Genotype-Phenotype Correlation in Long-Term Cohort of Japanese Patients with Moyamoya Disease

Abstract

Background: Homozygosity of this p.R4810K founder variant of RNF213moyamoya disease (MMD) susceptibility gene is known to influence the severity of the clinical disease phenotype at disease onset. However, the association between this genotype and long-term clinical manifestations has remained unclear. Objectives: The principal goal of this study was to investigate whether and how the p.R4810K variant of RNF213influences the long-term phenotype in Japanese patients with MMD. Method: This retrospective cohort study included 94 Japanese patients with MMD who underwent direct or combined bypass for revascularization with the p.R4810K genotype determined in our hospital. The following phenotypic parameters were analyzed at disease onset and over a long-term period: age and initial presentation at onset, recurrent stroke after initial revascularization, and final modified Rankin Scale. Results: The p.R4810K genotype was significantly associated with the phenotype at onset, especially in younger patients. Over a median follow-up period of 100 months, recurrent stroke occurred in 6 out of 94 patients: none out of 5 patients with the homozygous variant, 5 out of 64 with the heterozygous variant, and 1 out of 25 in the wild-type group. There were no significant differences among the genotypes. In particular, recurrent cerebral hemorrhage occurred in 5 patients, all possessing the heterozygous variant. The log-rank test showed no difference between the genotypes in the stroke-free survival rate. Furthermore, the p.R4810K genotype was not associated with a poor functional condition. Conclusions: The p.R4810K founder variant of RNF213 affects the phenotype at disease onset. However, the optimal revascularization may be effective, regardless of the genotype, even for the homozygous variant, which has been thought to be the most pathogenic. This genotype may not strongly influence the long-term clinical manifestations or poor prognosis in MMD.

Angiographic characteristics in Moyamoya disease with the p.R4810K variant: a propensity score‐matched analysis

“…found that Korean patients with GA were associated with cognitive impairment in long‐term outcome . In addition, our recent study showed that patients with GA were associated with better post‐operative collateral formation , whereas p.R4810K variant was not associated with either recurrent stroke or neurological status , similar to the Japanese study .…”

Different Subtypes of Collateral Vessels in Hemorrhagic Moyamoya Disease with p.R4810K Variant

“…And Takahashi et al found that posterior hemorrhage was associated with a higher rate of recurrent bleeding [7]. Nevertheless, the p.R4810K variant was not associated with clinical outcomes in MMD in previous studies [18]. In present study, no difference was observed in hemorrhagic sites between two matched groups.…”

“…Previous study showed that patients with GA or homozygous variant (AA) may have a younger age onset, higher prevalence of family history, more cerebral infarction, and more PCA involvement. The p.R4810K variant may not relate to clinical outcomes in MMD [17,18]. Although our previous study revealed that patients with GA might associate with better postoperative collateral formation than patients with GG [12], Nomura et al found that there was no difference in recurrent strokes and functional conditions [18], our previous study also had come to the same conclusion [17].…”

“…The p.R4810K variant may not relate to clinical outcomes in MMD [17,18]. Although our previous study revealed that patients with GA might associate with better postoperative collateral formation than patients with GG [12], Nomura et al found that there was no difference in recurrent strokes and functional conditions [18], our previous study also had come to the same conclusion [17]. Recently, we investigated the whether the p.R4810K variant was associated with angiographic characteristics in MMD, the results revealed that patients in GA group may have a different collateral circulation from patients in GG group [11].…”

Different subtypes of collateral vessels in hemorrhagic moyamoya disease with p.R4810K variant

“…Previous study showed that patients with GA or homozygous variant (AA) may have a younger age onset, higher prevalence of family history, more cerebral infarction, and more PCA involvement. The p.R4810K variant may not relate to clinical outcomes in MMD [19,20]. Although our previous study revealed that patients with GA might associate with better postoperative collateral formation than patients with GG [14], Nomura et al found that there was no difference in recurrent strokes and functional conditions [20], our previous study also had come to the same conclusion [19].…”