Association Between Clinical Features And RNF213 Genes P.R4810K Variant Polymorphism In Pediatric Familial Patients With Moyamoya Disease

Moyamoya disease(MMD)is a chronic cerebrovascular disease which is characterized by progressive stenosis and occlusion at the end of the internal carotid artery and the beginning of its branches,and the formation of a smoky vascular network in the basic of the brain.The etiology of moyamoya disease is not clear at present.Epidemiological studies have found that about 10% of patients with moyamoya disease presented with familial aggregation,suggesting that genetic factors may be one of the causes of moyamoya disease.Japanese scholars have found that there are differences between familial moyamoya disease patients and sporadic moyamoya disease patients in clinical characteristics.The main manifestations are early onset age,a higher proportion of female patients,and the most common first symptoms are ischemic symptoms.Family moyamoya disease could cause disability and death in many patients in a family.If it was not timely diagnosed and treated,it would bring a heavy burden to the family and society.The clinical characteristics of children with moyamoya disease are different from adults with moyamoya disease.Because of the early onset age of children with moyamoya disease,the progression of the disease is less affected by acquired factors than that of adults with moyamoya disease.RNF213 gene is the only moyamoya disease susceptibility gene that has been double confirmed by whole-exome sequencing and whole-genome association study.Mutation of its p.R4810 K locus can significantly increase the risk of moyamoya disease in the East Asia population of China,Japan and South Korea,and has become one of the hotspots in moyamoya disease research.The first part analyzes the clinical features and surgical efficacy of familial moyamoya disease in children.The second part analyzes the correlation between the clinical features of familial moyamoya disease in children and its RNF213 gene p.R4810 K locus gene polymorphism.We hope to explore the clinical characteristics and pathogenesis of familial moyamoya disease in children to provide more pieces of evidence for early diagnosis and treatment of moyamoya disease patients.Part 1:Clinical features and surgical outcomes analysis of pediatric patients with familial moyamoya diseaseObjective: The objective of this study was to investigate the clinical features and surgical outcomes of pediatric patients with familial moyamoya disease.Methods: The clinical data of 103 pediatric patients with familial moyamoya treated in the Fifth Medical Center of PLA General Hospital from August 2004 to June2018 were analyzed retrospectively,accounting for 9.1%(103/1138)of the pediatric patients treated in the same period.Among them,99 cases(183 sides of cerebral hemisphere)underwent Encephalo-duro-arterio-synangiosis(EDAS),and 4 cases were treated conservatively.Clinical efficacy and vascular reconstruction effect of patients were evaluated according to the system described by Matsushima.Stroke occurs were observed in follow-up.Factors affecting postoperative stroke events were analyzed by Cox Regression.Results: In the 103 patients the male to female ratio was 1.0∶0.9(55/48).The median age of onset is 6 years old and the peak age is 5 years old.Ninety-five cases(92.2%)showed ischemic symptoms first.90.3%(93/103)were affected by first-degree relatives,in which the father to child inheritance accounted for 40.9%(38/93),and the proportions of mother to child inheritance is 30.1%(28/93)and siblings is29.0%(27/93).3.1%(3/103)were second-degree relatives and 6.8%(7/103)were third-degree relatives.The Suzuki stage of IV-VI accounted for 78.6%(81/103).A total of 46 cases(44.7%)involved posterior cerebral arteries.The follow-up time of 99 cases received neurosurgical revascularization procedures was 3-137 months,and the median time was 38 months.87.9%(87/99)of the patients had good improvement in postoperative symptoms.Cerebral angiography was performed in 53 cases(104 sides).The patients with good grade(A or B)accounted for 87.5%(91/104).Stroke occurred in7 cases(7.1%)during the follow-up period.Of the 4 cases treated conservatively,1 case lost follow-up and 3 cases did not have stroke during follow-up.Cox regression analysis showed that age of onset,sex,initial symptom,Suzuki stage,unilateral moyamoya disease and posterior cerebral artery involvement were not risk factors for postoperative stroke events(P>0.05).Conclusion: The onset age of Chinese pediatric patients with familial MMD is earlier.The presentation was predominantly ischemic.It is more common to affect first-degree relatives.The EDAS surgery can effectively modified the ischemic symptom in pediatric patients.Part 2 Association between RNF213 genes p.R4810 K variant polymorphism and clinical features in pediatric familial patients with Moyamoya diseaseObjective: The objective of this study was to investigate the correlation between p.R4810 K polymorphism of RNF213 gene and clinical features in children with familial moyamoya disease in China.Methods: Children with familial moyamoya disease admitted from August 2004 to June 2018 at the Fifth Medical Center of PLA General Hospital were enrolled.The RNF213 gene p.R4810 K single nucleotide polymorphism was determined.The correlation between different genotypes and clinical features was analyzed.The patients were divided into the posterior cerebral artery involved group and the the posterior cerebral artery uninvolved group.the independent correlation between p.R4810 K polymorphism and posterior cerebral artery involvement was determined by multivariate logistic regression analysis.Results: A total of 65 patients with familial moyamoya disease were included.The median age of onset is 6 years old.Male 37(56.9%),55(84.6%)with first symptoms of cerebral ischemia and 37(56.9%)with involvement of posterior cerebral artery.The proportion of female in p.R4810 K G > A mutation genotype group was significantly higher than that in the non-mutation genotype group.Age,sex,onset symptoms,and genetic patterns in the posterior cerebral arterial involved group were not statistically significant(p>0.05).The p.R4810 K genotype distribution in the posterior cerebral artery involved group was statistically significant compared with that in the post cerebral artery uninvolved group(X2=5.124,p=0.024).Multivariate logistic regression analysis revealed that the p.R4810 K G > A mutation(odds ratio 3.240,95% confidence interval 1.082-9.705)was an independent risk factor for posterior cerebral artery involvement after correction of age and sex.Conclusion: The p.R4810 K G>A mutation group in children with familial moyamoya disease are more common in female,and it is more likely to involve the posterior circulation.