Genotype-Phenotype Correlation in Long-Term Cohort of Japanese Patients with Moyamoya Disease
Genotype-Phenotype Correlation in Long-Term Cohort of Japanese Patients with Moyamoya Disease
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DOI：
10.1159/000499699
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发表时间：
2019-01-01
影响因子：
2.9
通讯作者：
Kawamata, Takakazu
中科院分区：
文献类型：
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作者：
Nomura, Shunsuke;Yamaguchi, Koji;Kawamata, Takakazu
背景资料：已知RNF213烟雾病（MMD）易感基因的p.R4810K创始者变体的纯合性影响疾病发作时临床疾病表型的严重程度。然而，这种基因型和长期临床表现之间的关联仍不清楚。目的：本研究的主要目的是调查RNF213的p.R4810K变异是否以及如何影响日本MMD患者的长期表型。方法：这项回顾性队列研究纳入了94例日本MMD患者，这些患者接受了直接或联合搭桥术进行血运重建，并在我院确定了p.R4810K基因型。在疾病发作时和长期内分析以下表型参数：发病时的年龄和初始表现、初始血运重建后的复发性卒中和最终改良兰金量表。结果：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100个月的中位随访期内，94例患者中有6例发生复发性卒中：5例纯合子变异患者中无复发，64例杂合子变异患者中有5例复发，25例野生型患者中有1例复发。基因型间差异不显著。特别是，5例患者发生复发性脑出血，均具有杂合子变异。对数秩检验显示基因型间无卒中生存率无差异。此外，p.R4810K基因型与不良功能状况无关。结论：RNF213的p.R4810K创始者变体影响疾病发作时的表型。然而，最佳的血运重建可能是有效的，无论基因型如何，即使是被认为是致病性最高的纯合变异。该基因型可能对MMD的长期临床表现或不良预后无明显影响。
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.