Abstract

Leber’s hereditary optic neuropathy (LHON) is a rare maternally inherited disease caused by mutations in mitochondrial DNA (mtDNA) genes encoding subunits of complex I in the mitochondrial respiratory chain. The most common mutations causing LHON are G11778A, G3460A and T14484C, but there are also several less common mutations. LHON presents as acute or subacute bilateral visual loss, usually affecting young males. The aim of this study was to assess the clinical symptomatology and genetic analysis of Bulgarian patients with LHON. Twenty-two patients were diagnosed with LHON based on clinical evaluation and genetic examination (17 males and 5 females); 12 of them were previously reported, while 8 males and 2 females are newly diagnosed. A full neuroophthalmologic and genetic examination was performed. Eight patients had a family history of LHON, while 14 were isolated cases. The age at onset ranged from 3 to 43 years, and visual acuity ranged from counting fingers to 0.9. Genetic testing revealed various mutations, including a rare mutation G3635A in MT-ND1 in five affected members of one pedigree and digenic inheritance of G11778A and T14484C in three individuals from a different family. A variant m.15988A > G in the mitochondrial gene MT-TP with a high level of heteroplasmy was found in one patient. In addition to the most common mutations causing LHON, our patients also had rare mutations. These results suggest that genetic analysis of the entire mtDNA sequence is recommended in cases with strong clinical suspicion of LHON, since new rare mtDNA pathogenic variants are being identified.

摘要

莱伯氏遗传性视神经病 (LHON) 是一种罕见的母系遗传性疾病，由编码线粒体呼吸链中复合物 I 亚基的线粒体 DNA (mtDNA) 基因突变引起。导致 LHON 的最常见突变是 G11778A、G3460A 和 T14484C，但也有一些不太常见的突变。LHON 表现为急性或亚急性双侧视力丧失，通常影响年轻男性。本研究的目的是评估保加利亚 LHON 患者的临床症状和遗传分析。根据临床评估和基因检查，22 名患者被诊断为 LHON（17 名男性和 5 名女性）；其中12例是先前报告的病例，另外8例男性和2例女性是新诊断的。进行了全面的神经眼科和遗传学检查。8 名患者有 LHON 家族史，其中14例为孤立病例。发病年龄从3岁到43岁不等，视力从数手指到0.9不等。基因检测发现了多种突变，其中包括罕见突变 G3635A一个谱系的 5 个受影响成员中存在MT-ND1 ，来自不同家族的 3 个个体中存在 G11778A 和 T14484C 双基因遗传。在一名患者中发现线粒体基因MT-TP中存在高度异质性的变异 m.15988A > G。除了导致 LHON 的最常见突变外，我们的患者还存在罕见突变。这些结果表明，在临床上强烈怀疑 LHON 的病例中，建议对整个 mtDNA 序列进行遗传分析，因为正在鉴定新的罕见 mtDNA 致病变异。