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Moyamoya disease is an idiopathic vascular disorder of intracranial arteries. Its susceptibility locus has been mapped to 17q25.3 in Japanese families, but the susceptibility gene is unknown. Genome-wide linkage analysis in eight three-generation families with moyamoya disease revealed linkage to 17q25.3 (P<10(-4)). Fine mapping demonstrated a 1.5-Mb disease locus bounded by D17S1806 and rs2280147. We conducted exome analysis of the eight index cases in these families, with results filtered through Ng criteria. There was a variant of p.N321S in PCMTD1 and p.R4810K in RNF213 in the 1.5-Mb locus of the eight index cases. The p.N321S variant in PCMTD1 could not be confirmed by the Sanger method. Sequencing RNF213 in 42 index cases confirmed p.R4810K and revealed it to be the only unregistered variant. Genotyping 39 SNPs around RNF213 revealed a founder haplotype transmitted in 42 families. Sequencing the 260-kb region covering the founder haplotype in one index case did not show any coding variants except p.R4810K. A case-control study demonstrated strong association of p.R4810K with moyamoya disease in East Asian populations (251 cases and 707 controls) with an odds ratio of 111.8 (P = 10(-119)). Sequencing of RNF213 in East Asian cases revealed additional novel variants: p.D4863N, p.E4950D, p.A5021V, p.D5160E, and p.E5176G. Among Caucasian cases, variants p.N3962D, p.D4013N, p.R4062Q and p.P4608S were identified. RNF213 encodes a 591-kDa cytosolic protein that possesses two functional domains: a Walker motif and a RING finger domain. These exhibit ATPase and ubiquitin ligase activities. Although the mutant alleles (p.R4810K or p.D4013N in the RING domain) did not affect transcription levels or ubiquitination activity, knockdown of RNF213 in zebrafish caused irregular wall formation in trunk arteries and abnormal sprouting vessels. We provide evidence suggesting, for the first time, the involvement of RNF213 in genetic susceptibility to moyamoya disease.

Background Moyamoya 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. Methods By 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. Results The 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. Conclusion Clinical 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.

Moyamoya angiopathy (MMA) is a cerebral angiopathy affecting the terminal part of internal carotid arteries. Its prevalence is 10 times higher in Japan and Korea than in Europe. In East Asian countries, moyamoya is strongly associated to the R4810K variant in the RNF213 gene that encodes for a protein containing a RING-finger and two AAA+ domains. This variant has never been detected in Caucasian MMA patients, but several rare RNF213 variants have been reported in Caucasian cases. Using a collapsing test based on exome data from 68 European MMA probands and 573 ethnically matched controls, we showed a significant association between rare missense RNF213 variants and MMA in European patients (odds ratio (OR)=2.24, 95% confidence interval (CI)=(1.19-4.11), P=0.01). Variants specific to cases had higher pathogenicity predictive scores (median of 24.2 in cases versus 9.4 in controls, P=0.029) and preferentially clustered in a C-terminal hotspot encompassing the RING-finger domain of RNF213 (P<10 ). This association was even stronger when restricting the analysis to childhood-onset and familial cases (OR=4.54, 95% CI=(1.80-11.34), P=1.1 × 10 ). All clinically affected relatives who were genotyped were carriers. However, the need for additional factors to develop MMA is strongly suggested by the fact that only 25% of mutation carrier relatives were clinically affected.

BackgroundThe lacking awareness of healthcare providers bears the risk of delayed or false diagnoses in rare diseases. No systematic data about misdiagnoses of Moyamoya angiopathy (MMA) are available.ObjectiveTo evaluate the rate and pattern of missed diagnoses in MMA.MethodsRetrospective analysis of a consecutive case series from a single German referral center. Rates of missed or delayed diagnoses in Caucasian MMA patients were calculated based on discharge letters from other hospitals and systematic chart review.ResultsOut of 192 Caucasian patients eventually diagnosed with MMA at our center, an initial misdiagnosis was identified in 119 patients (62%). The time between onset and diagnosis was 1 year in 24 patients, 2 years in 23 patients, 3 years in 10 patients, and > 3 years in 49 patients (mean 5.28, median 3, standard deviation 5.11, and range 4–26 years). The most common misdiagnoses were cerebral vasculitis (31%), etiologically ill-defined stroke diagnoses (30.2%), and MS (3.6%).ConclusionsThis is the first systematic report which shows that patients with MMA are at high risk to be falsely diagnosed and treated. Depiction of typical vascular abnormalities in angiopathy is essential. Normal CSF cell counts, negative oligoclonal bands, and lack of infratentorial lesions as well as gadolinium-positive T1 lesions on MRI may be red flags differentiating this vasculopathy from vasculitis and MS.

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by stenosis of the internal carotid arteries with compensatory development of collateral vessels. Although a founder variant of RNF213, p.Arg4810Lys (c.14429G>A, rs112735431), is a major genetic risk factor for MMD in East Asians, the frequency and disease susceptibility of other variants in this gene remain largely unknown. In the present study, we investigated the association of RNF213 variants with MMD in Korean patients and population controls. For all RNF213 variants listed in the Human Gene Mutation Database (HGMD) as disease-causing or likely disease-causing mutations for MMD, genotyping was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Genetic data from 264 adult patients with MMD were analyzed and compared with two control populations comprised of 622 and 1,100 Korean individuals, respectively. Among the 30 RNF213 variants that were listed in the HGMD, p.Arg4810Lys was identified in 67.4% (178/264) of patients with MMD and showed a significantly higher allele frequency than in the controls, giving an odds ratio of 63.29 (95% confidence interval, 33.11-120.98) for the 622 controls and 48.55 (95% confidence interval, 31.00-76.03) for the 1100 controls. One additional variant, p.Ala5021Val (c.15062C>T, rs138130613), was identified in 0.8% (2/264) of patients; however, the allele frequencies were not significantly different from those in the controls. These results suggest that, in our cohort of Korean patients, the p.Arg4810Lys is the only variant that is strongly associated with MMD among the 30 RNF213 variants listed in the HGMD.

Background The etiology of Moyamoya disease (MMD) is still widely unknown. Several publications on Moyamoya describe differences of cytokine and growth factor concentrations in different specimen. We analyzed the DNA of patients with MMD for single nucleotide polymorphisms (SNPs) in and upstream of the genes for previously described associated cytokines and growth factors. Method Thirteen SNPs were genotyped in or upstream to four genes— basic fibroblast growth factor (BFGF) , cellular retinoic acid-binding protein 1 (CRABP1) , platelet derived growth factor receptor beta ( PDGFRB ), and transforming growth factor beta 1 ( TGFB1)— comparing 40 DNA samples of MMD patients to 68 healthy controls from central Europe. Genotyping was performed by sequencing the SNP-containing genetic regions with custom made primers. Findings We found association of two SNPs: rs382861 [A/C] ( p  = 0.0373, OR = 1.81, 95% CI = 1.03–3.17) in the promoter region of PDGFRB and rs1800471[C/G] ( p  = 0.0345, OR = 7.65, 95% CI = 0.97–59.95), located in the first exon of TGFB1 . Conclusion Our results indicate possible genetic risk factors for the genesis of MMD. TGFB1 and PDGFRB are involved in vascular growth and transformation processes which may play a role in the development of MMD. Further analyses in larger European cohorts and replication in patients of different ethnicity, as well as functional studies, may lead to possible early detection of patients at risk for developing MMD and subsequently to future preventive therapies.

Background: Moyamoya disease (MMD) is an uncommon cerebrovascular disease characterized by progressive stenosis of the intracranial internal carotid arteries and their proximal branches. The important role of genetic factors in the etiology and pathogenesis of MMD is being increasingly recognized. The study was designed to examine the association of single nucleotide polymorphisms in matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP) genes with MMD occurrence. Methods: A case-control study was performed. Five functional promoter polymorphisms in the MMP-2, MMP-3, MMP-9 and MMP-13 genes and a potentially functional promoter polymorphism in the TIMP-2 gene were determined by polymerase chain reaction-restriction fragment length polymorphism. Their associations with MMD were analyzed by multivariate logistic regression. Results: In total, 208 definite patients with MMD (including 31 familial MMD, FMMD, patients) and 224 healthy subjects were recruited. The frequency of the MMP-3 5A/6A and 5A/5A genotypes was significantly lower in MMD patients (OR = 0.57, 95% CI 0.38–0.86, p corr = 0.042) compared with healthy controls in a dominant genetic model. Significant differences of the MMP-3 5A/6A polymorphism were also detected between FMMD patients and controls both in the dominant genetic model (OR = 0.23, 95% CI 0.08–0.68, p corr = 0.048) and the additive genetic model (OR = 0.24, 95% CI 0.08–0.69, p corr = 0.048). Conclusion: The functional polymorphism in the MMP-3 promoter might be associated with susceptibility to both MMD and FMMD in the Chinese Han population. The findings need to be validated in further studies including more subjects from different populations.

Background: Epidemiological data of paediatric moyamoya disease/syndrome (MMD/MMS) in non-Asian populations are scarce. Methods: A questionnaire was sent to every French neuropaediatric academic centre to estimate the prevalence, incidence, familial form rate and location of paediatric MMD/MMS cases. Specific paediatric data were also retrieved from the most recent nationwide Japanese study. Results: A 100% response rate was obtained. The prevalence of paediatric MMD/MMS was estimated at 0.39/100,000 children (95% CI: 0.28–0.49), and the incidence was estimated at 0.065/100,000 children/year (95% CI: 0.025–0.12), with 7.5% familial cases. The prevalence was homogenous within the different administrative areas. Conclusions: This comprehensive survey of MMD/MMS in academic neuropaediatric centres suggests that the prevalence of the disease in children in France is approximately 1/20th of that estimated in Asia.

Moyamoya disease (MMD) is an idiopathic cerebrovascular occlusive-stenosis disorder at the terminal portion of internal carotid arteries and its main branches, accompanied by collateral vascular networks at the base of the circle of Willis (Takeuchi and Shimizu 1957; Suzuki and Takaku 1969). MMD has the highest prevalence in East Asian countries and a low prevalence in European countries (Goto and Yonekawa 1992; Kuroda and Houkin 2008). We have found that thep.R4810K variant in the ring nger protein 213 (RNF213) is a major founder susceptibility gene for East Asian MMD (Liu et al. 2010, 2011). In this study, we aimed to test whether there is a major founder susceptibility gene for Caucasian MMD using a genomewide association study (GWAS). We demonstrated that there was no major founder variant in Caucasian MMD as it is in East Asian MMD. We identied several suggestive association regions for Caucasian MMD.

Background The etiology and genetic susceptibility of Moyamoya angiopathy (MMA) (Moyamoya disease, Moyamoya syndrome and unilateral type of MMA) still remain unclear. In Asian patient cohorts several HLA markers were described to be associated with MMA, but in Caucasians very little is known about genetic susceptibility of this angiopathy. Method We analysed DNA of 33 Caucasian patients with MMA for HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1 markers, respectively. HLA frequencies of all 33 patients with MMA were compared with HLA-frequencies of Caucasian controls. Additionally, subgroup analysis of 22 patients with Moyamoya disease (MMD) and 11 patients with unilateral type of MMA was performed. Findings Significant association was observed for HLA-DRB1*03 and HLA-DRB1*13 in all 33 patients ( P c  < 0.001 and P c  < 0.001, respectively). Moreover, HLA-A*02 ( P c  = 0.009); HLA-B*08 ( P c  = 0.009), and HLA-DQB1*03 ( P c  = 0.003) frequencies were higher in all patients with MMA when compared with the controls. In addition, in 22 patients with MMD a higher frequency of HLA-DRB1*03 ( P c  < 0.001) was observed when compared with controls. Conclusions The results of this study indicate a putative association of HLA markers with MMA in Caucasian patients. Further studies are needed to elucidate the role of human MHC in the pathogenesis of this angiopathy.