The Association of Heterozygous p.R4810K of RNF213 and Long-Term Unfavorable Outcomes after Encephaloduroarteriosynangiosis in Chinese Pediatric Patients with Moyamoya Disease.

Previous studies have established that heterozygous mutation for the p.R4810K variant can influence the severity of the clinical phenotype in patients with moyamoya disease (MMD) at disease onset. However, the relationship between the p.R4810K variant and the clinical phenotype of long-term unfavorable outcomes in Chinese pediatric patients remains unclear. The primary aim of this study was to examine the association of heterozygous p.R4810K of RNF213 and long-term unfavorable outcomes after encephaloduroarteriosynangiosis (EDAS) in Chinese pediatric patients with MMD. In this retrospective cohort study, we included 259 pediatric patients with MMD who possessed the known p.R4810K genotype. These individuals underwent EDAS along with genotyping analysis for p.R4810K via a TaqMan probe and the QuantStudio 6 Flex Real-Time PCR System. Subsequently, we evaluated their long-term outcomes. The variables we assessed were age at diagnosis, gender, p.R4810K genotypes, initial modified Rankin scale (mRS), clinical manifestations (such as hemorrhage and ischemia), posterior cerebral artery (PCA) involvement combined with angiographic stage, and their history of risk factors like hyperlipidemia and hyperhomocysteinemia. Furthermore, we scrutinized long-term unfavorable outcomes using both univariate analyses and multivariate logistic regression to identify independent predictive factors. This study enrolled 259 Chinese pediatric patients with MMD, which included both newly and previously diagnosed cases, who underwent EDAS. The cohort comprised 130 male participants (50.19%) and 129 female participants (49.81%), with a median onset age of 8 years (median, IQR: 6-12 years). Among these patients, homozygous mutations were exceptionally rare, identified in only 4 individuals (1.54%), while the prevalence of heterozygous mutations was relatively higher, observed in 85 children (32.82%). The multivariate logistic regression showed that several factors were significantly associated with long-term unfavorable outcomes: older age at diagnosis (OR, 0.82 [95% CI, 0.7-0.96], P = 0.014), onset with hematoma (OR, 12.76 [95% CI, 1.52-106.89], P = 0.019), initial mRS (OR, 24.53 [95% CI, 6.51-92.41], P < 0.001), perioperative infarction (OR, 22.16 [95% CI, 1.45-337.96], P = 0.026), and infarction during follow-up (OR, 14.5 [95% CI, 2.04-103.12], P = 0.008). Furthermore, the cumulative incidence of initial infarction suggested that pediatric patients with homozygous or heterozygous mutations typically present at a younger age and exhibit a higher incidence of initial infarction compared to those carrying wild-type genotypes. The study suggests that the p.R4810K variant is associated with the onset age of MMD in Chinese pediatric patients, potentially impacting long-term outcomes. Surprisingly low recurrent stroke rates were observed across all genotypes, including homozygous individuals for the pathogenic variant, indicating that nongenetic factors may also play a role in the course and outcomes of MMD in this population.

Guo Q ，Hao F ，Wang QN ，Li J ，Liu S ，Zou Z ，Liu S ，Wang X ，Yu D ，Gao G ，Zhang Q ，Pei S ，Feng J ，Yang R ，Wang M ，Fu H ，Han C ，Bao X ，Duan L ... -  《-》

Isolated anterior cerebral artery occlusion: an atypical form of moyamoya disease.

The relationship between anterior cerebral artery (ACA) occlusion and moyamoya disease (MMD) has rarely been studied. In this study, we focused on a special type of MMD: isolated ACA-occlusive MMD. We investigated clinical attributes, genotypes and progression risk factors in patients with ACA-occlusive MMD, providing initial insights into the relationship between ACA occlusion and MMD. We retrospectively analysed digital subtraction angiography (DSA) from 2486 patients and diagnosed 139 patients with ACA-occlusive MMD. RNF213 p.R4810K (rs112735431) mutation analysis was performed. Patients were categorised into progression and non-progression groups based on whether they progressed to typical MMD. Differences in clinical characteristics, neuropsychological assessment, radiological findings and genotypes were evaluated. Logistic regression analyses identified risk factors for ACA-occlusive MMD progression. The median age of patients with ACA-occlusive MMD was 36 years, and the primary symptom was transient ischaemic attack (TIA). 72.3% of ACA-occlusive MMD patients had cognitive decline. Of 116 patients who underwent RNF213 gene mutation analysis, 90 patients (77.6%) carried the RNF213 p.R4810K GG allele and 26 (22.4%) carried the GA allele. Of 102 patients with follow-up DSA data, 40 patients (39.2%) progressed. Kaplan-Meier curve estimates indicated a higher incidence of ischaemic stroke in the progression group during follow-up (p=0.035). Younger age (p=0.041), RNF213 p.R4810K GA genotype (p=0.037) and poor collateral compensation from the middle cerebral artery (MCA) to ACA (p<0.001) were risk factors of ACA-occlusive MMD progression to typical MMD. Cognitive decline and TIA might be the main manifestations of ACA-occlusive MMD. Isolated ACA occlusion may be an early signal of MMD. The initial lesion site of MMD is not strictly confined to the terminal portion of the internal carotid artery. Younger patients, patients with RNF213 p.R4810K GA genotype or those with inadequate MCA-to-ACA compensation are more likely to develop typical MMD.

Liu SM ，Gao G ，Hao FB ，Liu ST ，Yang RM ，Zhang HD ，Wang MJ ，Zou ZX ，Yu D ，Zhang Q ，Guo QB ，Wang XP ，Fu HG ，Li JJ ，Han C ，Duan L ... -  《-》

Nomogram for Predicting Long-term Outcomes of Encephaloduroarteriosynangiosis in Toddlers with Moyamoya Disease: a Longitudinal and Cross-sectional Study.

We investigated the long-term outcomes of encephaloduroarteriosynangiosis (EDAS) for stroke prevention in toddlers with moyamoya disease (MMD) using nomogram. Between January 2005 and December 2018, 74 toddlers with MMD underwent surgery in the Fifth Medical Centre, Chinese PLA General Hospital, 69 were < 4 years of age and included in the analysis. The modified Rankin scale (mRS) during follow-up evaluated clinical outcomes. To measure the effectiveness of EDAS, the annual risk of symptomatic infarction within the operated brain hemispheres was calculated. The event-free survival rate was determined using Kaplan-Meier curves. A nomogram generated using multivariate logistic regression analysis identified potential predictors associated with unfavorable outcomes. Additionally, discrimination, calibration, and clinical utility were assessed. A favorable clinical outcome was observed in 81.2% of the patients. The operated hemispheres showed an annual risk of 0.87% of symptomatic infarction and 0.23% of hemorrhage. Moreover, the 10-year event-free survival rates were 92.8% and 97.0% for symptomatic infarction and hemorrhage. Multivariate logistic analysis indicated that onset with infarction, initial mRS ≥ 3, and perioperative adverse events had significant and independent associations with unfavorable outcomes. However, an age at diagnosis of ≥ 2 years showed an association with favorable outcomes. Using these four factors, our model attained a concordance index of 0.912 (95% confidence interval, 0.842-0.982), well-fitted calibration curve, and cutoff value of 0.212 for predicting unfavorable outcomes. EDAS may prevent recurrent stroke and improve overall long-term clinical outcomes in toddlers with MMD. The developed nomogram accurately predicted unfavorable outcomes and assisted surgeons in patient evaluation.

Guo Q ，Fan YN ，Wang QN ，Li J ，Han C ，Zou Z ，Liu S ，Wang X ，Yu D ，Hao F ，Gao G ，Zhang Q ，Pei S ，Feng J ，Yang R ，Wang M ，Fu H ，Bao X ，Duan L ... -  《-》

Impact of RNF213 p.R4810K variant on postoperative temporal muscle swelling used in encephalo-myo-synangiosis after combined revascularization for Moyamoya disease.

Postoperative neurological deterioration due to brain compression by the swollen temporal muscle pedicle used in encephalo-myo-synangiosis (EMS) is a potential complication of combined revascularization for Moyamoya disease (MMD). However, the factors contributing to this phenomenon remain poorly understood. This study aimed to identify factors associated with postoperative temporal muscle swelling following combined revascularization. A total of 37 consecutive combined revascularization using temporal muscle pedicle performed between 2021 and 2023 were analyzed. Postoperative temporal muscle volume was measured through serial CT scans on postoperative days (POD) 0, 1, 7, 14, and 30. Multiple regression analysis was performed to assess factors contributing to swelling, including RNF213 p.R4810K variant, a known genetic risk for Asian MMD. Surgical outcomes and collateral vessel development were also examined. Results showed a significant increase in muscle pedicle volume on POD 1 and 7 across all 37 hemispheres, followed by a marked decrease by POD 30, compared to POD 0. These chronological volume changes were significant in adults (n = 31) but not in pediatric patients (n = 6). Multiple regression analysis identified the RNF213 p.R4810K as sole significant factor positively associated with maximal muscle volume (regression coefficient 0.485, P = 0.0078). Favorable surgical outcomes were achieved in 36 of 37 cases (97.3%) over a mean follow-up of 2.2 years, with indirect collateral development confirmed in 27 adult (87%) and 6 pediatric (100%) hemispheres. Results suggest the RNF213 p.R4810K variant is associated with increased postoperative temporal muscle swelling after combined revascularization, especially in adult MMD patients, indicating a potential genetic influence on this complication.

Mizushima M ，Ito M ，Uchino H ，Sugiyama T ，Fujimura M ... -  《-》

Mortality impact, risks, and benefits of general population screening for ovarian cancer: the UKCTOCS randomised controlled trial.

Menon U ，Gentry-Maharaj A ，Burnell M ，Ryan A ，Kalsi JK ，Singh N ，Dawnay A ，Fallowfield L ，McGuire AJ ，Campbell S ，Skates SJ ，Parmar M ，Jacobs IJ ... -  《-》