Aplastic or twig-like middle cerebral artery and cardiogenic cerebral embolism mimicking moyamoya disease with RNF213 polymorphism: A case report

Progressive stenosis and occlusion of the bilateral internal carotid artery terminals and circle of Willis are typical features of Moyamoya disease. However, aplastic or twig-like middle cerebral artery (Ap/T-MCA)—wherein the unilateral main trunk of the middle cerebral artery (MCA) is not depicted, and a plexiform arterial network is formed—is similar to the findings of Moyamoya disease. Here, we describe a 78-year-old man who presented with mild right paralysis and aphasia. Magnetic resonance angiography (MRA) at admission did not show the bilateral MCAs. The findings were similar to those of Moyamoya disease, and his symptoms worsened after hospitalization. Endovascular treatment was performed, and the left MCA was completely recanalized. Later, paroxysmal atrial fibrillation was detected, and we finally determined that left MCA occlusion had occurred due to embolism. The right MCA was completely occluded at its origin, indicating an Ap/T-MCA. Embolic occlusion of the unilateral MCA and contralateral Ap/T-MCA made this case resemble Moyamoya disease in the acute stage. Even when chronic occlusion is suspected on MRA in acute cerebral infarction, endovascular treatment should be considered. Additionally, a heterotypic R4810K polymorphism was later found in the RNF213 gene. To our knowledge, this is the second report of Ap/T-MCA with the RNF213 gene polymorphism; however, their association remains unclear and requires further analyses.

The Genetic Basis of Moyamoya Disease

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive spontaneous bilateral occlusion of the intracranial internal cerebral arteries (ICA) and their major branches with compensatory capillary collaterals resembling a “puff of smoke” (Japanese: Moyamoya) on cerebral angiography. These pathological alterations of the vessels are called Moyamoya arteriopathy or vasculopathy and a further distinction is made between primary and secondary MMD. Clinical presentation depends on age and population, with hemorrhage and ischemic infarcts in particular leading to severe neurological dysfunction or even death. Although the diagnostic suspicion can be posed by MRA or CTA, cerebral angiography is mandatory for diagnostic confirmation. Since no therapy to limit the stenotic lesions or the development of a collateral network is available, the only treatment established so far is surgical revascularization. The pathophysiology still remains unknown. Due to the early age of onset, familial cases and the variable incidence rate between different ethnic groups, the focus was put on genetic aspects early on. Several genetic risk loci as well as individual risk genes have been reported; however, few of them could be replicated in independent series. Linkage studies revealed linkage to the 17q25 locus. Multiple studies on the association of SNPs and MMD have been conducted, mainly focussing on the endothelium, smooth muscle cells, cytokines and growth factors. A variant of the RNF213 gene was shown to be strongly associated with MMD with a founder effect in the East Asian population. Although it is unknown how mutations in the RNF213 gene, encoding for a ubiquitously expressed 591 kDa cytosolic protein, lead to clinical features of MMD, RNF213 has been confirmed as a susceptibility gene in several studies with a gene dosage-dependent clinical phenotype, allowing preventive screening and possibly the development of new therapeutic approaches. This review focuses on the genetic basis of primary MMD only.

MBRS-22. SIGNIFICANCE OF RNF213 IN TUMORGENICITY OF MEDULLOBLASTOMA

RNF213 gene, initially identified as a disease-causing gene for moyamoya cerebrovascular disease, has recently been recognized as a tumor regulator. The gene is known to be associated with WNT signaling, lipid metabolism, angiogenesis and genomic instability. The purpose of this study was to investigate the association of RNF213 in tumorgenicity of medulloblastoma. Incidence of medulloblastoma and histopathological findings were compared among ptch1+/-, ptch1+/- rnf213+/-, and ptch1+/- rnf213-/- mice. Knockout of rnf213 in ptch1+/- transgenic mouse model increased the incidence of spontaneous generation of medulloblastoma from 19.8% (ptch1+/-) to 76.5% (rnf213+/- ptch1+/-) at 9 months (p < 0.001). Heterozygous knockout was equivalent to homozygous knockout. Haploinsufficiency of rnf213 seems to be associated with tumorgenicity in medulloblastoma. Molecular mechanism of medulloblastoma generation needs to be further investigated.

RNF213 gene mutation of circulating tumor DNA in early diagnosis of NSCLC using targeted next-generation sequencing

Introduction To distinguish early stage lung cancer from benign disease of the lung nodules, especially the lesions with ground-glass opacity (GGO) or ground-glass nodule (GGN), we assessed gene mutations of the ctDNA in peripheral blood by using targeted next-generation sequencing (NGS). Methods Single lung nodule patients without mediastinal lymph nodes or symptoms hardly diagnosed by chest CT and biomarker of lung cancer were enrolled. All patients received minimally invasive surgery but refused preoperative biopsy. Gene mutations of pre-operative blood samples were detected by targeted NGS. Mutations with statistical differences were screened in lung cancer and benign disease grouped by postoperative pathology. Gene expression was determined by immunohistochemistry. Highly expressed genes were selected as biomarkers to verify the mutations in peripheral blood. Results In training set, RNF213, KMT2D, CSMD3 and LRP1B genes mutated more frequently in early stage lung cancer (25cases) than benign nodules (18cases) (P<0.05). High expressions of RNF213 gene in lung cancers and low expressions in benign diseases were evaluated by immunohistochemistry. RNF213 gene mutated in 25% lung cancer samples in the validation set of 28 samples and showed high specificity (100%) and low sensibility (25.9%). In GGO and GGN patients, RNF213 mutated more frequently in early stage lung cancer compared to benign diseases (P<0.05). Conclusions RNF213 gene mutation was observed more frequently in early stage lung cancer, but rather than benign nodules. Mutation of RNF213 gene in peripheral blood may be a high specificity biomarker and valuable for early diagnosis of lung cancer.

Abstract WP151: Genetic Variant RNF213 in non-MMD Intracranial Major Artery Stenosis/Occlusion in Chinese Han Population and HR-MRI Findings

Introduction: Ring finger protein 213 (RNF213) gene R4810K variant,a susceptibility locus for moyamoya disease disease (MMD) in eastern Asian, has also recently been identified as a susceptibility locus for non-MMD Intracranial Major Artery Stenosis/Occlusion (non-MMD ICASO). Due to genetic heterogeneity, further studies are needed to verify whether the R4810K variant of RNF213 is associated with ICASO in other populations. Methods: RNF213 gene R4810K variant was genotyped in 114 patients with non-MMD ICASO (male, 78.9%) and 268 healthy controls(male, 73.5%)from the Chinese Han population. Association between RNF213 gene R4810K variant and non-MMD ICASO was analyzed in a case-control study. Patients with RNF213 variant-related ICASO were scanned High resolution (HR)-MRI, and the presumptive diagnosis of these patients was made based on the HR-MRI characteristics. Results: The RNF213 R4810K variant was observed in 8 (7.0%, including 5 females) patients with non-MMD ICASO and only in 1 (0.4%) healthy control. The RNF213 R4810K variant was associated with non-MMD ICASO and increased the risk for non-MMD ICASO (P<0.01; OR, 20.2; 95% confidence interval, 2.5-163.1) (Figure 1A). Presumptive MMD based on HR-MRI findings was diagnosed in all female patients with RNF213 variant-related ICASO. However, presumptive intracranial atherosclerotic stenosis was diagnosed based on HR-MRI findings in one of three males harboring the RNF213 variant (Figure 1B). Conclusions: RNF213 R4810K appears to be a genetic risk variant for non-MMD ICASO among the Chinese Han population. HR-MRI supported that RNF213 variant-related ICASO should be identified as MMD in female patients. However, a similar relationship could not be established among male patients. Our data suggest that detection of R4810K in female patients with ICASO is a useful biomarker to differentiate MMD from other ICASO.