INTRODUCTION

Moyamoya disease (MMD) was first described by Takeuchi and Shimizu [1] in 1957. It is a rare cerebrovascular disorder characterized by the gradual narrowing and occlusion of the terminal portion of the internal carotid artery (ICA). This condition leads to the compensatory development of collateral vessels, which appear as a "puff of smoke" (from the Japanese term moyamoya) on cerebral angiography. MMD is a significant cause of stroke in East Asian countries, resulting in severe neurological deficits and cognitive impairments. The annual incidence rate of MMD in East Asia is reported to be between 0.5 and 1.5 cases per 100,000 individuals. In contrast, in regions such as North America, the incidence rate is lower, ranging from 0.1 to 0.5 cases per 100,000 individuals [2].

The etiology of MMD remains to be elucidated. However, in 2011, researchers identified the R4810K variant of ring finger protein 213 (RNF213) as a strong susceptibility gene for MMD [3,4]. Since then, significant insights have been gained regarding the function of RNF213, its association with the pathophysiology, and the clinical features of MMD [5]. In this review, we explore the clinical features and diagnostic criteria of MMD, examine the role of RNF213 in the pathophysiology of MMD, and summarize the genotype-phenotype correlation of the RNF213 gene.

CLINICAL PRESENTATION

The representative clinical manifestations of MMD include transient ischemic attacks (TIA), ischemic and hemorrhagic strokes, seizures, headaches, and cognitive deficits. Cerebral ischemic symptoms are notably the most common clinical presentation among these. Additionally, the manifestation and course of MMD are influenced by the age at onset [6]. The age of symptom onset in MMD shows a bimodal distribution pattern: the first peak occurs during the first decade of life, which corresponds to pediatric MMD, and the second peak occurs during the fourth or fifth decade of life, corresponding to adult MMD [6–8]. In pediatric patients with MMD, TIA or cerebral infarctions are predominantly observed. In contrast, adult MMD patients exhibit a higher frequency of cerebral hemorrhage compared to pediatric patients [9,10].

Cerebral ischemic symptoms are primarily attributed to cerebral hypoperfusion, which results from progressive stenosis or occlusion of major vessels. This condition can lead to TIA and ischemic strokes. In pediatric cases, ischemic events often follow episodes of hyperventilation triggered by vigorous exercise, crying, consuming hot food, or playing wind instruments. This hyperventilation leads to cerebral vessel contraction due to decreased blood carbon dioxide levels, resulting in cerebral hypoperfusion. In adults, cerebral infarction may occur due to the progression of MMD or as a result of compounded atherosclerosis, which reduces perfusion in the watershed areas between the anterior cerebral artery, middle cerebral artery, and posterior cerebral artery (PCA). It can also arise from vascular occlusion caused by an embolism. The symptoms largely depend on the location and size of the ischemic stroke and may include hemiparesis, sensory disturbances, speech impairments, and visual field defects. In patients who experience repeated ischemic attacks, brain atrophy may develop, leading to a decline in mental function and intelligence.

In patients with MMD, hemorrhagic strokes typically manifest after the age of 25 years and produce various neurological symptoms, which vary based on the bleed's location. Hemorrhagic events are exceedingly uncommon in pediatric MMD patients under the age of 5 years. In MMD cases, cerebral hemorrhages most frequently affect the basal ganglia, ventricles, and thalamus. Although the precise mechanism of cerebral hemorrhages in MMD is not fully understood, it is widely believed that they result from the rupture of delicate moyamoya vessels due to ongoing hemodynamic stress, coupled with the formation and eventual rupture of microaneurysms. Rebleeding, which occurs in about 40% of patients, is the primary cause of mortality.

Besides ischemic and hemorrhagic strokes, patients with MMD may experience headaches, including migraines, dizziness from orthostatic intolerance, syncope, movement disorders, seizures, and psychiatric symptoms such as depression and anxiety. Recently, there has been an increase in the prevalence of asymptomatic MMD cases, which is likely attributable to more frequent routine health screenings.

DIAGNOSTIC CRITERIA

The diagnostic criteria for MMD have evolved in response to a deeper understanding of the disease and advancements in diagnostic imaging. The most recent guidelines were issued in 2022 by the Research Committee on Moyamoya Disease of the Japanese Ministry of Health, Labour and Welfare (Table 1) [11]. Currently, a diagnosis of MMD can be confirmed using either traditional catheter angiography or magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). For a diagnosis via conventional angiography, two key findings are required: stenosis or occlusion at the terminal portion of the intracranial ICA; and the presence of abnormal vascular networks, known as moyamoya vessels, near the occlusive or stenotic lesions during the arterial phase.

For a diagnosis using MRI or MRA (1.5 T or higher), three key findings must be present: stenosis or occlusion at the terminal portion of the intracranial ICA; a reduction in the outer diameter of the terminal portion of the ICA and the horizontal portion of the middle cerebral artery bilaterally, as seen on heavy T2-weighted MRI; and the presence of abnormal vascular networks in the basal ganglia and/or periventricular white matter, as detected on MRA. Since the etiology of MMD remains unknown, radiologic findings that are associated with autoimmune diseases, meningitis, brain tumors, Down syndrome, neurofibromatosis type 1, or head irradiation are classified as quasi-MMD or moyamoya syndrome.

The diagnosis of MMD has been expanded to include both bilateral and unilateral cases, eliminating the previous categories of "definite" and "probable" from the diagnostic criteria [12]. This modification addresses the increasing incidence of unilateral cases and acknowledges that such cases frequently evolve into bilateral conditions [10,13–20]. Furthermore, studies demonstrating a similar genetic foundation for both unilateral and bilateral MMD have supported this expanded diagnostic framework [16,19,21–23]. The updated criteria also emphasize the importance of heavy T2-weighted MRI images in diagnosing MMD. Recent research indicates that arteries affected by MMD not only experience narrowing due to intimal thickening but also exhibit a decrease in outer diameter. This finding contrasts with atherosclerosis, where the narrowing occurs solely in the lumen without altering the vessel's outer diameter [24–27].

PATHOPHYSIOLOGY AND THE RNF213 GENE

The pathological hallmarks of MMD include fibrocellular thickening of the intima, driven by the proliferation of smooth muscle cells, irregular undulation of the internal elastic lamina, and thinning of the media. These changes contribute to the overall negative remodeling of the stenotic segment [28]. Moyamoya vessels are characterized by dilated perforating arteries that exhibit thinning of the vascular wall, fibrin deposition, fragmentation of the elastic lamina, and various other tissue changes, such as the formation of microaneurysms [29].

The R4810K variant of the RNF213 gene has been identified as a significant genetic susceptibility factor for MMD among the East Asian population [3,4]. The RNF213 gene encodes a 591 kDa protein that includes an E3 ubiquitin ligase and an AAA+ ATPase. The E3 ubiquitin ligase, which contains the R4810K variant within its coding region, is primarily responsible for the pathogenesis of MMD.

Nuclear factor of activated T-cells 1 (NFAT1) and filamin A have been identified as substrates of the RNF213 E3 ubiquitin ligase. NFAT1, a transcription factor, translocates to the nucleus upon activation and induces the expression of target genes associated with vessel regression and pruning. Consequently, abnormal vessel development, characterized by moyamoya vessels, may result from enhanced NFAT1 signaling due to the inability of mutated RNF213 to degrade NFAT1 [30]. Filamin A is involved in vascular remodeling by promoting a phenotypic shift in vascular smooth muscle cells from a “contractile” to a “synthetic” phenotype. The silencing of RNF213 also inhibits the degradation of filamin A, leading to the proliferation of synthetic vascular smooth muscle cells, a critical factor in negative remodeling [30,31]. Therefore, mutations in RNF213 impair the degradation of NFAT1 and filamin A, leading to abnormal vessel development and negative vascular remodeling, characteristic of MMD.

The role of RNF213 in vascular remodeling and pruning has been established through in vivo models. The knockdown of RNF213 in zebrafish resulted in abnormal sprouting of vessels in the craniocervical region, particularly around the optic vessels [4]. Additionally, using the transcription activator-like effector nuclease technique to mutate RNF213 led to abnormal angiogenesis and circulation defects in zebrafish [32]. However, RNF213 knockout mice displayed a normal anatomy of the circle of Willis and typical vascular wall thickness, suggesting that a mutation in RNF213 alone is insufficient to induce MMD [33,34]. Interestingly, inducing hypoperfusion by ligating the common carotid artery resulted in significantly thinner intima and medial layers. These findings support the double-hit hypothesis of MMD and the low penetrance of the R4810K variant [35,36].

GENOTYPE–PHENOTYPE CORRELATION OF THE RNF213 GENE

Following the identification of the RNF213 gene as a susceptibility factor for MMD, numerous studies have aimed to clarify the relationship between the RNF213 genotype and the MMD phenotype, primarily focusing on the East Asian populations. Recent meta-analyses, which include data from Korean, Japanese, and Chinese cohorts, have been published [37,38]. These studies indicate that the RNF213 R4810K variant is linked to an earlier age of onset, TIA, infarctions, and PCA involvement compared to the wild type. Although these phenotypes generally show consistency, there is noticeable heterogeneity in other phenotypes between different etiologies and across studies. Consequently, interpreting these results requires caution, as the distribution and impact of the RNF213 R4810K variant vary among Korea, Japan, and China. It is therefore essential to carefully analyze the outcomes of individual studies.

The correlations of clinical characteristics with RNF213 genotypes are summarized in Table 2 [16,39–46]. No association was found between sex and the presence of the RNF213 variant [10,39,40]. Studies across various ethnicities have consistently shown that the homozygous RNF213 variant is linked to an earlier age of onset, typically at or before 5 years of age [10,39–43]. While no association was found between heterozygous carriers and an earlier age of onset in Japanese and Korean populations, a significant association was noted in Chinese patients with the heterozygous RNF213 variant [43–45].

Several studies involving Japanese, Korean, and Chinese MMD patients have shown that the homozygous RNF213 variant is predictive of cerebral infarction at initial presentation [40,41,45,46]. However, studies by Ok et al. [10] and Nomura et al. [42] presented contradictory findings, showing no association despite similar ethnicity and study sizes. Ge et al. [44] identified an association between the RNF213 R4810K variant and TIA as the initial symptom in Chinese MMD patients. Nevertheless, most other studies found no such association. Additionally, there was no link found between cerebral hemorrhage and the RNF213 gene.

Studies conducted by Ok et al. [10], Miyatake et al. [41], and Wang et al. [43] have shown that patients carrying the RNF213 variant are more prone to PCA involvement, although there are reports with conflicting data [39,40]. Similarly, the link between bilateral vasculopathy and the RNF213 variant has shown inconsistencies across different studies. Considering that both cerebral infarction and PCA involvement are indicators of a poor prognosis, these results imply that the variant may be linked to a more severe manifestation of MMD. Additionally, Ishigami et al. [39] reported that patients with the RNF213 R4810K variant tend to have a more progressive disease course, as indicated by a Suzuki grade of 4 or higher.

Understanding the long-term outcomes of MMD is necessary for developing future management strategies. However, there are limited reports on the association between long-term manifestations and the RNF213 variant. Studies conducted with Japanese and Chinese populations found no significant associations between the RNF213 R4810K genotypes and recurrent stroke [42,44]. Intriguingly, Ok et al. [10] demonstrated that individuals carrying the homozygous RNF213 variant face an approximately sixfold higher risk of future infarction compared to those with the wild type. In a study of patients with unilateral MMD, the RNF213 variant was identified as a predictive factor for progression to bilateral presentation [16]. Nevertheless, due to the scarcity of reports on long-term manifestations associated with the RNF213 variant, further research is necessary.

Efforts have been made to elucidate the relationship between revascularization outcomes and the RNF213 variant. Patients with the RNF213 R4810K variant demonstrated more extensive collateral development associated with both direct and indirect revascularization [10,47,48]. Additionally, the RNF213 variant was predictive of perioperative complications, including cerebral hyperperfusion following superficial temporal artery to middle cerebral artery anastomosis [49].

CONCLUSIONS

In recent decades, extensive research on MMD has significantly enhanced our understanding of the condition. Despite these advancements, many patients still suffer due to the disease's variable prognosis and the absence of definitive treatment options. The discovery of the RNF213 gene as a key genetic susceptibility factor for MMD in East Asian populations has underscored its vital role in the disease's pathophysiology, phenotype, and prognosis. However, further research is crucial to fully elucidate the pathophysiology and genetics of MMD, enhance prognostic predictions, and develop new therapeutic strategies.

ARTICLE INFORMATION

Conflicts of interest

The author has no conflicts of interest to declare.

Funding

The author received no financial support for this study.

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