Moyamoya disease (MMD) is an idiopathic cerebrovascular disorder characterized by progressive stenosis of the internal carotid artery termini and the formation of an abnormal network of fragile perforators. Although the RNF213 gene has been implicated as a susceptibility factor for MMD, the precise genetic basis of the disease remains elusive. This study aimed to investigate other genetic factors contributing to differences in disease manifestation and vascular phenotypes. We conducted whole-exome sequencing of patients with RNF213-related vasculopathy and healthy controls. In total, 122 patients (comprising 69 with bilateral MMD, 13 with unilateral MMD, and 40 with intracranial artery stenosis [ICAS]) and 458 controls were enrolled. Following appropriate quality control measures, case-control analysis and in-case analysis (bilateral MMD vs. unilateral MMD and ICAS) were conducted using single-variant association testing and gene-based aggregation testing. Although no significant locus or gene was found in the case-control analysis, the PKHD1 gene emerged as a top candidate associated with bilateral MMD in the in-case analysis. Two rare damaging variants, p.Ile2364Asn and p.Ser3210Cys, were significantly more prevalent in the bilateral MMD group and were further validated in an independent cohort of 216 individuals. Publicly available single-cell transcriptome data of mouse cerebrovascular and perivascular cells revealed that Pkhd1 expression was significantly higher in specific endothelial-cell clusters. Despite some limitations, our study provides new insights into the potential role of the PKHD1 gene in bilateral MMD, highlighting the need for further investigation of endothelial gene expression in patients with RNF213 and PKHD1 mutations.

Moyamoya disease (MMD) is a rare, progressive cerebrovascular disorder marked by stenosis of the terminal internal carotid arteries and the formation of fragile collateral vessels, leading to reduced cerebral perfusion and heightened risks of ischemic and hemorrhagic strokes. Its pathophysiology involves endothelial dysfunction, aberrant angiogenesis, and genetic mutations, notably in the RNF213 gene. This paper examines normal cerebrovascular physiology, the pathological changes driving MMD, its clinical features, and current therapeutic approaches. Treatments, including medical management and surgical revascularization (e.g., direct and indirect bypass), aim to restore cerebral blood flow and mitigate stroke risk, with revascularization proving most effective. Elucidating the physiological underpinnings of MMD is vital for developing targeted therapies and enhancing patient outcomes.

Global research trends and emerging hotspots of RNF213 in Moyamoya disease: A bibliometric analysis (2011-2024).

Moyamoya disease is a rare and progressive cerebrovascular disorder marked by the occlusion or blockage of the distal internal carotid arteries and their main branches. In response, the brain develops a network of fragile collateral vessels, which appear as a “puff of smoke” on angiographic imaging—a characteristic feature that inspired the disease’s name. The condition primarily affects children and young adults, often presenting with transient ischemic attacks, strokes, seizures, or cerebral haemorrhage. Although the underlying mechanisms are not fully understood, genetic factors, particularly mutations in the RNF213 gene, have been closely associated with disease susceptibility, The major susceptibility gene for moyamoya disease in people investigation into the mechanisms of disease and potential treatment targets. The Arg4810Lys variant of the gene is most strongly associated with moyamoya disease, but the penetrance is lower than 1%, suggesting a synergistic relationship with additional environmental and genetic risk factors. A 11-year-old female patient presented with the complaints of sudden onset of left upper limb and lower limb transient weakness associated with bowel incontinence patient has a past medical history of seizures since 10 months with multiple seizure episodes Diagnostic evaluation typically involves magnetic resonance imaging, magnetic resonance angiography, and digital subtraction angiography, the latter of which remains the gold standard. Treatment strategies are primarily surgical, with revascularization procedures—either direct, indirect, or combined approaches—aimed at improving cerebral blood flow and reducing the risk of ischemic events . Based on laboratory investigations and radiological reports case was diagnosed as MOYAMOYA DISEASE preoperative and anaesthesia clearance patient was taken up for STA-MCA bypass (Superficial Temporal Artery to Middle Cerebral Artery Bypass) associated treatment with perivascular sympathectomy and superior cervical ganglionectomy may be useful but more investigation needs to be carried out into the pathogenesis of the disease before more definitive therapy is realized. This review outlines the latest developments in the understanding, diagnosis, and management of Moyamoya disease, with attention to its genetic background and surgical outcomes.

Genetic research on moyamoya disease(MMD) has advanced significantly following the identification of RNF213 as a susceptibility gene. Approximately 80% of Japanese patients with MMD harbor the RNF213 p.Arg4810Lys variant, which has been increasingly linked to variations in clinical phenotypes, including disease progression, mode of onset, and postoperative outcomes. Of note, this variant is also associated with intracranial arterial stenosis that does not meet the diagnostic criteria for MMD, as well as with systemic vascular conditions such as non-cardioembolic ischemic stroke, coronary artery disease, and pulmonary hypertension. Despite its strong association with the disease, the p.Arg4810Lys variant is present in approximately 2% of the general population, suggesting incomplete penetrance and the involvement of additional pathogenic factors. In parallel, researchers have examined the clinical relevance of RNF213 variants other than p.Arg4810Lys and have identified rare mutations that may contribute to disease severity. Moreover, large-scale genetic analyses have identified additional susceptibility genes, such as DIAPH1 and ANO1, whose roles in MMD pathogenesis remain under investigation. Although substantial advances have been made in elucidating the genetic architecture of MMD, the precise mechanisms underlying disease onset remain elusive and represent an important area of ongoing research.

Here, I briefly describe the determination of locus 17q25 on chromosome 17 for a moyamoya disease susceptibility gene, focusing on our study. At the beginning of the study, linkage analysis was challenging. However, our efforts finally achieved statistically significant results at locus 17q25 with a logarithm of odds(LOD) score of 3.11, a maximum LOD score of 4.58, and p-value of 0.00001 with parametric linkage analysis, multipoint analysis, and nonparametric Affected Pedigree Member analysis, respectively. This was due to the good fortune of choosing chromosome 17 as the primary target, given that neurofibromatosis type 1 and moyamoya disease occur simultaneously in some cases. Moreover, our success was largely due to the contributions of our collaborators who precisely determined the disease traits and collected DNA(leukocyte) samples from 103 individuals from 24 families. After our publication in 2000, a research group from Kyoto University searched for the locus 17q25.3 and discovered a mutation in RNF213 gene. Simultaneously, a group from Tohoku University performed a genome-wide association study and determined RNF213 to be a susceptibility gene for moyamoya disease. This occurred 11 years after our first results.

The p.R4810K variant of the RNF213 gene was identified as the founder variant of East Asian moyamoya disease. The association of the p.R4810K variant with non-moyamoya intracranial arterial stenosis has been demonstrated, and the concept of RNF213-related vasculopathy has been proposed, suggesting a continuous spectrum of moyamoya disease. Additionally, moyamoya disease is occasionally accompanied by polyvascular disease involving intracranial and neck vessels, coronary arteries(especially vasospastic angina), pulmonary arteries, aorta, abdominal visceral arteries, and peripheral arteries, which are associated with RNF213 variants, mainly p.R4810K. The severity of vascular diseases caused by the RNF213 variant is inconsistent, and some environmental and genetic factors are believed to jointly define the phenotype. RNF213 variants confer the greatest risk of cardiovascular diseases in East Asia. Therefore, successful targeting of these variants is essential for controlling cardiovascular diseases, including stroke, in East Asian countries.

Moyamoya disease (MMD) is a rare, progressive cerebrovascular disorder marked by stenosis of the terminal internal carotid arteries and the formation of fragile collateral vessels, leading to reduced cerebral perfusion and heightened risks of ischemic and hemorrhagic strokes. Its pathophysiology involves endothelial dysfunction, aberrant angiogenesis, and genetic mutations, notably in the RNF213 gene. This paper examines normal cerebrovascular physiology, the pathological changes driving MMD, its clinical features, and current therapeutic approaches. Treatments, including medical management and surgical revascularization (e.g., direct and indirect bypass), aim to restore cerebral blood flow and mitigate stroke risk, with revascularization proving most effective. Elucidating the physiological underpinnings of MMD is vital for developing targeted therapies and enhancing patient outcomes.

Moyamoya arteriopathy is an important cause of stroke across the lifespan, with high rates of incident and recurrent stroke in affected individuals. Although it affects adults and children globally, moyamoya is more prevalent in East Asian countries, particularly Japan and Korea. The R4810K variant of the RNF213 gene, most common in Asian populations, is associated with severe, early onset, multisystem vasculopathy. Neuroimaging is critical for moyamoya diagnosis and treatment planning, with conventional imaging, catheter angiography, perfusion imaging, and cerebrovascular reactivity assessment all having a place within moyamoya care. Medical management of moyamoya entails reducing the competing risks of ischemic and hemorrhagic stroke as well as managing coexisting conditions, such as headache, epilepsy, and neuropsychological sequelae. Antiplatelet therapy is commonly prescribed to prevent thromboembolic stroke, although data supporting this practice are limited and practice patterns vary globally. Promoting cerebral oxygen and nutrient delivery with sufficient fluid intake, maintaining adequate blood pressure, and avoiding anemia and hypoglycemia aid in stroke prevention in moyamoya. Definitive treatment of moyamoya is predicated on surgical revascularization, which aims to augment perfusion to at-risk brain tissue and decrease the risk of hemorrhage from fragile moyamoya collaterals. Although surgery is highly effective in appropriately selected patients, perioperative ischemic events occur following 4%-18% of cases. Perioperative medical management aims to mitigate this risk by optimizing brain oxygen delivery through adequate cerebral perfusion and blood oxygenation, pain/nausea control, minimizing metabolic demand, and preventing thrombosis. Long-term neuroimaging surveillance, evaluation of the neuropsychological effect of moyamoya, and screening for and management of headache and epilepsy resulting from moyamoya are important aspects of the chronic care of all patients with moyamoya. In this review, we summarize key aspects of neurologic evaluation and management for moyamoya across the lifespan, highlight key differences between adult and pediatric moyamoya, and discuss ongoing research efforts that aim to improve care of children and adults with moyamoya.

Introduction: Moyamoya disease (MMD) is a rare cerebrovascular disease causing nonatherosclerotic intracranial arterial stenosis in children and young adults. The RNF213 gene variant plays an important role in the pathophysiology of MMD, particularly among East Asian populations. However, this variant is rarely found in patients of other ethnicity. Previous studies have shown that RNF213 gene variant is related to vascular structures such as the extent of moyamoya collaterals and posterior cerebral artery involvement. In this study, we utilize an imaging-based approach to investigate vascular structural features in MMD, which may offer novel insights into the pathophysiology of MMD. Methods: We retrospectively reviewed 770 patients with MMD or Moyamoya syndrome (MMS) from diverse ethnic backgrounds at Stanford University Medical Center treated between 2015 and 2024 (Fig. 1). After selecting sporadic non-hemorrhagic bilateral MMD patients aged 18-50 years old, the vascular structures acquired on MRA were visually assessed to evaluate the degree of intracranial arterial stenosis and basal moyamoya collaterals. T2 weighted images were reviewed to assess negative remodeling - shrinkage of the outer diameter of middle cerebral arteries (MCA) and internal cerebral arteries (ICA) as defined by Kuroda et al.2015, Neurol Med Chir (Tokyo). Results: Detailed demographic and clinical characteristics of 107 patients evaluated were listed in Table 1. By reviewing MRA, we have identified a subset of patients with unique imaging features characterized by ICA stenosis localized proximal to the terminal portion of ICA, differing from the typical lesion sites seen in MMD (Fig. 2). This non-terminal ICA stenosis was more frequently observed in Caucasian than in Asian patients (17.5% vs. 5.7%, P=0.007). Compared to patients with terminal ICA and/or MCA stenosis, patients with non-terminal ICA stenosis were older (P=0.03), had less advanced disease stages (P<0.001), and displayed fewer basal moyamoya collaterals (P=0.002). Conclusion: Using the imaging-based approach of vascular structural features, we have identified a potential subtype of moyamoya disease characterized by non-terminal ICA stenosis. This subtype may have a different pathophysiology from patients with typical ICA terminal stenosis, potentially driven by distinct genetic and epigenetic factors. Ongoing investigations are focused on elucidating these factors and their implications in MMD.

Background: The p.R4810K founder mutation in the RNF213 gene confers susceptibility to moyamoya disease (MMD) and non-MMD intracranial artery disease. However, penetrance is incomplete, and the underlying molecular mechanism remains unknown. Methods and Results: Transcriptome analysis of peripheral blood was conducted with 9 MMD patients and 5 unaffected mutation carriers from 4 familial MMD pedigrees. Bayesian network analysis identified upregulated gene modules associated with lipid metabolism and leukocyte development (including GATA2 and SLC45A3 ), and EGFR signaling ( UBTD1 ). It also identified downregulated gene modules related to mitochondrial ribosomal proteins ( RPS3A and RPL26 ), and cytotoxic T cell immunity ( GZMA and TRGC1 ). The GATA2 network was replicated through WGCNA analysis and further examined in a case-control study, comprising 43 MMD patients, 16 non-MMD patients, 19 unaffected carriers, and 35 healthy controls. GATA2 exhibited a significant linear correlation with SLC45A3 and was significantly higher in MMD patients compared to age- and sex-matched unaffected carriers or wild-type controls. Among patients with the p.R4810K mutation, higher GATA2 expression was associated with an earlier age of onset, bilateral involvement, and symptomatic disease onset. Conclusions: Peripheral blood GATA2 expression was associated with increased penetrance of the RNF213 mutation and more severe clinical manifestations in MMD.

Moyamoya disease (MMD) is a vascular disorder characterized by steno-occlusive alterations in cerebral arteries, often resulting in ischemic or hemorrhagic events predominantly affecting the female population and more common in Asian populations. Despite its predominantly neurological manifestations, recent research suggests a potential association between MMD and cardiovascular diseases (CVDs). MMD involves various genetic and environmental factors, with mutations in the RNF213 gene being strongly implicated in disease susceptibility, with histopathological findings revealing intimal lesions and smooth muscle proliferation, contributing to vascular occlusion as well as dysregulation of circulating endothelial and smooth muscle progenitor cells further complicating MMD's pathogenesis. However, the exact nature of the relationship between MMD and CVD remains incompletely understood, and emerging evidence suggests a potential interplay between these pathologies. In this study, we discuss the potential link between MMD and CVD, exploring genetic factors, pathophysiological mechanisms, and studies highlighting cardiac manifestations in MMD patients.

BackgroundThe 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....

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by progressive stenosis of the terminal internal carotid arteries and the formation of compensatory collateral vessels, which appear as a “puff of smoke” on cerebral angiography. It is a significant cause of stroke in East Asia, with an incidence of 0.5 to 1.5 cases per 100,000 people annually. The etiology of MMD remains unclear; however, the identification of the RNF213 gene, particularly the R4810K variant, as a major susceptibility factor among the East Asian population, has provided crucial insights into the disease's pathophysiology and clinical manifestations. MMD typically presents with transient ischemic attacks, ischemic and hemorrhagic strokes, seizures, headaches, and cognitive deficits. Diagnostic criteria have evolved to emphasize advanced imaging techniques. Pathological features include fibrocellular intimal thickening, irregular undulation of the elastic lamina, and the formation of moyamoya vessels. The mutation in the RNF213 gene impairs the degradation of proteins involved in vessel development, leading to abnormal angiogenesis. Genotype-phenotype studies indicate that the RNF213 variant is associated with an earlier onset, transient ischemic attacks, infarctions, and involvement of the posterior cerebral artery, although its effects vary between regions. Additionally, the homozygous RNF213 variant consistently correlates with an earlier age of onset and a higher risk of cerebral infarction. However, further research is necessary to fully understand its long-term impacts and its relationship with revascularization outcomes. Ongoing research is crucial to fully comprehend the pathophysiology and genetics of MMD, improve prognostic predictions, and develop novel therapies.

Abstract Disclosure: B. Agrawal: None. V. mehta: None. R. Naseem: None. H. patel: None. Introduction: Moyamoya syndrome, characterized by progressive intimal hyperplasia in the terminal parts of the internal carotid artery and the circle of Willis, leads to stenosis followed by collateralization, resulting in a characteristic "smoky" appearance on angiography, known as "Moya-Moya." This rare vasculopathy has shown an increasing association with Graves' disease. Case Presentation: A 37-year-old female with a medical history of SLE, Graves' disease, Sjogren's syndrome, and hypertension presented with left facial droop and weakness lasting 24 hours. She had a similar episode four months prior, which resolved spontaneously. Initial CT scan revealed scattered areas of parenchymal attenuation in the periventricular white matter. Further imaging with CTA demonstrated steno-occlusive distal intracranial internal carotid artery and bilateral M1 segments, characteristic of Moyamoya syndrome. Concurrently, she had an enlarged multinodular goiter. Laboratory findings showed high t4 and low TSH due to non-compliance to medications. MRI confirmed a multifocal acute/subacute infarct in the right MCA territory. Vasculitis and hypercoagulable work up was negative. Neurosurgical intervention was deferred, and within 24 hours, the patient experienced complete resolution of symptoms with methimazole, aspirin and statin. Discussion Moyamoya syndrome, predominantly affecting Japanese and South Asian populations, often exhibits familial predisposition linked to the RNF213 gene. Typically affecting females with a mean age of 33, Moyamoya in Graves' disease presents with ischemic stroke or TIA during thyrotoxic states, characterized by suppressed TSH and elevated T4, which usually resolves with anti-thyroid therapy. Elevated thyroid autoantibodies are frequently observed in the cases reported so far. However, in contrast to strokes associated with Graves' disease, other autoimmune conditions such as T1DM and neurofibromatosis often manifest with haemorrhagic strokes. Angiography commonly reveals unilateral or asymmetrical vascular lesions, possibly linked to thyrotoxic states increasing cerebral metabolism and inducing multiple stenoses. Conclusion: In female patients presenting with transient ischemic attack (TIA) or ischemic stroke and diagnosed with Moyamoya syndrome on angiography, thyroid disorder screening is crucial. Elevated thyroid antibodies indicate a potential thyroid disorder, warranting initiation of anti-thyroid drugs alongside stroke management protocols to alleviate symptoms. This aims to improve patient outcomes by addressing both vascular and endocrine factors contributing to the pathology of Moyamoya syndrome in this specific demographic. Presentation: 6/1/2024

To discover the relationship between the RNF213 gene and acute myeloid leukemia (AML), and explore the effect of RNF213 on the proliferation and apoptosis of THP-1 cells. Analyze the expression of RNF213 gene in AML and its relationship with prognosis through the GEPIA database. Collecting 30 AML patients and non-tumor hematological patients who went to the Affiliated Hospital of Zunyi Medical University from January 2017 to January 2022. RT-qPCR and Western blot were used to detect the expression levels of RNF213 mRNA and protein. Perform survival of patients was analysed by Kaplan-Meier. Meanwhile, the expression levels of RNF213 mRNA and protein were detected in AML cell lines (THP-1, OCI-AML2 ). CRISPR-Cas9 was used to knockdown the RNF213 gene in THP-1 cells; flow cytometry was used to detect apoptosis rate of cell. CCK-8 and colony formation assay were used to detect cell proliferation. Western blot was used to detect the expression level of Cleaved-Caspase 3 protein. Compared with the control group, the expression level of RNF213 in AML patients was significantly increased, and patients with high expression of RNF213 have a worse prgnosis. Higher expression level of RNF213 protein in THP-1 cells. After knocking down the RNF213 gene of THP-1 cells, cell proliferation was significantly reduced, and the apoptosis rate and expression of apoptosis related protein Cleared-Caspase3 were significantly increased. AML patients have high expression of RNF213 , and the prognosis of high expression patients is poor. The RNF213 gene affects AML cell proliferation and apoptosis, and may be a prognostic marker and potential therapeutic target for AML.

Common and distinct risk profiles of asymptomatic extra- and intracranial atherosclerosis in the Nagahama cohort

Moyamoya disease (MMD) is a cerebrovascular disorder that is predominantly observed in women of East Asian descent, and is characterized by progressive stenosis of the internal carotid artery, beginning in early childhood, and a distinctive network of collateral vessels known as "moyamoya vessels" in the basal ganglia. Additionally, a prevalent genetic variant found in most MMD cases is the p.R4810K polymorphism of RNF213 on chromosome 17q25.3. Recent studies have revealed that RNF213 mutations are associated not only with MMD, but also with other systemic vascular disorders, including intracranial atherosclerosis and systemic vascular abnormalities such as pulmonary artery stenosis and coronary artery diseases. Therefore, the concept of "RNF213-related vasculopathy" has been proposed. This review focuses on polymorphisms in the RNF213 gene and describes a wide range of clinical and genetic phenotypes associated with RNF213-related vasculopathy. The RNF213 gene has been suggested to play an important role in the pathogenesis of vascular diseases and developing new therapies. Therefore, further research and knowledge sharing through collaboration between clinicians and researchers are required.

Robust postoperative bypass development is a characteristic of moyamoya disease (MMD); however, genetic factors mediating this phenomenon remain incompletely understood. Therefore, we aimed to elucidate the relationship between postoperative donor artery development and genetic variants. We retrospectively enrolled 63 patients (79 hemispheres) who underwent combined revascularization surgery. Postoperative development of the superficial temporal artery (STA), middle meningeal artery, and deep temporal artery (DTA) was assessed using the caliber-change ratio determined from magnetic resonance angiography measurements. We analyzed RNF213 and 36 other moyamoya angiopathy-related genes by whole-exome sequencing and extracted rare or damaging variants. Thirty-five participants carried RNF213 p.Arg4810Lys (all heterozygotes), whereas 5 had RNF213 rare variants (RVs). p.Arg4810Lys was significantly associated with postoperative DTA development, while age at surgery, hypertension, and hyperlipidemia were inversely associated. Multiple regression analysis revealed that age and p.Arg4810Lys held statistical significance (P = 0.044, coefficient − 0.015, 95% confidence interval (CI) − 0.029 to 0.000 and P = 0.001, coefficient 0.670, 95% CI 0.269 to 1.072, respectively). Those with RNF213 RV without p.Arg4810Lys exhibited a significant trend toward poor DTA development (P = 0.001). Hypertension demonstrated a significant positive association with STA development, which remained significant even after multiple regression analysis (P = 0.001, coefficient 0.303, 95% CI 0.123 to 0.482). Following Bonferroni correction for multiple comparisons, targeted analyses of RNF213 and 36 moyamoya angiopathy-related genes showed a significant association of only RNF213 p.Arg4810Lys with favorable DTA development (P = 0.001). A comprehensive analysis of RNF213, considering both p.Arg4810Lys and RVs, may provide a clearer prediction of postoperative DTA development.

BackgroundMoyamoya disease (MMD) is a rare disorder causing ischemic and hemorrhagic juvenile stroke. It is associated with the founder susceptibility variant p.R4810K in the RNF213 gene in East Asia. Our aim was to enhance understanding of MMD in so far poorly characterized Southeast Asians and exploring differences with Caucasian Europeans.MethodsBy retrospective analysis of medical records and systematic database search on PubMed for all published cases, we identified Southeast Asian patients with MMD. We extracted and pooled proportions using fixed-effects models. Our own cohort was tested for the East Asian RNF213 founder variant p.R4810K. One of our Southeast Asian patients underwent post-mortem histopathological examination.ResultsThe study cohort comprised 32 Southeast Asians. Mean age at onset in the entire cohort was 32.5 ± 20.3 years (n = 24), 43.4 ± 8.7 years in patients admitted to our center (n = 11), and 23.4 ± 22.4 years in patients from the international literature (n = 13). Female-to-male ratio was 1.6:1. MMD predominantly affected bilateral anterior intracranial vessels. Cerebral ischemia outnumbered transient ischemic attacks (TIAs) and intracranial hemorrhage. TIAs, arterial hypertension and obesity were significantly less frequent in Southeast Asian patients compared to Caucasian Europeans. p.R4810K was absent in all examined Southeast Asians despite of typical histopathological signs of MMD in one autopsy case.ConclusionClinical and histopathological manifestations of MMD in Southeast Asians are similar to those in Caucasian Europeans. The genotype of MMD in Southeast Asians differs from that of most East Asian patients.