{"paper_id":"28d6dd9d-bf12-4739-b63d-3ee09fa4e5e2","body_text":"Distinct Impact of RNF213 p.R4810K Genotype on Transdural Collateral Formation Across Japanese Asian and Polish Caucasian Moyamoya Patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Distinct Impact of RNF213 p.R4810K Genotype on Transdural Collateral Formation Across Japanese Asian and Polish Caucasian Moyamoya Patients Dariusz Szarek, Masaki Ito, Haruto Uchino, Katarzyna Lubkowska, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7226764/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Dec, 2025 Read the published version in Neurosurgical Review → Version 1 posted 9 You are reading this latest preprint version Abstract Interethnic differences in natural transdural collaterals—an angiographical hallmark of Moyamoya disease (MMD)—may reflect underlying genetic variation. However, comparative studies incorporating both angiographic and genetic data are limited. This study investigated differences in cerebral angioarchitecture and clinical presentation between Japanese Asian and Polish Caucasian patients with MMD, with a focus on the RNF213 p.R4810K variant, a known East Asian founder mutation. We retrospectively analyzed 94 Japanese and 33 Polish patients who underwent diagnostic cerebral angiography and RNF213 p.R4810K genotyping between 2015 and 2025. Suzuki’s angiographical stages and the presence of natural-transdural, periventricular, and posterior cerebral artery (PCA) collaterals were evaluated. Interethnic comparisons included adjustments for RNF213 p.R4810K genotype. The RNF213 p.R4810K wild-type was present in 31% of Japanese and 100% of Polish patients. A trend toward more hemorrhagic presentation in Japanese was noted (17% vs. 12%, P=0.10). Polish patients were significantly younger at diagnosis (P=0.001). Among 230 un-operated hemispheres, angiographic stages did not significantly differ (P=0.31). After adjustment, overall prevalence of natural transdural collaterals was similar (P=0.20), but significantly higher in Polish than in Japanese RNF213 wild-type patients (P=0.0098). Periventricular collaterals were significantly more common in Japanese, independent of genotype (P<0.0001). No interethnic difference was observed in PCA collaterals (P>0.99). In conclusion, Polish MMD patients exhibit more natural transdural and fewer periventricular collaterals than Japanese RNF213 wild-type patients. These differences suggest distinct mechanisms of collateral formation across ethnic groups, with implications for genotype-driven pathophysiology and clinical presentation in MMD. Moyamoya disease Collateral Circulation Ethnicity Genetic Variation RNF213 Cerebrovascular disorder Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Moyamoya disease (MMD) is a rare, progressive cerebrovascular disorder characterized by stenosis or occlusion of the internal carotid artery terminal and the development of fragile collateral networks at the base of the brain [1,2]. While MMD is recognized worldwide, its clinical features and angiographical presentation vary significantly across ethnic groups [3-5]. Notably, MMD is most prevalent in East Asia, with Japan and Korea accounting for the majority of reported cases. Genetic predisposition, particularly involving the RNF213 , plays a major role in the susceptibility of MMD, especially p.R4810K variant for Asian patients with MMD [6,7]. Approximately 70 to 80% of Japanese MMD patients harbor this founder mutation, whereas it is seldom found among Western Caucasians [4]. MMD patients with the RNF213 p.R4810K variant tend to exhibit familial aggregation, earlier disease onset, cerebral infarct at initial presentation, and involvement of posterior cerebral arteries (PCA) [6-8]. Moreover, genetic background may influence response to revascularization surgery, although this remains an area of ongoing investigation [9-12]. Despite extensive research in Asian populations, the genetic underpinnings of MMD in European Caucasians have not been clearly established [13]. A recent interethnic comparative study has revealed significant differences in angiographical features between Japanese and German patients [14]. However, few studies have directly compared natural, pre-existing transdural collateral formation via external carotid artery (ECA) system—a hallmark of MMD [15]—between Japanese Asian and Western Caucasian populations, especially after adjusting for RNF213 p.R4810K background. Therefore, we conducted a comparative study incorporating both angiographic and genetic analyses to investigate interethnic differences in cerebral angioarchitecture and clinical presentation of MMD, with a particular focus on the RNF213 p.R4810K—a well-known founder genetic variant in East Asian populations. Methods Study Design, Patient Selection, and Data Collection This study is an international collaborative and cross-sectional observation study with retrospective manner. Consecutive MMD patient cohorts, diagnosed between January 2015 and March 2025, were retrospectively collected from two international institutions where the authors affiliated. Inclusion criteria are available preoperative diagnostic catheter angiography, fulfilled concurrent diagnostic criteria of the Research Committee on Spontaneous Occlusion of the Circle of Willis, of the Ministry of Health, Labor, and Welfare, Japan [2], and available result for RNF213 p.R4810K genetic testing. Patients with quasi-MMD were included. Exclusion criteria is absence or incomplete preoperative angiography data and unavailable of the genetic testing results. Clinical data collected from patients’ records included age at diagnosis (years-of-age), age group (pediatrics: age < 18 years and adults: age of 18 years or older), sex, comorbidities (i.e., hypertension, diabetes mellitus, dyslipidemia, Down syndrome, Basedow disease, hypothyroidism, other autoimmune disease), and disease presentation (i.e., ischemic, hemorrhagic, asymptomatic, headache and epilepsy). Genetic Analysis For the genetic testing, peripheral blood samples were collected from all the participants from Japanese and Polish cohort. As described elsewhere [10], collected blood samples were subsequently analyzed for the RNF213 p.R4810K genotype (i.e., rs112735431) at Hokkaido University Hospital in accordance with the institutional review board-approved protocol. Briefly, total DNA was extracted from the peripheral blood, and Taqman single nucleotide polymorphism genotyping assay (TaqMan SNP Genotyping Assay, Catalog number 4351379, Thermo Fisher Sci. MA, USA) was employed to determine the allele type for RNF213 p.R4810K polymorphism, a known genetic risk for Asian individuals with MMD [4,6,7]. Catheter Angiography and Analysis Angiography evaluations were performed based on the features outlined in the Suzuki angiographical staging system [1] (see below) with minor modification. As Suzuki and Takaku originally described, this evaluation was primarily conducted using internal carotid artery (ICA) angiography to evaluate the antegrade blood supply to carotid terminus and its major branches—including middle cerebral artery (MCA) and anterior cerebral artery (ACA)—, then vertebral artery (VA) angiography to assess the posterior cerebral artery (PCA) circulation via vertebrobasilar system or posterior communicating artery (PcomA). The ECA circulations were separately visualized for the collateral assessment. Transdural collaterals were defined as blood supply to the cortex from branches of the ECA system or ophthalmic artery (OphA), characterized for each hemisphere according to the primary parent arteries—including, middle meningeal artery (MMA), superficial temporal artery (STA), occipital artery (OA), and ethmoidal artery (EthA) [15]. We rated them as either present or absent, as represented in Figure 1. The classification, definition of basal and periventricular collaterals—including lenticulostriate, thalamic, and choroidal PA—were based on the previously established criteria [16-18]. The development of each PA was categorized into three grades as grade 0—the perforating arteries do not dilate—, grade 1—the perforating arteries increase in caliber but provide blood flow to only their original territory—, and grade 2—the perforating arteries abnormally increase in caliber and start to provide collateral blood flow to the regions beyond their original territory— [18]. We paid special attention to whether the maximum grade 2 development was observed as represented in Figure 2. In addition, PCA-derived leptomeningeal collaterals retrogradely supplying the frontal, temporal, and parietal lobes of the ACA or MCA territories were assessed and rated as present or absent. We also evaluated anterior-to-posterior progression involving the PCA, which is known as poor prognostic factor for MMD as so-called PCA involvement [19]. All angiographical evaluations were independently performed by two authors (H.U. and M.I.) and finalized by consensus. Suzuki Angiographical Staging Overview [1] ・Stage 1 “Narrowing of the carotid fork”: Carotid fork is narrowed with absent abnormal basal moyamoya collateral networks. ・Stage 2 “Initiation of the Moyamoya”: Mild progression of stenosis at the carotid fork with dilation of intracranial arteries; early formation of moyamoya vessels is observed; ECA collaterals are basically absent (but not always). ・Stage 3 “Intensification of the Moyamoya”: Progressive stenosis of ACA and MCA with prominent development of moyamoya vessels. ・Stage 4 “Minimization of the Moyamoya”: Advanced steno-occlusive ICA, ACA and MCA with minimization of the basal moyamoya as well as gradual enlargement of ECA collaterals. As the occlusion of the ICA progresses to involve the region up to the origin of the PcomA, the PCA—which may have been visible previously—can eventually disappear from carotid angiogram. ・Stage 5 “Reduction of the Moyamoya”: Occlusion further extends downward as far as C2 or to above C3 segment of the ICA with complete disappearance of ACA and MCA and reduction of the basal moyamoya vessels. The collateral circulation from the ECA continues to increase. ・Stage 6 “Disappearance of the Moyamoya”: Complete disappearance of the ICA siphon; cerebral perfusion is maintained predominantly by collateral flow from the ECA and vertebrobasilar systems. Protocol Approval and Patient Consent Ethical approval was obtained from both the Institutional Ethics Committee at our institutions. Written informed consent was obtained from all participants (or their parent/legal guardian/next of kin) to participate in this study. Statistical Analysis Descriptive statistics were used to analyze the clinical features, including age at diagnosis, age group, sex, RNF213 p.R4810K genotype (variant or wild-type), diagnosis (MMD or quasi-MMD), comorbidities, disease presentation, Suzuki angiographical stage, transdural-, grade 2 PA-, and PCA-derived leptomeningeal collaterals, as well as the PCA involvement. Continuous variables were expressed as the mean ± standard deviation (SD), and categorical variables, including numbers with fraction of total for each experimental group, were displayed as a contingency table. To assess for differences between groups, continuous variables were compared using the Student t-test and contingency tables were analyzed using the Fisher’s exact test. All statistical analyses were performed using GraphPad Prism (version 10.4.0, Boston, MA, USA), and a value of P<0.05 was considered statistically significant. We first compared preoperative angiographical findings and clinical features between 94 Japanese Asian patients (173 affected hemispheres) and 33 Polish Caucasian patients (57 affected hemispheres). Subsequently, to account for angiographic stage and genetic background—specifically the RNF213 p.R4810K genotype—we conducted a focused comparison of natural transdural collateral formation between Japanese patients with the wild-type genotype (29 patients, 53 hemispheres) and Polish patients (33 patients, 57 hemispheres), as no RNF213 p.R4810K variant carriers were present in the Polish cohort. Given that the Japanese cohort consisted of individuals of Asian descent and the Polish cohort represented Caucasians, who differ not only genetically but also in social customs and environmental exposures, our findings may highlight broader ethnic and environmental influences on disease development and vascular remodeling in MMD. Results Clinical features in the ethnically distinct cohorts In this international, collaborative, retrospective observational study, the wild-type RNF213 p.R4810K genotype was present in 31% of Japanese Asian patients and in 100% of Polish Caucasian patients. In this study cohort, no homozygous variant with RNF213 p.R4810K genotype was present in both distinct ethnic groups. Most clinical features were similar between the groups, except for age at diagnosis, RNF213 p.R4810K variant status, and the prevalence of hypothyroidism. Regarding disease presentation, a trend toward an interethnic difference was observed (P=0.10), with hemorrhagic presentation more frequent in Japanese Asian patients (17%) than in Polish Caucasians (12%) (Table 1). After adjusting for RNF213 p.R4810K variant status, a significant difference in age at diagnosis persisted between Japanese wild-type patients and Polish wild-type patients (46±8.4 vs. 34±16 years, respectively; P=0.0004, Table 2). Preoperative Suzuki angiographical stages in the ethnically distinct cohorts Analysis of 230 affected preoperative hemispheres from 94 Japanese Asian and 33 Polish Caucasian patients revealed no significant difference in the distribution of angiographical stages between the two groups (P=0.31; Figure 3A). Further analysis of preoperative Suzuki angiographical staging, adjusted for RNF213 p.R4810K variant status, also showed no significant difference between Japanese wild-type and Polish patients (n = 53 and 57 hemispheres, respectively; P=0.26; Figure 3B). With respect to PCA involvement—an angiographical feature associated with poor prognosis in MMD—no significant interethnic difference was observed, regardless of adjustment for RNF213 p.R4810K variant status (Tables 1 and 2). Interethnic variations in natural collateral formation To assess interethnic differences in natural collateral formation among affected hemispheres not ever treated with extracranial–intracranial revascularization surgery, we evaluated the presence of transdural collaterals via the ECA system, prominent periventricular collaterals via the ICA system, and PCA-derived leptomeningeal collaterals, adjusting for Suzuki angiographical stage. As shown in Figure 4A, there was no significant interethnic difference in the prevalence of natural transdural collaterals after adjusting for angiographical stage (P=0.20). However, with additional adjustment for RNF213 p.R4810K variant status, Polish patients exhibited a significantly higher prevalence of natural transdural collaterals compared to Japanese patients with the wild-type genotype (P=0.0098; Figure 4B). In addition, as shown in the Supplementary Table and Figure, Japanese patients with the variant heterozygous genotype exhibited a significantly higher prevalence of natural transdural collaterals compared to Japanese patients with the wild-type genotype (P=0.0026). Furthermore, there was no significant difference in the prevalence of natural transdural collaterals between Polish and Japanese patients with the variant heterozygous genotype (P=0.65). In contrast, with respect to basal and periventricular collaterals, marked PA—defined by dilatation and extension of the lenticulostriate, choroidal, and thalamic perforating arteries—were significantly more common in Japanese patients, independent of RNF213 p.R4810K variant status (P<0.0001; Figure 5). No interethnic differences were observed in PCA-derived leptomeningeal collaterals (P>0.99). Taken together, as summarized in Table 3, these findings suggest that the RNF213 p.R4810K genotype contributes to interethnic differences in natural transdural collateral formation, based on comparisons between Japanese and Polish patients with the wild-type genotype. In contrast, the development of prominent periventricular collaterals appears to be influenced by ethnic background independently of RNF213 p.R4810K status, being more characteristic of Japanese patients. Meanwhile, PCA leptomeningeal collaterals demonstrated a comparable prevalence across both ethnic groups, regardless of RNF213 p.R4810K genotype. Discussion In this international, retrospective cross-sectional observational study, we found that Polish Caucasian patients with MMD exhibited a significantly higher prevalence of natural transdural collateral formation via ECA system compared to Japanese Asian patients with the wild-type RNF213 p.R4810K genotype, after adjusting for Suzuki angiographical stage (Table 3). A similar significant difference was also observed between Japanese patients with and without the p.R4810K variant (see Supplementary Table and Figure). In contrast, no significant difference was found when comparing the entire Japanese cohort with the Polish cohort, or when comparing Japanese patients harboring the heterozygous p.R4810K variant and Polish cohort. These observations suggested two key interpretations. First, the RNF213 p.R4810K variant may facilitate the development of natural transdural collaterals in Japanese Asian patients, while wild-type Japanese patients may require additional genetic or environmental cofactors. Second, in Polish Caucasian patients—none of whom carried the p.R4810K variant—other mechanisms, such as RNF213 variants other than p.R4810K, non- RNF213 genetic factors, or broader ethnic and environmental influences—may underlie the transdural collateral formation. These study highlights, we believe, are in line with 1) Japanese patients with MMD appear more prone to hemorrhagic presentation than Caucasian patients, potentially due to differing dilation patterns of periventricular collateral pathway [14], 2) the utility of preoperative angiography because transdural collaterals are present in nearly half of all preoperative arteriograms in patients with moyamoya especially in advanced disease stage, which is associated with stroke as a perioperative complication. In addition, we acknowledge the unanswered question of whether genetic and ethnic differences influence the outcomes of postoperative revascularization, particularly in terms of postoperative transdural collateral development. Although Suzuki angiographical stage distributions were similar between the Japanese and Polish cohorts, disease presentation differed: ischemic onset more frequent in Polish cohort, whereas hemorrhagic onset more common in the Japanese cohort (Table 1). Given the role of cerebral ischemia in stimulating collateral development [20-23], this difference may partly explain the higher prevalence of transdural collaterals observed in the Polish group. However, even after adjusting for both angiographical stage and RNF213 p.R4810K genotype, no significant disease presentation was observed between Polish patients and Japanese patients with the wild-type genotype (Table 2). Despite this, Polish patients still exhibited more robust transdural collateral formation, suggesting the involvement of additional biological drivers beyond ischemia alone. The clinical significance of spontaneous transdural collaterals has been previously documented [15]: (1) they are present in nearly half of preoperative arteriograms in MMD, with most commonly arising from the MMA; (2) they are more frequently observed in advanced angiographical stages; (3) their presence is associated with perioperative stroke complications; and (4) they may indicate an increased potential for indirect surgical collateral development following revascularization surgery. Previous studies have also shown that the RNF213 p.R4810K variant is associated with better development of indirect, but not direct, surgical collaterals following combined direct and indirect bypass surgery [10,11]. In addition, features such as preoperative negative remodeling of the ICA terminal portion and postoperative magnetic resonance fluid attenuation inversion recovery cortical hyperintensities have been correlated with favorable indirect bypass development [24]. While the underlying molecular mechanisms remain unclear, our present findings suggest that genetic and environmental factors likely interact to influence transdural collateral formation in MMD. These insights may contribute to the identification of novel biological drivers and could inform future strategies for risk stratification and therapeutic intervention across diverse populations. Our secondary findings revealed that prominent PA were significantly more frequent in Japanese patients, independent of RNF213 p.R4810K genotype. This observation aligns with the interethnic difference in disease presentation noted in our study, where hemorrhagic onset was more common in Japanese patients (17% in the entire cohort, 24% in patients with wild-type, and 17% in those with the variant) compared to Polish patients (12%) (see Tables 1 and 2). As previously reported [14], interethnic variations in periventricular collateral patterns may contribute to the higher susceptibility to hemorrhagic onset in Japanese patients with MMD. In contrast, we observed no interethnic differences in natural PCA-derived leptomeningeal collateral formation, regardless p.R4810K genotype. As we recently reported, PCA leptomeningeal collaterals constitute a critical collateral source in MMD, particularly in the extremely advanced stages, based on our analysis of a Japanese single-institution cohort comprising 156 patients and 280 affected hemispheres assessed with preoperative catheter angiography [25]. This is further supported by a previous study indicating that collateral channels via moyamoya vessels tend to shift longitudinally from anterior to posterior component during disease progression and aging―highlighting the increasing importance of the posterior circulation in sustaining cerebral perfusion in MMD [18]. Together, these findings suggest a consistent and potentially universal role of PCA leptomeningeal collaterals across ethnically distinct populations with MMD, in contrast to the more ethnically variable patterns seen in transdural and pronounced periventricular collateral formation. Limitations and Future Directions First, our study focused on two ethnically distinct populations―Japanese and Polish patients―representing Asian and European Caucasian descent, respectively. These groups differ not only in genetic background but also in social customs and environmental exposures. The limited inclusion of only two ethnic cohorts highlights the need for future study research involving a broader and more diverse range of populations. To our knowledge, this is the first study to investigate interethnic differences in natural transdural collateral formation in MMD with genetic analysis. However, our findings would benefit from validation through larger, multicenter, and multiethnic studies. Second, our assessment of cerebral ischemia was based on clinical presentation rather than advanced radiological metrics, such as cerebral blood flow, oxygen extraction fraction, or cerebral blood volume. As this was a retrospective international collaborative study, such imaging data were not uniformly available across cohorts. While we do not suggest omitting radiological assessment of cerebral blood flow and metabolism, we emphasize that catheter angiography remains an essential tool in the diagnostic evaluation of MMD—especially for visualizing natural pre-existing collateral pathways, which may provide important diagnostic information. Third, although we demonstrated interethnic differences in the prevalence of natural transdural collaterals and discussed potential genetic and environmental influences, our study does not directly investigate the biological mechanisms underlying collateral vessel development. Future research should focus on uncovering the molecular and cellular drivers of transdural collateral growth in MMD. Fourth, due to the retrospective, cross-sectional nature of our study, we cannot elucidate the dynamic and potentially reciprocal relationships among various types of collateral pathways—namely, transdural, basal, periventricular, and leptomeningeal routes. As the Suzuki angiographical staging system represents a chronological progression of angiographic changes in MMD [1], future prospective or longitudinal studies are necessary to map the evolution of these collateral pathways over time. Fifth, we acknowledge the unanswered question of whether genetic and ethnic differences influence the outcomes of postoperative revascularization, particularly in terms of indirect pial synangiosis. Our current study did not compare surgical outcomes between Japanese and Polish cohorts. Notably, our Japanese cohort typically underwent combined direct and indirect revascularization regardless of age [26-28], whereas Polish patients primarily received direct bypass procedures. Future prospective studies are needed to evaluate whether ethnicity or genetic background affects postoperative collateral development, particularly in response to indirect surgical techniques. Finally, we recognize that catheter angiography carries inherent risks, including arterial injury, stroke, and radiation exposure, as previously reported [14]. While such complications are rare in experienced centers, our institution in Japan has adopted an \"MRI-first\" strategy—utilizing MR imaging and MR angiography alone for preoperative diagnosis—to minimize these risks [27]. We previously reported that this approach was associated with low perioperative complication rates in pediatric patients. However, in adult patients, the incidence of hemorrhagic complications was notably higher, suggesting that detailed preoperative vascular evaluation—including assessment of basal and periventricular collaterals via catheter angiography—might be necessary for adult patients. Moreover, our data, together with prior findings, demonstrated the presence of natural, pre-existing transdural collaterals was not low. Therefore, we continue to advocate for the use of standardized cerebral angiography in all adolescent and adult patients (excluding infants, toddlers, and young children) undergoing surgical planning for MMD as routine clinical practice. This is in accordance with the Japanese clinical guidelines for the diagnosis of MMD. 2 Angiographic evaluation should include full visualization of the ICA, ECA, and posterior circulation, including the PCA and PcomA. Evaluations should encompass arterial, parenchymal, and late venous phases, with additional rotational or 3D reconstructions as needed. We acknowledge that in extremely advanced Suzuki stages―particularly in Stage 6―angiographical imaging may also depict vertebrobasilar-PcomA-derived anterior circulation extending into MCA or ACA territories, which we currently are conducting a study to investigate its clinical implication, and hope to report on the results of this work in the near future [25]. Conclusion Natural, pre-existing collateral angioarchitecture differs between Japanese Asian and Polish Caucasian MMD patients. Japanese patients more frequently exhibited prominent PA, whereas Polish patients demonstrated greater natural transdural collateral formation via the ECA system, particularly when adjusted for RNF213 p.R4810K genotype. In contrast, PCA-derived leptomeningeal collaterals were similarly developed across both ethnic groups, regardless of the RNF213 p.R4810K genotype. These findings suggest that a higher prevalence of natural transdural collaterals in the Polish patients may contribute to a lower incidence of prominent periventricular collaterals, hence leading to the interethnic difference of clinical presentation, particularly in the context of the RNF213 p.R4810K. Furthermore, genetic background may play a significant role in shaping natural collateral formation and contribute to interethnic differences in clinical and angiographical demonstration. Future prospective studies are warranted to determine whether genetic and ethnic factors also influence postoperative revascularization potential, particularly in response to indirect bypass procedures. Declarations Competing Interests: All authors declare no conflicts of interest in relation to this work. Ethics Approval: This study was approved by the institutional review board in our institutes (approval number: 023-0359, approval date: May 28, 2024 at Ethical Review Board for Life Science and Medical Research, Hokkaido University Hospital and approval number: 06/BNBO/2023, approval date: November 8, 2023 at Bioethics Committee of the Lower Silesian Medical Chamber). This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Consent to Participate: Written informed consent was obtained from all participants or the legal guardians of patients aged <18 years. Acknowledgments: The authors are grateful for substantive contributions to the research for this article to clinical biobank, clinical research and medical innovation center, Hokkaido university hospital and Eurofins GeneticLab Co., Ltd., Sapporo, Japan. 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Neurol Med Chir (Tokyo);55(3):204-209. https://doi.org/ https://doi.org/ 10.2176/nmc.oa.2014-0360 Funaki T, Takahashi JC, Yoshida K, Takagi Y, Fushimi Y, Kikuchi T, Mineharu Y, Okada T, Morimoto T, Miyamoto S. (2016) Periventricular anastomosis in Moyamoya disease: detecting fragile collateral vessels with MR angiography. J Neurosurg;124(6):1766-1772. https://doi.org/ 10.3171/2015.6.JNS15845 Yamamoto S, Hori S, Kashiwazaki D, Akioka N, Kuwayama N, Kuroda S. (2019) Longitudinal anterior-to-posterior shift of collateral channels in patients with moyamoya disease: an implication for its hemorrhagic onset. J Neurosurg;130(3):884-890. https://doi.org/10.3171/2017.9.JNS172231 Miyamoto S. Kikuchi H, Karasawa J, Nagata I, Ikota T, Takeuchi S. (1984) Delayed cerebral blood supply through the leptomeningeal anastomosis in children with Moyamoya disease. J Neurosurg;61(6):1032-1037. Kusaka N, Sugiu K, Tokunaga K, Katsumata A, Nishida A, Namba K, Hamada H, Nakashima H, Date I. (2005) Enhanced brain angiogenesis in chronic cerebral hypoperfusion after administration of plasmid human vascular endothelial growth factor in combination with indirect vasoreconstructive surgery. J Neurosurg;103(5):882-890. https://doi.org/10.3171/2017.9.JNS172231 Nishijima Y, Akamatsu Y, Weinstein PR, Liu J. (2015) Collaterals: implications in cerebral ischemic diseases and therapeutic interventions. Brain Res;1623:18-29. https://doi.org/10.1016/j.brainres.2015.03.006 Lim M, Cheshier S, Steinberg GK. (2006) New vessel formation in the central nervous system during tumor growth, vascular malformations, and Moyamoya. Curr Neurovasc Res;3(3):237-245. https://doi.org/ https://doi.org/10.1016/j.brainres.2015.03.006 Malek AM, Connors S, Robertson RL, Folkman J, Scott RM. (1997) Elevation of cerebrospinal fluid levels of basic fibroblast growth factor in Moyamoya and central nervous system disorders. Pediatr Neurosurg;27(4):182-189. https://doi.org/ 10.1159/000121249 Uchino H, Ito M, Kurisu K, Sugiyama T, Fujimura M. (2025) Association between intracranial vascular vulnerability and indirect revascularization development in Moyamoya disease. Neurosurg Rev;48(1):387. https://doi.org/10.1007/s10143-025-03544-8 Uchino H, Ito M, Fujimura M. Incidence and clinical characteristics of Moyamoya disease in advanced Suzuki disease stages. Neurol Med Chir (Tokyo). in press . Kazumata K, Ito M, Tokairin K, Ito Y, Houkin K, Nakayama N, Kuroda S, Ishikawa T, Kamiyama H. (2014) The frequency of postoperative stroke in Moyamoya disease following combined revascularization: a single-university series and systematic review. J Neurosurg.121(2):432-440. https://doi.org/10.1007/s10143-025-03544-8 Okuyama T, Kawabori M, Ito M, Sugiyama T, Kazumata K, Fujimura M. (2022) Outcomes of Combined Revascularization Surgery for Moyamoya Disease without Preoperative Cerebral Angiography. World Neurosurg;165:e446-e451. https://doi.org/10.1016/j.wneu.2022.06.067 Kurisu K, Ito M, Uchino H, Sugiyama T, Fujimura M. (2024) Long-term Outcomes of Combined Revascularization Surgery for Moyamoya Disease in the Elderly: A Single Institute Experience. Neurol Med Chir (Tokyo);64(3):108-115. https://doi.org/ 10.2176/jns-nmc.2023-0219 Tables Table 1 Clinical characteristics of Moyamoya disease patients across two distinct ethnicities enrolled in this study. Japanese entire cohort Polish P value Significance Patient, number 94 33 Age at diagnosis, years Mean, SD 43±13 34±16 0.0014 ** Age group Pediatrics:Adults 8:86 5:28 0.32 none Sex Male:Female 21:73 7:26 >0.99 none Diagnosis MMD:quasi-MMD 82:12 25:8 0.16 none RNF213 , p.R4810K Variant:Wild-type 65:29 0:33 <0.0001 **** Co-morbidities, number (%) Hypertension 33 (35%) 17 (52%) 0.10 none Diabetes mellitus 10 (11%) 5 (15%) 0.53 none Dyslipidemia 15 (16%) 3 (9.1%) 0.40 none Down syndrome 1 (1.1%) 1 (3.0%) 0.45 none Basedow disease 6 (6.4%) 0 (0%) 0.34 none Hypothyroidism 2 (2.1%) 5 (15%) 0.013 * Other autoimmune diseases 5 (5.3%) 1 (3.0%) >0.99 none Disease presentation, number (%) 0.10 none Ischemic 65 (69%) 26 (79%) Hemorrhagic 16 (17%) 4 (12%) Asymptomatic 11 (12%) 1 (3.0%) Headache 0 (0%) 2 (6.1%) Epilepsy 2 (2.1%) 0 (0%) Affected hemispheres, number 173 57 Suzuki angiographical stage, number (%) 0.31 none Stage 1 20 (12%) 2 (3.5%) Stage 2 30 (17%) 9 (16%) Stage 3 40 (23%) 15 (26%) Stage 4 48 (28%) 20 (35%) Stage 5 33 (19%) 9 (16%) Stage 6 2 (1.2%) 2 (3.5%) PCA involvement 30 (17%) 10 (18%) >0.99 none MMD: Moyamoya disease, SD: standard deviation, PCA: posterior cerebral artery *: P<0.05, **: P<0.01, ****: P<0.0001 Table 2 Clinical characteristics of Moyamoya disease between Japanese patients with RNF213 p.R4810K wild-type and Polish patients. Japanese RNF213 p.R4810K wild-type Polish P value Significance Patient, number 29 33 Age at diagnosis, years Mean, SD 46±8.4 34±16 0.00040 *** Age group Pediatrics:Adults 0:29 5:28 0.060 none Sex Male:Female 8:21 7:26 0.77 none Diagnosis MMD:quasi-MMD 25:4 25:8 0.35 none RNF213 , p.R4810K Variant:Wild-type 0:29 0:33 >0.99 none Co-morbidities, number (%) Hypertension 13 (45%) 17 (52%) 0.62 none Diabetes mellitus 5 (17%) 5 (15%) >0.99 none Dyslipidemia 5 (17%) 3 (9.1%) 0.46 none Down syndrome 0 (0%) 1 (3.0%) >0.99 none Basedow disease 3 (10%) 0 (0%) 0.10 none Hypothyroidism 1 (3.5%) 5 (15%) 0.20 none Other autoimmune diseases 2 (6.9%) 1 (3.0%) 0.60 none Disease presentation, number (%) 0.39 none Ischemic 20 (69%) 26 (79%) Hemorrhagic 7 (24%) 4 (12%) Asymptomatic 1 (3.4%) 1 (3.0%) Headache 0 (0%) 2 (6.1%) Epilepsy 1 (3.4%) 0 (0%) Affected hemispheres, number 53 57 Suzuki angiographical stage, number (%) 0.26 none Stage 1 8 (15%) 2 (3.5%) Stage 2 7 (13%) 9 (16%) Stage 3 12 (23%) 15 (26%) Stage 4 12 (23%) 20 (35%) Stage 5 12 (23%) 9 (16%) Stage 6 2 (3.8%) 2 (3.5%) PCA involvement 7 (13%) 10 (19%) 0.60 none Note that the wild-type RNF213 p.R4810K genotype was present in 100% of Polish Caucasian patients. MMD: Moyamoya disease, SD: standard deviation, PCA: posterior cerebral artery ***: P<0.001 Table 3 Comparison of angiographical stages and natural collateral formation among Polish Caucasian patients, Japanese entire cohort, and Japanese patients with RNF213 p.R4810K wild-type genotype with Moyamoya disease. Japanese entire cohort Japanese RNF213 p.R4810K wild-type Polish P value Affected hemispheres, number 173 53 57 Polish vs Japanese entire cohort Polish vs Japanese wild-type Suzuki angiographical stage, number Stage 1 20 8 2 0.31 0.26 Stage 2 30 7 9 Stage 3 40 12 15 Stage 4 48 12 20 Stage 5 33 12 9 Stage 6 2 2 2 Transdural collateral, number, percentage of total for each stage (%) Stage 1 0 (0%) 0 (0%) 0 (0%) 0.20 0.0098 ** Stage 2 5 (17%) 2 (29%) 2 (22%) Stage 3 15 (38%) 3 (25%) 7 (47%) Stage 4 25 (52%) 4 (33%) 15 (75%) Stage 5 25 (76%) 8 (67%) 8 (89%) Stage 6 1 (50%) 1 (50%) 2 (100%) Grade2 PA collateral, number, percentage of total for each stage (%) Stage 1 0 (0%) 0 (0%) 0 (0%) <0.0001 **** <0.0001 **** Stage 2 3 (10%) 3 (43%) 0 (0%) Stage 3 16 (40%) 4 (33%) 3 (20%) Stage 4 23 (48%) 4 (33%) 4 (20%) Stage 5 12 (36%) 0 (0%) 0 (0%) Stage 6 0 (0%) 0 (0%) 0 (0%) PCA collateral, number, percentage of total for each stage (%) Stage 1 2 (10%) 0 (0%) 0 (0%) >0.99 >0.99 Stage 2 22 (73%) 7 (100%) 9 (100%) Stage 3 32 (80%) 9 (75%) 12 (80%) Stage 4 47 (98%) 12 (100%) 19 (95%) Stage 5 33 (100%) 12 (100%) 8 (89%) Stage 6 2 (100%) 2 (100%) 2 (100%) **: P<0.01, ****: P<0.0001 Additional Declarations No competing interests reported. Supplementary Files SupplementTableandFigure.docx Cite Share Download PDF Status: Published Journal Publication published 18 Dec, 2025 Read the published version in Neurosurgical Review → Version 1 posted Editorial decision: Revision requested 09 Nov, 2025 Reviews received at journal 23 Sep, 2025 Reviewers agreed at journal 16 Sep, 2025 Reviews received at journal 16 Sep, 2025 Reviewers agreed at journal 15 Sep, 2025 Reviewers invited by journal 14 Sep, 2025 Editor assigned by journal 14 Sep, 2025 Submission checks completed at journal 28 Jul, 2025 First submitted to journal 27 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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07:42:13\",\"extension\":\"jpg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":532747,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eRepresentative cerebral angiographical images demonstrating transdural collateral formation via different external carotid artery branches in Moyamoya disease. (A, B): Collaterals via the ethmoidal artery (arrowheads). (C, D): Collaterals via the middle meningeal artery (arrowheads). (E, F): Collaterals via the occipital artery (arrowheads).\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"FIG1.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7226764/v1/1668c1d88cb77dc2629007f5.jpg\"},{\"id\":91962691,\"identity\":\"894bb035-ea6e-40ea-bb9d-348e6acea9a2\",\"added_by\":\"auto\",\"created_at\":\"2025-09-23 07:58:14\",\"extension\":\"jpg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":567718,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eRepresentative cerebral angiographical images demonstrating grade 2 periventricular anastomosis as marked dilation and abnormal branch extensions of the perforating arteries serving blood supply towards cerebral cortical regions. The findings on the perforators of lateral striatal (A, B), thalamoperforating (C, D), and anterior choroidal artery (E, F) were rated as grade 2 periventricular anastomosis (arrows).\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"FIG2.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7226764/v1/8316a0a692aeeb4396f8da79.jpg\"},{\"id\":91958254,\"identity\":\"43636ef6-4ec4-433a-a7d0-ef7139418708\",\"added_by\":\"auto\",\"created_at\":\"2025-09-23 07:34:13\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":54566,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eInterethnic comparison of Suzuki angiographical demonstration at the diagnosis of Moyamoya disease between the entire cohort of Japanese Asian patients and Polish Caucasian patients with Moyamoya disease (A), as well as between Japanese patients with \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K wild-type (WT) and Polish patients (B). ns: not significant\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"FIG3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7226764/v1/503a933d31464c3e5024c91f.png\"},{\"id\":91960040,\"identity\":\"4a5468de-3f6a-4b80-96e3-287c5c1a446d\",\"added_by\":\"auto\",\"created_at\":\"2025-09-23 07:42:13\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":58745,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eInterethnic comparison of natural transdural collateral formation of Moyamoya disease after adjusting for angiographical stage between the entire cohort of Japanese Asian patients and Polish Caucasian patients with Moyamoya disease (A), as well as between Japanese patients with \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K wild-type (WT) and Polish patients (B). ns: not significant, **: P\\u0026lt;0.01\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"FIG4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7226764/v1/177021e0eedaa6cc32aec59a.png\"},{\"id\":91958255,\"identity\":\"80526884-1810-420c-aa01-6df1d4800045\",\"added_by\":\"auto\",\"created_at\":\"2025-09-23 07:34:13\",\"extension\":\"png\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":53677,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eInterethnic comparison of prominent grade 2 periventricular anastomosis (PA) collateral formation of Moyamoya disease after adjusting for angiographical stage between the entire cohort of Japanese Asian patients and Polish Caucasian patients with Moyamoya disease (A), as well as between Japanese patients with \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K wild-type (WT) and Polish patients (B). ****: P\\u0026lt;0.0001\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"FIG5.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7226764/v1/04d75ae4ed90ccf032361352.png\"},{\"id\":98815038,\"identity\":\"19a672a5-7cad-4554-91b0-e1f7f65ce53b\",\"added_by\":\"auto\",\"created_at\":\"2025-12-22 16:13:15\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":2090482,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7226764/v1/c393c6f5-8ecd-4faf-ab40-4741e0b4c67e.pdf\"},{\"id\":91958256,\"identity\":\"26a0d46e-4634-4236-adae-1799a02465eb\",\"added_by\":\"auto\",\"created_at\":\"2025-09-23 07:34:13\",\"extension\":\"docx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":672575,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"SupplementTableandFigure.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7226764/v1/4d483883829ff8015b127853.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Distinct Impact of RNF213 p.R4810K Genotype on Transdural Collateral Formation Across Japanese Asian and Polish Caucasian Moyamoya Patients\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eMoyamoya disease (MMD) is a rare, progressive cerebrovascular disorder characterized by stenosis or occlusion of the internal carotid artery terminal and the development of fragile collateral networks at the base of the brain [1,2]. While MMD is recognized worldwide, its clinical features and angiographical presentation vary significantly across ethnic groups [3-5]. Notably, MMD is most prevalent in East Asia, with Japan and Korea accounting for the majority of reported cases. Genetic predisposition, particularly involving the \\u003cem\\u003eRNF213\\u003c/em\\u003e, plays a major role in the susceptibility of MMD, especially p.R4810K variant for Asian patients with MMD [6,7]. Approximately 70 to 80% of Japanese MMD patients harbor this founder mutation, whereas it is seldom found among Western Caucasians [4]. MMD patients with the \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K variant tend to exhibit familial aggregation, earlier disease onset, cerebral infarct at initial presentation, and involvement of posterior cerebral arteries (PCA) [6-8]. Moreover, genetic background may influence response to revascularization surgery, although this remains an area of ongoing investigation [9-12]. Despite extensive research in Asian populations, the genetic underpinnings of MMD in European Caucasians have not been clearly established [13]. A recent interethnic comparative study has revealed significant differences in angiographical features between Japanese and German patients [14]. However, few studies have directly compared natural, pre-existing transdural collateral formation via external carotid artery (ECA) system\\u0026mdash;a hallmark of MMD [15]\\u0026mdash;between Japanese Asian and Western Caucasian populations, especially after adjusting for \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K background. Therefore, we conducted a comparative study incorporating both angiographic and genetic analyses to investigate interethnic differences in cerebral angioarchitecture and clinical presentation of MMD, with a particular focus on the \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K\\u0026mdash;a well-known founder genetic variant in East Asian populations.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eStudy Design, Patient Selection, and Data Collection\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study is an international collaborative and cross-sectional observation study with retrospective manner. Consecutive MMD patient cohorts, diagnosed between January 2015 and March 2025, were retrospectively collected from two international institutions where the authors affiliated. Inclusion criteria are available preoperative diagnostic catheter angiography, fulfilled concurrent diagnostic criteria of the Research Committee on Spontaneous Occlusion of the Circle of Willis, of the Ministry of Health, Labor, and Welfare, Japan [2], and available result for \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K genetic testing. Patients with quasi-MMD were included. Exclusion criteria is absence or incomplete preoperative angiography data and unavailable of the genetic testing results. Clinical data collected from patients\\u0026rsquo; records included age at diagnosis (years-of-age), age group (pediatrics: age \\u0026lt; 18 years and adults: age of 18 years or older), sex, comorbidities (i.e., hypertension, diabetes mellitus, dyslipidemia, Down syndrome, Basedow disease, hypothyroidism, other autoimmune disease), and disease presentation (i.e., ischemic, hemorrhagic, asymptomatic, headache and epilepsy).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eGenetic Analysis\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eFor the genetic testing, peripheral blood samples were collected from all the participants from Japanese and Polish cohort. As described elsewhere [10], collected blood samples were subsequently analyzed for the \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K genotype (i.e., rs112735431) at Hokkaido University Hospital in accordance with the institutional review board-approved protocol. Briefly, total DNA was extracted from the peripheral blood, and Taqman single nucleotide polymorphism genotyping assay (TaqMan SNP Genotyping Assay, Catalog number 4351379, Thermo Fisher Sci. MA, USA) was employed to determine the allele type for \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K polymorphism, a known genetic risk for Asian individuals with MMD [4,6,7].\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCatheter Angiography and Analysis\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAngiography evaluations were performed based on the features outlined in the Suzuki angiographical staging system [1] (see below) with minor modification. As Suzuki and Takaku originally described, this evaluation was primarily conducted using internal carotid artery (ICA) angiography to evaluate the antegrade blood supply to carotid terminus and its major branches\\u0026mdash;including middle cerebral artery (MCA) and anterior cerebral artery (ACA)\\u0026mdash;, then vertebral artery (VA) angiography to assess the posterior cerebral artery (PCA) circulation via vertebrobasilar system or posterior communicating artery (PcomA). The ECA circulations were separately visualized for the collateral assessment. Transdural collaterals were defined as blood supply to the cortex from branches of the ECA system or ophthalmic artery (OphA), characterized for each hemisphere according to the primary parent arteries\\u0026mdash;including, middle meningeal artery (MMA), superficial temporal artery (STA), occipital artery (OA), and ethmoidal artery (EthA) [15]. We rated them as either present or absent, as represented in Figure 1. The classification, definition of basal and periventricular collaterals\\u0026mdash;including lenticulostriate, thalamic, and choroidal PA\\u0026mdash;were based on the previously established criteria [16-18]. The development of each PA was categorized into three grades as grade 0\\u0026mdash;the perforating arteries do not dilate\\u0026mdash;, grade 1\\u0026mdash;the perforating arteries increase in caliber but provide blood flow to only their original territory\\u0026mdash;, and grade 2\\u0026mdash;the perforating arteries abnormally increase in caliber and start to provide collateral blood flow to the regions beyond their original territory\\u0026mdash; [18]. We paid special attention to whether the maximum grade 2 development was observed as represented in Figure 2. In addition, PCA-derived leptomeningeal collaterals retrogradely supplying the frontal, temporal, and parietal lobes of the ACA or MCA territories were assessed and rated as present or absent. We also evaluated anterior-to-posterior progression involving the PCA, which is known as poor prognostic factor for MMD as so-called PCA involvement [19]. All angiographical evaluations were independently performed by two authors (H.U. and M.I.) and finalized by consensus.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eSuzuki Angiographical Staging Overview [1]\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e・Stage 1 \\u0026ldquo;Narrowing of the carotid fork\\u0026rdquo;: Carotid fork is narrowed with absent abnormal basal moyamoya collateral networks.\\u003c/p\\u003e\\n\\u003cp\\u003e・Stage 2 \\u0026ldquo;Initiation of the Moyamoya\\u0026rdquo;: Mild progression of stenosis at the carotid fork with dilation of intracranial arteries; early formation of moyamoya vessels is observed; ECA collaterals are basically absent (but not always).\\u003c/p\\u003e\\n\\u003cp\\u003e・Stage 3 \\u0026ldquo;Intensification of the Moyamoya\\u0026rdquo;: Progressive stenosis of ACA and MCA with prominent development of moyamoya vessels.\\u003c/p\\u003e\\n\\u003cp\\u003e・Stage 4 \\u0026ldquo;Minimization of the Moyamoya\\u0026rdquo;: Advanced steno-occlusive ICA, ACA and MCA with minimization of the basal moyamoya as well as gradual enlargement of ECA collaterals. As the occlusion of the ICA progresses to involve the region up to the origin of the PcomA, the PCA\\u0026mdash;which may have been visible previously\\u0026mdash;can eventually disappear from carotid angiogram.\\u003c/p\\u003e\\n\\u003cp\\u003e・Stage 5 \\u0026ldquo;Reduction of the Moyamoya\\u0026rdquo;: Occlusion further extends downward as far as C2 or to above C3 segment of the ICA with complete disappearance of ACA and MCA and reduction of the basal moyamoya vessels. The collateral circulation from the ECA continues to increase.\\u003c/p\\u003e\\n\\u003cp\\u003e・Stage 6 \\u0026ldquo;Disappearance of the Moyamoya\\u0026rdquo;: Complete disappearance of the ICA siphon; cerebral perfusion is maintained predominantly by collateral flow from the ECA and vertebrobasilar systems.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eProtocol Approval and Patient Consent\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eEthical approval was obtained from both the Institutional Ethics Committee at our institutions. Written informed consent was obtained from all participants (or their parent/legal guardian/next of kin) to participate in this study.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eStatistical Analysis\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eDescriptive statistics were used to analyze the clinical features, including age at diagnosis, age group, sex, \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K genotype (variant or wild-type), diagnosis (MMD or quasi-MMD), comorbidities, disease presentation, Suzuki angiographical stage, transdural-, grade 2 PA-, and PCA-derived leptomeningeal collaterals, as well as the PCA involvement. Continuous variables were expressed as the mean \\u0026plusmn; standard deviation (SD), and categorical variables, including numbers with fraction of total for each experimental group, were displayed as a contingency table. To assess for differences between groups, continuous variables were compared using the Student t-test and contingency tables were analyzed using the Fisher\\u0026rsquo;s exact test. All statistical analyses were performed using GraphPad Prism (version 10.4.0, Boston, MA, USA), and a value of P\\u0026lt;0.05 was considered statistically significant.\\u003c/p\\u003e\\n\\u003cp\\u003eWe first compared preoperative angiographical findings and clinical features between 94 Japanese Asian patients (173 affected hemispheres) and 33 Polish Caucasian patients (57 affected hemispheres). Subsequently, to account for angiographic stage and genetic background\\u0026mdash;specifically the \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K genotype\\u0026mdash;we conducted a focused comparison of natural transdural collateral formation between Japanese patients with the wild-type genotype (29 patients, 53 hemispheres) and Polish patients (33 patients, 57 hemispheres), as no \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K variant carriers were present in the Polish cohort. Given that the Japanese cohort consisted of individuals of Asian descent and the Polish cohort represented Caucasians, who differ not only genetically but also in social customs and environmental exposures, our findings may highlight broader ethnic and environmental influences on disease development and vascular remodeling in MMD.\\u003c/p\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eClinical features in the ethnically distinct cohorts\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eIn this international, collaborative, retrospective observational study, the wild-type \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K genotype was present in 31% of Japanese Asian patients and in 100% of Polish Caucasian patients. In this study cohort, no homozygous variant with \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K genotype was present in both distinct ethnic groups. Most clinical features were similar between the groups, except for age at diagnosis, \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K variant status, and the prevalence of hypothyroidism. Regarding disease presentation, a trend toward an interethnic difference was observed (P=0.10), with hemorrhagic presentation more frequent in Japanese Asian patients (17%) than in Polish Caucasians (12%) (Table 1). After adjusting for \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K variant status, a significant difference in age at diagnosis persisted between Japanese wild-type patients and Polish wild-type patients (46\\u0026plusmn;8.4 vs. 34\\u0026plusmn;16 years, respectively; P=0.0004, Table 2).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003ePreoperative Suzuki angiographical stages in the ethnically distinct cohorts\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAnalysis of 230 affected preoperative hemispheres from 94 Japanese Asian and 33 Polish Caucasian patients revealed no significant difference in the distribution of angiographical stages between the two groups (P=0.31; Figure 3A). Further analysis of preoperative Suzuki angiographical staging, adjusted for \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K variant status, also showed no significant difference between Japanese wild-type and Polish patients (n = 53 and 57 hemispheres, respectively; P=0.26; Figure 3B). With respect to PCA involvement\\u0026mdash;an angiographical feature associated with poor prognosis in MMD\\u0026mdash;no significant interethnic difference was observed, regardless of adjustment for \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K variant status (Tables 1 and 2).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eInterethnic variations in natural collateral formation\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eTo assess interethnic differences in natural collateral formation among affected hemispheres not ever treated with extracranial\\u0026ndash;intracranial revascularization surgery, we evaluated the presence of transdural collaterals via the ECA system, prominent periventricular collaterals via the ICA system, and PCA-derived leptomeningeal collaterals, adjusting for Suzuki angiographical stage. As shown in Figure 4A, there was no significant interethnic difference in the prevalence of natural transdural collaterals after adjusting for angiographical stage (P=0.20). However, with additional adjustment for \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K variant status, Polish patients exhibited a significantly higher prevalence of natural transdural collaterals compared to Japanese patients with the wild-type genotype (P=0.0098; Figure 4B). In addition, as shown in the Supplementary Table and Figure, Japanese patients with the variant heterozygous genotype exhibited a significantly higher prevalence of natural transdural collaterals compared to Japanese patients with the wild-type genotype (P=0.0026). Furthermore, there was no significant difference in the prevalence of natural transdural collaterals between Polish and Japanese patients with the variant heterozygous genotype (P=0.65). In contrast, with respect to basal and periventricular collaterals, marked PA\\u0026mdash;defined by dilatation and extension of the lenticulostriate, choroidal, and thalamic perforating arteries\\u0026mdash;were significantly more common in Japanese patients, independent of \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K variant status (P\\u0026lt;0.0001; Figure 5). No interethnic differences were observed in PCA-derived leptomeningeal collaterals (P\\u0026gt;0.99). Taken together, as summarized in Table 3, these findings suggest that the \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K genotype contributes to interethnic differences in natural transdural collateral formation, based on comparisons between Japanese and Polish patients with the wild-type genotype. In contrast, the development of prominent periventricular collaterals appears to be influenced by ethnic background independently of \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K status, being more characteristic of Japanese patients. Meanwhile, PCA leptomeningeal collaterals demonstrated a comparable prevalence across both ethnic groups, regardless of \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K genotype.\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eIn this international, retrospective cross-sectional observational study, we found that Polish Caucasian patients with MMD exhibited a significantly higher prevalence of natural transdural collateral formation via ECA system compared to Japanese Asian patients with the wild-type \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K genotype, after adjusting for Suzuki angiographical stage (Table 3). A similar significant difference was also observed between Japanese patients with and without the p.R4810K variant (see Supplementary Table and Figure). In contrast, no significant difference was found when comparing the entire Japanese cohort with the Polish cohort, or when comparing Japanese patients harboring the heterozygous p.R4810K variant and Polish cohort. These observations suggested two key interpretations. First, the \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K variant may facilitate the development of natural transdural collaterals in Japanese Asian patients, while wild-type Japanese patients may require additional genetic or environmental cofactors. Second, in Polish Caucasian patients\\u0026mdash;none of whom carried the p.R4810K variant\\u0026mdash;other mechanisms, such as \\u003cem\\u003eRNF213\\u003c/em\\u003e variants other than p.R4810K, non-\\u003cem\\u003eRNF213\\u003c/em\\u003e genetic factors, or broader ethnic and environmental influences\\u0026mdash;may underlie the transdural collateral formation. These study highlights, we believe, are in line with 1) Japanese patients with MMD appear more prone to hemorrhagic presentation than Caucasian patients, potentially due to differing dilation patterns of periventricular collateral pathway [14], 2) the utility of preoperative angiography because transdural collaterals are present in nearly half of all preoperative arteriograms in patients with moyamoya especially in advanced disease stage, which is associated with stroke as a perioperative complication. In addition, we acknowledge the unanswered question of whether genetic and ethnic differences influence the outcomes of postoperative revascularization, particularly in terms of postoperative transdural collateral development.\\u003c/p\\u003e\\n\\u003cp\\u003eAlthough Suzuki angiographical stage distributions were similar between the Japanese and Polish cohorts, disease presentation differed: ischemic onset more frequent in Polish cohort, whereas hemorrhagic onset more common in the Japanese cohort (Table 1). Given the role of cerebral ischemia in stimulating collateral development [20-23], this difference may partly explain the higher prevalence of transdural collaterals observed in the Polish group. However, even after adjusting for both angiographical stage and \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K genotype, no significant disease presentation was observed between Polish patients and Japanese patients with the wild-type genotype (Table 2). Despite this, Polish patients still exhibited more robust transdural collateral formation, suggesting the involvement of additional biological drivers beyond ischemia alone. The clinical significance of spontaneous transdural collaterals has been previously documented [15]: (1) they are present in nearly half of preoperative arteriograms in MMD, with most commonly arising from the MMA; (2) they are more frequently observed in advanced angiographical stages; (3) their presence is associated with perioperative stroke complications; and (4) they may indicate an increased potential for indirect surgical collateral development following revascularization surgery. Previous studies have also shown that the \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K variant is associated with better development of indirect, but not direct, surgical collaterals following combined direct and indirect bypass surgery [10,11]. In addition, features such as preoperative negative remodeling of the ICA terminal portion and postoperative magnetic resonance fluid attenuation inversion recovery cortical hyperintensities have been correlated with favorable indirect bypass development [24]. While the underlying molecular mechanisms remain unclear, our present findings suggest that genetic and environmental factors likely interact to influence transdural collateral formation in MMD. These insights may contribute to the identification of novel biological drivers and could inform future strategies for risk stratification and therapeutic intervention across diverse populations.\\u003c/p\\u003e\\n\\u003cp\\u003eOur secondary findings revealed that prominent PA were significantly more frequent in Japanese patients, independent of \\u003cem\\u003eRNF213\\u0026nbsp;\\u003c/em\\u003ep.R4810K genotype. This observation aligns with the interethnic difference in disease presentation noted in our study, where hemorrhagic onset was more common in Japanese patients (17% in the entire cohort, 24% in patients with wild-type, and 17% in those with the variant) compared to Polish patients (12%) (see Tables 1 and 2). As previously reported [14], interethnic variations in periventricular collateral patterns may contribute to the higher susceptibility to hemorrhagic onset in Japanese patients with MMD. In contrast, we observed no interethnic differences in natural PCA-derived leptomeningeal collateral formation, regardless p.R4810K genotype. As we recently reported, PCA leptomeningeal collaterals constitute a critical collateral source in MMD, particularly in the extremely advanced stages, based on our analysis of a Japanese single-institution cohort comprising 156 patients and 280 affected hemispheres assessed with preoperative catheter angiography [25]. This is further supported by a previous study indicating that collateral channels via moyamoya vessels tend to shift longitudinally from anterior to posterior component during disease progression and aging―highlighting the increasing importance of the posterior circulation in sustaining cerebral perfusion in MMD [18]. Together, these findings suggest a consistent and potentially universal role of PCA leptomeningeal collaterals across ethnically distinct populations with MMD, in contrast to the more ethnically variable patterns seen in transdural and pronounced periventricular collateral formation.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eLimitations and Future Directions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eFirst, our study focused on two ethnically distinct populations―Japanese and Polish patients―representing Asian and European Caucasian descent, respectively. These groups differ not only in genetic background but also in social customs and environmental exposures. The\\u0026nbsp;limited inclusion of only two ethnic cohorts highlights the need for future study research involving a broader and more diverse range of populations. To our knowledge, this is the first study to investigate interethnic differences in natural transdural collateral formation in MMD with genetic analysis. However, our findings would benefit from validation through larger, multicenter, and multiethnic studies.\\u003c/p\\u003e\\n\\u003cp\\u003eSecond, our assessment of cerebral ischemia was based on clinical presentation rather than advanced radiological metrics, such as cerebral blood flow, oxygen extraction fraction, or cerebral blood volume. As this was a retrospective international collaborative study, such imaging data were not uniformly available across cohorts. While we do not suggest omitting radiological assessment of cerebral blood flow and metabolism, we emphasize that catheter angiography remains an essential tool in the diagnostic evaluation of MMD\\u0026mdash;especially for visualizing natural pre-existing collateral pathways, which may provide important diagnostic information.\\u003c/p\\u003e\\n\\u003cp\\u003eThird, although we demonstrated interethnic differences in the prevalence of natural transdural collaterals and discussed potential genetic and environmental influences, our study does not directly investigate the biological mechanisms underlying collateral vessel development. Future research should focus on uncovering the molecular and cellular drivers of transdural collateral growth in MMD.\\u003c/p\\u003e\\n\\u003cp\\u003eFourth, due to the retrospective, cross-sectional nature of our study, we cannot elucidate the dynamic and potentially reciprocal relationships among various types of collateral pathways\\u0026mdash;namely, transdural, basal, periventricular, and leptomeningeal routes. As the Suzuki angiographical staging system represents a chronological progression of angiographic changes in MMD [1], future prospective or longitudinal studies are necessary to map the evolution of these collateral pathways over time.\\u003c/p\\u003e\\n\\u003cp\\u003eFifth, we acknowledge the unanswered question of whether genetic and ethnic differences influence the outcomes of postoperative revascularization, particularly in terms of indirect pial synangiosis. Our current study did not compare surgical outcomes between Japanese and Polish cohorts. Notably, our Japanese cohort typically underwent combined direct and indirect revascularization regardless of age [26-28], whereas Polish patients primarily received direct bypass procedures. Future prospective studies are needed to evaluate whether ethnicity or genetic background affects postoperative collateral development, particularly in response to indirect surgical techniques.\\u003c/p\\u003e\\n\\u003cp\\u003eFinally, we recognize that catheter angiography carries inherent risks, including arterial injury, stroke, and radiation exposure, as previously reported [14]. While such complications are rare in experienced centers, our institution in Japan has adopted an \\u0026quot;MRI-first\\u0026quot; strategy\\u0026mdash;utilizing MR imaging and MR angiography alone for preoperative diagnosis\\u0026mdash;to minimize these risks [27]. We previously reported that this approach was associated with low perioperative complication rates in pediatric patients. However, in adult patients, the incidence of hemorrhagic complications was notably higher, suggesting that detailed preoperative vascular evaluation\\u0026mdash;including assessment of basal and periventricular collaterals via catheter angiography\\u0026mdash;might be necessary for adult patients. Moreover, our data, together with prior findings, demonstrated the presence of natural, pre-existing transdural collaterals was not low. Therefore, we continue to advocate for the use of standardized cerebral angiography in all adolescent and adult patients (excluding infants, toddlers, and young children) undergoing surgical planning for MMD as routine clinical practice. This is in accordance with the Japanese clinical guidelines for the diagnosis of MMD.\\u003csup\\u003e2\\u003c/sup\\u003e Angiographic evaluation should include full visualization of the ICA, ECA, and posterior circulation, including the PCA and PcomA. Evaluations should encompass arterial, parenchymal, and late venous phases, with additional rotational or 3D reconstructions as needed. We acknowledge that in extremely advanced Suzuki stages―particularly in Stage 6―angiographical imaging may also depict vertebrobasilar-PcomA-derived anterior circulation extending into MCA or ACA territories, which we currently are conducting a study to investigate its clinical implication, and hope to report on the results of this work in the near future [25].\\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eNatural, pre-existing collateral angioarchitecture differs between Japanese Asian and Polish Caucasian MMD patients. Japanese patients more frequently exhibited prominent PA, whereas Polish patients demonstrated greater natural transdural collateral formation via the ECA system, particularly when adjusted for \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K genotype. In contrast, PCA-derived leptomeningeal collaterals were similarly developed across both ethnic groups, regardless of the \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K genotype. These findings suggest that a higher prevalence of natural transdural collaterals in the Polish patients may contribute to a lower incidence of prominent periventricular collaterals, hence leading to the interethnic difference of clinical presentation, particularly in the context of the \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K. Furthermore, genetic background may play a significant role in shaping natural collateral formation and contribute to interethnic differences in clinical and angiographical demonstration. Future prospective studies are warranted to determine whether genetic and ethnic factors also influence postoperative revascularization potential, particularly in response to indirect bypass procedures.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eCompeting Interests:\\u003c/strong\\u003e All authors declare no conflicts of interest in relation to this work.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthics Approval:\\u003c/strong\\u003e This study was approved by the institutional review board in our institutes (approval number: 023-0359, approval date: May 28, 2024 at Ethical Review Board for Life Science and Medical Research, Hokkaido University Hospital and approval number: 06/BNBO/2023, approval date: November 8, 2023 at Bioethics Committee of the Lower Silesian Medical Chamber). This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent to Participate:\\u003c/strong\\u003e Written informed consent was obtained from all participants or the legal guardians of patients aged \\u0026lt;18 years.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgments:\\u003c/strong\\u003e The authors are grateful for substantive contributions to the research for this article to clinical biobank, clinical research and medical innovation center, Hokkaido university hospital and Eurofins GeneticLab Co., Ltd., Sapporo, Japan.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding:\\u003c/strong\\u003e This work was partially supported by Japanese Society for Promotion of Science, KAKENHI (Grant numbers 20K22775 [K.T] , 24K12213 [M.I.], and 23H03015 [M.F.]).\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eSuzuki J, Takaku A (1969) Cerebrovascular \\u0026ldquo;moyamoya\\u0026rdquo; disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol 20(3):288\\u0026ndash;299. https:// doi. org/ 10. 1001/ archn eur. 1969.00480 09007 6012\\u003c/li\\u003e\\n\\u003cli\\u003eKuroda S, Fujimura M, Takahashi JC, Kataoka H, Ogasawara K, Iwama T, Tominaga T, Miyamoto S; Research Committee on Moyamoya Disease (Spontaneous Occlusion of Circle of Willis) of the Ministry of Health, Labor, and Welfare, Japan. Diagnostic Criteria for Moyamoya Disease - 2021 Revised Version. Neurol Med Chir (Tokyo). 2022;62(7):307-312; https://doi.org/10.2176/jns-nmc.2022-0072\\u003c/li\\u003e\\n\\u003cli\\u003eShoemaker LD, Clark MJ, Patwardhan A, Chandratillake G, Garcia S, Chen R, Morgan AA, Leng N, Kirk S, Chen R, Cook DJ, Snyder M, Steinberg GK (2015) Disease variant landscape of a large multiethnic population of Moyamoya patients by exome sequencing. G3 (Bethesda) 6(1):41-49. https://doi.org/10.1534/g3.115.020321\\u003c/li\\u003e\\n\\u003cli\\u003eIhara M, Yamamoto N, Hattori Y, Liu W, Kobayashi H, Ishiyama H, Yoshimoto T, Miyawaki S, Clausen T, Bang OY, Steinberg GK, Tournier-Lasserve E, Koizumi A (2022) Moyamoya disease: diagnosis and interventions. Lancet Neurol. 21(8):747-758. https://doi.org/10.1016/S1474-4422(22)00165-X\\u003c/li\\u003e\\n\\u003cli\\u003eScott RM, Smith ER (2009) Moyamoya disease and Moyamoya syndrome. N Engl J Med. 360(12):1226-1237. https://doi.org/10.1056/NEJMra0804622\\u003c/li\\u003e\\n\\u003cli\\u003eKamada F, Aoki Y, Narisawa A, Abe Y, Komatsuzaki S, Kikuchi A, Kanno J, Niihori T, Ono M, Ishii N, Owada Y, Fujimura M, Mashimo Y, Suzuki Y, Hata A, Tsuchiya S, Tominaga T, Matsubara Y, Kure S. (2011) A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet. 56(1):34-40. https://doi.org/10.1038/jhg.2010.132\\u003c/li\\u003e\\n\\u003cli\\u003eLiu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, Hashikata H, Matsuura N, Yamazaki S, Toyoda A, Kikuta K, Takagi Y, Harada KH, Fujiyama A, Herzig R, Krischek B, Zou L, Kim JE, Kitakaze M, Miyamoto S, Nagata K, Hashimoto N, Koizumi A. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One.2011;6:e22542; https://doi.org/10.1371/journal.pone.0022542\\u003c/li\\u003e\\n\\u003cli\\u003eMiyatake S, Miyake N, Touho H, Nishimura-Tadaki A, Kondo Y, Okada I, Tsurusaki Y, Doi H, Sakai H, Saitsu H, Shimojima K, Yamamoto T, Higurashi M, Kawahara N, Kawauchi H, Nagasaka K, Okamoto N, Mori T, Koyano S, Kuroiwa Y, Taguri M, Morita S, Matsubara Y, Kure S, Matsumoto N. Homozygous c.14576G\\u0026gt;A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology.2012;78(11):803-810; https://doi.org/10.1212/WNL.0b013e318249f71f.\\u003c/li\\u003e\\n\\u003cli\\u003eGe P, Zhang Q, Ye X, Liu X, Deng X, Wang J, Wang R, Zhang Y, Zhang D, Zhao J. Angiographic characteristics in Moyamoya disease with the p.R4810K variant: a propensity score-matched analysis. Eur J Neurol. 2020,27:856\\u0026ndash;863; https://doi.org/10.1111/ene.14184\\u003c/li\\u003e\\n\\u003cli\\u003eIto M, Kawabori M, Sugiyama T, Tokairin K, Tatezawa R, Uchino H, Kazumata K, Houkin K, Fujimura M. Impact of RNF213 founder polymorphism (p.R4810K) on the postoperative development of indirect pial synangiosis after direct/indirect combined revascularization surgery for adult Moyamoya disease. Neurosurg Rev.2022; 45(3):2305-2313; https://doi.org/10.1007/s10143-022-01749-9.\\u003c/li\\u003e\\n\\u003cli\\u003eKawabori M, Ito M, Kazumata K, Tokairin K, Hatanaka KC, Ishikawa S, Houkin K, Fujimura M. Impact of RNF213 c.14576G\\u0026gt;A Variant on the Development of Direct and Indirect Revascularization in Pediatric Moyamoya Disease. Cerebrovasc Dis.2023;52(2):171-176; https://doi.org/10.1159/000526089.\\u003c/li\\u003e\\n\\u003cli\\u003eMizushima M, Ito M, Uchino H, Sugiyama T, Fujimura M. (2024) Impact of RNF213 p.R4810K variant on postoperative temporal muscle swelling used in encephalo-myo-synangiosis after combined revascularization for Moyamoya disease. Neurosurg Rev. 48(1):15. https://doi.org/10.1007/s10143-024-03165-7\\u003c/li\\u003e\\n\\u003cli\\u003eUnda SR, Antoniazzi AM, Fluss R, Yassari N, Esenwa C, Haranhalli N, Altschul DJ. (2023) Ethnic-associated phenotype variations in Moyamoya cerebrovascular outcomes. Cerebrovasc Dis 52(5):519-525. https://doi.org/ 10.1159/000528055\\u003c/li\\u003e\\n\\u003cli\\u003eHori S, Kashiwazaki D, Yamamoto S, Acker G, Czabanka M, Akioka N, Kuwayama N, Vajkoczy P, Kuroda S. (2019) Impact of interethnic difference of collateral angioarchitectures on prevalence of hemorrhagic stroke in Moyamoya disease. Neurosurgery;85(1):134-146. https://doi.org/ https://doi.org/ 10.1159/000528055\\u003c/li\\u003e\\n\\u003cli\\u003eStorey A, Scott RM, Robertson R, Smith E. (2017) Preoperative transdural collateral vessels in Moyamoya as radiographic biomarkers of disease. J Neurosurg Pediatr.19(3):289-295. https://doi.org/ https://doi.org/ 10.3171/2016.9.PEDS16161\\u003c/li\\u003e\\n\\u003cli\\u003eFunaki T, Fushimi Y, Takahashi JC, Takagi Y, Araki Y, Yoshida K, Kikuchi T, Miyamoto S. (2015) Visualization of periventricular collaterals in Moyamoya disease with flow-sensitive black-blood magnetic resonance angiography: preliminary experience. Neurol Med Chir (Tokyo);55(3):204-209. https://doi.org/ https://doi.org/ 10.2176/nmc.oa.2014-0360\\u003c/li\\u003e\\n\\u003cli\\u003eFunaki T, Takahashi JC, Yoshida K, Takagi Y, Fushimi Y, Kikuchi T, Mineharu Y, Okada T, Morimoto T, Miyamoto S. (2016) Periventricular anastomosis in Moyamoya disease: detecting fragile collateral vessels with MR angiography. J Neurosurg;124(6):1766-1772. https://doi.org/ 10.3171/2015.6.JNS15845\\u003c/li\\u003e\\n\\u003cli\\u003eYamamoto S, Hori S, Kashiwazaki D, Akioka N, Kuwayama N, Kuroda S. (2019) Longitudinal anterior-to-posterior shift of collateral channels in patients with moyamoya disease: an implication for its hemorrhagic onset. J Neurosurg;130(3):884-890. https://doi.org/10.3171/2017.9.JNS172231\\u003c/li\\u003e\\n\\u003cli\\u003eMiyamoto S. Kikuchi H, Karasawa J, Nagata I, Ikota T, Takeuchi S. (1984) Delayed cerebral blood supply through the leptomeningeal anastomosis in children with Moyamoya disease. J Neurosurg;61(6):1032-1037.\\u003c/li\\u003e\\n\\u003cli\\u003eKusaka N, Sugiu K, Tokunaga K, Katsumata A, Nishida A, Namba K, Hamada H, Nakashima H, Date I. (2005) Enhanced brain angiogenesis in chronic cerebral hypoperfusion after administration of plasmid human vascular endothelial growth factor in combination with indirect vasoreconstructive surgery. J Neurosurg;103(5):882-890. https://doi.org/10.3171/2017.9.JNS172231\\u003c/li\\u003e\\n\\u003cli\\u003eNishijima Y, Akamatsu Y, Weinstein PR, Liu J. (2015) Collaterals: implications in cerebral ischemic diseases and therapeutic interventions. Brain Res;1623:18-29. https://doi.org/10.1016/j.brainres.2015.03.006\\u003c/li\\u003e\\n\\u003cli\\u003eLim M, Cheshier S, Steinberg GK. (2006) New vessel formation in the central nervous system during tumor growth, vascular malformations, and Moyamoya. Curr Neurovasc Res;3(3):237-245. https://doi.org/ https://doi.org/10.1016/j.brainres.2015.03.006\\u003c/li\\u003e\\n\\u003cli\\u003eMalek AM, Connors S, Robertson RL, Folkman J, Scott RM. (1997) Elevation of cerebrospinal fluid levels of basic fibroblast growth factor in Moyamoya and central nervous system disorders. Pediatr Neurosurg;27(4):182-189. https://doi.org/ 10.1159/000121249\\u003c/li\\u003e\\n\\u003cli\\u003eUchino H, Ito M, Kurisu K, Sugiyama T, Fujimura M. (2025) Association between intracranial vascular vulnerability and indirect revascularization development in Moyamoya disease. Neurosurg Rev;48(1):387. https://doi.org/10.1007/s10143-025-03544-8\\u003c/li\\u003e\\n\\u003cli\\u003eUchino H, Ito M, Fujimura M. Incidence and clinical characteristics of Moyamoya disease in advanced Suzuki disease stages. Neurol Med Chir (Tokyo). \\u003cem\\u003ein press\\u003c/em\\u003e.\\u003c/li\\u003e\\n\\u003cli\\u003eKazumata K, Ito M, Tokairin K, Ito Y, Houkin K, Nakayama N, Kuroda S, Ishikawa T, Kamiyama H. (2014) The frequency of postoperative stroke in Moyamoya disease following combined revascularization: a single-university series and systematic review. J Neurosurg.121(2):432-440. https://doi.org/10.1007/s10143-025-03544-8\\u003c/li\\u003e\\n\\u003cli\\u003eOkuyama T, Kawabori M, Ito M, Sugiyama T, Kazumata K, Fujimura M. (2022) Outcomes of Combined Revascularization Surgery for Moyamoya Disease without Preoperative Cerebral Angiography. World Neurosurg;165:e446-e451. https://doi.org/10.1016/j.wneu.2022.06.067\\u003c/li\\u003e\\n\\u003cli\\u003eKurisu K, Ito M, Uchino H, Sugiyama T, Fujimura M. (2024) Long-term Outcomes of Combined Revascularization Surgery for Moyamoya Disease in the Elderly: A Single Institute Experience. Neurol Med Chir (Tokyo);64(3):108-115. https://doi.org/ 10.2176/jns-nmc.2023-0219\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"},{\"header\":\"Tables\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eTable 1\\u0026nbsp;\\u003c/strong\\u003eClinical characteristics of Moyamoya disease patients across two distinct ethnicities enrolled in this study.\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"99%\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003eJapanese entire cohort\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003ePolish\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eP value\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eSignificance\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003ePatient, number\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e94\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e33\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eAge at diagnosis, years\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eMean, SD\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e43\\u0026plusmn;13\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e34\\u0026plusmn;16\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.0014\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e**\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eAge group\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003ePediatrics:Adults\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e8:86\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e5:28\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.32\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eSex\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eMale:Female\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e21:73\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e7:26\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026gt;0.99\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eDiagnosis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eMMD:quasi-MMD\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e82:12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e25:8\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.16\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eRNF213\\u003c/em\\u003e, p.R4810K\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eVariant:Wild-type\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e65:29\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e0:33\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;0.0001\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e****\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eCo-morbidities, number (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eHypertension\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e33 (35%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e17 (52%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eDiabetes mellitus\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e10 (11%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e5 (15%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.53\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eDyslipidemia\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e15 (16%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e3 (9.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.40\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eDown syndrome\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e1 (1.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e1 (3.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.45\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eBasedow disease\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e6 (6.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.34\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eHypothyroidism\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e2 (2.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e5 (15%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.013\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e*\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eOther autoimmune diseases\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e5 (5.3%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e1 (3.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026gt;0.99\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eDisease presentation, number (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"6\\\" valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"6\\\" valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eIschemic\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e65 (69%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e26 (79%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eHemorrhagic\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e16 (17%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e4 (12%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eAsymptomatic\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e11 (12%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e1 (3.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eHeadache\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e2 (6.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eEpilepsy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e2 (2.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eAffected hemispheres, number\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e173\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e57\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"4\\\" style=\\\"width: 66px;\\\"\\u003e\\n \\u003cp\\u003eSuzuki angiographical stage, number (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"7\\\" valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.31\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"7\\\" valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eStage 1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e20 (12%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e2 (3.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eStage 2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e30 (17%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e9 (16%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eStage 3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e40 (23%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e15 (26%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eStage 4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e48 (28%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e20 (35%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eStage 5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e33 (19%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e9 (16%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eStage 6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e2 (1.2%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e2 (3.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003ePCA involvement\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17px;\\\"\\u003e\\n \\u003cp\\u003e30 (17%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 15px;\\\"\\u003e\\n \\u003cp\\u003e10 (18%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026gt;0.99\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003eMMD: Moyamoya disease, SD: standard deviation, PCA: posterior cerebral artery\\u003c/p\\u003e\\n\\u003cp\\u003e*: P\\u0026lt;0.05, **: P\\u0026lt;0.01, ****: P\\u0026lt;0.0001\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTable 2\\u0026nbsp;\\u003c/strong\\u003eClinical characteristics of Moyamoya disease between Japanese patients with \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K wild-type and Polish patients.\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"99%\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eJapanese \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K wild-type\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003ePolish\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eP value\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eSignificance\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003ePatient, number\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e29\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e33\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eAge at diagnosis, years\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eMean, SD\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e46\\u0026plusmn;8.4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e34\\u0026plusmn;16\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.00040\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e***\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eAge group\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003ePediatrics:Adults\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0:29\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e5:28\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.060\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eSex\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eMale:Female\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e8:21\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e7:26\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.77\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eDiagnosis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eMMD:quasi-MMD\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e25:4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e25:8\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.35\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eRNF213\\u003c/em\\u003e, p.R4810K\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003eVariant:Wild-type\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0:29\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0:33\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026gt;0.99\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eCo-morbidities, number (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eHypertension\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e13 (45%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e17 (52%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.62\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eDiabetes mellitus\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e5 (17%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e5 (15%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026gt;0.99\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eDyslipidemia\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e5 (17%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e3 (9.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.46\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eDown syndrome\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e1 (3.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026gt;0.99\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eBasedow disease\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e3 (10%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eHypothyroidism\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e1 (3.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e5 (15%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.20\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eOther autoimmune diseases\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e2 (6.9%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e1 (3.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.60\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eDisease presentation, number (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"6\\\" valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.39\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"6\\\" valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eIschemic\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e20 (69%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e26 (79%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eHemorrhagic\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e7 (24%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e4 (12%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eAsymptomatic\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e1 (3.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e1 (3.0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eHeadache\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e2 (6.1%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eEpilepsy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e1 (3.4%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eAffected hemispheres, number\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e53\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e57\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"4\\\" style=\\\"width: 66px;\\\"\\u003e\\n \\u003cp\\u003eSuzuki angiographical stage, number (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"7\\\" valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.26\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"7\\\" valign=\\\"top\\\" style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eStage 1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e8 (15%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e2 (3.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eStage 2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e7 (13%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e9 (16%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eStage 3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e12 (23%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e15 (26%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eStage 4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e12 (23%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e20 (35%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eStage 5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e12 (23%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e9 (16%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003eStage 6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e2 (3.8%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e2 (3.5%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 33px;\\\"\\u003e\\n \\u003cp\\u003ePCA involvement\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e7 (13%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e10 (19%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003e0.60\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 16px;\\\"\\u003e\\n \\u003cp\\u003enone\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003eNote that the wild-type \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K genotype was present in 100% of Polish Caucasian patients.\\u003c/p\\u003e\\n\\u003cp\\u003eMMD: Moyamoya disease, SD: standard deviation, PCA: posterior cerebral artery\\u003c/p\\u003e\\n\\u003cp\\u003e***: P\\u0026lt;0.001\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTable 3\\u0026nbsp;\\u003c/strong\\u003eComparison of angiographical stages and natural collateral formation among Polish Caucasian patients, Japanese entire cohort, and Japanese patients with \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K wild-type genotype with Moyamoya disease.\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"100%\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" valign=\\\"top\\\" style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003eJapanese\\u003c/p\\u003e\\n \\u003cp\\u003eentire cohort\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003eJapanese \\u003cem\\u003eRNF213\\u003c/em\\u003e p.R4810K wild-type\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003ePolish\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eP value\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eAffected hemispheres, number\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e173\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e53\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e57\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003ePolish vs Japanese entire cohort\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003ePolish vs Japanese wild-type\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"7\\\" style=\\\"width: 100px;\\\"\\u003e\\n \\u003cp\\u003eSuzuki angiographical stage, number\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e20\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e8\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"6\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0.31\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"6\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0.26\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e30\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e7\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e9\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e40\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e15\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e48\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e20\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e33\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e9\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"7\\\" style=\\\"width: 100px;\\\"\\u003e\\n \\u003cp\\u003eTransdural collateral,\\u0026nbsp;number, percentage of total for each stage (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"6\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0.20\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"6\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0.0098\\u003cstrong\\u003e\\u003csup\\u003e**\\u003c/sup\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e5 (17%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e2 (29%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e2 (22%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e15 (38%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e3 (25%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e7 (47%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e25 (52%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e4 (33%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e15 (75%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e25 (76%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e8 (67%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e8 (89%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e1 (50%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e1 (50%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e2 (100%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"7\\\" style=\\\"width: 100px;\\\"\\u003e\\n \\u003cp\\u003eGrade2 PA collateral, number,\\u0026nbsp;percentage of total for each stage (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"6\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;0.0001\\u003cstrong\\u003e\\u003csup\\u003e****\\u003c/sup\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"6\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;0.0001\\u003cstrong\\u003e\\u003csup\\u003e****\\u003c/sup\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e3 (10%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e3 (43%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e16 (40%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e4 (33%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e3 (20%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e23 (48%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e4 (33%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e4 (20%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e12 (36%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"7\\\" style=\\\"width: 100px;\\\"\\u003e\\n \\u003cp\\u003ePCA collateral, number,\\u0026nbsp;percentage of total for each stage (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e2 (10%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e0 (0%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"6\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026gt;0.99\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"6\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026gt;0.99\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e22 (73%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e7 (100%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e9 (100%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e32 (80%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e9 (75%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e12 (80%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e47 (98%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e12 (100%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e19 (95%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e33 (100%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e12 (100%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e8 (89%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 28px;\\\"\\u003e\\n \\u003cp\\u003eStage 6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e2 (100%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e2 (100%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 14px;\\\"\\u003e\\n \\u003cp\\u003e2 (100%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003e**: P\\u0026lt;0.01, ****: P\\u0026lt;0.0001\\u003c/p\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"neurosurgical-review\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"nrev\",\"sideBox\":\"Learn more about [Neurosurgical Review](https://www.springer.com/journal/10143)\",\"snPcode\":\"10143\",\"submissionUrl\":\"https://submission.nature.com/new-submission/10143/3\",\"title\":\"Neurosurgical Review\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false},\"keywords\":\"Moyamoya disease, Collateral Circulation, Ethnicity, Genetic Variation, RNF213, Cerebrovascular disorder\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7226764/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7226764/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"Interethnic differences in natural transdural collaterals—an angiographical hallmark of Moyamoya disease (MMD)—may reflect underlying genetic variation. However, comparative studies incorporating both angiographic and genetic data are limited. This study investigated differences in cerebral angioarchitecture and clinical presentation between Japanese Asian and Polish Caucasian patients with MMD, with a focus on the RNF213 p.R4810K variant, a known East Asian founder mutation. We retrospectively analyzed 94 Japanese and 33 Polish patients who underwent diagnostic cerebral angiography and RNF213 p.R4810K genotyping between 2015 and 2025. Suzuki’s angiographical stages and the presence of natural-transdural, periventricular, and posterior cerebral artery (PCA) collaterals were evaluated. Interethnic comparisons included adjustments for RNF213 p.R4810K genotype. The RNF213 p.R4810K wild-type was present in 31% of Japanese and 100% of Polish patients. A trend toward more hemorrhagic presentation in Japanese was noted (17% vs. 12%, P=0.10). Polish patients were significantly younger at diagnosis (P=0.001). Among 230 un-operated hemispheres, angiographic stages did not significantly differ (P=0.31). After adjustment, overall prevalence of natural transdural collaterals was similar (P=0.20), but significantly higher in Polish than in Japanese RNF213 wild-type patients (P=0.0098). Periventricular collaterals were significantly more common in Japanese, independent of genotype (P\\u003c0.0001). No interethnic difference was observed in PCA collaterals (P\\u003e0.99). In conclusion, Polish MMD patients exhibit more natural transdural and fewer periventricular collaterals than Japanese RNF213 wild-type patients. These differences suggest distinct mechanisms of collateral formation across ethnic groups, with implications for genotype-driven pathophysiology and clinical presentation in MMD.\",\"manuscriptTitle\":\"Distinct Impact of RNF213 p.R4810K Genotype on Transdural Collateral Formation Across Japanese Asian and Polish Caucasian Moyamoya Patients\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-09-23 07:34:08\",\"doi\":\"10.21203/rs.3.rs-7226764/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2025-11-09T14:06:53+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-09-23T13:01:34+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"39033822526148946120182793689767501845\",\"date\":\"2025-09-16T21:50:41+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-09-16T12:21:30+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"156526273420292995828402969227222543826\",\"date\":\"2025-09-15T14:00:03+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2025-09-14T16:04:31+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2025-09-14T16:03:14+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2025-07-28T10:43:27+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Neurosurgical Review\",\"date\":\"2025-07-27T14:12:19+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"neurosurgical-review\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"nrev\",\"sideBox\":\"Learn more about [Neurosurgical Review](https://www.springer.com/journal/10143)\",\"snPcode\":\"10143\",\"submissionUrl\":\"https://submission.nature.com/new-submission/10143/3\",\"title\":\"Neurosurgical Review\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false}}],\"origin\":\"\",\"ownerIdentity\":\"24386a32-4803-4f02-a696-410bd8e42b72\",\"owner\":[],\"postedDate\":\"September 23rd, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-12-22T16:08:50+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-7226764\",\"link\":\"https://doi.org/10.1007/s10143-025-04023-w\",\"journal\":{\"identity\":\"neurosurgical-review\",\"isVorOnly\":false,\"title\":\"Neurosurgical Review\"},\"publishedOn\":\"2025-12-18 15:58:05\",\"publishedOnDateReadable\":\"December 18th, 2025\"},\"versionCreatedAt\":\"2025-09-23 07:34:08\",\"video\":\"\",\"vorDoi\":\"10.1007/s10143-025-04023-w\",\"vorDoiUrl\":\"https://doi.org/10.1007/s10143-025-04023-w\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7226764\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7226764\",\"identity\":\"rs-7226764\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}