Optic Neurodegeneration: Time to Act

Optic neuropathies are frequently associated with mitochondrial dysfunction and the associated vision loss has a severe impact on the patient’s quality of life. Our understanding of disease progression of one of the most frequent mitochondrial disorders, Leber’s hereditary optic neuropathy (LHON), together with results of recent clinical trials might provide us with new insights that are relevant not only to the progression of the disease but more importantly also for therapeutic intervention. One of the crucial hallmarks of LHON is the occasional recovery of vision in some patients. This rare and spontaneous process highlights that blindness in LHON patients is not irreversible per se and suggests that this process could potentially be induced by pharmacological intervention. Strikingly, spontaneous recovery of vision has been reported in some patients several years after disease onset, which indicates the presence of an extended time window where recovery is still possible, before over time the terminal loss of retinal neurons renders visual recovery impossible. Several recent encouraging trials in LHON and related disorders support this view and extend this model to other optic neuropathies that are not associated with spontaneous recovery. This concept provides hope not only to mitochondrial optic neuropathy patients, but also to patients that suffer from one of the major ocular disorders such as glaucoma. LHON as Example of a Neurodegenerative Retinal Disease Among many of the known neurodegenerative diseases, disorders that affect vision are ideally suited to test potential therapeutic interventions. This advantage is a direct consequence of the possibility to monitor and quantify degenerative processes in a timely and noninvasive manner, using standardized tests to easily quantify visual acuity and retinal pathology. In their own right, optic neuropathies are a major public health issue with glaucoma being one of the most prominent disorders. However, a relatively rare disorder, Leber’s hereditary optic neuropathy (LHON; OMIM 535000), might serve as a promising model system for the experimental analysis of a range of optic nerve diseases. LHON was first described by German ophthalmologist Theodor Leber in 1871 as a distinct clinical entity [1]. For North-East England, a minimum prevalence of 1 in 31 000 was estimated for LHON [2] and a recent meta-analysis suggests a prevalence of 1 in 48 000 across Europe [3]. LHON is characterized by acute or sub-acute vision loss in one eye, generally followed by loss of visual acuity in the second eye within 2 to 4 months [4,5]. Initially, LHON patients experience painless vision loss, which is severe and associated with dense central or centrocecal scotoma and impaired colour vision. Typically, LHON affects young adult males of all ethnic groups, with a peak of onset in young adulthood. While in most cases vision loss is permanent, a minority of patients show spontaneous recovery of visual acuity [4,6] by a mechanism that is not yet understood. Consequently, for the vast majority of young patients the diagnosis of LHON is associated with a significant reduction in their quality of life, even when compared to other ophthalmic disorders [7]. LHON is a mitochondrial disease that is caused by well characterized mutations in mitochondrial DNA (mtDNA), with a prevalence of carriers of about 1 in 300 [8]. In 95% of all cases, LHON is caused by one of three point mutations in subunits of complex I: 3460G>A in MTND1, 11778G>A in MTND4, and 14484T>C in MTND6 [8]. The 11778G>A mutation is generally the most abundant, although there is considerable variation in the relative frequency of the three primary LHON mutations worldwide. In addition to the primary mtDNA mutations and the overall load of mutants versus wild-type mtDNA, the individual genetic mitochondrial haplotype also plays a major role for disease onset and severity [9]. A significantly increased risk of vision loss was observed when the 11778G>A and 14484T>C mutations were present in a carrier with mtDNA haplogroup J background. On the other hand, 3460G>A carriers were more likely to lose vision when also belonging to the mtDNA haplogroup K. In contrast, haplogroup H was associated with a protective effect in combination with the 11778G>A mutation [9]. Biochemical defects in LHON cells It is striking that all of the three main primary LHON mutations result in amino acid changes in subunits of complex I (NADH:ubiquinone oxidoreductase) of the mitochondrial respiratory chain. Experimental evidence strongly connects complex I dysfunction to reduced mitochondrial membrane potential, decreased ATP synthesis and elevated levels of oxidative stress. Consistent with the 11778G>A mutation being associated with the most severe disease phenotype, this mutation is also associated with the most pronounced reduction in mitochondrial ATP synthesis followed by the 14484T>C and then the 3460G>A mutation [10-12]. However, it is important to point out that with regards to reduced ATP synthesis no major differences between LHON patients and unaffected carriers have been demonstrated so far. This entirely mutation-dependent reduction in energy supply is supported by studies using cybrids carrying LHON mutations as well as peripheral lymphocytes from patients and mutation carriers [13]. Biology and Medicine Nuri Gueven, Biol Med 2014, 1:1 http://dx.doi.org/10.4172/0974-8369.S1-001 Review article Open Access Biol Med Novel Treatment Strategies for Neurological and Neurodegenerative Diseases ISSN:0974-8369 BLM, an open access