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.

Background: Homozygosity of this p.R4810K founder variant of RNF213moyamoya disease (MMD) susceptibility gene is known to influence the severity of the clinical disease phenotype at disease onset. However, the association between this genotype and long-term clinical manifestations has remained unclear. Objectives: The principal goal of this study was to investigate whether and how the p.R4810K variant of RNF213influences the long-term phenotype in Japanese patients with MMD. Method: This retrospective cohort study included 94 Japanese patients with MMD who underwent direct or combined bypass for revascularization with the p.R4810K genotype determined in our hospital. The following phenotypic parameters were analyzed at disease onset and over a long-term period: age and initial presentation at onset, recurrent stroke after initial revascularization, and final modified Rankin Scale. Results: The p.R4810K genotype was significantly associated with the phenotype at onset, especially in younger patients. Over a median follow-up period of 100 months, recurrent stroke occurred in 6 out of 94 patients: none out of 5 patients with the homozygous variant, 5 out of 64 with the heterozygous variant, and 1 out of 25 in the wild-type group. There were no significant differences among the genotypes. In particular, recurrent cerebral hemorrhage occurred in 5 patients, all possessing the heterozygous variant. The log-rank test showed no difference between the genotypes in the stroke-free survival rate. Furthermore, the p.R4810K genotype was not associated with a poor functional condition. Conclusions: The p.R4810K founder variant of RNF213 affects the phenotype at disease onset. However, the optimal revascularization may be effective, regardless of the genotype, even for the homozygous variant, which has been thought to be the most pathogenic. This genotype may not strongly influence the long-term clinical manifestations or poor prognosis in MMD.

Objective: Hyponatremia is a common electrolyte disorder in patients with stroke, which leads to various fatal complications. We performed a systematic review and meta-analysis to investigate the outcomes of acute stroke patients with hyponatremia. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library databases for relevant literature in English published up to March 2020. Two review authors independently screened and selected the studies by assessing the eligibility and validity based on the inclusion criteria. Mortality at 90 days was set as the primary end point, and in-hospital mortality and length of hospital stay were set as the secondary end points. We conducted the data synthesis and analyzed the outcomes by calculating the odds ratio (OR) and mean difference. Results: Of 835 studies, 15 studies met the inclusion criteria (n = 10,745). The prevalence rate of stroke patients with hyponatremia was 7.0-59.2%. They had significantly higher 90-day mortality (OR, 1.73; 95% confidence interval (CI), 1.24-2.42) and longer length of hospital stay (mean difference, 10.68 days; 95% CI, 7.14-14.22) than patients without hyponatremia. Patients with hyponatremia had a higher tendency of in-hospital mortality than those without hyponatremia (OR, 1.61; 95% CI, 0.97-2.69). Conclusions: The development of hyponatremia in the clinical course of stroke is associated with higher short-term mortality and a longer hospital stay. Although the causal relationship is unclear, hyponatremia could be a significant predictor of poor outcomes after stroke.

A 20-year-old woman presented with subarachnoid hemorrhage (SAH) in the frontal interhemispheric fissure, and a cystic lesion in the left frontal lobe. Cerebral angiography demonstrated no aneurysm or vascular abnormalities. T 1 -weighted magnetic resonance imaging with contrast medium revealed an enhanced lesion along the falx. The lesion and cyst were removed, and histological examination revealed a pilocytic astrocytoma. Spontaneous intracranial hemorrhage from pilocytic astrocytoma is rare, with only 15 reported cases mostly involving intratumoral hemorrhage in the parenchyma of hypothalamic and cerebellar tumors. SAH caused by cerebral hemisphere pilocytic astrocytoma is extremely rare. This case suggests that interhemispheric fissure SAH, not associated with aneurysm or abnormal vascularity, could originate from small, low-grade glioma in the superficial cerebral hemisphere.

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A 60-year-old man presented with a rare cerebellar inflammatory myofibroblastic tumor (IMT) manifesting as gait disturbance and dysarthria. Brain magnetic resonance imaging demonstrated an intra-axial round-shaped isointense mass homogeneously enhanced with gadolinium in the right cerebellar hemisphere, as well as perifocal edema extending to the brain stem and right thalamus. The tumor was elastic hard and was resected en bloc with a clear margin. Histological examination revealed IMT with spindle cells and collagen, but negative for anaplastic lymphoma kinase expression. IMT most commonly affects the lung, but may involve many other parts of the body. There is some debate regarding the disease entity of IMT in the central nervous system (IMT-CNS) because of its rarity and high frequency of recurrence. IMT-CNS is an important differential diagnosis among tumor-like intracranial lesions and total resection is required.