OPEN Eye (2014) 28, 521–537 & 2014 Macmillan Publishers Limited All rights reserved 0950-222X/14 www.nature.com/eye P Yu-Wai-Man1,2,3,4, M Votruba5,6, AT Moore3,4 Treatment strategies REVIEW and PF Chinnery1,2 for inherited optic neuropathies: past, present and future Abstract Bilateral visual loss secondary to inherited Introduction optic neuropathies is an important cause of Hereditary optic nerve disorders result in registrable blindness among children and significant chronic visual morbidity, and the young adults. The two prototypal disorders minimum prevalence of affected individuals in seen in clinical practice are Leber hereditary the population has been estimated at 1 in 10 000.1 1Wellcome Trust Centre for optic neuropathy (LHON) and autosomal Leber hereditary optic neuropathy (LHON) and Mitochondrial Research, dominant optic atrophy (DOA). About 90% autosomal dominant optic atrophy (DOA) are Institute of Genetic of LHON cases are due to one of three Medicine, Newcastle the two classical paradigms for this group of mitochondrial DNA (mtDNA) point muta- University, Newcastle upon disorders, and they account for most of the tions: m.3460G4A, m.11778G4A, and Tyne, UK inherited optic atrophy cases seen in clinical m.14484T4C, which affect critical complex I practice. LHON is caused by mitochondrial 2Departments of Neurology subunits of the mitochondrial respiratory DNA (mtDNA) point mutations, whereas, in and Ophthalmology, Royal chain. The majority of patients with DOA DOA, the majority of cases are due to pathogenic Victoria Infirmary, Newcastle harbour pathogenic mutations within upon Tyne, UK mutations in the OPA1 gene, which codes for an OPA1, a nuclear gene that codes for a multi- 1,2 inner mitochondrial membrane protein. 3 functional inner mitochondrial membrane Moorfields Eye Hospital, Strikingly, both LHON and DOA share the same protein. Despite their contrasting genetic London, UK characteristic pathological features with selective basis, LHON and DOA share overlapping degeneration of the retinal ganglion cell (RGC) 4NIHR Biomedical Research pathological and clinical features that serve to layer, leading to progressive optic nerve Centre, UCL Institute of highlight the striking tissue-specific vul- degeneration and the onset of visual symptoms.3 Ophthalmology, University nerability of the retinal ganglion cell (RGC) College London, Rarer autosomal recessive optic atrophy genes layer to disturbed mitochondrial function. In London, UK have also been identified and a common theme is addition to severe visual loss secondary to emerging, with all of them so far encoding for 5 progressive optic nerve degeneration, School of Optometry and key components of the mitochondrial Vision Sciences, Cardiff a subgroup of patients will also develop a machinery.1,2 RGCs are therefore exquisitely University, Cardiff, UK more aggressive syndromic phenotype sensitive to mitochondrial dysfunction, and the marked by significant neurological deficits. 6 elucidation of the mechanisms involved is Cardiff Eye Unit, University The management of LHON and DOA remains Hospital of Wales, opening the way for therapeutic interventions largely supportive, but major advances in our Cardiff, UK targeting different stages of the disease process. understanding of the mechanisms underpin- In this review, recent advances in our Correspondence: ning RGC loss in these two disorders are P Yu-Wai-Man, Wellcome understanding of LHON and DOA will be paving the way for novel forms of treatment Trust Centre for discussed, in addition to the practical aimed at halting or reversing visual Mitochondrial Research, management of this group of patients and Institute of Genetic deterioration at different stages of the disease emerging treatment options. Medicine, Newcastle process. In addition to neuroprotective University, Newcastle upon strategies for rescuing RGCs from irreversible Tyne NE1 3BZ, UK. cell death, innovative in vitro fertilisation Mitochondrial disorders Tel: +44 (0)191 241 8854; techniques are providing the tantalising pro- Fax: +44 (0)191 241 8666. Oxidative phosphorylation E-mail: Patrick.Yu-Wai-Man@ spect of preventing the germline transmission ncl.ac.uk of pathogenic mtDNA mutations, eradicating Mitochondria are ubiquitous intracellular in so doing the risk of disease in future organelles present in all nucleated eukaryotic Received: 4,5 30 December 2013 generations. cells. They form a highly interconnected Accepted: 22 January 2014 Eye (2014) 28, 521–537; doi:10.1038/eye.2014.37; network extending throughout the cell’s Published online: published online 7 March 2014 structure and their overall morphology is 7 March 2014 Treatment of inherited optic neuropathies P Yu-Wai-Man et al 522 dictated by the balance between mitochondrial fusion under both physiological and pathological conditions. and fission. Mitochondria are bounded by two Furthermore, the large number of mtDNA molecules membranes and this arrangement creates two distinct present in each cell creates two possible genetic anatomical compartments, namely, the intermembrane situations, referred to as homoplasmy or heteroplasmy. space and the internal matrix space. The mitochondrial In the heteroplasmic state, two or more mtDNA variants respiratory chain consists of five multi-subunit are present at a specific nucleotide position, and this complexes (I-V) embedded within the inner genetic admixture has been implicated in the variable mitochondrial membrane, and it accounts for the bulk of disease expression that typifies mitochondrial disorders.6 the cell’s adenosine triphosphate (ATP) production Most pathogenic mtDNA mutations are heteroplasmic, through the process of oxidative phosphorylation and mitochondrial respiratory chain activity becomes (OXPHOS).4,5 In order to increase the effective surface compromised when the level of the mutant species area available for mitochondrial biogenesis, the inner exceeds a critical threshold (60–80%), which is both mitochondrial membrane is thrown into multiple mutation and tissue specific.4,5 In terms of genetic infoldings, known as cristae, and, unsurprisingly, counselling, the mitochondrial genome shows strict aberrant cristae morphology is a frequent ultrastructural maternal inheritance and male mutation carriers can be feature of disorders caused by mitochondrial reassured that transmission to their own offspring will not dysfunction. OXPHOS is a tightly regulated process that occur. In contrast, all the children of a homoplasmic female involves the donation of high-energy electrons to carrier will harbour their mother’s mtDNA mutation. complex I by the intermediate products (NADH and The situation is rather more complex for a heteroplasmic FADH2) generated from the beta-oxidation of fatty acids mother as she could transmit a higher or a lower level and glycolysis. As these electrons shuttle along the of her mtDNA mutation to a particular offspring, which mitochondrial respiratory chain, a significant amount of could influence the latter’s risk of becoming clinically energy is released and this is used to actively pump affected. The sometimes rapid shifts in mitochondrial allele protons from the matrix compartment into the frequencies that occur between maternally related intermembrane space. Ubiquinone is a fat-soluble generations have been explained by a ‘mitochondrial molecule present at a very high concentration within the bottleneck’ operating in the female germline.7 inner mitochondrial membrane, and it has a unique role in OXPHOS as the only carrier that can efficiently transfer Nuclear–mitochondrial interactions electrons from complexes I and II to complex III. The electrochemical proton gradient generated across the inner Mitochondria have limited autonomy and they rely mitochondrial membrane is eventually harnessed by heavily on the nuclear genome for the vast majority of complex V (ATP synthase) for the conversion of ATP from proteins required for mtDNA replication, transcription, adenosine diphosphate (ADP) and inorganic phosphate. and translation.4,5 In 1988, two seminal papers were published linking for the first time specific mtDNA mutations with human disease: large-scale single Mitochondrial genetics mtDNA deletions in patients with mitochondrial Mitochondria are unique in possessing their own genetic myopathies and the m.11778G4A point mutation in material in the form of a double-stranded circular families with LHON.8,9 Families segregating classical DNA molecule about 16 569 base-pair long.4,5 The mitochondrial phenotypes in a clear-cut Mendelian mitochondrial genome is therefore very compact, but it pattern of inheritance were subsequently reported, and codes for structural and functional components that are the existence of nuclear genetic defects disrupting indispensable for normal mitochondrial function, mitochondrial proteins was widely suspected. This including two ribosomal RNAs (12S and 16S rRNA), 22 hypothesis was confirmed in 2001, when mutations in the transfer RNAs (tRNAs), and 13 polypeptide subunits of nuclear genes, POLG and PEO1, were identified in the mitochondrial respiratory chain complexes (I, III, V, families with autosomal dominant chronic progressive and V). Another remarkable feature of mitochondrial external ophthalmoplegia (CPEO).10 The pathological genetics is its very high copy number with several hallmark of all these nuclear mitochondrial disorders is thousands of mtDNA molecules being present in mtDNA instability, which can be quantitative in nature metabolically active cells such as neurons. Unlike nuclear