Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan,
Tokyo Women's Medical University Institute for Integrated Medical Sciences (TIIMS), Tokyo, Japan,
Cerebrovasc Dis. 2019;47(3-4):105-111. doi: 10.1159/000499699. Epub 2019 Apr 4.
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.
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.
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.
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.
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.
已知 RNF213moyamoya 病（MMD）易感性基因的这个 p.R4810K 纯合变异会影响疾病发作时临床疾病表型的严重程度。然而，这种基因型与长期临床表现之间的关系仍不清楚。
本研究的主要目的是探讨 RNF213 的 p.R4810K 变异是否以及如何影响日本 MMD 患者的长期表型。
本回顾性队列研究纳入了 94 例在我院确定了 p.R4810K 基因型的日本 MMD 患者，这些患者接受了直接或联合旁路血运重建。在疾病发作时和长期随访中分析了以下表型参数：年龄和首发表现、初次血运重建后复发脑卒中以及最终改良 Rankin 量表评分。
p.R4810K 基因型与发病时的表型显著相关，尤其是在年轻患者中。在中位随访 100 个月期间，94 例患者中有 6 例复发脑卒中：5 例纯合变异患者中无一例，64 例杂合变异患者中有 5 例，25 例野生型患者中有 1 例。基因型之间无显著差异。特别是，5 例患者发生了复发性脑出血，均携带杂合变异。对数秩检验显示基因型在无卒中生存率方面无差异。此外，p.R4810K 基因型与不良功能状态无关。
RNF213 的这个 p.R4810K 起始变异影响疾病发作时的表型。然而，无论基因型如何，最佳的血运重建可能是有效的，即使对于被认为是最具致病性的纯合变异也是如此。该基因型可能不会强烈影响 MMD 的长期临床表现或不良预后。
