular accidents. Although an aneurysm can be effectively managed by surgery or endovascular therapy, delayed cerebral ischemia is diagnosed in a high percentage of patients resulting in significant morbidity and mortality. Cerebral vasospasm occurs in more than half of all patients after aneurysm rupture and is recognized as the leading cause of delayed cerebral ischemia after SAH. Hemodynamic strategies and endovascular procedures may be considered for the treatment of cerebral vasospasm. In recent years, the mechanisms contributing to the development of vasospasm, abnormal reactivity of cerebral arteries and cerebral ischemia following SAH, have been investigated intensively. A number of pathological processes have been identified in the pathogenesis of vasospasm, including endothelial injury, smooth muscle cell contraction from spasmogenic substances produced by the subarachnoid blood clots, changes in vascular responsiveness and inflammatory response of the vascular endothelium. To date, the current therapeutic interventions remain ineffective as they are limited to the manipulation of systemic blood pressure, variation of blood volume and viscosity and control of arterial carbon dioxide tension. In this scenario, the hormone erythropoietin (EPO) has been found to exert neuroprotective action during experimental SAH when its recombinant form (rHuEPO) is administered systemically. However, recent translation of experimental data into clinical trials has suggested an unclear role of recombinant human EPO in the setting of SAH. In this context, the aim of the current review is to present current evidence on the potential role of EPO in cerebrovascular dysfunction following aneurysmal subarachnoid hemorrhage.

CCM3/SERPINI1 bidirectional promoter variants in patients with cerebral cavernous malformations: a molecular and functional study.

BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular anomalies of the nervous system mostly located in the brain presenting sporadically or familial. Causes of familial forms are mutations in CCM1 (Krit1), CCM2 (MGC4607) and CCM3 (PDCD10) genes. Sporadic forms with no affected relative most often have only one lesion and no germ line mutations. However, a number of sporadic cases with multiple lesions have been reported and are indeed genetic cases with a de novo mutation or a mutation inherited from an asymptomatic parent. METHODS: Here, we performed an analysis of regulatory region of CCM genes in 60 sporadic patients, negative for mutations in coding region and intron-exon boundaries and large deletion/duplications in CCM genes by direct sequencing and MLPA. Among 5 variants identified in 851-bp region shared by CCM3 and SERPINI1 genes and acting as asymmetric bidirectional promoter, two polymorphisms c.-639 T > C/rs9853967 and c.-591 T > C/rs11714980 were selected. A case-control study was performed to analyze their possible relationships with sporadic CCMs. Promoter haplotypes activities on CCM3/SERPINI1 genes expression were tested by dual-luciferase assay. RESULTS: No variants were identified in CCM1 and CCM2 regulatory regions. In CCM3/SERPINI1 asymmetric bidirectional promoter 5 variants, 2 of them unknown and 3 corresponding to polymorphisms c.-639 T > C/rs9853967, c.-591 T > C/rs11714980 and c.-359G > A/rs9834676 were detected. While rs9853967 and rs11714980 polymorphisms fall in a critical regulatory fragment outside the minimal promoter in intergenic region, other variants had no effects on transcription factor binding according to RegRNA tool. Case-control study performed on 60 patients and 350 healthy controls showed frequencies of the mutated alleles significantly higher in the control group than in patients. Furthermore, the functional assay showed a significant reduction of CCM3 expression for C-C haplotype even more than for T-C and C-T haplotypes. In SERPINI1 direction, the reduction was not statistically significant. CONCLUSIONS: Our data indicated that rs9853967 and rs11714980 polymorphisms could be associated with a protective role in CCM disease.

Optic radiations evaluation in patients affected by high-grade gliomas: a side-by-side constrained spherical deconvolution and diffusion tensor imaging study.

INTRODUCTION: The need to improve surgical efficacy in patients affected by high-grade gliomas has led to development of advanced pre-surgical MRI-based techniques such as tractography. This study investigates pre-surgical planning of optic radiations (ORs) in patients affected by occipito-temporo-parietal high-grade gliomas, by means of constrained spherical deconvolution (CSD) and diffusion tensor imaging (DTI) tractography. METHODS: Twelve patients with occipito-temporo-parietal high-grade gliomas were recruited and analyzed using a 3 T MRI scanner. Diffusion-weighted imaging (DWI) was conducted with 64 gradient diffusion directions. OR alterations were assessed qualitatively and quantitatively to evaluate the effectiveness of CSD- and DTI-based pre-surgical planning. RESULTS: CSD-based tractography provided better qualitative evaluation of affected white matter tracts when compared to DTI; by thresholding tractographic probabilistic maps coming from all reconstructions, we detected, at the highest cutoff level, OR involvement in 75 % of patients (vs 41.67 % of patients with probabilistic DTI). Quantitative analysis of diffusion parameters revealed a statistically significant decrease in fractional anisotropy (FA) in the affected side following CSD-based reconstructions; on the contrary, DTI-based reconstructions did not show any significant quantitative alteration. CONCLUSION: Our results showed improvement in pre-surgical planning of high-grade gliomas involving ORs with use of CSD-based tractography. This technique provided more useful information regarding the white matter spatial relationship with brain neoplasm and its involvement in the glioma, when compared to DTI. Using CSD model for OR evaluation may optimize safe surgical resection margins, helping to reduce risk of post-operative visual deficits.

Embolized meningiomas: risk of overgrading and neo-angiogenesis.

Pre-operative embolization (POE) of meningiomas may induce histological changes which simulate malignancy, possibly resulting in overgrading. Aims of the present study were to identify clues to distinguish malignancy-related features from POE-related changes and to test for overgrading the grading scheme currently in use, in embolized meningiomas. In addition, we aimed to analyze whether the POE procedure may stimulate neo-angiogenesis in meningiomas. The histological features of a series of embolized meningiomas were evaluated and considered for grading assessment. In the same cases neo-angiogenesis was quantified by the evaluation of microvessel density (MVD) and correlated with the interval between POE and surgery. Necrosis and macronucleoli represented common findings in embolized meningiomas. Nonetheless, in most of the cases, necrosis showed an abrupt line of demarcation from the viable tumour tissue, and macronucleoli were restricted to peri-necrotic areas. Suggesting that these were POE-associated changes, exclusion of necrotic areas with an abrupt line of transition and focal macronucleoli from grading assessment resulted in increased specificity and positive predictive value in the identification of recurring meningiomas. In our cohort, MVD significantly increased with the time between POE and surgery, suggesting that POE procedure may induce neo-angiogenesis in meningiomas. In conclusion, a risk of overgrading there exists in embolized meningiomas, as a consequence of the frequent evidence of necrosis and prominent nucleoli in these tumours. In order to avoid overgrading, we suggest that necrosis showing an abrupt line of demarcation and focal peri-necrotic macronucleoli are not included in grading assessment. Also, caution should be used in the interpretation of MVD as a prognostic factor in embolized meningioma, as it may also result from POE procedure.

Integration of functional neuroimaging in CyberKnife radiosurgery: feasibility and dosimetric results.

OBJECT: The integration of state-of-the-art neuroimaging into treatment planning may increase the therapeutic potential of stereotactic radiosurgery. Functional neuroimaging, including functional MRI, navigated brain stimulation, and diffusion tensor imaging-based tractography, may guide the orientation of radiation beams to decrease the dose to critical cortical and subcortical areas. The authors describe their method of integrating functional neuroimaging technology into radiosurgical treatment planning using the CyberKnife radiosurgery system. METHODS: The records of all patients who had undergone radiosurgery for brain lesions at the CyberKnife Center of the University of Messina, Italy, between July 2010 and July 2012 were analyzed. Among patients with brain lesions in critical areas, treatment planning with the integration of functional neuroimaging was performed in 25 patients. Morphological and functional imaging data sets were coregistered using the Multiplan dedicated treatment planning system. Treatment planning was initially based on morphological data; radiation dose distribution was then corrected in relation to the functionally relevant cortical and subcortical areas. The change in radiation dose distribution was then calculated. RESULTS: The data sets could be easily and reliably integrated into the Cyberknife treatment planning. Using an inverse planning algorithm, the authors achieved an average 17% reduction in the radiation dose to functional areas. Further gain in terms of dose sparing compromised other important treatment parameters, including target coverage, conformality index, and number of monitor units. No neurological deficit due to radiation was recorded at the short-term follow-up. CONCLUSIONS: Radiosurgery treatments rely on the quality of neuroimaging. The integration of functional data allows a reduction in radiation doses to functional organs at risk, including critical cortical areas, subcortical tracts, and vascular structures. The relative simplicity of integrating functional neuroimaging into radiosurgery warrants further research to implement, standardize, and identify the limits of this procedure.

Advanced virtual magnetic resonance imaging (MRI) techniques in neurovascular conflict: bidimensional image fusion and virtual cisternography.

PURPOSE: The aim of this study was to evaluate the advantages and limits of virtual magnetic resonance techniques in planning surgery for microvascular decompression in patients with neurovascular conflict. MATERIALS AND METHODS: Between December 2010 and December 2011, we prospectively observed 32 patients (30 with trigeminal neuralgia and two with hemifacial spasm), with a suspected clinical diagnosis of neurovascular conflict. To assess the contact between nerve and vessel, magnetic resonance imaging (MRI) by three-dimensional (3D) constructive interference in steady state (CISS) and high-resolution MR angiography (MRA) were performed in all cases. Moreover, we performed presurgical simulation of microvascular decompression using MR two-dimensional image fusion and virtual cisternography. The neuroradiological findings were compared with the surgical findings. RESULTS: In all cases, we demonstrated the anatomical relations between cranial nerves and offending vessels with an optimal correlation between radiological and surgical patterns. CONCLUSIONS: Advanced virtual MRI techniques, such as image fusion and virtual cisternography, are able to depict the complex anatomical relationships between neural and vascular structures within the cisternal spaces of the skull base. These techniques can be considered an optimal presurgical tool to support traditional MRI evaluation of this region.

Innovative therapeutic strategies in the treatment of brain metastases.

Brain metastases (BM) are the most common intracranial tumors and their incidence is increasing. Untreated brain metastases are associated with a poor prognosis and a poor performance status. Metastasis development involves the migration of a cancer cell from the bulk tumor into the surrounding tissue, extravasation from the blood into tissue elsewhere in the body, and formation of a secondary tumor. In the recent past, important results have been obtained in the management of patients affected by BM, using surgery, radiation therapy, or both. Conventional chemotherapies have generally produced disappointing results, possibly due to their limited ability to penetrate the blood-brain barrier. The advent of new technologies has led to the discovery of novel molecules and pathways that have better depicted the metastatic process. Targeted therapies such as bevacizumab, erlotinib, gefitinib, sunitinib and sorafenib, are all licensed and have demonstrated improved survival in patients with metastatic disease. In this review, we will report current data on targeted therapies. A brief review about brain metastatic process will be also presented.

Amplification of protease-activated receptors signaling in sporadic cerebral cavernous malformation endothelial cells.

In the central nervous system, thrombin-mediated activation of protease-activated receptors (PARs) results in neuroinflammation and increased vascular permeability. These events have been linked to cancer and neurodegeneration. Endothelial cells (ECs) isolated from sporadic cerebral cavernous malformation (CCM) specimens showed dysregulation of genes involved in "thrombin-mediated PAR-1 activation" signaling. CCM is a vascular disease involving brain capillaries. In CCM, ECs show defective cell junctions. Oxidative stress and neuroinflammation play a key role in disease onset and progression. In order to confirm the possible role of thrombin pathway in sporadic CCM pathogenesis, we evaluated PARs expression in CCM-ECs. We found that sporadic CCM-ECs overexpress PAR1, PAR3 and PAR4, together with other coagulation factor encoding genes. Moreover, we investigated about expression of the three familial CCM genes (KRIT1, CCM2 and PDCD10) in human cerebral microvascular ECs, following thrombin exposure, as well as protein level. Thrombin exposure affects EC viability and results in dysregulation of CCM gene expression and, then, in decreased protein level. Our results confirm amplification of PAR pathway in CCM suggesting, for the first time, the possible role of PAR1-mediated thrombin signaling in sporadic CCM. Thrombin-mediated PARs over activation results in increased blood-brain barrier permeability due to loss of cell junction integrity and, in this context, also the three familial CCM genes may be involved.

Intradural chordoma of the Meckel's cave: a challenging differential diagnosis.

Chordomas are midline tumors that arise from embryonic remnants of the notochord and are considered to be malignant tumors because of their tendency to invade and destroy the involved bone. Cases of intradural chordomas without bone involvement have been rarely described with a predilection for prepontine location. The absence of bony invasion renders the complete excision of these tumors more feasible and is related to their better prognosis in comparison to conventional chordomas. Herein we report the first intradural chordoma arising in the Meckel's cave. The intradural location of the lesion, outside midline structures, in the absence of bone infiltration, made the differential diagnosis versus other meningeal lesions such as chordoid meningioma challenging. The intense and strong immunohistochemical expression of pan-cytokeratins, S100, cytokeratin-19 and of the notochordal marker brachyury allowed differential diagnosis toward other tumors showing chordoid morphology. The expression of brachyury, which had not been previously analyzed in intradural chordoma, definitely links the histogenesis of this neoplasia to the notochord, similar to that of conventional chordoma. We also show that, different from conventional chordoma, intradural chordoma does not express the metallo-proteinases (MMPs) -2 and -9, which may account for its indolent biological behavior.

Could nanoparticle systems have a role in the treatment of cerebral gliomas?

Malignant brain tumors are difficult to manage clinically and are associated with high rates of morbidity and mortality. Late diagnosis and the limitations of conventional therapies that may result from inefficient delivery of the therapeutic or contrast agent to brain tumors due to the blood-brain barrier and nonspecificity of the agents, are major reasons for this unsolved clinical problem. Nanotechnology involves the design, synthesis, and characterization of materials and devices that have a functional organization in at least one dimension on the nanometer scale. The nanoparticle has emerged as a potential vector for brain delivery, able to overcome the difficulties of modern strategies. Moreover, multifunctionality can be engineered into a single nanoplatform so that it can provide tumor-specific detection, treatment, and follow-up monitoring. This review reports the latest research in nanoparticle-based glioma treatment. FROM THE CLINICAL EDITOR: In recent years, nanoparticles have emerged as potential delivery vectors targeting brain tumors, including multifunctional NP-s allowing tumor-specific detection, treatment, and follow-up monitoring. This review summarizes the latest research in nanoparticle-based glioma treatment.

Imaging features of perineural and perivascular spread in rapidly progressive rhino-orbital-cerebral mucormycosis: A case report and brief review of the literature.

BACKGROUND: Rhinocerebral mucormycosis (ROCM) is an opportunistic fungal infection originating from the paranasal sinuses with extension to the brain. A delayed diagnosis can rapidly result in a poor prognosis. ROCM commonly affects patients with diabetes or immunocompromised states with a variable progression. CASE DESCRIPTION: We report the case of a 59-year old patient with an untreated diabetes who developed a ROCM with rapidly progressive neurological symptoms. From the onset of sinus pain, nasal congestion, he rapidly developed facial swelling and masticatory dysfunction. The patient underwent sinus surgery which allowed Rhizopus oryzae to be isolated. Accordingly, a systemic therapy by intensive intravenous amphotericin B was started. Nevertheless, the infection rapidly resulted in bilateral cavernous sinuses thrombosis and occlusion of the left internal carotid artery providing the subsequent patient death. CONCLUSION: Mucormycosis is a life-threatening fungal infection in diabetic and/or immunosuppressed patients. Our case demonstrates the three main mechanisms for infection spreading that are direct, perineural, and perivascular diffusion. Clear identification of the main risk factors, proper assessment of clinical features, and radiological findings may improve the chance for an early diagnosis and patient survival.

An Unusual But Possible Complication After Endoscopic Third Ventriculostomy.

BACKGROUND: We present an unusual but possible complication after ETV for the treatment of acute hydrocephalus due to malfunction of a previously implanted V-P shunt. CASE DESCRIPTION: A 12-year-old male patient was urgently operated upon by means of an endoscopic third-ventriculostomy and the positioning of a temporary external ventricular catheter because of the malfunction of a previously implanted V-P shunt; immediately after the operation, the tip of the external catheter caused an obstruction of the ostomy, which was resolved with the withdrawn of catheter for circa 1 cm, left closed and ultimately removed after 4 days. The patient did not present any further symptom and remained shunt-free at the last 2-year follow-up visit. CONCLUSIONS: One should consider such occurrence in cases of early ETV failure when a ventricular catheter is left in situ, even though temporarily.

Hirayama disease - Early MRI diagnosis of subacute medullary ischemia: A case report.

BACKGROUND: Hirayama disease (HD) is a rare, benign, and self-limiting motor neuron disorder that results in selective motor impairment of the C7-T1 myotomes. It is characterized by progressive, unilateral, or bilateral asymmetric muscle atrophy of the distal upper extremities and myelopathy. CASE DESCRIPTION: A 23-year-old male presented with bilateral atrophy of the thenar/hypothenar eminences/ interosseous muscles, plus left-hand weakness. The cervical MRI documented subacute ischemic damage of the distal cervical cord. To rule out a tumor and reduce questionable cord compression, the patient underwent a C5-C6 anterior cervical discectomy and fusion (ACDF) immediately followed by a laminectomy with durotomy and to obtain a spinal cord biopsy. When the histology confirmed focal cord ischemia consistent with HD, it was clear that both operations were unnecessary. CONCLUSION: Establishing the diagnosis of HD is based on clinical findings and MRI/flexion MR features which include the demonstration of an increased T2-weighted intramedullary cord signal, enlargement of the posterior epidural space, and segmental spinal cord atrophy. The presence of HD should be recognized as a "nonsurgical entity," and conservative nonsurgical management should be employed.

Transcriptome analysis provides new molecular signatures in sporadic Cerebral Cavernous Malformation endothelial cells.

Cerebral cavernous malformations (CCM) are lesions affecting brain capillaries that appear with a mulberry-like morphology. This shape results from the enlarged and tangled microvessels having defective endothelial cell junctions, few surrounding pericytes and dense extracellular collagen-rich matrix. Three genes KRIT1, CCM2 and PDCD10 are linked to disease onset. However, a variable percentage of patients harbour no mutations at these loci, encouraging hypothesis of further genetic factors involved in CCM pathogenesis. Here we present data obtained by transcriptome analysis on endothelial cells isolated by CCM specimens, with the aim to identify dysregulated pathways involved in lesion onset. Lesions belonged to two patients carried neither germline nor somatic mutations at the three CCM genes. By comparison with Human brain microvascular endothelial cells (HBMECs) expression profile, we identified 1325 differentially expressed genes (Bonferroni pValue <0.05) common for the two samples. Functional enrichment analysis clustered these genes in 80 terms related to neuroinflammation, extra-cellular matrix remodelling, cell junction impairment, reactive oxygen species metabolism. In addition, CCM genes expression values resulted slightly altered in only one of the two CCM endothelial cell samples when compared to HBMECs, suggesting as further genetic factors can contribute to CCM development. Following expression analysis, we suggests that the molecular shift from canonical to non-canonical Wnt pathway might be a key event in CCM pathogenesis. Moreover, our results provide novel potential genetic targets to investigate for the development of more selective therapies.

High-Throughput Sequencing to Detect Novel Likely Gene-Disrupting Variants in Pathogenesis of Sporadic Brain Arteriovenous Malformations.

Molecular signaling that leads to brain arteriovenous malformation (bAVM) is to date elusive and this is firstly due to the low frequency of familial cases. Conversely, sporadic bAVM is the most diffuse condition and represents the main source to characterize the genetic basis of the disease. Several studies were conducted in order to detect both germ-line and somatic mutations linked to bAVM development and, in this context, next generation sequencing technologies offer a pivotal resource for the amount of outputted information. We performed whole exome sequencing on a young boy affected by sporadic bAVM. Paired-end sequencing was conducted on an Illumina platform and filtered variants were validated by Sanger sequencing. We detected 20 likely gene-disrupting variants affecting as many loci. Of these variants, 11 are inherited novel variants and one is a de novo nonsense variant, affecting STK4 gene. Moreover, we also considered rare known variants affecting loci involved in vascular differentiation. In order to explain their possible involvement in bAVM pathogenesis, we analyzed molecular networks at Cytoscape platform. In this study we focus on some genetic point variations detected in a child affected by bAVM. Therefore, we suggest these novel affected loci as prioritized for further investigation on pathogenesis of bAVM lesions.