Rapid Progression of Unilateral Moyamoya Disease in a Patient with a Family History and an &lt;b&gt;&lt;i&gt;RNF213&lt;/i&gt;&lt;/b&gt; Risk Variant

Mineharu, Yohei; Takagi, Yasushi; Takahashi, Jun; Hashikata, Hirokuni; Liu, Wanyang; Hitomi, Toshiaki; Kobayashi, Hatasu; Miyamoto, Susumu

doi:10.1159/000352065

Cited by 38 publications

(23 citation statements)

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“…A very strong association between MMD and a missense variant in RNF213 (p.R4810K) has been reported by several studies in East Asian patients. This variant, which is present in 1-2% of the Japanese control population, was found in more than 90% of MMD patients [82,83,87,88] . However, although this variant has been established as a susceptibility factor for MMD in East Asia, it may explain only part of the disease susceptibility in this population and it is probably not involved in Caucasian patients.…”

Section: Discussionmentioning

confidence: 97%

“…Of note, in these studies, the p.R4810K variant was found in 1-2% of Japanese controls and in 0.4% of Chinese Han controls, and therefore, it should be considered as a MMD susceptibility variant rather than a MMD causing variant. It was also suggested that presence of the p.R4810K variant, when present in an homozygous state, was associated with an earlier onset and a more severe disease course, suggesting a value of this variant as a biomarker for predicting prognosis [83,86,87] .…”

Section: Genome-wide Linkage Studiesmentioning

confidence: 99%

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Research Progresses in Understanding the Pathophysiology of Moyamoya Disease

et al. 2016

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Background: The pathogenesis of moyamoya disease (MMD) is still unknown. The detection of inflammatory molecules such as cytokines, chemokines and growth factors in MMD patients' biological fluids supports the hypothesis that an abnormal angiogenesis is implicated in MMD pathogenesis. However, it is unclear whether these anomalies are the consequences of the disease or rather causal factors as well as these mechanisms remain insufficient to explain the pathophysiology of MMD. The presence of a family history in about 9-15% of Asian patients, the highly variable incidence rate between different ethnic and sex groups and the age of onset support the role of genetic factors in MMD pathogenesis. However, although some genetic loci have been associated with MMD, few of them have been replicated in independent series. Recently, RNF213 gene was shown to be strongly associated with MMD occurrence with a founder effect in East Asian patients. However, the mechanisms leading from RNF213 mutations to MMD clinical features are still unknown. Summary: The research on pathogenic mechanism of MMD is in its infancy. MMD is probably a complex and heterogeneous disorder, including different phenotypes and genotypes, in which more than a single factor is implicated. Key Message: Since the diagnosis of MMD is rapidly increasing worldwide, the development of more efficient stratifying risk systems, including both clinical but also biological drivers became imperative to improve our ability of predict prognosis and to develop mechanism-tailored interventions.

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Section: Discussionmentioning

confidence: 97%

Section: Genome-wide Linkage Studiesmentioning

confidence: 99%

Research Progresses in Understanding the Pathophysiology of Moyamoya Disease

et al. 2016

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“…1, 28–30 Prevention of strokes and the resulting comorbidities depends on the early identification of at risk individuals predisposed to MMD. Early diagnosis allows for timely surgical intervention to reduce the risk of stroke and possibly decrease cognitive deficits.…”

Section: Discussionmentioning

confidence: 99%

RNF213 Rare Variants in an Ethnically Diverse Population With Moyamoya Disease

Cecchi

Guo

Zhao

et al. 2014

Stroke

139

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Background and Purpose Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease resulting from occlusion of the distal internal carotid arteries. A variant in the Ring Finger 213 gene (RNF213), altering arginine at position 4810 (p.R4810K), is associated with MMD in Asian populations. However, there is a lack of data on the role of RNF213 in MMD patients of additional ethnicities and diasporic Asian populations. We investigate the contribution of RNF213 alterations to MMD in an ethnically diverse population based in the United States (U.S). Methods We initially sequenced RNF213 exons 43, 44, 45 (encoding the eponymous RING finger domain), and exon 60 (encoding p.R4810K), in 86 ethnically diverse patients with MMD. Comprehensive exome sequencing data from 24 additional MMD patients was then analyzed to globally identify RNF213 variants. Segregation of variants with MMD and other vascular diseases was assessed in families. Results RNF213 p.R4810K was identified in 56% (9/16) of MMD patients of Asian descent, and not in 94 patients of non-Asian descent. 3.6% (4/110) of patients had variants in the exons encoding the RING finger domain. Seven additional variants were identified in 29% (7/24) of MMD patients who underwent exome sequencing. Segregation analysis supported an association with MMD for two variants, and a lack of association with disease for one variant. Conclusions These results confirm that alterations in RNF213 predispose patients of diverse ethnicities to MMD, and that the p.R4810K variant predisposes individuals of Asian descent in the U.S. to MMD.

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“…7,17,18,21,28 Several single nucleotide polymorphisms (SNPs) in RNF213, including c.14576G>A (p.R4859K) and c.14429G>A (p.R4810K), were identified as variants with a strong susceptibility for MMD. 7,18,20,21 The risk of MMD was significantly increased with the c.14576G>A (p.R4859K) variant, with an odds ratio (OR) of 190.8, 7 and homozygotes exhibited severe and diverse vasculopathy phenotypes in a Japanese study. 21 The c.14429G>A (p.R4810K) variant was suggested to have the ischemic-type MMD in the Chinese Han population.…”

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confidence: 97%

Importance of RNF213 polymorphism on clinical features and long-term outcome in moyamoya disease

Kim¹,

Yum²,

Ra³

et al. 2016

JNS

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F ound in East Asia, particularly Korea and Japan, moyamoya disease (MMD) is an uncommon cerebrovascular disease characterized by progressive occlusion of the terminal portions of the internal carotid arteries (ICAs). 11,12 Recent epidemiological study has revealed that the number of patients with MMD in Korea is increasing and that the prevalence rate of MMD per 100,000 people increased to 9.0 in 2008 from 5.2 in 2004. 5 Moyamoya disease is a relatively common cause of childhood stroke, 1,19 and it can lead to irreversible neurological deficits and cognitive impairment; therefore, early diagnosis and proper therapeutic approaches are important.The etiology of MMD remains unclear, but several epidemiological risk factors are apparent. These include East Asian ethnicity, female sex, and family history of MMD. Some known genetic disorders present with moyamoyalike findings on cerebral angiography, suggesting that genetic factors may underlie MMD pathogenesis.13,25 AlabbreviatioNs ICA = internal carotid artery; MCA = middle cerebral artery; MMD = moyamoya disease; PCA = posterior cerebral artery; SNP = single nucleotide polymorphism; TIA = transient ischemic attack.

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Rapid Progression of Unilateral Moyamoya Disease in a Patient with a Family History and an <b><i>RNF213</i></b> Risk Variant

Cited by 38 publications

References 19 publications

Research Progresses in Understanding the Pathophysiology of Moyamoya Disease

Research Progresses in Understanding the Pathophysiology of Moyamoya Disease

RNF213 Rare Variants in an Ethnically Diverse Population With Moyamoya Disease

Importance of RNF213 polymorphism on clinical features and long-term outcome in moyamoya disease

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