Materiały źródłowe

• #1 The Pathophysiology of Moyamoya Disease: An Update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4747070/

  Moyamoya disease (MMD) is a unique cerebrovascular disease characterized by the progressive stenosis of large intracranial arteries and a hazy network of basal collaterals called moyamoya vessels. […] The purpose of this review is to summarize the recent advances in MMD pathophysiology, including the genetic and circulating factors related to disease development. […] There is growing evidence that MMD is primarily a proliferative disease of the intima. […] The complicated pathologic features of the stenotic segments of MMD (e.g., a coexistence of proliferation and shrinkage) and the unknown nature of the neo-vascularization (e.g., an aberrant vs. compensatory process) suggest that MMD pathophysiology is a complex process. […] The exact function of RNF213 is unknown. […] These negative results could be consistent with the low penetrance rate of the RNF213 polymorphisms in patients with MMD, and may indicate the importance of environmental factors in addition to the genetic factors.

• #2 The Pathophysiology of Moyamoya Disease: An Update

  https://www.j-stroke.org/journal/view.php?doi=10.5853/jos.2015.01760

  Moyamoya disease (MMD) is a unique cerebrovascular disease characterized by the progressive stenosis of large intracranial arteries and a hazy network of basal collaterals called moyamoya vessels. […] This review summarizes the recent advances in MMD pathophysiology, including the genetic and circulating factors related to disease development. Genetic and environmental factors may play important roles in the development of the vascular stenosis and aberrant angiogenesis in complex ways. […] With a better understanding of MMD pathophysiology, nonsurgical approaches targeting MMD pathogenesis may be available to stop or slow the progression of this disease. […] The complicated pathologic features of the stenotic segments of MMD (e.g., a coexistence of proliferation and shrinkage) and the unknown nature of the neo-vascularization (e.g., an aberrant vs. compensatory process) suggest that MMD pathophysiology is a complex process.

• #3 The Pathophysiology of Moyamoya Disease: An Update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4747070/

  The MMD pathology is characterized by smooth muscle cell hyperplasia in the intima. […] Aberrant angiogenesis was an active angiogenetic process that may cause both stenosis through the proliferation of endothelial and/or smooth muscle cells and abnormal collateral formation. […] Although the pathogenic mechanisms of MMD are still unknown, there is growing evidence that it is primarily a proliferative disease, such that endothelial and smooth muscle proliferation results in the development of an occlusion, and enhanced, but aberrant, angiogenesis (i.e., moyamoya vessels).

• #4 Moyamoya Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535455/

  Moyamoya disease (MMD) is an isolated chronic, usually bilateral, vasculopathy of undetermined etiology characterized by progressive narrowing of the terminal intracranial portion of the internal carotid artery and circle of Willis. […] A fragile network of abundant collateral vessels as a reaction to chronic brain ischemia develops predominantly at the base of the brain known as moyamoya vessels. […] The pathophysiology of MMD remains unclear, though genetic predisposition is theorized in East Asian countries. Mutations in BRCC3/MTCP1 and GUCY1A3 genes are implicated in Moyamoya syndrome. Affected individuals are found to have concentric and eccentric fibro cellular thickening of intima within the intracranial portion of ICA. Chronic brain ischemia resulting from the narrowing is believed to be causing an overexpression of proangiogenic factors (fibroblast growth factor and hepatocyte growth factor) which, in turn, would cause the development of a fragile network of collateral vessels. […] Suzuki stages explain the process from the beginning of stenosis in the terminal portion of ICA and the appearance of a deep but fragile network of collaterals (moyamoya) to the reduction of moyamoya vessels with the simultaneous development of supply from external carotid artery branches.

• #5 Clinical and Immunopathological Features of Moyamoya Disease | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0036386

  Moyamoya disease (MMD) is a cerebrovascular disease characterized by progressive stenosis or occlusion of the terminal portion of internal carotid arteries and the formation of a vascular network at the base of the brain. The pathogenesis of MMD is still unclear. […] The pathogenesis of MMD is still unclear, although extensive studies have been carried out all over the world. […] Histopathology findings of intracranial vessels revealed a narrowed lumen due to intimal fibrous thickening without significant inflammatory cell infiltration, the vascular wall was thickened. The internal elastic lamina was markedly tortuous and stratified. […] Immunohistochemical examination showed -SMA-positive cells in the thickened intima, which suggested that vascular smooth muscle cells migrated into the intima and proliferated. Strikingly, S100A4 protein and IgG immunoreactivity were strongly positive in the media and intima of the major arteries in MMD patients.

• #6 Moyamoya Disease: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/1180952-overview

  Moyamoya disease is a progressive, occlusive disease of the cerebral vasculature with particular involvement of the circle of Willis and the arteries that feed it. […] Pathologically, moyamoya disease is characterized by intimal thickening in the walls of the terminal portions of the internal carotid vessels bilaterally. The proliferating intima may contain lipid deposits. The anterior, middle, and posterior cerebral arteries that emanate from the circle of Willis may show varying degrees of stenosis or occlusion. This is associated with fibrocellular thickening of the intima, waving of the internal elastic lamina, and thinning of the media. […] The term moyamoya (Japanese for „puff of smoke”) refers to the appearance on angiography of abnormal vascular collateral networks that develop adjacent to the stenotic vessels. The steno-occlusive areas are usually bilateral, but unilateral involvement does not exclude the diagnosis.

• #7 Moyamoya disease – Wikipedia

  https://en.wikipedia.org/wiki/Moyamoya_disease

  The arterial constrictions in moyamoya disease are unlike the constrictions in atherosclerosis. In atherosclerosis, the walls of arteries are damaged, leading to the deposition of fat and immune cells, and ultimately the accumulation of immune cells laden with fat. In moyamoya, the inner layer of the carotid artery proliferates within the arterial lumen. The artery also fills with blood clots, which may cause strokes. […] The disease causes constrictions primarily in the internal carotid artery, and often extends to the middle and anterior cerebral arteries, branches of the internal carotid artery inside the skull. When the internal carotid artery becomes completely blocked, the fine collateral circulation that it supplies is obliterated. Patients often survive on the collateral circulation from the back (posterior) of the circle of Willis, arising from the basilar artery.

• #8 Moyamoya Disease

  https://fpnotebook.com/CV/Vessel/MymyDs.htm

  Noninflammatory progressive Occlusion of the intracranial carotid arteries, triggering CVA findings, typically in children. […] Results from arterial wall thickening, endothelial hyperplasia and fibrosis either with associated conditions (MMS) or genetic/idiopathic (MMD). […] Internal Carotid Artery Stenosis progresses to affect the anterior cerebral arteries and middle cerebral arteries. […] Secondary formation of collateral arteries from the Circle of Willis in a netlike configuration (appears as „Puff of Smoke”, or in Japanase Moyamoya). […] Collateral vessels expand at the lenticulostriate, leptomeningial, thalamoperforating and dural arteries over the course of years into adulthood. […] Collateral vessels are fragile and more prone to rupture.

• #9 Genetics of Moyamoya disease | Journal of Human Genetics

  https://www.nature.com/articles/jhg2010103

  Moyamoya disease (MMD) is a disease pattern consisting of bilateral stenosis of the intracranial internal carotid arteries (ICA) accompanied by a network of abnormal collateral vessels that bypass the stenosis. […] The etiology of MMD is still unknown, although few associations with other diseases and environmental factors have been described. Strong regional differences in epidemiological data, as well as known familial cases, turned the focus to genetics for the insight into the disease’s pathogenesis. […] In the search for a better understanding of the pathogenesis of MMD, three major approaches may be considered: idiopathic, environmental or genetic causes, or a combination of any of the three. […] Evidence for a genetic contribution to MMD is suggested by the highly variable incidence rates between different ethnic groups, as described above, as well as the many familial occurrences described in the literature.

• #10 Moyamoya Disease: A Rare Vascular Disease of the CNS | IntechOpen

  https://www.intechopen.com/chapters/68650

  Moyamoya disease (MMD) is a rare disease affecting the cerebral vasculature of the central nervous system (CNS) with a reported incidence of 0.350.94 per 100,000 populations. […] The pathology is narrowing of blood vessels supplying anterior circulation and rarely posterior circulation. […] It was believed that the disease is genetic in origin, but environmental factors also play a role. […] Ten to fifteen percent of moyamoya disease (MMD) is familial in origin which indicates a genetic association. […] East Asian populations with RNF213 gene on chromosome 17q25.3 are susceptible to MMD. […] In another report from Japan, it was observed that a variant of RNF213 (c.14576G) was present in 41 patients with familial MMD (95%), 163 patients with sporadic MMD (79%), and 283 normal control subjects (2%).

• #10 Moyamoya Disease: A Rare Vascular Disease of the CNS | IntechOpen

  https://www.intechopen.com/chapters/68650

  Several inducers of angiogenesis such as fibroblast growth factor, transforming growth factor beta1, and hepatocyte growth factor which promote neovascularization were found in high levels in patients with MMD. […] In patients with this condition, large intracerebral arteries show a variable degree of stenosis and occlusions. […] Vascular intima shows fibrocellular thickening; elastic internal lamina will be tortuous, duplicate or triplicate; and the media show attenuation. […] The hallmark of MMD is the meshwork of dilated vessels called moyamoya vessels.

• #11

  https://journals.lww.com/cmj/fulltext/2024/11050/rnf213_in_moyamoya_disease__genotype_phenotype.5.aspx

  Moyamoya disease (MMD) is a cerebrovascular disorder characterized by a steno-occlusive internal carotid artery and compensatory vascular network formation. […] Although the precise pathogenic mechanism remains elusive, genetic association studies have identified RNF213 as the principal susceptibility gene for MMD, with the single nucleotide polymorphism p.R4810K recognized as the founder variant predominantly in the Asian populations. […] This heterogeneity, in conjunction with the observed low disease penetrance of RNF213 mutations, suggests that the presence of these mutations may not be sufficient to cause MMD, underscoring the potential influence of other genetic or environmental factors. […] Although the current research might not have fully identified these additional contributors, experimental evidence points toward the involvement of RNF213 in angiogenesis, lipid metabolism, and the immune response.

• #12 Exploring RNF213 in Ischemic Stroke and Moyamoya Disease: From Cellular Models to Clinical Insights

  https://www.mdpi.com/2227-9059/13/1/17

  RNF213 (Ring Finger Protein 213; Mysterin) is the main susceptibility gene for MMD, a rare, progressive ischemic cerebrovascular disorder. MMD is characterized by progressive, non-atherosclerotic stenosis and occlusion of the carotid arteries, particularly affecting the terminal portion of the intracranial internal carotid artery (ICA), proximal portions of the middle cerebral artery (MCA), and anterior cerebral artery (ACA). […] Although the exact cause of MMD is unknown, MMD is much more common in those with East Asian ancestry (especially Japan, Korea, and China), and a positive family history is observed in 9–15% of patients. […] The RNF213 gene is large (591 kD, 67 coding exons, and 5207 amino acids) and harbors multiple pathogenic missense variants that have been implicated in MMD. RNF213 p.R4810K (c.14576G>A) is the MMD founder variant with allele frequencies of up to 0.283% among East Asian populations.

• #12 Exploring RNF213 in Ischemic Stroke and Moyamoya Disease: From Cellular Models to Clinical Insights

  https://www.mdpi.com/2227-9059/13/1/17

  Advances in stroke genetics have highlighted the critical role of rare genetic variants in cerebrovascular diseases, with RNF213 emerging as a key player in ischemic stroke and Moyamoya disease (MMD). Initially identified as the primary susceptibility gene for MMD, RNF213—notably the p.R4810K variant—has been strongly linked to intracranial artery stenosis (ICAS) and various ischemic stroke subtypes, particularly in East Asian populations. This gene encodes an E3 ubiquitin ligase with diverse roles in angiogenesis, vascular remodeling, lipid metabolism, and cerebral blood flow regulation, yet its exact mechanisms in cerebrovascular pathology remain incompletely understood. […] Key mechanisms by which RNF213 variants contribute to disease pathogenesis are explored, alongside discussions on their clinical utility as biomarkers and therapeutic targets.

• #13 Moyamoya disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/moyamoya-disease/

  The RNF213 gene provides instructions for making a protein whose function is unknown. However, research suggests that the RNF213 protein is involved in the proper development of blood vessels. […] Changes in the RNF213 gene involved in moyamoya disease replace single protein building blocks (amino acids) in the RNF213 protein. The effect of these changes on the function of the RNF213 protein is unknown, and researchers are unsure how the changes contribute to the narrowing of blood vessels or the characteristic blood vessel growth of moyamoya disease. For unknown reasons, people with moyamoya disease have elevated levels of proteins involved in cell and tissue growth, including the growth of blood vessels (angiogenesis). An excess of these proteins could account for the growth of new blood vessels characteristic of moyamoya disease. It is not clear if changes in the RNF213 gene are involved in the overproduction of these proteins.

• #14 Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism | eLife

  https://elifesciences.org/articles/56185

  RNF213 is the major susceptibility factor for Moyamoya disease, a progressive cerebrovascular disorder that often leads to brain stroke in adults and children. […] Moreover, we show that pathologic MMD mutations cluster in the composite E3 domain, likely interfering with substrate ubiquitination. […] The major obstacle in understanding RNF213 is the lack of structural and biochemical data, hampered by the enormous size and complexity of the protein. Notably, with a mass of 591 kDa, RNF213 is the largest E3 ubiquitin ligase in the human proteome. […] The ubiquitin ligase activity of RNF213 is expected to depend on the E3-RING domain, which is located on top of the E3 scaffold composed by the E3-back, E3-shell, and E3-core domains. […] To characterize the E3 function of RNF213, we used auto-ubiquitination as a proxy readout for its catalytic activity. Our data demonstrate that RNF213 collaborates with UbcH7, a cysteine-reactive E2 enzyme typically stimulating ubiquitination activity of HECT and RBR E3 ligases.

• #15 The Pathophysiology of Moyamoya Disease: An Update

  https://www.j-stroke.org/journal/view.php?doi=10.5853/jos.2015.01760

  The exact function of RNF213 is unknown. […] These negative results could be consistent with the low penetrance rate of the RNF213 polymorphisms in patients with MMD, and may indicate the importance of environmental factors in addition to the genetic factors. […] The MMD pathology is characterized by smooth muscle cell hyperplasia in the intima. […] Aberrant angiogenesis was an active angiogenetic process that may cause both stenosis through the proliferation of endothelial and/or smooth muscle cells and abnormal collateral formation. […] The findings suggest an important role for retinoid signaling in MMD pathogenesis by controlling the growth factor expression. […] Although the pathogenic mechanisms of MMD are still unknown, there is growing evidence that it is primarily a proliferative disease, such that endothelial and smooth muscle proliferation results in the development of an occlusion, and enhanced, but aberrant, angiogenesis (i.e., moyamoya vessels).

• #16

  https://journals.lww.com/cmj/fulltext/2024/11050/rnf213_in_moyamoya_disease__genotype_phenotype.5.aspx

  Future research is required to unveil the molecular mechanisms and identify the factors that synergize with RNF213 in the pathogenesis of MMD. […] The identification of RNF213 as a susceptibility gene for MMD was supported by Liu et al. […] Extensive studies have been conducted on the founder variant p.R4810K, which has been confirmed to significantly correlate with MMD in East Asia. […] The presence of phenotypic heterogeneity in RNF213 polymorphisms suggests that RNF213 may act as a susceptibility gene rather than a causal factor. […] The penetrance of RNF213 p.R4810K variant is low and is estimated to be 1 per 300 carriers in East Asia. […] Therefore, a large number of unaffected carriers were observed in the East Asian population, owing to the inconsistency between the incidence rate and MAF.

• #17 Ocular Manifestations of Moyamoya Disease – EyeWiki

  https://eyewiki.org/Ocular_Manifestations_of_Moyamoya_Disease

  Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disorder affecting the terminal portions of the bilateral internal carotid arteries or proximal portions of the anterior and middle cerebral arteries. The progressive ischemia results in the formation of a collateral vascular network in the base of the brain. […] The etiology of MMD is largely unknown, but due to the higher incidence of this disease in Japanese populations and the presence of familial cases, it is thought that MMD could be a multifactorial disease. Some genetic studies of familial MMD propose that responsible genetic loci are located on chromosomes 3, 6, and 17. Additionally, many cytokines such as VEGF, bFGF, and TGF-1 have been found in MMD patients. These cytokines are associated with causing vessel narrowing and occlusion by promoting smooth muscle proliferation into the tunica intima, but it is still unknown if they are the cause of MMD. It is likely that multiple factors are linked that underlie the pathophysiology of MMD.

• #18 The mechanobiological theory: a unifying hypothesis on the pathogenesis of moyamoya disease based on a systematic review in: Neurosurgical Focus Volume 51 Issue 3 (2021) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/51/3/article-pE6.xml

  Moyamoya angiopathy (MMA) affects the distal internal carotid artery and is designated as moyamoya disease (MMD) when predisposing conditions are absent, or moyamoya syndrome (MMS) when it occurs secondary to other causes. There is compelling evidence to suggest that MMA is a phenomenon that occurs due to stereotyped mechanobiological processes. […] A preliminary evaluation of the literature led us to believe that vascular homeostasis was balanced by six key factors: arterial tortuosity, vascular angles, wall shear stress (WSS), molecular factors, blood rheology/viscosity, and blood vessel wall strength. […] Based on the available literature, the authors have proposed a unifying theory for the pathogenesis of MMA. The moyamoya phenomenon appears to be the culmination of an interplay of vascular anatomy, hemodynamics, rheology, blood vessel wall strength, and a plethora of intricately linked mechanobiological molecular mediators that ultimately results in the mechanical process of occlusion of the blood vessel, stimulating angiogenesis and collateral blood supply in an attempt to perfuse the compromised brain.

• #19 Moyamoya disease – Wikipedia

  https://en.wikipedia.org/wiki/Moyamoya_disease

  Moyamoya disease is a disease in which certain arteries in the brain are constricted. Blood flow is blocked by constriction and blood clots (thrombosis). A collateral circulation develops around the blocked vessels to compensate for the blockage, but the collateral vessels are small, weak, and prone to bleeding, aneurysm, and thrombosis. […] Over the last six decades since the disease was first described, pathogenesis of moyamoya disease remained elusive, although the gene ring finger protein 213 (RNF213) has been implicated. In September 2021, a south Indian researcher has proposed a pathbreaking theory on moyamoya pathogenesis. Coined the „Mechano-biological theory”, the disease has a multifactorial pathogenesis. The authors provide a tangible explanation of the occurrence of moyamoya phenomenon in the idiopathic and syndromic variants of the disease. In short, the authors report that moyamoya disease likely occurs due to a number of factors (e.g., differences in vascular anatomy) that ultimately contribute to broad cerebral blood vessel occlusion and consequent shifts in vessel connections to try to provide blood for the compromised brain.

• #20 The mechanobiological theory: a unifying hypothesis on the pathogenesis of moyamoya disease based on a systematic review in: Neurosurgical Focus Volume 51 Issue 3 (2021) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/51/3/article-pE6.xml

  The complex interaction between the molecular mechanobiological pathways and their resultant mechanical changes which lead to endothelial and smooth muscle proliferation and result in intimal thickening and luminal occlusion is depicted in Fig. 4. Morphological determinants, including loss of tortuosity of the ICA, a lower BA-PCA angle, and a higher and variable CAV-SCL angle, subject the distal vasculature to higher hemodynamic stresses. The hemodynamic stress (WSS) acting on a weak blood vessel wall induces a series of downstream derangements in cytokines and biochemical factors that result in endothelial proliferation, SMC migration, and proliferation, resulting in intimal thickening and internal elastic lamina disintegration. […] The mechanobiological theory of MMA is proposed as follows: moyamoya is a phenomenon of development of collateral blood supply that evolves after occlusion of the distal ICA and/or BA in order to provide alternative channels for blood supply to the brain; the occlusion of the major blood vessels occurs due to a combination of mechanobiological factors that are genetic, developmental, hemodynamic, rheological, immunological, biochemical, and mechanical.

• #21 The Pathogenetic Mechanism for Moyamoya Vasculopathy Including a Possible Trigger Effect of Increased Flow Velocity | JMA Journal

  https://www.jmaj.jp/detail.php?id=10.31662%2Fjmaj.2022-0104

  Moyamoya disease (MMD), which commonly exhibits moyamoya vasculopathy characterized by chronic progressive steno-occlusive lesions in the circle of Willis with moyamoya collateral vessels, has been well known for its unique demographic and clinical features. […] Although the discovery of the susceptibility gene RNF213 for MMD revealed the factor for its predominance in East Asians, the mechanisms underlying other predominant conditions (females, children, young to middle-aged adults, and anterior circulation) and lesion formation are yet to be determined. […] Thus, we herein consider a common trigger from a novel perspective on blood flow dynamics. Increased flow velocity in the middle cerebral arteries is an established predictor of stroke in sickle cell disease, which is often complicated by MMS.

• #22 The Pathogenetic Mechanism for Moyamoya Vasculopathy Including a Possible Trigger Effect of Increased Flow Velocity | JMA Journal

  https://www.jmaj.jp/detail.php?id=10.31662%2Fjmaj.2022-0104

  Flow velocity is also increased in other diseases complicated by MMS (Down syndrome, Graves disease, irradiation, and meningitis). […] In addition, increased flow velocity occurs under the predominant conditions of MMD (females, children, young to middle-aged adults, and anterior circulation), suggesting a relationship between flow velocity and susceptibility to moyamoya vasculopathy. […] In a pathogenetic overview of chronic progressive steno-occlusive lesions, a novel perspective including the trigger effect of increased flow velocity may provide insights into the mechanisms underlying their predominant conditions and lesion formation. […] Therefore, further studies are needed to elucidate the pathogenetic mechanisms of MMD. […] We herein focused on flow velocity and proposed increased flow velocity as a common trigger for the development of moyamoya vasculopathy.

• #23 The Pathogenetic Mechanism for Moyamoya Vasculopathy Including a Possible Trigger Effect of Increased Flow Velocity | JMA Journal

  https://www.jmaj.jp/detail.php?id=10.31662%2Fjmaj.2022-0104

  If increased flow velocity is a common trigger for the development of moyamoya vasculopathy, it must be detected in MMD patients. […] Therefore, increased flow velocity in the majority of MMD cases has been attributed to the stenotic changes of moyamoya vasculopathy. […] However, an increase in flow velocity has been suggested in MMD premorbid conditions. […] Therefore, shorter and lesser tortuous ICAs may contribute to smaller reductions in flow velocity, resulting in the maintenance of a higher flow velocity at the end of ICAs. […] If flow velocity is increased for an idiopathic reason (MMD) or secondary reason (MMS) accompanied by the following conditions that are associated with an increased flow velocity, namely, child, female, sympathetic activation, anemia, apnea, and hormonal factors, it may strengthen shear stress under the conditions of insufficient vasodilation.

• #24 The Pathogenetic Mechanism for Moyamoya Vasculopathy Including a Possible Trigger Effect of Increased Flow Velocity | JMA Journal

  https://www.jmaj.jp/detail.php?id=10.31662%2Fjmaj.2022-0104

  This may, in turn, initiate the amplified process of lesion formation, leading to steno-occlusive negative remodeling. […] The perspective including the trigger effect of increased flow velocity may be a rational explanation for the predominant conditions and initial process of the vascular remodeling of MMD.

• #25 Clinical and Immunopathological Features of Moyamoya Disease | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0036386

  The deposits of IgG in vascular wall may underlie the disruption of internal elastic lamina, facilitating S100A4-positive SMCs migrate into intima. […] We speculate that MMD might be caused by immune-related factors and then internal elastic lamina disrupted, smooth muscle cells in the media changed morphologically and functionally, by, for example, vacuolar degeneration in the smooth muscle cells and migrated into intima, resulting in lumen stenosis or occlusion. […] Histopathological and immunohistochemical findings of intracranial vessels from 3 autopsy cases suggested that immune-related factors may involved in the functional and morphological changes of smooth muscle cells, which finally caused the thickened intima.

• #26 Characterization of PANoptosis-related genes and the immune landscape in moyamoya disease | Scientific Reports

  https://www.nature.com/articles/s41598-024-61241-w

  Moyamoya disease (MMD) is a cerebrovascular narrowing and occlusive condition characterized by progressive stenosis of the terminal portion of the internal carotid artery and the formation of an abnormal network of dilated, fragile perforators at the base of the brain. […] However, the role of PANoptosis, an apoptotic mechanism associated with vascular disease, has not been elucidated in MMD. […] These results suggest that the PANoptosis-related genes may contribute to the pathogenesis of MMD through multiple mechanisms. […] Despite extensive investigation, the molecular etiology and pathogenesis of MMD angiopathy remain unclear. […] Therefore, it is reasonable to hypothesize that a decrease in apoptosis may be associated with the proliferation of vascular smooth muscle cells and contribute to the pathogenesis of MMD.

• #27 Increased Prevalence of Potential Right-to-Left Shunting in Children with Moyamoya: A Potential Mechanism for Disease Development – Pediatric Stroke Journal

  https://pediatricstrokejournal.com/increased-prevalence-of-potential-right-to-left-shunting-in-children-with-moyamoya-a-potential-mechanism-for-disease-development/

  Moyamoya (MM) is a rare progressive stenosis of anterior cerebral circulation of unknown etiology that occurs at higher prevalence in patients with sickle cell disease, trisomy 21, neurofibromatosis 1, and East Asians. […] We hypothesized that vasoactive substances, normally inactivated in the lungs, can escape inactivation through potential right-to-left shunting and thereby act upon the endothelium in at-risk patients and contribute to the development of moyamoya. […] These observations support our hypothesis that shunting could contribute to moyamoya development, possibly through unknown vasoactive substances escaping inactivation in the pulmonary vascular bed, subsequently inducing vascular changes in patients with predisposing conditions. […] We noted that the pulmonary vascular bed has significant enzymatic function and serves to inactivate a host of inflammatory and vasoactive factors.

• #28 Increased Prevalence of Potential Right-to-Left Shunting in Children with Moyamoya: A Potential Mechanism for Disease Development – Pediatric Stroke Journal

  https://pediatricstrokejournal.com/increased-prevalence-of-potential-right-to-left-shunting-in-children-with-moyamoya-a-potential-mechanism-for-disease-development/

  If such factors foster the development of moyamoya in predisposed individuals, then those who experience right-to-left shunting would be at risk of having their cerebral vasculature exposed to higher levels of these active factors via the mechanism of paradoxical embolization, which would presumably increase their risk of developing moyamoya vasculopathy. […] Our study, to our knowledge, is the only study evaluating the prevalence of potential right-to-left shunting in children with moyamoya in comparison with a well-studied control group of children without stroke or moyamoya. […] While we cannot conclude that shunting causes the development of moyamoya from such a case-control study, the data support our hypothesis that moyamoya development in predisposed populations may relate, in part, to unknown factors avoiding enzymatic inactivation in the lungs, possibly via shunting / paradoxical embolization.

• #29 Moyamoya disease | STROKE MANUAL

  https://www.stroke-manual.com/moyamoya-disease/

  progressive stenoocclusive disorder affecting the terminal segment of the internal carotid artery (ICA) and proximal segments of the arteries forming the circle of Willis (ACA, MCA, PCA) […] proliferation and thickening of the intima of the terminal ICA segment and proximal MCA segment predominate; the proliferating intima may contain lipid deposits, but there is no evidence of inflammation […] associated neovascularization occurs as a compensatory mechanism (collateral circulation) […] the moyamoya pattern may be caused by other inherited vasculopathies (Grange syndrome, ACTA2 mutations, etc.) […] mutations testing in the RNF213 gene located on 17q25 (in Asians) […] hemodynamic assessment (by CT, MRI, SPECT, PET, and ultrasound) is suggested for all patients with MMA (ESO guidelines, 2023, consensus) […] the staging system, initially described by Suzuki and Takaku in 1969, is still used […] disease progression is more rapid in children compared to adolescents or adults.

• #30 The Pathophysiology of Moyamoya Disease: An Update

  https://www.j-stroke.org/journal/view.php?doi=10.5853/jos.2015.01760

  Non-surgical approaches may include the application of (a) certain trophic factors or chemicals that increase angiogenesis, (b) anti-cancer drugs to decrease the smooth muscle cell proliferation, (c) retinoid to attenuate growth factor-stimulated smooth muscle cell migration and proliferation, (d) several strategies to increase caveolin-1 levels, and (e) stem cell therapy to replace or restore function of impaired EPCs or SPCs.

• #31 The Pathophysiology of Moyamoya Disease: An Update | Journal of Stroke;: 12-20, 2016. | WPRIM

  https://pesquisa.bvsalud.org/portal/resource/pt/wpr-135899

  Moyamoya disease (MMD) is a unique cerebrovascular disease characterized by the progressive stenosis of large intracranial arteries and a hazy network of basal collaterals called moyamoya vessels. […] There is no specific treatment to prevent MMD progression. This review summarizes the recent advances in MMD pathophysiology, including the genetic and circulating factors related to disease development. Genetic and environmental factors may play important roles in the development of the vascular stenosis and aberrant angiogenesis in complex ways. […] With a better understanding of MMD pathophysiology, nonsurgical approaches targeting MMD pathogenesis may be available to stop or slow the progression of this disease. The possible strategies include targeting growth factors, retinoic acid, caveolin-1, and stem cells.

• #32 Moyamoya Disease Portal – Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum (SCTIMST)

  https://moyamoya.sctimst.ac.in/professional.php

  Moyamoya disease is a rare cause of stroke, that occurs in children and sometimes adults. In this disease, the major blood vessels supplying blood to the brain (the internal carotid arteries) become progressively narrow and finally get occluded resulting in stroke. […] In Moyamoya disease, the main blood vessels are affected after their entry into the cavity of the skull, housing the brain. In this disease process, these vessels progressively get narrowed and finally, occluded. During this progressive phase, the blood supply to the brain is compromised and the patient suffers strokes, known as ischemic strokes (brain damage caused due to loss of blood supply). […] The exact cause of Moyamoya disease is unknown. Genetic predisposition due to mutation in RNF213 gene has been described. […] The mechanism of the disease process that results in the blockage of the major blood vessels supplying the brain, is unknown. The occlusive changes of the blood vessels are thought to occur due to molecular mechanisms and mechanical causes. […] Moyamoya disease results in progressive, irreversible narrowing of the major blood vessels supplying blood to the brain. […] Surgical revascularisation techniques (direct, immediate and indirect, long-term) are the only durable method of preventing stroke induced disability in Moyamoya disease.

• #33 Moyamoya Disease: Stroke in the Young | Published in Journal of Brown Hospital Medicine

  https://bhm.scholasticahq.com/article/77634-moyamoya-disease-stroke-in-the-young

  Moyamoya disease is a rare cerebrovascular disease characterized by progressive stenosis of the distal bilateral internal carotid arteries and their proximal branches with compensatory lenticulostriate collaterals that is described as a puff of smoke (Moyamoya in Japanese). […] Genetic predisposition is implicated in the pathogenesis of Moyamoya disease, and individuals with first-degree family history of Moyamoya disease has 132-fold higher risk of developing the disease than those without. […] There is no curative treatment for Moyamoya disease. Symptomatic, supportive treatment such as maintaining euvolemia to maintain sufficient cerebral blood flow is essential.

• #34 The Pathogenetic Mechanism for Moyamoya Vasculopathy Including a Possible Trigger Effect of Increased Flow Velocity | JMA Journal

  https://www.jmaj.jp/detail.php?id=10.31662/jmaj.2022-0104

  Flow velocity is also increased in other diseases complicated by MMS (Down syndrome, Graves disease, irradiation, and meningitis). […] In addition, increased flow velocity occurs under the predominant conditions of MMD (females, children, young to middle-aged adults, and anterior circulation), suggesting a relationship between flow velocity and susceptibility to moyamoya vasculopathy. […] In a pathogenetic overview of chronic progressive steno-occlusive lesions, a novel perspective including the trigger effect of increased flow velocity may provide insights into the mechanisms underlying their predominant conditions and lesion formation. […] One major reason for the lack of an effective medical treatment may be that the pathogenetic mechanisms of moyamoya vasculopathy have not yet been elucidated in detail.

• #35 The Pathogenetic Mechanism for Moyamoya Vasculopathy Including a Possible Trigger Effect of Increased Flow Velocity | JMA Journal

  https://www.jmaj.jp/detail.php?id=10.31662/jmaj.2022-0104

  Therefore, further studies to clarify the underlying pathogenetic mechanisms are needed not only for scientific interest, but also for therapeutic development. […] Although the discovery of this susceptibility gene was expected to clarify the pathogenetic mechanisms underlying MMD, gene-targeting experiments have not yet reproduced moyamoya vasculopathy; therefore, the underlying mechanisms remain unclear despite this genomic breakthrough. […] Therefore, further studies are needed to elucidate the pathogenetic mechanisms of MMD. […] We herein focused on flow velocity and proposed increased flow velocity as a common trigger for the development of moyamoya vasculopathy. […] If increased flow velocity is a common trigger for the development of moyamoya vasculopathy, it must be detected in MMD patients.

• #36 The Pathophysiology of Moyamoya Disease: An Update

  https://dspace.kci.go.kr/handle/kci/524001

  Moyamoya disease (MMD) is a unique cerebrovascular disease characterized by the progressive stenosis of large intracranial arteries and a hazy network of basal collaterals called moyamoya vessels. […] Because the etiology of MMD is unknown, its diagnosis is based on characteristic angiographic findings. […] This review summarizes the recent advances in MMD pathophysiology, including the genetic and circulating factors related to disease development. […] Genetic and environmental factors may play important roles in the development of the vascular stenosis and aberrant angiogenesis in complex ways. […] These factors include the related changes in circulating endothelial/smooth muscle progenitor cells, cytokines related to vascular remodeling and angiogenesis, and endothelium, such as caveolin which is a plasma membrane protein. […] With a better understanding of MMD pathophysiology, nonsurgical approaches targeting MMD pathogenesis may be available to stop or slow the progression of this disease. […] The possible strategies include targeting growth factors, retinoic acid, caveolin-1, and stem cells.

• #37 Moyamoya Disease: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/1180952-overview

  The cause of moyamoya disease is not known. The disease is believed to be genetic. […] A genome-wide association study identified RNF213 as the first gene associated with moyamoya. […] One meta-analysis demonstrated that there are strong associations between p.R4859K and p.R4810K polymorphisms of the RNF213 gene and moyamoya disease. […] However, it suggests that immune abnormalities and several others as listed below may play some role in moyamoya disease. […] There is still lots of work to be done, as there are still many unresolved issues about moyamoya disease and syndrome, including lack of clear diagnostic criteria, particular biomarkers, precise understanding of the underlying pathophysiology, and stronger evidence for treatment guidelines.

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