Leber遗传性视神经病变患者外显率和视网膜神经纤维层及黄斑厚度观察

Observation of penetrance and retinal nerve fiber layer and macular thickness in patients with Leber's hereditary optic neuropathy

目的观察Leber遗传性视神经病变(LHON)患者外显率及不同发病时间、位点突变对患者视盘神经纤维层(RNFL)、黄斑厚度的影响。方法横断面观察性研究。2015年至2017年就诊于解放军总医院第一医学中心眼科并经线粒体基因检测确诊为LHON患者88例及其母系亲属(基因携带者)1492人纳入研究。母系亲属1492人中,男性694人,女性798人。所有受试者抽取外周静脉血进行线粒体DNA检测,计算外显率;行BCVA、频域OCT检查117人,其中患者82例,基因携带者35人。BCVA采用Snellen视力表,记录时换算为logMAR视力;频域OCT仪测量视盘RNFL及黄斑区节细胞复合体(GCC)、内界膜(ILM)-RPE层各象限厚度。平均随访时间(50.02±86.27)个月。82例患者中,81例患者根据发病时间分为≤3、4~6、7~12、>12个月组。对比观察不同发病时间、不同位点突变患者与未发病基因携带者视盘RNFL、黄斑区GCC和ILM-RNFL厚度变化。不同发病时间、不同位点突变患者与未发病基因携带者视网膜OCT参数的比较采用协方差分析;分类变量以百分率表示,多组间比较采用χ^2检验。结果母系亲属1492人中,确诊LHON和临床表现高度疑似患者285例(外显率19.10%),其中男性190例(外显率27.38%),女性95例(外显率11.90%)。11778、14484、罕见突变位点总外显率分别为19.84%(228/1149)、20.50%(33/161)、13.19%(24/182);男性外显率分别为28.87%(153/530)、27.78%(20/72)、18.48%(17/92);女性外显率分别为12.12%(75/619)、14.61%(13/89)、7.78%(7/90)。不同位点突变者总外显率(χ^2=4.732)及不同性别者外显率(χ^2=4.263、2.108)比较,差异均无统计学意义(P=0.094、0.110、0.349)。与未发病基因携带者比较,发病时间≤3、4~6、7~12、>12个月组患者视盘RNFL厚度及黄斑区GCC、ILM-RPE各象限厚度均随发病时间延长逐渐薄变(P=0.000)。不同位点突变患者黄斑区GCC、ILM-RPE层各象限厚度差异均有统计学意义(P<0.05),其中11778、3460位点突变患者黄斑区GCC、ILM-RPE层各象限厚度最薄,其次为14484位点突变患者;罕见位点突变患者黄斑区GCC及ILM-RPE层除中心区外其他各象限厚度最厚。结论LHON患者外显率为19.10%;随发病时间延长,视盘RNFL及黄斑区GCC、ILM-RPE层各象限逐渐薄变。14484、罕见突变位点患者视盘RNFL、黄斑区GCC和ILM-RPE厚度损害轻于11778、3460位点突变患者。

Objective To observe the effects of penetrance, different time of onset and mutation sites on retinal nerve fiber layer (RNFL) and macular thickness in patients with Leber's hereditary optic neuropathy(LHON). Methods This was a cross-sectional observational study. A total of 88 patients with LHON and 1492 relatives of the maternal relatives (gene carriers) who received treatment in People’s Liberation Army General Hospital from 2015 to 2017 were included in the study. Among the 1492 family members, there were694 males and 798 females. Peripheral venous blood was extracted from all subjects for mitochondrial DNA testing, and penetrance was calculated. A total of 117 patients underwent BCVA and SD-OCT examinations, including 82 patients and 35 gene carriers. The BCVA examination was performed using the Snellen visual acuity chart, which was converted into logMAR visual acuity. The thickness of RNFL, ganglion cell complex(GCC) and inner limiting membrane (ILM)-RPE were measured with OCT instrument. The mean follow-up was 50.02±86.27 months. The disease course was divided into 6 stages including ≤3 months, 4-6 months, 7-12 months and >12 months. The thickness of RNFL, GCC and ILM-RPE in patients with different time of onset and mutation sites were comparatively analyzed by covariance analysis. Categorical variables were expressed as a percentage, and the χ^2 test was used for comparison among multiple groups. Results Among the 1492 family members, 285 were diagnosed with LHON and highly suspected clinical manifestations (19.10%), including 190 males (21.98%) and 95 females (11.90%). The total penetrance rates of 11778, 14484 and rare mutation sites were 19.84%(228/1149), 20.50%(33/161), and 13.19%(24/182) respectively;male penetrance rates were 28.87%(153/530), 27.28%(20/72), and 18.48%(17/92) and female penetrance rates were 12.12%(75/619),14.61%(13/89) and 7.78%(7/90). There was no significant difference in total (χ2=4.732), male (χ^2=4.263) and female(χ^2=4.263) penetrance between different mutation sites (P=0.094, 0.110, 0.349). Compared with non-pathogenic carriers, the thickness of the RNFL, GCC and ILM-RPE were all different in the four stages (≤3months, 4-6 months, 7-12 months and >12 months). The thickness of RNFL, GCC and ILM-RPE decreased with the time of onset (P=0.000). There were significant differences in the thickness of each of the GCC and ILM-RPE layers in the macular area of LHON patients with different mutation sites (P<0.05). Among them, the site 11778 and 3460 had the most severe damage in all quadrants of macular GCC and ILM-RPE layer, followed by 14484 site, and the rare site had the least damage in all quadrants. Conclusions The penetrance of LHON patients is 19.10%. With the extension of the onset time (within 1 year), the RNFL layer of the optic disc and all quadrants of the macular GCC and ILM-RPE layer gradually thinned. Compared with 11778 and rare site, 14484 site, and the rare site had the lighter damage on the thickness of RNFL, GCC and ILM-RPE.