Familial Moyamoya Disease Research Articles

Long-term outcomes after conservative and EDAS treatment for 111 elderly patients with moyamoya disease: longitudinal and cross-sectional study.

This study aimed to explore the clinical features of moyamoya disease (MMD) and the efficacy of encephaloduroarteriosynangiosis (EDAS) in elderly patients with MMD and to identify the risk factors for long-term stroke events. Clinical data were retrospectively collected on elderly patients with MMD (age ≥ 60 years) who had been treated at the authors' center from May 2007 to December 2017. Clinical features, angiographic findings, and long-term outcomes (> 5-year follow-up) were analyzed. Cox regression analysis was performed to determine the risk factors for postoperative stroke events. Long-term stroke events were analyzed using Kaplan-Meier curves. The mean age at symptom onset was 62.9 ± 3.0 years among 111 elderly patients with MMD. Vascular comorbidities were present in 80 (72.1%) patients. The ratio of female to male patients was 1:1.2. Familial MMD was found in 7 (6.3%) patients. Cerebral ischemia was the most common clinical manifestation observed in 82 (73.9%) patients. Most patients (59.5%) presented with Suzuki stages 5 and 6 MMD, and 29 (26.1%) patients presented with stenosis or occlusion of the posterior circulation. Unilateral MMD was present in 17 (15.3%) patients. Among the 58 (52.3%) patients who underwent EDAS, 28 (48.3%) and 30 (51.7%) underwent bilateral and unilateral surgeries, respectively. Overall, 53 (47.7%) patients were treated conservatively using internal medicine. After a median follow-up duration of 8.2 years, stroke incidence in the EDAS and conservative treatment groups was respectively 17.2% (7 and 3 cases of cerebral infarction and hemorrhage, respectively) and 49.1% (22 and 4 cases of cerebral infarction and hemorrhage, respectively). The stroke incidence rate was higher in the conservative group than in the EDAS group, with a statistically significant difference (p = 0.001) according to results of the Kaplan-Meier analysis. The identified predictor of postoperative stroke events was initial hemorrhage in the EDAS group and advanced age, aneurysm, and initial ischemia in the conservative treatment group. The postoperative long-term stroke rate among elderly patients with MMD was lower in the EDAS group than in the conservative treatment group. Long-term stroke events were associated with advanced age, aneurysm, and initial ischemia after conservative treatment and only initial hemorrhage after EDAS.

Risk Factors for Massive Cerebral Infarction in Pediatric Patients With Moyamoya Disease

BackgroundTo explore the risk factors for preoperative massive cerebral infarction (MCI) in pediatric patients with moyamoya disease (MMD). MethodsPediatric patients with MMD treated between 2017 and 2022 were enrolled. Logistic regression analysis was performed to identify risk factors for MCI among the patients, and a nomogram was constructed to identify potential predictors of MCI. Receiver operating characteristic (ROC) curves and areas under the curves were calculated to determine the effects of different risk factors. ResultsThis study included 308 pediatric patients with MMD, including 36 with MCI. The MCI group exhibited an earlier age of onset than the non-MCI group. Significant intergroup differences were observed in familial MMD history, postcirculation involvement, duration from diagnosis to initiation of treatment, Suzuki stage, magnetic resonance angiography (MRA) score, collateral circulation score, and RNF213 p.R4810K variations. Family history, higher MRA score, lower collateral circulation score, and RNF213 p.R4810K variations were substantial risk factors for MCI in pediatric patients with MMD. The nomogram demonstrated excellent discrimination and calibration capabilities. The integrated ROC model, which included all the abovementioned four variables, showed superior diagnostic precision with a sensitivity of 67.86%, specificity of 87.01%, and accuracy of 85.11%. ConclusionsThis study showed that family history, elevated MRA score, reduced collateral circulation score, and RNF213 p.R4810K variations are risk factors for MCI in pediatric patients with MMD. The synthesized model including these variables demonstrated superior predictive efficacy; thus, it can facilitate early identification of at-risk patients and timely initiation of appropriate interventions.

Meta-analysis of the association between RNF213 polymorphisms and clinical features of moyamoya disease in Asian population

BackgroundWe performed this study to explore the relationship between ring finger protein 213 (RNF213) gene polymorphisms and clinical features in moyamoya disease (MMD). MethodsElectronic databases (PubMed, Google Scholar, Embase, Scopus, Cochrane Library) were conducted from inception to May 15th, 2022. Odds ratios (ORs) with 95 % confidence intervals (CIs) were generated as effect size for binary variants. Subgroup analyses were performed by the RNF213 polymorphisms. Sensitivity was used to examine the robustness of associations. ResultsA total of 16 articles and 3061 MMD patients were included and the association of five RNF213 polymorphisms on 9 clinical features of MMD were identified. Patients under 18 years of age at onset, familial MMD, cerebral ischemic stroke and posterior cerebral artery involvement (PCi) were significantly more common in mutant type compared with wild type of RNF213. Compared with each wild type, subgroup analysis showed that rs11273543 and rs9916351 remarkably increased risk of MMD on early onset, but rs371441113 evidently delayed the onset of MMD. Rs112735431 in mutant type was significantly higher than wild type in patients with PCi. Subgroup analysis in mutant type showed that rs112735431 conspicuously decreased intracerebral/ intraventricular hemorrhage (ICH/IVH) risk and yet rs148731719 obviously increased the risk in ICH/IVH. ConclusionMore attention should be paid to patients on whom the ischemic MMD occurs younger than 18 years old. RNF213 polymorphism screening and cerebrovascular imaging examination should be performed to evaluate intracranial vascular involvement, to achieve early detection and early treatment and avoid more serious cerebrovascular events.

First Report: Rare RNF213 Variant Associated with Familial Moyamoya Disease in an African American Family

ObjectiveTo investigate potential genetic susceptibility for moyamoya disease (MMD) in an African American family. Materials and methodsNeurovascular imaging and analyses of MMD susceptibility genes RNF213 and/or ACTA2 in a young proband with MMD and two first-degree relatives. ResultsThe proband presented with pseudobulbar affect and chorea, then had a right hemispheric ischaemic stroke and rapidly fatal course. One relative had a mild haemorrhagic thalamic stroke and clinically silent ischaemic infarct. Despite evidence of slowly progressive disease, he remained clinically stable. Another relative was neurologically intact with normal cerebrovascular imaging to date. All three have the rare R4131C (p.Arg4131Cys or p.R4131C, c.12391C>T) variant of the RNF213 gene. They are the first Black people and only the 5th family worldwide known to harbour this variant. MMD was confirmed in both of the patients with neurological events. ConclusionsOur report provides compelling evidence that MMD is a clinically complex, heritable genetic disease. It supports the probable pathogenicity of R4131C. Furthermore, it illustrates the wide phenotypic spectrum of R4131C, from asymptomatic carrier to late presenting, mild disease to catastrophic, rapidly fatal childhood disease. To our knowledge, this is also the first report of heritable MMD in a Black family. Finally, this study highlights the importance of racially and ethnically diverse participants in biomedical research.

Abstract P588: A Rare RNF213 Variant is Associated With Moyamoya Disease in an African American Family

Objective: To investigate potential genetic susceptibility for moyamoya disease (MMD) in an African American family. Methods: A young girl with MMD (proband), her father and paternal half-brother underwent cerebrovascular imaging with MRI and MRA. Cerebral angiography was also performed on the girl and her father. Genetic analysis of the MMD susceptibility gene RNF213 was conducted on all three relatives, while ACTA2 gene was analysed in the proband only. Results: The proband presented with pseudobulbar affect and chorea, then subsequently had a right hemispheric ischaemic stroke and rapid, ultimately fatal clinical decline. Detailed family history raised suspicion for familial MMD and investigation of her relatives. Her father had a small haemorrhagic thalamic stroke without residual neurologic deficits; a clinically silent ischaemic infarct was incidentally discovered on neuroimaging. He remains clinically stable despite slowly progressive disease on imaging. Her brother is neurologically intact and has normal cerebrovascular imaging to date. They are all heterozygous for the rare Arg4131Cys variant in RNF213. They are the first Black people and only the 3rd, 4th and 5th people in the world known to harbour this variant. MMD was confirmed in the girl and her father with cerebral angiogram. Conclusions: This study illuminates the clinical and genetic complexity of familial MMD. It underscores the importance of genetic testing and surveillance cerebrovascular imaging even in asymptomatic relatives of probands with MMD. Although the clinical significance of Arg4131Cys remains unclear, modest variant-disease segregation in this family is consistent with a growing body of evidence supporting its probable pathogenicity. Furthermore, our study illustrates its wide phenotypic spectrum, from asymptomatic carrier to late presenting, mild disease to fulminant, rapidly fatal childhood disease. To our knowledge, this is also the first report of heritable MMD in a Black family. We demonstrate the value of considering diseases more predominant in one specific ancestry when evaluating patients from other ethnic backgrounds. Finally, we highlight the importance of racially and ethnically diverse participants in biomedical research.

Encephaloduroarteriosynangiosis for pediatric moyamoya disease: long-term follow-up of 100 cases at a single center.

OBJECTIVE The object of this study was to summarize the long-term effect of encephaloduroarteriosynangiosis (EDAS) for the treatment of pediatric moyamoya disease (MMD) and to investigate factors influencing the clinical outcomes of EDAS. METHODS Clinical features, angiographic findings, and clinical outcomes were analyzed among MMD patients younger than 18 years who had been treated with EDAS between 2002 and 2007 at the authors' institution. The Kaplan-Meier method was used to estimate stroke risk after EDAS. Predictors of neurological outcome were assessed. RESULTS One hundred fifteen patients were identified. The mean age at symptom onset was 7.3 ± 4.0 years. The incidence of familial MMD was 11.3%. The female/male ratio was 1:1.16. A total of 232 EDAS procedures were performed, and the incidence of postoperative complications was 3%. Postoperative digital subtraction angiography was performed in 54% of the patients, and about 80% of the hemispheres showed good or excellent results. Neovascularization showed significant correlations with delay time (from symptom onset to first operation), Suzuki stage, and preoperative stroke (all p < 0.05). Clinical follow-up was available in 100 patients with a mean follow-up of 124.4 ± 10.5 months. Ten-year cumulative survival was 96.5% after surgery, and the risk of stroke was 0.33%/person-year. An independent life with no significant disability was reported by 92% of the patients. A good outcome correlated with a low Suzuki stage (p = 0.001). Older children and those without preoperative stroke had better clinical outcomes (p < 0.05). CONCLUSIONS On the basis of long-term follow-up data, the authors concluded that EDAS is a safe and effective treatment for pediatric MMD, can reduce the risk of subsequent neurological events, and can improve quality of life. The risk of ischemia-related complications was higher in younger patients, and older children showed better outcomes. Compensation was greater with more prominent cerebral ischemia. The long-term clinical outcome largely depended on the presence and extent of preoperative stroke.

Abstract TP448: Genome-wide CNV Array Analysis Following Post-hoc Targeted Amplicon Sequencing Revealed Genetic Anticipation in Parent-offspring Pairs with Moyamoya Disease

Introduction: Molecular mechanisms underlying clinical observation of progressively earlier age of onset of Moyamoya disease (MMD) as it is passed on to the next generation, as known as clinical anticipation, is still obscure. This study investigates copy number variation (CNV) in parent-offspring pairs with MMD with and without clinical anticipation using genome-wide CNV array following high-throughput DNA sequencing. Methods: Fifteen out of 25 consecutive Japanese parent-offspring pairs with MMD treated at our institute since 1980 were enrolled. Demographics, inheritance pattern, angiographical stage, disease type at onset were reviewed. Using genomic DNA from whole blood, rs112735431 in RNF213 gene was genotyped, then genome-wide CNV analysis was conducted using a 2.6 M oligonucleotide array to compare CNV profile in parent-offspring pairs with and without clinical anticipation. Amplicon Sequencing was further conducted using Miseq. Results: Clinical anticipation was observed in 10 pairs (67%) and was not in 5 pairs (33%). In clinical anticipation group, mean age at onset was significantly lower in the offsprings than in the parents (p&lt;0.001). There were no significant differences in other clinical and genetic backgrounds, including the genotype in RNF213 between the generations and between the groups with and without clinical anticipation. Genome-wide CNV profiling revealed that 10 CNV in chr7q, 8p, 9q, 14q, 16p, 19p, 20q, and 22q were overlapped for more than 3 individuals in the whole studied population. Of these CNV, copy number was different only in chr16p13.3 between the generations in clinical anticipation group (P=0.06). Fourteen genes were observed in this locus, including GNPTG gene, whose mutation is known to be associated with mucolipidosis. Amplicon sequence targeting these 14 genes revealed significant copy number loss at GNPTG gene locus, in the offsprings compared to their parent (P = 0.02, copy number = 1.8 and 2.0, respectively). Conclusion: These data suggest clinical anticipation of MMD in Japanese population can be observed regardless of the RNF213 genotype. This is the first genome-wide CNV profiling, suggesting the CNV in chr16p13.3 might be underlying mechanism for anticipation in familial MMD by reducing gene dosage.

Differences in the Genotype Frequency of the RNF213 Variant in Patients with Familial Moyamoya Disease in Kyushu, Japan.

The p.R4810K (rs11273543, c.14429G > A) variant of the RNF213 gene is associated with increased risk of Moyamoya disease (MMD), which is an idiopathic progressive intracranial vascular steno-occlusive disease, in Asian populations. Numerous variant association studies for this MMD variant have been performed in Japan to date. Since another genetic study that utilized approximately 140,000 single nucleotide polymor (SNPs) has indicated that there still are genetic differences among mainland Japanese, there is a possibility that the variant distribution in patients with MMD and normal individuals varies between different Japanese regions. Additionally, the majority of variant association studies have used Sanger sequencing, which is labor-intensive, time-consuming, and costly. In this study, we analyzed the frequency of the variant genotype in patients with MMD and normal individuals in Kyushu using pyrosequencing, which is an accurate, cost-effective, and automated method. We found differences in the genotype frequencies in familial patients from Kyushu and normal populations in Tohoku compared with west Japan, which suggested that there were differences in the frequency of the variant among different regions in Japan.

Single Nucleotide Polymorphism in Patients with Moyamoya Disease.

Moyamoya disease (MMD) is a chronic, progressive, cerebrovascular occlusive disorder that displays various clinical features and results in cerebral infarct or hemorrhagic stroke. Specific genes associated with the disease have not yet been identified, making identification of at-risk patients difficult before clinical manifestation. Familial MMD is not uncommon, with as many as 15% of MMD patients having a family history of the disease, suggesting a genetic etiology. Studies of single nucleotide polymorphisms (SNPs) in MMD have mostly focused on mechanical stress on vessels, endothelium, and the relationship to atherosclerosis. In this review, we discuss SNPs studies targeting the genetic etiology of MMD. Genetic analyses in familial MMD and genome-wide association studies represent promising strategies for elucidating the pathophysiology of this condition. This review also discusses future research directions, not only to offer new insights into the origin of MMD, but also to enhance our understanding of the genetic aspects of MMD. There have been several SNP studies of MMD. Current SNP studies suggest a genetic contribution to MMD, but further reliable and replicable data are needed. A large cohort or family-based design would be important. Modern SNP studies of MMD depend on novel genetic, experimental, and database methods that will hopefully hasten the arrival of a consensus conclusion.

The natural clinical course of hemodynamically stable adult moyamoya disease.

Moyamoya disease (MMD) is a rare cerebrovascular disease and its natural history is still unclear. The authors aimed to investigate the natural course of hemodynamically stable cases of adult MMD, with the analysis of stroke risk factors. Two hundred forty-one patients were included in this retrospective study. One hundred sixty-six (68.9%) were female, and mean age (± SD) at first visit was 41.3 ± 12.0 years (range 18-69 years). Unilateral involvement was identified in 33 patients, and 19 patients (7.9%) had a family history of MMD. According to the clinical presentations, patients were classified into hemorrhagic (n = 62, 25.7%), ischemic (n = 144, 59.8%), and asymptomatic (n = 35, 14.5%) groups. The mean duration of follow-up was 82.5 ± 62.9 months (range 7.3-347.0 months). The annual stroke risk was 4.5%, and the annual risks of rebleeding in the hemorrhagic group and recurrent ischemic events in the ischemic group were 4.3% and 3.0%, respectively. There was no significant difference in cumulative stroke risk between the 3 groups (p = 0.461). Risk factors included thyroid disease for overall strokes (HR 2.56, 95% CI 1.16-5.67), initial hemorrhagic presentation for hemorrhagic strokes (HR 2.53, 95% CI 1.24-5.17), and initial ischemic presentation for ischemic strokes (HR 2.69, 95% CI 1.15-6.27). Familial MMD was a common risk factor for all types of stroke. Among the 3 clinical groups, the hemorrhagic group showed the worst clinical status at discharge and at most recent follow-up. Twenty-three patients (9.5%) eventually underwent revascularization surgery. There was no statistically significant difference in the incidence of stroke in the different clinical groups; clinical status, however, was most severe in patients with hemorrhagic presentation. In patients who experienced stroke during the follow-up period, the stroke type tended to correspond to their initial presentation. Close follow-up is needed in patients with thyroid disease and a family history of MMD.

Prospective Screening of Family Members with Moyamoya Disease Patients

BackgroundGenetic factors play an important role in the pathogenesis of moyamoya disease (MMD). Previous studies concentrated on familial MMD patients. In this study, we focused on family members of sporadic MMD patients, and aimed to gain a clearer understanding of the role that genetic factors play in MMD.MethodsThe immediate family members of MMD patients were initially screened by transcranial Doppler sonography (TCD) and positive cases were verified by magnetic resonance angiography (MRA).ResultsFrom July 2011 to March 2013, there were 527 MMD patients managed in our hospital, including 38 familial MMD cases. In this study, 285 immediate family members of 245 sporadic MMD patients were screened. Another 41 cases of familial MMD cases were identified, which included 21 family members and 20 corresponding sporadic MMD patients who had family members confirmed positive with MMD. As a result, the proportion of familial MMD patients increased from 7% (38/527) to 15% (79/527) in this period. For the main segments of the circle of Willis, Kappa values between TCD and MRA for the anterior cerebral arteries, middle cerebral arteries and posterior cerebral arteries were 0.91, 0.72, and 0.47, respectively. Familial cases confirmed by our screening showed a significantly higher percentage of asymptomatic patients (57%) compared with 9% from the control group who had a clear family history before.ConclusionsFamilial MMD patients may account for a higher percentage among all cases than previously thought. Some family members of MMD patients may also have MMD, but not have any obvious symptoms. Routine screening should be implemented for all family members of MMD patients to improve the detection rate for this part of the patient base. TCD has a high diagnostic agreement with MRA for MMD. TCD may be the preferred choice for screening because it is inexpensive and safe.

Nationwide survey on quasi-moyamoya disease in Japan

Moyamoya disease (MMD) is a unique occlusive disease of the bilateral internal carotid arteries with moyamoya vessels. Inherited or acquired disorders and conditions may present in conjunction with MMD. This condition is known as quasi-moyamoya disease. To identify the clinical features of quasi-MMD in Japan, a nationwide survey was conducted. A questionnaire was mailed directly to 241 departments that had acknowledged treating quasi-MMD patients in the primary survey. We ascertained the sex, age, family history, clinical manifestation, radiological findings, treatments, course of the disease, and daily activity of the patients. A total of 114 departments replied to the questionnaire. The data of 108 patients (66 female and 42 male; female to male ratio 1.57) were registered and analyzed. Mean age was 30.6years old, with a peak in children. Seven patients (7%) exhibited familial MMD. The initial clinical manifestation was motor weakness, followed by transient ischemic attack and headache. Their imaging study type included ischemic type in 64 patients (63.4%), bleeding type in seven (6.9%), and normal in 27 (26.7%). Stenoocclusive lesion was seen in the internal carotid artery in more than half of the patients. Development of moyamoya vessels was mild in approximately 40% of the patients. Almost all cases were accompanied by cerebral hypoperfusion. About half of them were unilateral lesion. Vascular reconstruction was employed for the approximately 60% patients. The prognosis did not change significantly. Clinical features of quasi-MMD were revealed in the nationwide study. In quasi-MMD, unilateral lesion is dominant, and the development of moyamoya vessels and intracranial hemorrhage are less dominant.

Abstract T P165: Prospective Screening of Family Members With Moyamoya Disease Patients

Background: Genetic factor plays an important role in the pathogenesis of moyamoya disease (MMD). Previous studies concentrated on the familial patients. In this study, we focus on the family members of sporadic MMD patients, and aim to gain a clearer understanding of the role that genetic factor plays in MMD. Methods: The immediate family members of MMD patients were initially screened by Transcranial Doppler Sonography (TCD) and the positive cases were verified by Magnetic Resonance Angiography (MRA). A total of 285 immediate family members of 245 sporadic MMD patients (2011.07-2013.03) were screened. Results: 33 cases were confirmed positive at 11.6% detection rate. 21 cases (from 20 index MMD patients) was validated by MRA. As a result, the proportion of familial MMD patients in our hospital increased from 7% (38/527) to 15% (79/527) in this period. For the main segments of the circle of Willis, which include the anterior cerebral arteries (ACA), middle cerebral arteries (MCA) and posterior cerebral arteries (PCA), the accordant rate between TCD and MRA was 95% (91/96). Kappa values for ACA, MCA and PCA were 0.91, 0.72 and 0.47 respectively. The familial cases confirmed by our screening showed a significant higher percentage of asymptomatic patients (57%) comparing to the 9% from the 38 familial MMD patients who had a clear family history before. Conclusions: Familial MMD patients may account for a higher percentage among all cases than previously thought. Some of the family member of MMD patients may also have MMD but present with asymptomatic. A routine screening should be implemented for all family members of MMD patients to improve the detection rate for this part of patient base. TCD has a high diagnostic agreement with MRA for MMD. By contrast, TCD may be a preferred choice for screening, because it’s inexpensive and safe.

Contralateral progression and its risk factor in surgically treated unilateral adult moyamoya disease with a review of pertinent literature

The fate of the contralateral unaffected side of the surgically treated unilateral moyamoya disease (MMD) in adults has not been well described due to the limited number of cases and the heterogeneous ages and treatment methods. The aim of this study was to evaluate the contralateral angiographic progression rate and its risk factors in homogeneous adult MMD patients who underwent surgical revascularization, with a review of pertinent literature. Forty-one surgically treated unilateral MMD patients were retrospectively evaluated. We reviewed medical and radiological records including data on gender, age, hypertension (HTN), smoking, familial MMD, presenting symptom, surgical method, Suzuki stage, and contralateral progression. Then, we conducted univariate and multivariate analyses to determine risk factors. Six of the 41 cases (14.6%) exhibited contralateral progression during the mean follow-up of 34 months. Four of those six patients (66.7%) were asymptomatic. Additional revascularization surgery was performed in the two symptomatic patients. The presence of a contralateral angiographic abnormality on initial angiography was a statistically significant risk factor for progression (OR, 49.00; p = 0.04). Younger age at diagnosis (32.7 ± 7.8 years in progression group vs. 42.5 ± 10.3 years in non-progression group, p = 0.046) was statistically significant in the univariate analysis, but age was not a significant factor in the multivariate analysis (p = 0.82). Other variables, such as gender (p = 0.13), HTN (p = 0.24), smoking (p = 0.47), and familial MMD (p = 0.20), did not show statistical significance. The presence of a contralateral angiographic abnormality on initial angiography was a significant risk factor for progression in surgically treated unilateral adult MMD. Consequently, patients with contralateral abnormalities should be monitored closely.

Clinical features of familial juvenile cases of moyamoya disease: analysis of patients treated in a single institute over a 28-year period

The authors compared the clinical features between familial and sporadic cases of moyamoya disease (MMD) by retrospectively analyzing data on patients with MMD registered in the database of Tokyo Medical and Dental University over a period of 28 years. In total, 383 patients with hospital records at Tokyo Medical and Dental University from 1980 to 2007 were registered into the database. The data on all of these patients were retrospectively reviewed to clarify the occurrence of familial cases. Clinical features of child or adolescent patients (< 20 years of age) with MMD were compared between familial and sporadic cases in a subgroup of patients who were registered after 1995, initially diagnosed using MR angiography, and assessed using an intelligence scale. Familial occurrence was observed in 59 patients (15.4%) in 40 pedigrees. The clinical features of juvenile patients were analyzed in 124 patients, 22 (17.7%) of whom had familial histories. In comparison with the sporadic cases, patients with familial histories were significantly younger at onset (4.7 vs 6.6 years old), had significantly more cortical infarction (59.1% vs 25.5%), and had significantly more stenoocclusive lesions in the posterior cerebral artery (45.4% vs 24.5%). The rate of patients with intellectual disturbance (intelligence quotient < 75) was significantly larger in the familial cases (47.4%) than in the sporadic cases (17.8%). This survey of the clinical features of familial MMD suggests that patients with familial MMD had a more serious clinical course in childhood than the sporadic MMD cases.

In Reply

In Reply: We thank Dr Kapoor for his interest in our article on sex differences in clinical presentation and treatment outcomes in moyamoya disease (MMD), and share in his enthusiasm for research on genetic factors that underlie the susceptibility and clinical course of MMD. Several lines of evidence have long supported an underlying genetic susceptibility to MMD as reviewed by Achrol et al.1 Familial occurrence in as many as 15% of individuals with MMD, concordance rates as high as 80% in monozygotic twins with MMD, and apparent autosomal dominant transmission with incomplete penetrance in Japanese families with MMD, were all previously described. Further work suggested the autosomal dominant transmission of MMD in Japanese families mapped to chromosome 17q25.2 Chromosome 17 was already of interest given the association between MMD and neurofibromatosis Type 1, for which the causative gene (NF1) had been identified on chromosome 17q11.2. Using microsatellite markers and an affected-member-only approach in Japanese families, a candidate locus was suggested at 17q25.3 A separate analysis in 15 extended Japanese families using genome-wide parametric linkage analysis also identified a candidate locus at 17q25.3.2 Collectively, these data provided compelling evidence that a pathogenic gene associated with familial MMD in Japanese patients might be found on chromosome 17q25. The recent Kamada et al4 genome-wide association follow-up analysis of 785,720 SNPs demonstrated that SNPs in the 17q25-ter region reached a significance of P < 10−8. Their locus-specific association study of 384 SNP markers within the chromosome 17q25-ter region found that SNP markers most highly associated with MMD fell entirely within the RNF213 locus. Almost simultaneously, Liu et al5 discovered an RNF213 variant using exome analysis of 8 index cases of familial MMD. Additional single-gene mutations have also been closely associated with MMD. Mutations in smooth muscle alpha actin (ACTA2) can cause MMD, as well as premature coronary artery disease and thoracic aortic disease.6 Recently Xq28 deletions removing MTCP1/MTCP1NB and BRCC3 have been shown to cause a type of X-linked familial moyamoya syndrome.7 While these results mark a major genetic advance toward understanding the underlying pathogenesis of MMD and elucidating potential pathways for therapeutic intervention, they should be interpreted with certain caveats in mind. For example, it could not be demonstrated that variants of RNF213 altered or impaired physiological function or mRNA levels and therefore it remains unclear how these variants could contribute to the development of MMD. Furthermore, it is unclear why the disease prevalence in this population (1 in 100 000) is lower than expected given the much higher minor allele frequency of 1%. Importantly, neither the p.R4859K mutation found by Kamada et al4 nor the p.R4810K mutation found by Liu et al5 were observed in any of the Caucasian patients and controls tested, suggesting the genetic background of MMD in Japanese populations may be distinct from that in Western populations, and that RNF213 may represent a founder mutation specific to these Japanese families. It should also be noted, even when limited to Japanese families, genetic linkage studies have reported varied results, with 5 different chromosomal regions of interest reported in the past: 3p24.2–p26, 6q25, 8q23, 12p12, and 17q25 (reviewed in Achrol et al1). Taken together with the fact that RNF213 minor allele frequency appears much more prevalent than disease prevalence and that the same variants present in Japanese patients were not found in Caucasian patients, these data suggest that much work remains to be done to elucidate the pathogenesis of MMD. We share in Dr Kapoor's enthusiasm for these recent major genetic advancements, and believe these results should serve to encourage further research on genetic factors that underlie the susceptibility and clinical course of MMD. Disclosure The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.

Homozygous c.14576G&gt;A variant of RNF213 predicts early-onset and severe form of moyamoya disease

RNF213 was recently reported as a susceptibility gene for moyamoya disease (MMD). Our aim was to clarify the correlation between the RNF213 genotype and MMD phenotype. The entire coding region of the RNF213 gene was sequenced in 204 patients with MMD, and corresponding variants were checked in 62 pairs of parents, 13 mothers and 4 fathers of the patients, and 283 normal controls. Clinical information was collected. Genotype-phenotype correlations were statistically analyzed. The c.14576G>A variant was identified in 95.1% of patients with familial MMD, 79.2% of patients with sporadic MMD, and 1.8% of controls, thus confirming its association with MMD, with an odds ratio of 259 and p < 0.001 for either heterozygotes or homozygotes. Homozygous c.14576G>A was observed in 15 patients but not in the controls and unaffected parents. The incidence rate for homozygotes was calculated to be >78%. Homozygotes had a significantly earlier age at onset compared with heterozygotes or wild types (median age at onset 3, 7, and 8 years, respectively). Of homozygotes, 60% were diagnosed with MMD before age 4, and all had infarctions as the first symptom. Infarctions at initial presentation and involvement of posterior cerebral arteries, both known as poor prognostic factors for MMD, were of significantly higher frequency in homozygotes than in heterozygotes and wild types. Variants other than c.14576G>A were not associated with clinical phenotypes. The homozygous c.14576G>A variant in RNF213 could be a good DNA biomarker for predicting the severe type of MMD, for which early medical/surgical intervention is recommended, and may provide a better monitoring and prevention strategy.

Association of a Functional Polymorphism in the MMP-3 Gene with Moyamoya Disease in the Chinese Han Population

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.

Clinical Features of Unilateral Moyamoya Disease

Moyamoya disease is characterized by progressive occlusion of the internal carotid artery or its terminal branches, associated with formation of extensive collateral vessels (moyamoya vessels) at the base of the brain. Whether unilateral moyamoya disease, confirmed by typical angiographic evidence of moyamoya disease unilaterally and normal or equivocal findings contralaterally, is an early form of definite (bilateral) moyamoya disease remains controversial. The present study investigated the incidence and clinical features of unilateral moyamoya disease in a series of patients treated for moyamoya disease. Fifty-two patients were diagnosed with definite moyamoya disease and nine patients with unilateral moyamoya disease. Sex, age, signs at onset, neuroimaging findings, treatment, course of the disease, and family history of unilateral moyamoya disease were reviewed. Among the nine patients with unilateral moyamoya disease, there were twice as many females as males, and mean age at onset was 39.0 years. The clinical presentation was ischemic in three patients, bleeding in one, and asymptomatic in five. Two had familial moyamoya disease. Progression to bilateral lesions is known to occur in pediatric patients and patients with stenotic changes of the contralateral internal carotid artery bifurcation. Some unilateral cases are caused by the same genetic defects as definite cases, and others seem to be an unusual form of stenoocclusive process of cerebral arteries. Surgical treatment on the symptomatic side followed by close observation for bilateral involvement is recommended.

Familial Moyamoya Disease Associated With Graves' Disease in a Mother and Daughter -Two Case Reports-

A mother and daughter presented with a rare combination of moyamoya disease and Graves' disease. A 19-year-old woman experienced numbness in her right hand due to cerebral infarction during therapy for Graves' disease. Cerebral angiography demonstrated stenoses of the bilateral internal carotid arteries and net-like abnormal collateral vessels indicative of moyamoya disease. Her 52-year-old mother with a history of Graves' disease presented with left hemiparesis due to intracerebral hemorrhage; she recovered after hematoma evacuation. Postoperative angiography demonstrated stenoses of the bilateral internal carotid arteries and net-like abnormal collateral vessels indicative of moyamoya disease. Another otherwise healthy daughter manifested slight stenosis of the left internal carotid artery. After cerebral revascularization surgery the patients were able to return to their normal daily lives. These familial cases of moyamoya disease and Graves' disease indicate hereditary involvement in both diseases.