Ali Layla, Hazzard Iyawnna, Tehrani Niloufar S, Ansari Ubaid, Ali Adam, Kumar Preyasi, Ali Nadia, Gakhal Gurkiranjeet, Lui Forshing
Office of Research, College of Medicine, California Northstate University, Elk Grove, California 95757, United States of America.
Department of Translational Science, Rush University Medical Center, Chicago, Illinois 60612, United States of America.
J Biol Methods. 2025 May 14;12(2):e99010055. doi: 10.14440/jbm.2024.0113. eCollection 2025.
Leber hereditary optic neuropathy (LHON) is a rare inherited mitochondrial disease that leads to mitochondrial dysfunction, resulting in optic nerve damage and vision loss. Systemic involvement has been reported in several LHON cases, referred to as LHON+ disorders. However, the causes and presentations of such conditions have been poorly studied. It is suggested that 90% of mitochondrial dysfunction is caused by one of three primary point mutations in mitochondrial DNA that affect respiratory complex I (referred to as mtDNA LHON), with unresolved cases of LHON being caused by other variants, known as autosomal recessive LHON. The cardiac, musculoskeletal, neurological, and auditory systems are commonly affected in LHON. For example, hypertrophic cardiomyopathy and sudden cardiac death have been linked to specific mutations. Neurological effects - such as dystonia, epilepsy, polyneuropathy, and ataxia - as well as hearing loss, have also been observed in patients with specific mitochondrial mutations. These findings highlight the need for a more comprehensive evaluation beyond standard ophthalmic assessments. LHON is typically diagnosed based on a combination of ophthalmic imaging, patient age and gender, clinical course (bilateral, rapidly progressive, and sequential visual loss), family history, maternal inheritance, and fundus appearance. However, the advent of genetic testing has significantly expanded the recognized phenotype. In terms of treatment, idebenone is the only FDA-approved therapy for LHON; however, intravitreal gene therapy yields promising improvement, especially for the most common m.11778G>A mutation, which accounts for 70% of causative mutations. At present, these therapies are confined to ocular treatment.
This review highlights the importance of recognizing systemic manifestations of LHON, which are frequently overlooked in clinical practice.
Early detection of these systemic manifestations, especially in cardiac and neurological systems, could help with prompt intervention and improve patient outcomes. Further research into gene therapy and mitochondrial replacement techniques holds promising potential for developing more effective treatment strategies.
Leber遗传性视神经病变（LHON）是一种罕见的遗传性线粒体疾病，可导致线粒体功能障碍，进而引起视神经损伤和视力丧失。在几例LHON病例中曾有全身受累的报道，称为LHON+疾病。然而，此类病症的病因和表现尚未得到充分研究。据推测，90%的线粒体功能障碍是由线粒体DNA中的三种主要点突变之一引起的，这些突变影响呼吸链复合体I（称为mtDNA LHON），而未确诊的LHON病例则由其他变异引起，称为常染色体隐性LHON。心脏、肌肉骨骼、神经和听觉系统在LHON中常受影响。例如，肥厚型心肌病和心源性猝死与特定突变有关。在具有特定线粒体突变的患者中也观察到了神经方面的影响，如肌张力障碍、癫痫、多发性神经病和共济失调，以及听力丧失。这些发现凸显了在标准眼科评估之外进行更全面评估的必要性。LHON通常根据眼科成像、患者年龄和性别、临床病程（双侧、快速进展和相继性视力丧失）、家族史、母系遗传和眼底表现进行综合诊断。然而，基因检测的出现显著扩展了已被认识的表型。在治疗方面，艾地苯醌是唯一获得美国食品药品监督管理局（FDA）批准用于LHON的疗法；然而，玻璃体内基因治疗产生了有希望的改善效果，特别是对于最常见的m.11778G>A突变，该突变占致病突变的70%。目前，这些疗法仅限于眼部治疗。
本综述强调了认识LHON全身表现的重要性，这些表现在临床实践中经常被忽视。
早期发现这些全身表现，尤其是在心脏和神经系统中的表现，有助于及时干预并改善患者预后。对基因治疗和线粒体替代技术的进一步研究在开发更有效的治疗策略方面具有广阔的潜力。
