Cox Kyle F, Kerr Natalie C, Kedrov Marina, Nishimura Darryl, Jennings Barbara J, Stone Edwin M, Sheffield Val C, Iannaccone Alessandro
University of Tennessee Health Science Center, Hamilton Eye Institute, Memphis, TN 38163, USA.
Vision Res. 2012 Dec 15;75:77-87. doi: 10.1016/j.visres.2012.08.005. Epub 2012 Aug 24.
To characterize the phenotype of Bardet-Biedl syndrome (BBS) patients homozygous for the BBS1 M390R mutation.
Three patients [PT1, F, 27 years old (yo) at last examination, 14-year follow-up (F/U) PT2, F, 15-yo PT3, M, 15-yo, both 1-year F/U] underwent eye exams, Goldmann visual fields (GVFs), dark- (DA) and light-adapted (LA) electroretinograms (ERGs), spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF). Vision and systemic history were also collected.
All patients had night blindness, hyperopic astigmatism, ptosis or mild blepharospasm, foot polydactyly, 5th finger clinodactyly, history of headaches, and variable, diet-responsive obesity. Two had asthma, PT1 was developmentally delayed, PT2 had Asperger-like symptoms, and PT3 had normal cognition. At age 14, acuity was 20/100 in PT1, who had nystagmus since age 2, 20/40 in PT2 and 20/30 in PT3. By 27yo PT1 progressed to 20/320, by 15 yo PT2 was 20/60 and PT3 remained stable. PT1 had well preserved peripheral GVFs, with minimal progression over 10 years of F/U. PT2 and PT3 presented with ring scotomas and I4e<5°. All patients had severe generalized visual sensitivity depression. ERGs were consistently recordable (also rod ERG in PT3 after 60 min DA), but progressed to non-recordable in PT1. Mixed DA ERGs exhibited electronegativity. In PT3, this was partly due to a bleaching effect during bright-flash DA averaging, partly to ON≫OFF LA response compromise. PT2 and 3 had, on SD-OCTs, generalized macular thinning, normal retinal lamination, and widespread photoreceptor outer/inner segment attenuation except foveally, and multiple rings of abnormal FAF configuring a complex bull's eye-pattern. PT1 had macular atrophy. All patients also had peripapillary nerve fiber layer thickening.
The observed phenotype matches very closely that reported in patients by Azari et al. (IOVS 2006) and in the Bbs1-M390R knock-in mouse model, and expands it to the characterization of important ERG response characteristics that provide insight in the pathogenesis of retinopathy in these patients. Our findings confirm the consistent pathogenicity of the BBS1 M390R mutation.
对BBS1基因M390R突变纯合的巴德-比德尔综合征（BBS）患者的表型进行特征描述。
三名患者[PT1，女性，最后一次检查时27岁，随访14年；PT2，女性，15岁；PT3，男性，15岁，均随访1年]接受了眼科检查、Goldmann视野检查（GVF）、暗适应（DA）和明适应（LA）视网膜电图（ERG）、频域光学相干断层扫描（SD-OCT）和眼底自发荧光（FAF）检查。还收集了视力和全身病史。
所有患者均有夜盲、远视散光、上睑下垂或轻度眼睑痉挛、足部多指畸形、第五指尺侧偏斜、头痛病史以及可变的、饮食可调节的肥胖。两名患者有哮喘，PT1发育迟缓，PT2有阿斯伯格样症状，PT3认知正常。14岁时，PT1的视力为20/100，自2岁起有眼球震颤；PT2为20/40，PT3为20/30。到27岁时，PT1进展至20/320，15岁时PT2为20/60，PT3保持稳定。PT1周边GVF保存良好，随访10年进展极小。PT2和PT3出现环形暗点且I4e<5°。所有患者均有严重的全身性视觉敏感度降低。ERG均可记录（PT3在暗适应60分钟后杆体ERG也可记录），但PT1进展至不可记录。混合暗适应ERG表现为电负性。在PT3中，这部分是由于强光闪光暗适应平均过程中的漂白效应，部分是由于明适应时ON≫OFF反应受损。PT2和PT3在SD-OCT上表现为黄斑普遍变薄、视网膜分层正常、除黄斑中心凹外广泛的光感受器外/内节衰减以及多个异常FAF环构成复杂的靶心图案。PT1有黄斑萎缩。所有患者还均有视乳头周围神经纤维层增厚。
观察到的表型与Azari等人（《国际眼科杂志》2006年）报道的患者以及Bbs1-M390R基因敲入小鼠模型中的表型非常匹配，并将其扩展至重要的ERG反应特征的描述，这些特征为了解这些患者视网膜病变的发病机制提供了线索。我们的发现证实了BBS1基因M390R突变的一致致病性。
