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次形态RPE65突变引起的视网膜营养不良视觉功能障碍

Hull S, Holder GE, Robson AG, et al.

期刊名称:British Journal of Ophthalmology

卷期:2016年第100卷第11期

摘要

背景/目的:旨在描述4个非典型,轻度,隐性RPE65相关性视网膜营养不良家族的4例患者详细的表型和分子学结果,并讨论对基因替代治疗的潜在影响。方法:4例患有早期视网膜营养不良的患者进行临床检查,视网膜成像和电生理检测。对所有外显子和RPE65内含子-外显子边界进行双向Sanger测序。结果:所有患者在儿童早期表现为夜盲症,但直至19岁前表现为轻度表型,且视敏度良好。所有患者的视网膜电图上普遍存在视网膜功能障碍。那些视力良好患者的光学相干断层扫描显示的中央黄斑厚度不变。1例患者整个视网膜具有广泛的白点,使人想起眼底白癜风,且有延长暗适应后部分视杆细胞功能恢复的电生理学证据。 Sanger测序确定所有患者存在RPE65突变,包括可能代表次形态等位基因的三个错义变体。结论:RPE65的同型突变与保持良好视力到成年期儿童的轻度疾病相关,在罕见病例中,可能与眼底白斑类似的视网膜外观相关。RPE65次形态突变患者的视力正常显示,转导可能不是改善基因替代治疗试验中视力的限制因素。相反,为了视力的最佳恢复,可能需要在儿童早期更早地给予基因替代治疗。

Background/aims To present detailed phenotypic and molecular findings in four patients from four families with atypical, mild, recessive RPE65-related retinal dystrophy and discuss potential implications for gene replacement therapy.Methods Four patients from four families with early onset retinal dystrophy underwent clinical examination, retinal imaging and electrophysiological testing. Bidirectional Sanger sequencing of all exons and intron–exon boundaries of RPE65 was performed.Results All patients presented with nyctalopia in early childhood but demonstrated a mild phenotype with good visual acuity until at least 19years of age. All had generalised retinal dysfunction on electroretinography. Central macular thickness on optical coherence tomography was preserved in those patients with good visual acuity. One patient had extensive white dots throughout the retina reminiscent of fundus albipunctatus with electrophysiological evidence of partial recovery of rod function after prolonged dark adaptation. Sanger sequencing identified RPE65 mutations in all patients including three missense variants likely to represent hypomorphic alleles.Conclusions Hypomorphic mutations of RPE65 are associated with mild disease in childhood with preservation of good visual acuity into adulthood; they may in rare cases be associated with a flecked retina appearance similar to fundus albipunctatus. The presence of normal visual acuity in patients with hypomorphic mutations in RPE65 suggests that efficiency of transduction may not be the limiting factor in improving visual acuity in trials of gene replacement therapy. Rather, it suggests that for optimal recovery of visual acuity gene replacement therapy may need to be given much earlier in childhood.


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