BackgroundA founder variant of RNF213, p.R4810K (c.14429G>A, rs112735431), was recently identified as a major genetic risk factor for moyamoya disease (MMD) in Japan. Although the association of p.R4810K was reported to be highly significant and reproducible, the disease susceptibility of other RNF213 variants remains largely unknown. In the present study, we systematically evaluated the coding variants detected in Japanese patients and controls for associations with MMD.Methods and ResultsTo detect variants of RNF213, all coding exons were sequenced in 27 Japanese MMD patients without p.R4810K. We also validated all previously reported variants in our case–control samples and tested for associations in combination with previous Japanese study cohorts, including the 1000 Genomes Project data set, as population-based controls. Forty-six missense variants other than p.R4810K were identified among 370 combined patients and 279 combined controls in Japan. Sixteen of 46 variants were polymorphisms with minor allele frequency >1%, and, after conditioning on the p.R4810K genotype, were not associated with MMD. We conducted a variable threshold test using Combined Annotation-Dependent Depletion on the remaining 30 rare variants (minor allele frequency <1%), and the results showed that the frequency of potentially functional variants was significantly higher in patients than in controls (permutation, minimum P=0.045).ConclusionsNot only p.4810K but also other functional missense variants of RNF213 conferred susceptibility to MMD. Our analysis also revealed that ≈20% of Japanese MMD patients did not harbor susceptibility variants of RNF213, indicating the presence of other susceptibility genes for MMD.

Object Surgical revascularization is considered an effective treatment for juvenile patients with moyamoya disease (MMD). Yet the long-term outcome in surgically treated patients still needs to be clarified. More than 30 years have passed since the authors' department started intensively treating pediatric patients with MMD using indirect anastomosis techniques. In this study the authors surveyed the current status of these patients. Methods Activities of daily living (ADLs) were surveyed and present clinical status was assessed based on the modified Rankin Scale (mRS). Cerebrovascular events subsequent to surgical treatment were also recorded. Results Since 1979, 208 patients younger than 19 years of age with MMD were surgically treated and followed up for > 3 years. Data were available on 172 patients (83%), who had been followed up for a mean of 14.3 years (range 3–32 years). Activity of daily living outcomes were as follows: 138 patients (80.2%) had mRS scores of 0–2, 29 (16.9%) a score of 3, 1 (0.6%) a score of 4, 1 (0.6%) a score of 5, and 3 (1.7%) a score of 6. Cerebrovascular events occurred 8 or more years after surgery in 6 patients (3.4%), that is, 6 hemorrhages and 3 infarctions. The cumulative risk of late-onset stroke at 10, 20, and 30 years after surgical intervention was 0.8%, 6.3%, and 10.0%, respectively. Conclusions This long-term survey demonstrated that most surgically treated pediatric patients with MMD maintain good ADL outcomes. However, a significant number of new cerebrovascular events occurred more than 10 years after the initial surgery. Additional follow-up will help to identify which events may occur during the adult years of patients treated as children.

Moyamoya disease is a progressive steno-occlusive condition of the main intracranial arteries that results in the compensatory formation of fragile moyamoya vessels at the base of the brain. RNF213 is the most significant susceptibility gene and is often found with the p.Arg4810Lys founder variant in East Asian patients. We identified three putatively deleterious variants of this gene from three pediatric patients: two were novel, and one was a recurrent missense variant previously reported in other pediatric patients.

DSC-MRI, dynamic susceptibility contrast magnetic resonance imagingMMD, moyamoya diseaseMTT, mean transit timeROI, region of interest.

abbreviatioNs CBF = cerebral blood flow; CBV = cerebral blood volume; CPP = cerebral perfusion pressure; MMD = moyamoya disease; MTT = mean transit time; OEF = oxygen extraction fraction; STA = superficial temporal artery. The object of this study was to analyze the pathology of collateral vessels newly induced by indirect bypass surgery for moyamoya disease (MMD). An autopsy analysis was conducted on a 39-year-old woman with MMD who had died of a brainstem infarction. The patient had undergone bilateral indirect bypass surgeries 22 years earlier. Sufficient revascularization via bilateral external carotid arterial systems was confirmed by cerebral angiography before her death. Macroscopic observation of the operative areas revealed countless meandering vessels on the internal surface of the dura mater connected with small vessels on the brain surface and in the subpial brain tissue. Notably, microscopic analysis of these vessels revealed the characteristic 3-layer structure of an arterial wall. This autopsy analysis was the first to confirm that indirect bypass surgery had induced the formation of a new arterial network (arteriogenesis) and that this network had been maintained for more than 20 years to compensate for the chronic cerebral ischemia caused by the MMD.