目的：本研究旨在表征临床特征，Leber先天性黑蒙（LCA）或早发性重度视网膜营养不良（EOSRD）患者的遗传发现和基因型-表型相关性。
方法：回顾性病例系列。
方法：这项研究连续招募了来自47个家庭的51名患者，这些患者的临床诊断为LCA/EOSRD，这些患者在AIPL1基因中具有致病变异，从2021年10月到2023年9月。分子遗传学发现,病史,和眼科评估，包括视力（VA），对多模态视网膜成像和电生理评估进行了综述.
结果：在51例患者中（32例LCA和19例EOSRD），27人（53%）为女性，上次审查的年龄范围为0.5-58.4岁。我们确定了28个致病的AIPL1变体，18、小说在EOSRD患者中，右眼和左眼的平均（范围）VA分别为1.3（0.7-2.7）logMAR和1.3（0.5-2.3）logMAR，logMAR年平均下降0.03(R2=0.7547,P<0.01)。对于LCA患者，VA范围从光感知到计数手指。光学相干断层扫描成像显示，在5例最年轻的EOSRD患者和9例LCA儿童中保留了中央凹椭圆体区。视网膜电图显示78.6%(11/14)的EOSRD患者出现严重的锥棒模式,而在所有可用于检查的LCA患者中均记录了经典的熄灭模式。最常见的突变是c.421C>T的无义变体，am等位基因频率为53.9%。所有EOSRD患者都携带至少一个错义突变，其中13人确定为c.152A>G，5人确定为c.572T>C。26例LCA患者携带两种无效的AIPL1变体，而18是纯合的c.421C>T，和6是杂合的c.421C>T，具有另一个功能丧失变体。
结论：本研究揭示了AIPL1相关LCA和EOSRD的不同临床特征和变异谱。至少有一个非无效突变的患者,尤其是c.152A>G和c.572T>C，与具有两个无效突变的人相比，更有可能具有更温和的EOSRD表型。在最年轻的患者中观察到的残余中央凹视网膜外结构提示基因增强治疗的早期窗口。
OBJECTIVE: This study aimed to characterize the clinical features, genetic findings, and genotype-phenotype correlations of patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD) harboring biallelic
AIPL1 pathogenic variants.
METHODS: Retrospective case series.
METHODS: This study consecutively enrolled 51 patients from 47 families with a clinical diagnosis of LCA/EOSRD harboring disease-causing variants in the
AIPL1 gene, from October 2021 to September 2023. Molecular genetic findings, medical history, and ophthalmic evaluation including visual acuity (VA), multimodal retinal imaging, and electrophysiologic assessment were reviewed.
RESULTS: Of the 51 patients (32 with LCA and 19 with EOSRD), 27 (53%) were females, and age at last review ranged from 0.5 to 58.4 years. We identified 28 disease-causing
AIPL1 variants, with 18 being novel. In patients with EOSRD, the mean (range) VA was 1.3 (0.7-2.7) logMAR and 1.3 (0.5-2.3) logMAR for right and left eyes respectively, with an average annual decline of 0.03 logMAR (R2 = 0.7547, P < .01). For patients with LCA, the VA ranged from light perception to counting fingers. Optical coherence tomography imaging demonstrated preservation of foveal ellipsoid zone in the 5 youngest EOSRD patients and 9 LCA children. Electroretinography showed severe cone-rod patterns in 78.6% (11/14) of patients with EOSRD, while classical extinguished pattern was documented in all patients with LCA available for the examination. The most common mutation was the nonsense variants of c.421C>T, with an allele frequency of 53.9%. All patients with EOSRD carried at least one missense mutation, of whom 13 identified with c.152A>G and 5 with c.572T>C. Twenty-six patients with LCA harbored two null
AIPL1 variants, while 18 were homozygous for c.421C>T and 6 were heterozygous for c.421C>T with another loss-of-function variant.
CONCLUSIONS: This study reveals distinct clinical features and variation spectrum between
AIPL1-associated LCA and EOSRD. Patients harboring at least one nonnull mutation, especially c.152A>G and c.572T>C, were significantly more likely to have a milder EOSRD phenotype than those with two null mutations. Residual foveal outer retinal structure observed in the youngest proportion of patients suggests an early window for gene augmentation therapy.
