Abnormal Collateral Vessels Research Articles

Abstract #1395609: Moyamoya Syndrome in a Patient with Thyroid Storm; Role of Plasmapheresis?

Moyamoya syndrome is a rare cerebrovascular disorder that can be associated with Graves’ disease. We are presenting a case of young woman with Graves’ disease who developed acute neurologic symptoms. She was treated with plasmapheresis and developed cerebral edema after one procedure. A 28-year-old Hispanic female with 3 years history of Graves’ disease presented to ER with worsening symptoms of thyrotoxicosis. She was not taking antithyroid medications for the previous months. She was admitted for severe hyperthyroidism symptoms. Antithyroid medication was resumed on admission. A day later she developed sudden weakness of the right upper and lower extremities, then she became unresponsive. TSH was < 0.007 uIU/mL [0.36-3.7 mIU/mL], free T4 >8.0 ng/dl [0.76-1.46 ng/dl], total T3 2.75 ng/mL [0.6-1.8 ng/mL]. Brain imaging demonstrated occlusion of the right and left internal carotid arteries consistent with the diagnosis of Moyamoya disease. Treatment for thyroid storm with Propylthiouracil and steroids were initiated. The patient’s mental status did not improve, and plasmapheresis was initiated to improve her symptoms and neurologic outcome. Patient was hemodynamically stable during plasmapheresis with no signs of fluid shift. Several hours after the 1st session, the patient neurologically deteriorated, pupils were fixed and dilated, and corneal reflex was negative. Repeated brain imaging showed cerebral herniation, which ultimately led to brain death. Moyamoya disease is an isolated vascular disorder and a rare cause of stroke. It involves endothelial hyperplasia and narrowing of the proximal portion of the internal carotid arteries, leading to development of abnormal collateral vessels. There are several studies correlating increased thyroid hormone and auto-antibody levels with Moyamoya disease. Therapeutic plasma exchange is used to achieve rapid improvement in symptoms due to the long half-life of thyroid hormones and to eliminate the autoantibodies. It is considered a safe procedure with low incidence of adverse events. However, in patients with severe comorbidities, especially those in the intensive care unit (ICU), the prevalence of adverse events during plasmapheresis is reported to be higher. In this case, no water imbalance was reported during the procedure, and it is unknown whether the plasmapheresis played a role in cerebral edema and herniation. In general, Plasmapheresis is considered a relatively safe for patients hospitalized in ICU in literature reviews, with no reports of cerebral edema as a complication of plasmapheresis in these literatures. However, close monitoring of patients in the ICU is essential for procedure-related safety.

Does Advanced Imaging Aid in the Preoperative Evaluation of Patients With Moyamoya Disease?

Background Moyamoya disease is characterized by progressive nonatherosclerotic stenosis and eventual occlusion of the supraclinoid cerebral arteries with the associated development of abnormal collateral vessels. Treatment of moyamoya disease revolves around restoring cerebral blood flow (CBF) distal to the steno-occlusive disease. Numerous modalities can be used to assess hemodynamic parameters. We sought to determine the impact of preoperative imaging on surgical decision-making. Methods A retrospective review was performed of all patients seen with the diagnosis of moyamoya. Patients were grouped on presentationbased on CT/MRI findings of infarction, hemorrhage, or normal. Patients who did not have all of the preoperative tests were excluded. Preoperative radiological results were dichotomized as either normal or abnormal. Results During a five-year period, 34 patients with moyamoya met the inclusion criteria. All patients had an abnormal magnetic resonance angiography (MRA) Non-invasive Optimal Vessel Analysis (NOVA; VasSol, Inc, River Forest, IL). Three patients had normal initial MRI. All symptomatic patients had abnormal preoperative workup and underwent revascularization, as all were found to have abnormal single photon emission computed tomography (SPECT). The only occasion where the decision for surgery or type of surgery was influenced by imaging findings was in patients with nonclassical or minimal symptoms. Conclusion Although hemodynamic imaging studies can aid in establishing a preoperative baseline of CBF and cerebral vascular reserve (CVR) for follow-up studies, the true implication of these tests in the preoperative evaluation of clearly symptomatic moyamoya patients is debatable. In asymptomatic/mildly symptomatic patients, hemodynamic studies are necessary to determine the need for treatment. For symptomatic patients, surgery can be performed without an exhaustive and costly preoperative hemodynamic evaluation.

A Magnetic Resonance Angiography-Based Study Comparing Machine Learning and Clinical Evaluation: Screening Intracranial Regions Associated with the Hemorrhagic Stroke of Adult Moyamoya Disease

ObjectivesMoyamoya disease patients with hemorrhagic stroke usually have a poor prognosis. This study aimed to determine whether hemorrhagic moyamoya disease could be distinguished from MRA images using transfer deep learning and to screen potential regions that contain rich distinguishing information from MRA images in moyamoya disease. Materials and methodsA total of 116 adult patients with bilateral moyamoya diseases suffering from hemorrhagic or ischemia complications were retrospectively screened. Based on original MRA images at the level of the basal cistern, basal ganglia, and centrum semiovale, we adopted the pretrained ResNet18 to build three models for differentiating hemorrhagic moyamoya disease. Grad-CAM was applied to visualize the regions of interest. ResultsFor the test set, the accuracies of model differentiation in the basal cistern, basal ganglia, and centrum semiovale were 93.3%, 91.5%, and 86.4%, respectively. Visualization of the regions of interest demonstrated that the models focused on the deep and periventricular white matter and abnormal collateral vessels in hemorrhagic moyamoya disease. ConclusionA transfer learning model based on MRA images of the basal cistern and basal ganglia showed a good ability to differentiate between patients with hemorrhagic moyamoya disease and those with ischemic moyamoya disease. The deep and periventricular white matter and collateral vessels at the level of the basal cistern and basal ganglia may contain rich distinguishing information.

Dynamic Changes of Collateral Vessels After Encephaloduroarteriosynangiosis in Moyamoya Disease: Childhood to Adulthood

Moyamoya disease (MMD) often presents as ischemic stroke in pediatric patients and hemorrhage in adults. This situation raises questions as to whether the phenotype of moyamoya disease changes with age. We performed self-precontrol and postcontrol observation monitoring until adulthood on abnormal collateral vessels (ACVs) with the potential risk of bleeding to evaluate the chance of further hemorrhage. Fifteen pediatric patients with >10 years angiography-based follow-up were analyzed. The Matsushima grades were divided into 2 groups (good group, representing Matsushima stage A; and mild group, representing Matsushima stages B and C) to investigate the relationship between Matsushima grades and ACVs derived from vessels likely to cause intracranial hemorrhage. Four patients (26.7%) had infarction type and 11 (73.3%) patients had transient ischemic attack type. No patient experienced late-onset cerebral hemorrhagic events. One patient experienced recurrent ischemic stroke 6 months after the second surgery and recovered completely after the third surgery. The angiography-based follow-up was conducted at least 10 years after theencephaloduroarteriosynangiosis (EDAS). The good Matsushima group showed a significant positive correlation with the reduction of the anterior choroidal artery (odds ratio, 56.00; P= 0.003), whereas the posterior communicating artery showed no significant decrease before and after the EDAS procedure (odds ratio, 2.00; P= 1.00). The EDAS procedure can effectively attenuate the dilation and ACVs of the anterior choroidal artery, which may reduce the incidence of further hemorrhage in adulthood.

Moyamoya Disease in a Young Female With Neurofibromatosis Type 1

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive stenosis of the terminal portions of the internal carotid arteries (ICAs) and the development of a network of abnormal collateral vessels. This case depicts a 25-year-old African American female patient with neurofibromatosis type 1 (NF-1), whose initial hospital presentation occurred in a hypertensive emergency setting. Surveillance studies with magnetic resonance imaging (MRI) revealed multiple asymptomatic right cortical strokes. Genetic testing evidenced a novel, unique pathogenic variant on the NF-1 gene. The patient underwent combined bypass surgery first and then was placed on aspirin and a blood pressure control regimen. Our case illustrates the need for clinicians to include moyamoya disease in the list of differential diagnoses when encountering a young patient, without major risk factors, presenting with ischemic stroke. It should be considered even with no known history of previously diagnosed MMD or NF-1, as these pathologies may have yet to be evaluated in subclinical cases.

Headache as unusual presentation in moyamoya disease

Our case highlights basics of clinical presentations, causes, risk factors, epidemiology, physiology, and pathophysiology in Moyamoya diseases, along with introduction to terminologies, prospect of evaluation and various modalities available for diagnosis. Moyamoya angiopathy is characterized by a progressive stenosis of the terminal portion of the internal carotid arteries and the development of a network of abnormal collateral vessels. This chronic cerebral angiopathy is observed in children and adults. It mainly leads to brain ischemic events in children, and to ischemic and hemorrhagic events in adults. This is a rare condition, with a marked prevalence gradient between Asian countries and Western countries. Two main nosological entities are identified. On the one hand, moyamoya disease corresponds to isolated moyamoya angiopathy, defined as being “idiopathic” according to the Guidelines of the Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis. This entity is probably multifactorial and polygenic in most patients. On the other hand, moyamoya syndrome is a moyamoya angiopathy associated with an underlying condition and forms a very heterogeneous group with various clinical presentations, various modes of inheritance, and a variable penetrance of the cerebrovascular phenotype. Diagnostic and evaluation techniques rely on magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) conventional angiography, and cerebral hemodynamics measurements. Revascularization surgery can be indicated, with several techniques. Characteristics of genetic moyamoya syndromes are presented, with a focus on recently reported mutations in BRCC3/MTCP1 and GUCY1A3 genes. Identification of the genes involved in moyamoya disease and several monogenic moyamoya syndromes unravelled different pathways involved in the development of this angiopathy. Studying genes and pathways involved in monogenic moyamoya syndromes may help to give insights into pathophysiological models and discover potential candidates for medical treatment strategies.

S2193 Splenic Artery Collaterals Masquerading as Gastric Varices: An Uncommon Cause of Massive Upper GI Bleed

INTRODUCTION: Upper gastrointestinal bleeding (UGIB) is most commonly due to peptic ulcer disease (PUD). However in patients with splenic artery thrombosis, collateral arterial vessels can develop. If these abnormal vessels erode into the stomach mucosa, massive UGIB can occur. Here we present a case of UGIB from submucosal splenic collateral arteries. CASE DESCRIPTION/METHODS: A 56 year old male with history of Factor 5 Leiden and antiphospholipid antibody syndrome (APLS) presented with melena and hematemesis. Esophagogastroduodenoscopy (EGD) showed possible gastric varices in the fundus with an area of ulceration (Figure 1). The patient’s prior history of heavy alcohol use and the presence of a nodular liver on CT scan suggested underlying cirrhosis and portal hypertension as the etiology for the gastric varices. However the patient was found to have a low hepatic venous pressure gradient (2 mmHg) and a subsequent liver biopsy did not reveal cirrhosis. The splenic vein was also noted to be patent on CT scan. Several days after admission, the patient experienced another episode of hematemesis with associated hypotension and tachycardia. CT angiogram at the time did not reveal any active bleeding, but did show a splenic artery thrombosis with several collateral vessels. Subsequent angiogram demonstrated large arterial collaterals in the gastric fundus with outflow to the spleen, bypassing the occluded splenic artery (Figure 2). These collateral vessels were embolized successfully and he had no further bleeding. DISCUSSION: This case highlights the importance of multidisciplinary patient care and careful assessment of a patient’s medical history and anatomy to accurately diagnose and treat underlying pathology. While our patient was thought to have varices on EGD, he did not have cirrhosis, splenic vein thrombosis or portal hypertension which made the diagnosis of gastric varices unlikely. However, he did have a splenic artery thrombosis due to underlying APLS which led to the formation of submucosal gastric arterial collateral vessels and UGIB. Submucosal arterial collateral vessels are a rare cause of UGIB and there are only a few cases described in the literature. They can form as a result of splenic artery thrombosis due to underlying coagulopathy, pancreatitis, abdominal trauma or congenital absence of the splenic artery. If these abnormal collateral vessels erode through the stomach mucosa, they can lead to UGIB. Treatment involves surgery (partial gastrectomy and splenectomy) or embolization.Figure 1.: Possible gastric varix in the stomach fundus with an area of ulceration seen on EGD.Figure 2.: Angiogram demonstrating large arterial collaterals in the gastric fundus with outflow to the spleen, bypassing an occluded splenic artery.

Intracranial arterial stenosis associated with Hashimoto\u2019s disease: angiographic features and clinical outcomes

BackgroundHashimoto’s disease has reportedly been associated with stroke; however, cerebrovascular morphology and clinical course remain poorly documented. The present study aimed to determine the angiographic features and clinical outcomes of intracranial arterial stenosis (IAS) associated with Hashimoto’s disease in a retrospective cohort.MethodsOverall, 107 adult patients with IAS were screened for anti-thyroid antibodies; of these, 26 patients tested positive. The 42 affected hemispheres were classified into subgroups according to the steno-occlusion site and the development of abnormal collateral (moyamoya) vessels. These subgroups were dichotomized into moyamoya vessels positive (MM type) and negative (non-MM type). The initial presentation, IAS progression, and vascular events during the follow-up period were compared.ResultsThe following sites of stenosis were identified: the bifurcation of the internal carotid artery in 11 (26.2%), M1 or A1 in 29 (69.0%), and more distal (M2-M4/A2-A4) in 2 (4.8%) hemispheres. Further, 17 hemispheres were categorized into the MM type and 25 were classified into the non-MM type. During the follow-up period (mean 2.5 years), IAS progression was identified in 8 (32%) hemispheres of the non-MM type and 0 (0%) hemispheres of the MM type (p = 0.041). Ischemic attacks occurred in 5 (20.0%) hemispheres of the non-MM type (4.6%/year) and 0 hemispheres of the MM type (p = 0.08). Further, 4 (23.5%) hemispheres of the MM type experienced intracerebral hemorrhage, whereas none of the non-MM type hemorrhaged (p = 0.012).ConclusionsHashimoto’s disease-associated IAS exhibits various angiographic morphologies, resulting in different clinical presentations. Screening for anti-thyroid antibodies and careful management based on vascular morphology appears important in adults with IAS.

Significance of Serum Angiopoietin-2 in Patients with Hemorrhage in Adult-Onset Moyamoya Disease.

Background Moyamoya disease (MMD) is a progressive occlusive cerebrovascular disease that is characterized by abnormal angiogenesis at the base of the brain. This pathological abnormal angiogenesis is susceptible to disturbances, including spontaneous hemorrhage and vasogenic edema. However, the underlying mechanisms of pathological angiogenesis and occurrence of hemorrhage are unclear. Angiopoietins play a fundamental role in the pathophysiology of central nervous system disorders in angiogenesis. This study was aimed at examining whether angiopoietins are associated with formation of abnormal collateral vessels and the occurrence of hemorrhage in adult-onset moyamoya disease (HMMD). Methods A total of 27 consecutive adult patients with HMMD were enrolled from June 2011 to May 2017. Serum levels of angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) were examined by enzyme-linked immunosorbent assay. Patients with HMMD were compared with those with spontaneous hemorrhage (controls) and nonhemorrhagic-onset MMD (NHMMD). Results Serum Ang-2 levels were significantly higher in patients with adult HMMD than in those with spontaneous hemorrhage and NHMMD. The ROC curve identified that a baseline serum Ang-2 level > 1230 ng/ml may be associated with adult HMMD with 88.39% sensitivity and 70.37% specificity (area under the curve (AUC), 0.89; 95% CI, 0.808-0.973; P < 0.001). Moreover, serum Ang-2 levels were significantly elevated in stages II, III, and IV. In subgroup analysis of a high and low degree of moyamoya vessels, serum Ang-2 levels were significantly higher in the high moyamoya vessel group than in the low moyamoya vessel group. Serum Ang-2 levels were also significantly higher in the low moyamoya vessel group compared with the control group. Serum Ang-1 levels were not significantly different among the groups. Conclusion Increased serum Ang-2 levels may contribute to pathological abnormal angiogenesis and/or to the instability of vascular structure and function, thus causing brain hemorrhage in adult HMMD.

Clinical Characteristics of Moyamoya Angiopathy in a Pediatric Cohort.

Moyamoya angiopathy is a rare cerebral vasculopathy characterized by a progressive stenosis of the terminal portion of the internal carotid arteries and the development of abnormal collateral vessels. Children with moyamoya angiopathy become symptomatic because of cerebral ischemic complications, and many patients eventually need revascularization. In most pediatric patients with this disease, the etiology is likely genetic. We aim to report clinical characteristics of a single-center cohort of pediatric patients with moyamoya. We performed a retrospective chart review of patients <18 years with angiographically confirmed moyamoya disease evaluated at our institution. An in-house text search tool, Advanced Cohort Explorer, was used to filter electronic medical records for patients with a diagnosis of moyamoya angiopathy from January 1999 to December 2018. The inclusion criteria were age <18 years at the time of onset of disease and a diagnosis confirmed at Mayo clinic. Fifty-one patients met the inclusion criteria. Fifty-five percent of our cohort were male, and the median age was 9 years. Three patients had a family history of moyamoya disease. Approximately half of our patients had bilateral disease. Sixteen patients had a genetic or chromosomal diagnosis (Down syndrome and NF1 being most common). Congenital anomalies like heart defects and renal dysplasia were also noted. This study is unique in that it was a large study on pediatric patients with moyamoya angiopathy. It also highlights the importance of considering genetic syndromes as an underlying cause when moyamoya angiopathy starts early in life.

Abnormal Collateral Vessels in Behçet’s Disease Revealed by Gastrointestinal Bleeding Scintigraphy with 99mTc-RBC

Abnormal Collateral Vessels in Behçet’s Disease Revealed by Gastrointestinal Bleeding Scintigraphy with 99mTc-RBC

De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy

BackgroundMoyamoya angiopathy (MMA) is characterised by a progressive stenosis of the terminal part of the internal carotid arteries and the development of abnormal collateral deep vessels. Its pathophysiology is unknown....

Acute Chorea Onset after Hot Food Consumption in a Patient with Moyamoya Disease.

Acute Chorea Onset after Hot Food Consumption in a Patient with Moyamoya Disease.

Periventricular anastomosis in moyamoya disease: detecting fragile collateral vessels with MR angiography

OBJECT The authors' aim in this paper was to determine whether periventricular anastomosis, a novel term for the abnormal collateral vessels typical of moyamoya disease, is reliably measured with MR angiography and is associated with intracranial hemorrhage. METHODS This cross-sectional study sampled consecutive patients with moyamoya disease or moyamoya syndrome at a single institution. Periventricular anastomoses were detected using MR angiography images reformatted as sliding-thin-slab maximum-intensity-projection coronal images and were scored according to 3 subtypes: lenticulostriate, thalamic, and choroidal types. The association between periventricular anastomosis and hemorrhagic presentation at onset was evaluated using multivariate analyses. RESULTS Of 136 eligible patients, 122 were analyzed. Eighteen (14.8%) patients presented with intracranial hemorrhage with neurological symptoms at onset. Intra- and interrater agreement for rating of the periventricular anastomosis score was good (κw = 0.65 and 0.70, respectively). The prevalence of hemorrhagic presentation increased with the periventricular anastomosis score: 2.8% for Score 0, 8.8% for Score 1, 18.9% for Score 2, and 46.7% for Score 3 (p < 0.01 for trend). Univariate analysis revealed that age (p = 0.02) and periventricular anastomosis score (p < 0.01) were factors tentatively associated with hemorrhagic presentation. The score remained statistically significant after adjustment for age (OR 3.38 [95% CI 1.84-7.00]). CONCLUSIONS The results suggest that periventricular anastomosis detected with MR angiography can be scored with good intra- and interrater reliability and is associated with hemorrhagic presentation at onset in moyamoya disease. The clinical utility of periventricular anastomosis as a predictor for hemorrhage should be validated in further prospective studies.

Frequency of the moyamoya-related RNF213 p.Arg4810Lys variant in 1,516 Korean individuals.

BackgroundMoyamoya disease (MMD) is a progressive steno-occlusive vasculopathy that involves large intracranial arteries accompanied by abnormal collateral vessels. Recently, RNF213 was identified as a susceptibility gene for MMD and p.Arg4810Lys (rs112735431) is the most common variant in East Asian MMD patients. Interestingly, many studies have reported that a certain proportion of the general population in Japan, Korea, and China also has this variant. In this study, we investigated the frequency of this variant and estimated an odds ratio of MMD using two different Korean populations.MethodsA total of 1,516 anonymous DNA samples, 799 from an umbilical cord blood bank and 717 from routine health-checked adults, were genotyped using targeted Sanger sequencing.ResultsThe p.Arg4810Lys variant was detected at genotype frequencies of 2.25 % (18/799; 95 % confidence interval (CI), 1.43-3.53 %) in cord blood samples and 2.65 % (19/717; 95 % CI, 1.70-4.10 %) in adult samples, respectively. This variant showed a strong association with MMD (P < 0.001), giving an odds ratio of 162.7 (95 % CI, 65.5–403.9) and 137.8 (95 % CI, 55.8–339.9) based on the cord blood and adults samples, respectively.ConclusionsThese results confirm that the RNF213 p.Arg4810Lys variant is not uncommon in the general Korean population and provide reference data for the association of this variant and MMD.

Moyamoya disease-associated protein mysterin/RNF213 is a novel AAA+ ATPase, which dynamically changes its oligomeric state

Moyamoya disease is an idiopathic human cerebrovascular disorder that is characterized by progressive stenosis and abnormal collateral vessels. We recently identified mysterin/RNF213 as its first susceptibility gene, which encodes a 591-kDa protein containing enzymatically active P-loop ATPase and ubiquitin ligase domains and is involved in proper vascular development in zebrafish. Here we demonstrate that mysterin further contains two tandem AAA+ ATPase modules and forms huge ring-shaped oligomeric complex. AAA+ ATPases are known to generally mediate various biophysical and mechanical processes with the characteristic ring-shaped structure. Fluorescence correlation spectroscopy and biochemical evaluation suggested that mysterin dynamically changes its oligomeric forms through ATP/ADP binding and hydrolysis cycles. Thus, the moyamoya disease-associated gene product is a unique protein that functions as ubiquitin ligase and AAA+ ATPase, which possibly contributes to vascular development through mechanical processes in the cell.

Abstract 2786: Moyamoya Syndrome Associated With Graves' Disease: Report Of 16 Cases

Background and purpose Moyamoya disease is a cerebrovascular disorder characterized by bilateral progressive stenosis and occlusion of terminal portions of internal carotid artery (ICA) accompanying by typical net-like collateral vessels. Patients with both the characteristic moyamoya vasculopathy and the associated conditions are categorized as moyamoya syndrome. These conditions include sickle cell disease, neurofibromatosis type 1, Down’s disease, cranial therapeutic irradiation and other rare diseases. Moyamoya syndrome associated with Graves’ disease has been rarely reported and the underlying coexisting mechanism remains unclear. The aim of this study is to identify the clinical and radiological findings of the patients with simultaneous diagnosis of moyamoya syndrome and Graves’ disease. Possible mechanisms predisposing these individuals to ischemic accidents are discussed. Methods We retrospectively identified 12 patients in Peking Union Medical College Hospital and 4 patients in 307 hospital of PLA between May 2000 and December 2010. All patients were female and mean age (range) was 35.13±12.34 years (11-57 years). The patients were diagnosed with Graves’ disease in endocrinology clinic which meet the full diagnostic criteria and no atherosclerotic factor was found in them. Moyamoya vasculopathy was definitely or probably diagnosed by digital subtract angiography or magnetic resonance angiography. The clinical characteristics and prognosis, laboratory data, vascular radiological characteristics were all collected. Results Stenosis or occlusion of bilateral distal ICA and/or proximal anterior /middle cerebral arteries was found in 13 patients. Three patients had unilateral distal ICA stenosis and abnormal collateral vessels. PCA stenosis was found in 2 patients. Fifteen patients presented with infarction or transient ischemic attack and one with dizziness. Interestingly, thyroid function tests demonstrated predominantly elevated thyroxine and suppressed thyroid stimulating hormone level in 15 patients when cerebrovascular accidents occurred. All patients received antithyroid therapy and two had recurrent ischemic attack after several months of drug withdrawal. Four patients underwent revascularization procedures after normalization of their hormonal conditions in 307 Hospital of PLA and their neurologic status has remained stable during follow-up. Conclusions: Compared with classical moyamoya disease, moyamoya syndrome associated Graves’ disease more commonly presented asymmetric stenosis or occlusion and PCA lesions. Cerebrovascular hemodynamic changes attributable to thyrotoxicosis might be responsible for ischemic attack and further studies are required to verify this hypothesis.

Intracranial Vasculopathy in a Patient with Systemic Sclerosis: Atherosclerotic or Moyamoya-Like Disease?

Intracranial Vasculopathy in a Patient with Systemic Sclerosis: Atherosclerotic or Moyamoya-Like Disease?

A genome-wide association study identifies RNF213 as the first Moyamoya disease gene

Moyamoya disease (MMD) shows progressive cerebral angiopathy characterized by bilateral internal carotid artery stenosis and abnormal collateral vessels. Although ∼ 15% of MMD cases are familial, the MMD gene(s) remain unknown. A genome-wide association study of 785,720 single-nucleotide polymorphisms (SNPs) was performed, comparing 72 Japanese MMD patients with 45 Japanese controls and resulting in a strong association of chromosome 17q25-ter with MMD risk. This result was further confirmed by a locus-specific association study using 335 SNPs in the 17q25-ter region. A single haplotype consisting of seven SNPs at the RNF213 locus was tightly associated with MMD (P = 5.3 × 10(-10)). RNF213 encodes a really interesting new gene finger protein with an AAA ATPase domain and is abundantly expressed in spleen and leukocytes. An RNA in situ hybridization analysis of mouse tissues indicated that mature lymphocytes express higher levels of Rnf213 mRNA than their immature counterparts. Mutational analysis of RNF213 revealed a founder mutation, p.R4859K, in 95% of MMD families, 73% of non-familial MMD cases and 1.4% of controls; this mutation greatly increases the risk of MMD (P = 1.2 × 10(-43), odds ratio = 190.8, 95% confidence interval = 71.7-507.9). Three additional missense mutations were identified in the p.R4859K-negative patients. These results indicate that RNF213 is the first identified susceptibility gene for MMD.

Genetics of Moyamoya disease

Moyamoya disease (MMD) is a disease pattern consisting of bilateral stenosis of the intracranial internal carotid arteries (ICA) accompanied by a network of abnormal collateral vessels that bypass the stenosis. Once symptomatic, insufficient cerebral blood flow or rupture of the fragile collaterals may cause stroke or hemorrhage, resulting in severe neurological dysfunction or death. The etiology of MMD is still unknown, although few associations with other diseases and environmental factors have been described. Strong regional differences in epidemiological data, as well as known familial cases, turned the focus to genetics for the insight into the disease's pathogenesis. Thus far, several reports have suggested specific genetic loci and individual genes as predisposing to MMD, but none have demonstrated reproducible results in independent cohorts. Small sample sizes, as well as a likely multifactorial origin, seem to be the most challenging tasks in identifying the disease-causing mechanisms. Once identified, susceptibility genes may allow preventive screening and a possible development of novel therapeutic options.