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Title: [A study of clinical and genetic characteristics of a Leber hereditary optic neuropathy family with the heteroplasmic m.14484T>C mutation].
Author: Sun Y, Lei K, Xu ZL, Geng Y.
Journal: Zhonghua Yan Ke Za Zhi; 2018 Jul 11; 54(7):526-534. PubMed ID: 29996615.
Abstract:
Objective: To study clinical and genetic characteristics of a Leber hereditary optic neuropathy (LHON) family with the heteroplasmic m.14484T>C mutation. Methods: A cross-sectional study. The objects of the study included a 31-year-old male LHON patient with the heteroplasmic m.14484T>C mutation (the proband) who visited Department of Ophthalmology in the Affiliated Central Hospital of Qingdao University in March 2015 and other 36 matrilineal relatives in a four-generation family (12 males and 24 females aged 2-81 years, median 27 years). The visual acuity, intraocular pressure, fundus, color vision, visual field, visual evoked potential and optical coherence tomography were evaluated in maternal members. The mitochondrial DNA (mtDNA) sequence of fragments including m.14484 loci was detected by Sanger sequencing in 33 members. The sequencing peaks were analyzed by QSVanalyzer software to get the heteroplasmy levels of m.14484T>C mutation. The mtDNA of the proband was amplified by PCR and sequenced. Assembled sequence of mtDNA was compared with the updated consensus Cambridge sequence. The differences in visual evoked potential, optical coherence tomography and heteroplasmy levels were compared between two groups by the t-test, and among multiple groups by the single factor variance analysis. Results: Among the 33 maternal members of the family, 4 patients, 28 carriers and 1 person without a mutation were confirmed. The penetrance was 12.5% (4/32) . In addition to 4 patients with obvious abnormality on the ophthalmic examination, 5 carriers also appeared anomaly on the electrophysiological and visual function examinations. Compared to carriers, the amplitude of P100 was obviously decreased in the LHON patients[ (5.6±2.6) μV vs. (15.6±9.6) μV, t=2.880, P=0.006]. Significantly reduced values were seen in the average retinal nerve fiber layer thickness[ (71±17) μm vs. (99±11) μm, t=5.969, P< 0.001], in each side of the sub-area macular thickness, and in the nasal side of the lateral sub-area macular thickness [ (260±16) μm vs. (291±12) μm, t=5.593, P<0.001] between the LHON patients and carriers. The heteroplasmic levels were 80%±3% in the LHON patients, and 27%±18% in the unaffected members;the difference was significant (t=-8.395, P<0.001). The average degree of heteroplasmy had no difference between male and female members (48%±34% vs. 35%±28%, t=-1.147, P=0.258). The average mutation load was 29%±14% in the second generation members, 36%±29% in the third generation members, and 51%±36% in the fourth generation members;the differences were not statistically significant (F=1.152, P=0.330). The difference in the heteroplasmic levels was not statistically significant between mothers and their offspring (31%±25% vs. 42%±32%, t=1.165, P=0.251). Compared to Cambridge consensus sequence, 41 mutations was found in mtDNA of the proband, of which, 10 were missense mutations, including mutations m.4216T>C and m.3394T>C. According to the phylogenetic tree, the haplotype of the proband was M9a (M9a1a1c1a). Conclusions: In the family with the heteroplasmic m.14484T>C mutation, clinical manifestations of LHON appear in the individuals whose heteroplasmic level is more than 75%, and all of patients show typical chronic optic atrophy on the ophthalmic examination. The carriers with the m.14484T>C mutation also appear anomaly on the electrophysiological and visual function examinations. The heteroplasmic level of m.14484T>C mutation has a tendency to increase during the transmission in the family. The primary mutation m.14484T>C coordinate mutations m.4216T>C and m.3394T>C to increase the penetrance and incidence of abnormal visual function in carriers. (Chin J Ophthalmol, 2018, 54: 526-534). 目的： 研究携带m.14484T>C异质性突变的Leber遗传性视神经病变（LHON）家系的临床及遗传学特征。 方法： 横断面研究。研究对象为2015年3月在青岛大学附属中心医院眼科就诊的1例基因检测为m.14484T>C异质性突变的31岁男性LHON患者（先证者）及其四代同堂家系中的其他36名母系成员[男性12名，女性24名，中位年龄27岁（2~81岁）]。对家系成员进行病史采集及视力、眼压、眼底、色觉、视野、视觉诱发电位（VEP）和相干光层析成像术（OCT）等眼科常规检查；其中33名家系成员抽取静脉血进行线粒体DNA（mtDNA）14484位点的Sanger测序，采用QSVanalyzer软件计算14484位点突变的异质性比例。先证者进行全线粒体基因组分析，与剑桥参考序列进行比对。VEP、OCT及突变的异质性比例两组间比较采用t检验，多组间比较采用单因素方差分析。 结果： 33名母系成员中发现m.14484T>C突变的LHON患者4例、突变携带者28名和无14484位点突变者1名，患病外显率为12.5%（4/32）。除4例患者眼科检查明显异常外，5名携带者也出现眼电生理和视功能异常。家系中患者和基因突变携带者的VEP结果相比，患者P100振幅低[（5.6±2.6）μV与（15.6±9.6）μV比较，t=2.880，P=0.006]；OCT结果相比，患者视网膜神经纤维层（RNFL）平均厚度薄[（71±17）μm与（99±11）μm比较，t=5.969，P<0.001]，内子区黄斑区视网膜厚度在各象限均变薄，外子区黄斑区视网膜厚度仅在鼻侧象限明显变薄[（260±16）μm与（291±12）μm比较，t=5.593，P<0.001]。LHON患者的基因突变异质性比例高达80%±3%，未患病的家系成员的异质性比例平均为27%±18%，差异有统计学意义（t=-8.395，P<0.001）。男女成员间突变异质性比例差异无统计学意义（48%±34%与35%±28%比较，t=-1.147，P=0.258）。家系中的第Ⅱ、Ⅲ、Ⅳ代成员突变异质性比例分别为29%±14%、36%±29%、51%±36%，有逐渐升高的趋势但差异无统计学意义（F=1.152，P=0.330）。13名母亲与27名后代的突变异质性比例差异无统计学意义（31%±25%与42%±32%比较，t=1.165，P=0.251）。先证者mtDNA与剑桥参考序列进行比对共发现41个突变位点，其中错义突变10个，包括m.3394T>C和m.4216T>C突变。根据线粒体进化树分析，先证者单体型为M9a（M9a1a1c1a）。 结论： 该家系中携带m.14484T>C突变的个体当异质性水平超过75%时出现LHON临床表现，呈现典型的慢性期视神经萎缩的表现。突变携带者也有眼电生理和视功能异常的表现。m.14484T>C异质性突变在该家系的传递过程中有异质性水平增高的趋势。原发突变m.14484T>C协同继发突变m.3394T>C和m.4216T>C，可能提高该家系发病的外显率和突变携带者视功能异常的比例。（中华眼科杂志，2018，54：526-534）.

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