Mitochondrial disorders and the eye

Journal Pre-proof Mitochondrial Disorders And The Eye Eli Kisilevsky, Paul Freund, Edward Margolin PII:

S0039-6257(19)30288-7

DOI:

https://doi.org/10.1016/j.survophthal.2019.11.001

Reference:

SOP 6911

To appear in:

Survey of Ophthalmology

Received Date: 15 May 2019 Revised Date:

16 November 2019

Accepted Date: 18 November 2019

Please cite this article as: Kisilevsky E, Freund P, Margolin E, Mitochondrial Disorders And The Eye, Survey of Ophthalmology (2019), doi: https://doi.org/10.1016/j.survophthal.2019.11.001. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.

MITOCHONDRIAL DISORDERS AND THE EYE

Eli Kisilevsky1, Paul Freund1, Edward Margolin1

1

University of Toronto Department of Ophthalmology and Vision Sciences

Corresponding Author: Edward Margolin, MD, FRCSC, Dipl. ABO Associate Professor, University of Toronto Dept. of Ophthalmology and Visual Sciences Dept. of Medicine, Division of Neurology Chief of Service, Neuro-Ophthalmology 801 Eglinton Ave West, Suite 301 Toronto ON M5N 1E3 Tel (647) 748-8377 Fax (416) 619-5539 [email protected]

ABSTRACT

Mitochondria are cellular organelles that play a key role in energy metabolism and oxidative phosphorylation. Malfunctioning of mitochondria has been implicated as the cause of many disorders with variable inheritance, heterogeneity of systems involved, and varied phenotype. Metabolically active tissues are more likely to be affected, causing an anatomic and physiologic disconnect in the treating physicians mind between presentation and underlying pathophysiology. We shall focus on disorders of mitochondrial metabolism relevant to an ophthalmologist. These disorders can affect all parts of the visual pathway (crystalline lens, extraocular muscles, retina, optic nerve, and retro-chiasmaly) . After the introduction reviewing mitochondrial structure and function each disorder is reviewed in detail, including approaches to its diagnosis and most current management guidelines. INTRODUCTION The mitochondrion is an important cellular organelle most widely known for its role in energy metabolism and oxidative phosphorylation. It also plays a role in apoptosis, steroid biosynthesis, nucleotide metabolism, calcium regulation and reactive species generation and scavenging124. As the site of oxidative phosphorylation, mitochondria facilitate aerobic respiration, an integral part of energy metabolism in eukaryotes. Oxidative phosphorylation occurs in the inner membrane of the mitochondrion and involves 5 protein complexes that sequentially undergo reduction-oxygen reactions ultimately producing adenosine triphosphate (ATP),the major source of energy for many cell types. This crucial role in energy production biases mitochondrial disorders to preferentially affect tissues with high metabolic demand such as muscles, central nervous system, peripheral nerves, heart, adrenal glands, renal tubules and the eyelp38. The mitochondrion is the only organelle that contains its own genetic material as well as the transcription and translation machinery to produce RNA and proteins separate from the rest of the cell. Mitochondrial DNA (mtDNA) in humans contains 16,569 base pairs (bp) encoding 37 mitochondrial proteins: 13 genes encoding proteins involved in oxidative phosphorylation and 24 genes encoding proteins involved in mtDNA translation38. All other mitochondrial proteins are transcribed and translated from nuclear DNA (nDNA) and transported to the mitochondrion. The oxidative-phosphorylation pathway requires more than 70 proteins to function and the mitochondrion as a whole contains more than 1,000 proteins, the majority of which are encoded by nDNA23. This dual genetic source leads mitochondrial disorders to be influenced by both classic Mendelian inheritance patterns, as well as mitochondrial inheritance patterns. Mitochondrial inheritance is unique in that it is dependent on maternal inheritance, mitotic segregation, heteroplasmy, and the threshold effect. Maternal inheritance

During fertilization, maternal mitochondria are retained in the oocyte while no paternal mitochondria entry from the sperm. Thus the gamete contains only maternal mitochondria that propagate within all cells. Mitochondria are also retained within the cytoplasm, and during replication unequal numbers of mitochondria are distributed between two daughter cells. In the case of a mitochondrial mutation unequal distribution during mitosis leads to unequal distribution of mutation-carrying mitochondria in the progenitor cells. Each mitochondrion also contains multiple copies of mtDNA and can carry mutated and wild-type genes concurrently. This heterogeneous distribution leads to the concept of heteroplasmy where each mitochondrion carries a different mutation load and each cell contains varying proportions of mutated mitochondria. Any genetic change that occurs within one mitochondrion will only propagate in its own progeny. Therefore threshold affect occurs for each genetic variation and only when a critical proportion of mitochondria in a cell carry a specific trait will it affect the cell’s function as a whole. This threshold is different for each cell type depending on its energy requirements and function. Mitochondrial disorders can be divided into primary and secondary. Primary disorders occur secondary to mutations of the mtDNA or nDNA that encodes mitochondrial proteins. Secondary disorders occur as a result of intra- and extra-cellular environmental stress that leads to damage to mtDNA or nDNA. Mitochondrial disorders that affect the eye are frequently primary, but the role of mitochondrial dysfunction in acquired chronic progressive ocular diseases such as diabetic retinopathy and age-related macular degeneration is now better understood 86. Mitochondrial disorders are often multi-organ disorders given that all human cells contain mitochondria but not all tissues are affected equally. Many mitochondrial disorders can specifically affect the eye given the high-energy demand by ocular tissues. It is not currently understood why each disease affects tissues differently even when the mutation affects the same gene. Heteroplasmy and the threshold effect explain some of the variation in expression among tissues within an individual but would not explain the propensity for specific tissues to be affected. The genetic variability of different mitochondrial disorders is also not fully understood. For example, mutations in the ND gene encoding NADH dehydrogenase which is part of complex I in the respiratory chain most often cause Leber hereditary optic neuropathy (LHON), but some mutations can lead to MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome or even a LHON/MELAS overlap syndrome20. On the other hand, MELAS syndrome is most often caused by a mutation in TL1 gene encoding mitochondrial transfer RNA (tRNA) leucine 1 which is part of the mitochondrial transcription machinery44. This variability in genotypes and phenotypes contributes to the difficulty of diagnosis and treatment of mitochondrial disorders. Ocular manifestations of mitochondrial disorders vary widely and several ocular and extraocular tissues can be affected including the retina, optic nerve, lens and extraocular muscles54. Ocular manifestations can be isolated or part of complex multi-organ disorders. While most mitochondrial disorders preferentially affects one ocular tissue, involvement of many others has been documented in case reports and is summarized in Figure 1.

LEBER HEREDITARY OPTIC NEUROPATHY LHON was the first condition to be determined to be a mitochondrial disorder in 1988 when a causative mtDNA point mutation was isolated by Wallace and coworkers194. It became a model for the study of mitochondrial disorders. Classically, patients with LHON present with acute worsening central visual acuity in one eye followed by involvement of the fellow eye within weeks to months. Patients with “Leber plus” phenotype have additional abnormalities including cardiac conduction defects and peripheral neuropathy. Insert 1 describes clinical presentation of a typical patient with LHON. Epidemiology LHON is the most common mitochondrial disease worldwide, with an estimated prevalence of 1 in 27,000-45,00060; 156. Variable penetrance between and within carrier families makes accurate estimation of the true prevalence difficult161. Young males are preferentially affected, and the age of onset is typically 15 to 3560; 119. Men are affected about 4 times more often than women 156 . This preferential sex prevalence cannot be explained by mitochondrial genetics alone. Genetics LHON arises from mutations in one of the 6 maternally inherited mitochondrial genes encoding components of complex 1 of the respiratory chain. Three mutations (m.11778G>A (MT-ND4), m.14484T>C (MT-ND6) and m.3460G>A (MT-ND1)) account for 95% of clinical cases of vision loss115. Of the three, m.11778G>A is the most common mutation and carries the worst prognosis119. Other pathogenic mutations include G13730A, G14459A, C14482G, A14495G, C14498T and T14596A198. Penetrance varies between 50% for males and 10% for females208. Incomplete penetrance interferes with the detection of all mutations and is not completely understood. Factors contributing to variable penetrance include heteroplasmy, genetic modifiers and environmental factors. The majority of patients have homoplasmic mutations (All mitochondria within a cell contain the same mutation) but some carry heteroplasmic mutations which are more common in patients with the m.11778G>A mutation113. The threshold effect of heteroplasmic mutations (percentage of mitochondria with the mutation) is approximately 60% with only 7% of patients with a mitochondrial mutation load of <60% experiencing vision loss28. The strong male predominance is still not fully understood but is thought to be due to an Xlinked modifier that has been isolated to the Xp21 locus associated with a 35-fold risk of vision loss in patients with the m.11778G>A and m.14484T>C mutations87. Another cause for male predominance could be due to estrogens having a protective effect against visual loss58. Environmental factors including tobacco smoking and excessive alcohol also play a key role in the phenotypic expression of the underlying mutation and in a large cohort of LHON carriers and patients, tobacco and alcohol use were the two strongest risk factors for development of LHON162. Other environmental triggers such as drugs that affect mitochondrial metabolism, including anti-retroviral therapy and ethambutol, have also been demonstrated to trigger onset of visual loss in LHON mutation carriers35; 81; 114. Clinical course

Patients typically first present in the 2nd to 4th decade of life with acute painless loss of central visual acuity in one eye208. Visual fields demonstrate central and cecocentral scotomas spanning at least 25-30 degrees of central vision135. Color vision is affected early in the disease and can precede central vision loss151; 191. The fellow eye is involved within weeks to months, and the majority of patients have bilateral involvement within 1 year, hence longstanding unilateral involvement should prompt investigation of other potential etiologies. Visual acuity deteriorates to worse than 20/200 in most patients. Spontaneous recovery of vision occurs in 35% to 65% of patients with the m.14484T>C mutation, whereas only 4% of patients with the m.11778G>A mutations report any visual recovery88; 138; 179. Slowly progressive disease and childhood onset are also correlated with milder disease phenotype12. The papillomacular bundle (PMB) is preferentially affected in LHON. Smaller caliber axons in the PMB corresponding to the P-cell population are disproportionality lost compared to peripheral fibers and the M-cell population is spared164. This is thought to be due to increased metabolic demand on axons of the macula as well as a mismatch between metabolic demand and energy supply of small caliber nerves139. Diagnosis of LHON is clinical and requires a complete ophthalmological exam including visual acuity, colour vision, funduscopic examination, formal visual fields, peripapillary ocular coherence tomography (OCT) and ganglion cell analysis of the macular complex. Funduscopy is often normal, but sometimes demonstrates optic nerve head hyperemia, dilation and tortuosity of optic nerve head vessels, retinal and disc hemorrhages, macular edema, exudates, retinal striations, and obscuration of the disc margins131. A pathognomonic triad includes circumpapillary telangiectatic microangiopathy, peripapillary nerve fiber layer swelling (pseudoedema), and absence of leakage from the disc or papillary region on fluorescein angiography132. Progression of the disease can be divided into four phases: 1) In the pre-symptomatic phase, funduscopic and peripapillary OCT testing can be within normal limits or reveal the characteristic changes listed above including microangiopathic disease, pseudoedema and hyperemia of the optic nerve head13; 131. 2) Weeks to months after first clinical changes, in the early acute phase, patients begin to experience symptoms of vision loss, dyschromatopsia and develop central scotomas at which point they commonly seek medical attention. Increased swelling of the temporal and inferior arcades and rapid loss of the axons in the papillomacular bundle occur concurrently with symptoms 131; 175. 3) Within 6 months to 1 year after onset, symptoms stabilize and optic nerve pallor sets in as temporal peripapillary retinal nerve fiber layer thins out. Changes on formal visual fields and pRNFL and GCC thinning on OCT reach a plateau as PMB atrophies. During this time the fellow eye becomes involved if it was previously asymptomatic.

4) A quiescent, chronic phase follows with poor vision and relative stability of symptoms and fundus appearance. Spontaneous visual recovery can occur within months to years after onset depending on the pathogenic mutation, age of onset and course of disease 88; 138; 179. OCT Advancements in OCT technology continue to provide more information for the surveillance of patients with LHON. OCT scans of the pRNFL, macular GCC and now OCTA are useful adjuncts to monitor changes throughout different stages of disease. OCT of the pRNFL was first to be shown to detect thickening in patients with early LHON followed by thinning in later stages. Early on, peripapillary OCT shows increased thickness of the temporal and inferior papillary retinal nerve fiber layer (pRNFL) quadrants while unaffected carriers can also show some thickening of the RNFL 166. Macular OCT can reveal variable changes of the ganglion cell layer and the inner plexiform layer (ganglion cell complex or GCC) even in the pre-symptomatic phase73; 126. In the early acute phase OCT of the pRNFL continues to show thickening while Macular OCT reveals thinning that continues to progress. In the late acute phase, pRNFL begins thinning as the PMB atrophies. 10; 11. Early differences between pRNFL and GCC make OCT with ganglion cell analysis a good early biomarker of disease progression. Eventually in the chronic stage both temporal pRNFL and GCC show thinning consistent with the atrophic nerve appearance. OCT angiography (OCTA) can also detect changes in vessel density and peripapillary capillary network that reflect changes in other layers of the retina. Its utility for diagnosis and monitoring is being investigated 9; 21. Electrophysiologic testing Electrophysiologic testing of retinal and optic nerve function including visual evoked potentials (VEP) and electroretinogram (ERG) have been integral in early understanding of LHON. VEP measures optic nerve function in response to a visual stimuli. Unsurprisingly, VEP testing shows decreased amplitude and increased latency in the P100 wave in patients affected by LHON25; 85. mfVEP demonstrates that axons from the central retina are affected more than those in the periphery, in keeping with the tendency of PMB dysfunction216. mfERG also demonstrates dysfunction of the inner retina, including retinal ganglion cells, in patients affected by LHON108. Unaffected carriers have more variable changes on VEP and ERG 65; 110; 159; 217. Systemic disease Although most patients present with isolated visual complaints, “Leber plus” patients can present with cardiac conduction abnormalities and peripheral neuropathies. Cardiac pre-excitation syndromes including Wolff-Parkinson-White and Lown-Ganong-Levine can be seen in up to 10% of patients121; 133. Some patients, particularly those with the m.11778G>A mutation, present with symptoms and signs consistent with multiple sclerosis at onset of progressive vision loss69; 137 . Several families of LHON patients are afflicted with a particularly severe constellation of symptoms including ataxia, dystonia, encephalopathy and psychiatric abnormalities in addition to optic neuropathy. These have been linked to modifier mtDNA variants36; 78; 184.

Management and emerging therapies Supportive therapy and regular follow-up are integral to the management of LHON. Regular monitoring of visual acuity, color vision, visual fields, peripapillary OCT and ganglion cell analysis of the macular complex is important especially in the acute and sub-acute phases of LHON and in asymptomatic carriers24. Risk factor management including cessation and avoidance of tobacco and heavy alcohol use are universally recommended, both for symptomatic patients and asymptomatic carriers. Tobacco and alcohol increase levels of ROS contributing to cell death and loss of RNFL thickness. Currently there is no consensus on screening of maternally related family members of patients, but a discussion with the patient and patient’s family can determine their preferences. Patients demonstrating extra-ocular neurologic deficits should be assessed with brain MRI. Baseline ECG should be performed for assessment of cardiac conduction abnormalities. Multiple treatment modalities have been proposed in the past, with varying degrees of success. Vitamin supplementation, specifically those with antioxidant properties and mitochondrial coenzymes, have been suggested in an attempt to reduce oxidative stress and improve mitochondrial function183. Vitamins B2, B12, C, E, glutathione and decylubiquinone have been proposed in the past but no human trials show benefit. Topical brimonidine, an alpha-2 agonist used for its IOP lowering effect, has been shown to have a neuroprotective effect in animal models by upregulating Bcl-2 and preventing mitochondrially induced apoptosis197. Human trials did not show benefit in prevention of second eye involvement in LHON130. Coenzyme Q10 (CoQ10) is an integral part of the mitochondrial respiratory chain as it acts as a cofactor for electron transport from complex I and II to complex III. This function has made it an important target for treatment in LHON as it can bypass a dysfunctional complex I to deliver electrons downstream. CoQ10 supplementation has showed success in patients with CoQ10 deficiency but in LHON results are conflicting183. Similarly an EPI-743, an experimental redox agent, was designed to act as a powerful redox agent and showed promising results in a group of 5 patients with LHON163. Idebenone (Raxone®, Santhera Pharmaceuticals, Liestal, Switzerland), a CoQ10 analogue, is an antioxidant and acts as an electron donor that can by-pass complex 1 in the respiratory chain thus contributing to ATP synthesis despite a dysfunctioning complex 1 67. Idebenone has been used experimentally for LHON since 1992 with promising results120. The Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) was the first double-blind, placebo-controlled trial that despite not achieving its main outcome, demonstrated benefit of daily use of idepenone in patients with discordant visual acuities (difference of logMAR >0.2 between eyes). Use of idebenone’s for LHON is the only treatment modality for a mitochondrial disorder that has been approved by the European Medicine Agency. Its use for treatment of subacute and dynamic disease (less than 1 year since symptom onset) is supported by several expert consensus statements 24; 169. The recommended dose is 900 mg/day for at least 1 year to assess therapeutic

response. Once a clinically relevant improvement of at least 2 lines of best corrected visual acuity (BCVA) on ETDRS chart is reached the treatment should continue for at least an additional year. One should be mindful that the true treatment effect of idebenone has to be confirmed in other well-designed studies as with the current evidence it is not possible to differentiate spontaneous recovery sometimes seen in LHON from the treatment effect of this medication.

Estrogen’s role in LHON is not yet fully understood but phytoestrogen and 17β-estradiol supplementation was shown to rescue cell models of LHON, reducing apoptosis, mitochondrial fragmentation and ROS and increasing mitochondrial biogenesis58; 146. This has not been tested in vivo to date, but side effects of estrogen including gynecomastia, decreased libido and breast and endometrial cancers would have to be weighed against potential benefits. Gene therapy is a promising avenue for treatment of mitochondrial disease especially in the eye given its relative ease of access for delivery of gene vectors. Since LHON is caused by a mtDNA mutation, several strategies exist to repair the defective gene. Allotropic expression of mitchondrially encoded genes is the most studied approach for gene therapy in LHON. Intravitreal injection of adeno-associated virus vector carrying a wildtype sequence of the mutated gene. Addition of a terminal targeting sequence for mitochondrial import allows for cytoplasmic transcription and translation of complex 1 subunits destined for the mitochondrion. Wild type expression of complex 1 subunits is meant to compete with endogenous mutant ones in order to create aritificial heteroplasmy. Several animal models demonstrated rescue of RGCs transfected with AAV vector49 and several human trials demonstrated that intravitreal injection of AAV vectors carrying wildtype genes are safe and show some promise in improvement of visual acuity, RNFL thickness and electroretinography51; 64. Ongoing human trials will continue to advance treatment for this disease. AUTOSOMAL DOMINANT OPTIC ATROPHY Autosomal dominant optic atrophy (ADOA) is the most common inherited optic neuropathy with prevalence of 1:12,000 to 1:50,000101; 205; 207. Usually symptoms are limited to the eye but other systemic manifestations such as sensorineuroal hearing loss, myopathy, ataxia, ophthalmoplegia and peripheral neuropathy can occur in the so-called ADOA-plus syndromes. The typical patient with ADOA experiences an insidious onset of very slowly progressive decline in central vision during the first, second and third decades of life. Often the patients are completely asymptomatic and symmetric optic nerve pallor is detected on routine eye examination. Most cases are caused by mutation in the OPA1 gene with over 500 pathologic mutations identified to date50. Insert 2 presents a typical case of ADOA. Pathophysiology and genetics OPA1 and OPA3 are the two causative genes accountable for most cases of ADOA. As the name implies, DOA is inherited in an autosomal dominant manner. Mutations in the OPA1 gene account for 65-90% of ADOA cases in some cohorts2; 34. Interestingly, OPA1 is a gene located in

the nuclear DNA on chromosome 3q28-2943 but it encodes a protein (dynamin-related GTPase) that functions in the mitochondria. Thus, the OPA1 gene product plays a role in oxidative phosphorylation, mtDNA stability, inner mitochondrial membrane fusion, cristae formation, calcium homeostasis and cytochrome c regulation47; 57; 111; 136. Most mutations leading to the ADOA phenotype are splice variants, nonsense or missense mutations leading to haploinsufficiency142. Haploinsufficiency means that not enough of the functioning gene product is produced to allow for normal functioning of the cell leading to a dominant effect of a heterozygous mutation. Mutation of the OPA1 leads to mitochondrial fragmentation and eventual apoptosis136. Mutations in the OPA3 gene have been reported to cause ADOA with cataracts but these mutations are rare and were found in only several families 154. The OPA3 gene is also associated with type III 3-methylglutaconic aciduria, a rare disorder characterized by optic atrophy, ataxia, chorea, and spastic paresis200. Other loci including OPA4 on 8q12.2-q12.3, OPA5 on 22q12.1q13.1 and OPA8 on 16q21-q22 have been reported to cause a phenotype similar to ADOA in several families but the causative genes have yet to be identified37. Similarly to patients with LHON, retinal ganglion cells and particularly the ones in the papillomacular bundle are preferentially affected in ADOA74. Clinically this is seen as thinning of papillomacular RNFL on OCT of the optic nerve and the macula with a corresponding reduction in blood flow83; 84. The predilection for retinal nerve fibers and specifically the papillomacular axons is thought to be due to the high energy demands and unique anatomy of the optic nerve but it is still not fully understood32. The wide spectrum of ADOA phenotypes can also be attributed to variable penetrance and expressivity with penetrance varying from 43% to 100%185; 187. Clinical course Patients with ADOA are often incidentally picked up to have temporal “wedge-shaped” optic nerve pallor. Sometimes patients will seek care because they notice insidiously progressive bilateral visual loss in their first, second or third decades of life. While the age of onset is very variable, more than 80% of patients develop some degree of optic nerve pallor prior to age 1033. Visual acuity can range between 20/20 and light perception but more than 80% of patients maintain better than 20/200 vision193. Many patients with ADOA are mistakenly treated for glaucoma as they often have mild degree of optic nerve cupping but there is invariably some degree of temporal pallor associated with it. Visual loss is usually slowly progressive and is dependent on duration of disease with wide variability in the disease severity57. On formal visual field testing central or cecocentral scotomas are often seen and if formal color vision testing is performed there are deficits in the blue-yellow (tritan) axis but complete dyschromatopsia is sometimes seen as well. There is characteristic macular inner retinal thinning on OCT and as well as thinning of the temporal and superior quadrants of peripapillary retinal nerve fiber layer84. Visual evoked potential show nonspecific decreased latency while electroretinography demonstrates an abnormal N95:P50 ratio suggesting ganglion cell dysfunction37. Systemic disease

Although ADOA is confined to the eye it can also be associated with various neurological phenotypes including deafness, multiple sclerosis-like episodes and severe neurological deficits in ‘ADOA plus’ disease. Patients with “ADOA plus” disease have specific mutations that lead to multiple mtDNA deletions contributing to a more severe phenotype3. Patients with multisystem syndromes of ADOA exhibit so-called dominant negative affect where the mutated OPA1 gene product has a deleterious effect on the wildtype functioning protein, effectively reducing the functionality of both alleles3. These patients usually develop optic atrophy at a young age followed by variable multi-systemic dynsfunction including sensorineuronal hearing loss, ataxia, peripheral neuropathy, myopathy and chronic progressive ophthalmoplegia4; 79. Other syndromes caused by autosomal mutations that effect mitochondria dysfunction also can feature optic neuropathies as part of their constellations of symptoms. The optic neuropathies can present with more insidious vision loss similar to ADOA or severe loss as seen in LHON. Syndromes featuring optic neuropathy include deafness-dystonia-optic neuronopathy (MohrTranebjaerg syndrome), caused by mutations in the TIMM8A gene at Xq2277; 188Friedreich’s ataxia, caused by mutations in FXN at 9q21.11;55; 118 Charcot-Marie-Tooth Disease type 2A, caused by mutations in the MFN2 gene at 1p36.2;157 Hereditary spastic paraplegia Type 7, caused by mutations in the SPG7 gene at 16q24.3; 102; 172 Hereditary motor and sensory neuropathy type VIB, caused by mutations in the SLC25A46 gene at 5q22.1; Infantile encephalopathy, caused by mutations in the DLP1 gene at 12p11.21;196 and familial dysautonomia/hereditary sensory and autonomic neuropathy type III (Riley-Day syndrome), caused by mutations in the IKBKAP gene at 9q31.3 123; 189. Therapy Currently there are no approved therapies for ADOA. Due to the phenotypic resemblance of ADOA and LHON most treatments previously studied for ADOA are ones adapted from LHON protocols. Patients with isolated optic neuropathy should be referred for low vision assessment and aids. Antioxidants and other nutritional supplements are often recommended and it is noteworthy that vitamin E showed reversal of the ADOA phenotype in dorsophilla, however, nutritional supplements have not been studied in humans203. Genetic counselling should be offered to patients for family planning and to identify any other affected relatives but given the variable penetrance and expressivity it is still difficult to predict the burden of disease. Patients expressing symptoms of ADOA plus disease should be referred to a multidisciplinary team with experience in mitochondrial disorders. Idebenone has been studied in a pilot study of 7 patients. Five patients reported some improvement in visual acuity, visual fields and color vision after 1 year follow-up but no randomized controlled studies have been conducted to date14. QS10 (an idebenone metabolite), zolpidem and papaverine are among some compounds that have been tested in vitro or in animal models of ADOA showing increased cell survival and visual function59; 209. Gene therapy which is he only potential for true cure in ADOA still remains only a potential possibility and Sarzi and coworkers studied an adeno-associated virus vector carrying wild-type OPA1 in a mouse model of DOA showing successful transfection and expression of OPA1 with functional improvement in vision165; however, human trials are needed to further test this model.

Chronic progressive external ophthalmoplegia Chronic progressive external ophthalmoplegia (CPEO), first described in 1868, is part of a spectrum of mitochondrial disorders that share the common clinical characteristics of progressive bilateral ophthalmoparesis and ptosis.192 CPEO can present in isolation with these core features or with other neurologic or non-neurologic symptoms as a CPEO-plus syndrome. Systemic myopathies (myotonic dystrophy or oculopharyngeal dystrophy) or metabolic disorders (Refsum disease or abetalipoproteinemia) can also have ocular phenotypes that mimic the ophthalmoparesis of CPEO but lack the same underlying pathophysiology as CPEO and fall out of the scope of this review. Epidemiology The prevalence of CPEO is difficult to ascertain due to the lack of defined diagnostic criteria, the spectrum of symptoms between isolated CPEO and CPEO-plus syndromes, and multiple phenotypes caused by the same mitochondrial mutations129. The estimated prevalence of CPEO in the United Kingdom is 3.39 per 100 000206. The mean age at diagnosis of CPEO ranges from 18-56 years6; 75; however, the onset of symptoms can occur at any age206. CPEO is more common in women with the ratio of about 1.8-2.5:175; 144. Etiology and Genetics CPEO develops sporadically in approximately 50% of cases due to large scale mtDNA deletions122. The other 50% of cases are familial, the result of autosomal dominant, autosomal recessive or maternally inherited point mutations in mitochondrial RNA. There is heterogeneity within families and variable expressivity. The same single nucleotide mutation can express as multiple phenotypes, as in the case of a mother with CPEO and her son with Pearson marrowpancreas syndrome or the m.3243A>G mutation causing both CPEO and MELAS phenotypes125; 173 . Pathology The stereotypical pathological finding in CPEO is subsarcolemmal accumulation of mitochondria stained with Gomori trichrome described as ‘red ragged fibres’. A more sensitive finding is the presence of cytochrome c oxidase (COX)-deficient fibres.180 The diagnostic criteria for mitochondrial cytopathies are presence of more than 2% of red ragged fibres on muscle biopsy for patients of any age, more than 2% COX-negative fibres if patient is less than 50 years of age, or more than 5% of COX-negative fibres if a patient is older than 50 years of age19. Functional assays of the ATP synthesis rate or enzymatic assays of respiratory chain complexes can also be performed in cases of diagnostic equipoise. Extraocular muscles are most commonly affected in CPEO due to a high density of mitochondria and higher metabolic rate compared to skeletal muscle26; 210. Extraocular muscles have a higher proportion of muscle with COX-deficient fibers (about 40%) compared to skeletal muscle (around 15%) in CPEO63. COX-deficiency is associated with normal aging but the rate of increase in COX-deficient muscle fibres is higher in extra-ocular muscles in CPEO127. The predilection for extraocular muscles to be deficient in this key enzyme in the respiratory electron

transport change reflects the increased metabolic rate of extraocular muscles which predisposes the extraocular muscles to the myopathy seen in CPEO. Interestingly, comparison of the extraocular muscles in LHON to CPEO shows that LHON muscle fibres have a compensatory increase in mitochondrial number. This compensatory reaction may be why LHON spares the extraocular muscles and pathology is limited to the papillomacular bundle where this compensatory strategy is less effective27. There is a tendency for individuals with large-scale mtDNA deletions to have progressive fat replacement of their muscles, compared to individuals with single nucleotide mtDNA who demonstrate a similar degree of oxidative phosphorylation deficits. This progressive fat replacement can be seen in vivo with MRI imaging of extraocular muscles: the muscles are atrophic, but also have T1 hyperintensities and prolonged T2 signal, which is postulated to represent increased fat content in the atrophic muscles147. Clinical manifestations Key clinical features of CPEO are ptosis that often develops first and ophthalmoparesis. Significantly impaired strength of both levator palpebrae and orbicularis mucscles is often present with resulting poor blink reflex and tear secretion putting these patients at high risk for exposure keratitis174. Unlike other causes of ophthalmoparesis, in patients with CPEO the limitations of ocular motility are usually very symmetric with movements of both eyes within 5 degrees in many patients 155. Motility restrictions vary with the stage of the disease and worsen as disease progresses and can limit eye excursions to 10% of normal in advanced cases143. Because of symmetric limitation of motility, diplopia is reported in only 1/3 to 2/3 of patients with CPEO144. Most patients exhibit exotropias (seen in up to 90% of patients)155; 186. Individuals with CPEO will also have mild-to-moderate proximal muscle weakness, up to half will have dysphagia, and sensorineural hearing loss is presents in 50-75% of patients72; 75; 106; 144 Biochemical changes include elevated serum alanine, lactate, and CK levels and abnormal urine organic acid profiles.75 CPEO-plus syndromes can present with a variety of symptoms including sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO); pigmentary retinopathy, cardiac conduction deficits, endocrinopathy, and other non-muscular neurologic dysfunction (KearnsSayre syndrome); gastrointestinal dysmotility and leukoencephalopathy (mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and pediatric sideroblastic anemia with pancreatic dysfunction (Pearson marrow-pancreas syndrome)68; 134. Differential diagnosis The differential diagnosis for CPEO includes the spectrum of CPEO-plus syndromes, ocular myasthenia gravis, thyroid related orbitopathy, chronic orbital myositis, oculopharyngeal muscular dystrophy, myotonic dystrophy type 1, congenital fibrosis of the extraocular muscles, abetalipoproteinemia, and Refsum disease.

Rarely, a CPEO-like syndrome can develop in HIV-positive patients receiving antiretroviral therapy145. This could be mitochondrial toxicity from HAART. HMG-CoA reductase inhibitors also have rare associations with external ophthalmoplegia symptoms resembling CPEO40; 56.This effect may be related to statin-induced myopathy or a distinct mechanism relating to mitochondrial toxicity, but the clinical findings are reversible with discontinuation of the offending drug. Treatment Most important first step in approaching a patient with CPEO should be smoking cessation: Heighton and coworkers found a higher rate of smoking in a CPEO cohorts compared to the general population75. Further, female smokers with CPEO had worse skeletal muscle strength compared to non-smoking females with CPEO, suggesting that smoking had unmasked the disease phenotype and contributed to worsening of CPEO symptoms. Thus, smoking cessation is paramount in all individuals diagnosed with CPEO. The ophthalmoparesis of CPEO often progresses asymptomatically, which is often attributed to the symmetric development of the disease ensuring that individuals will remain orthophoric in primary position, albeit with severely limited version movements. This theory though does not account for up to 90% of patients with CPEO who have exophorias155. Approximately half of these individuals though will develop suppression scotomas and remain asymptomatic. If diplopia develops the management will include of the four possibilities available for treatment any binocular diplopia: observation, occlusion, prisms in the glasses and monovision. If strabismus surgery is pursued, one has to remember that because of the inherent weakness and atrophy of extraocular muscles, resections are more effective than recessions176. In fact, the atrophy and weakening of the extraocular muscles in CPEO can be significant enough to increase intraoperative complications of strabismus surgery89. If force duction testing reveals a restrictive fibrosis associated with the atrophy then a recession of the restricted muscle is more appropriate195. The effect of surgery in CPEO is frequently overestimated by standard surgical tables and amount of surgery planned should be increased to improve outcomes176; 195. Botulinum toxin injections have also been shown to have beneficial effects in smaller angle deviations or patients who have already undergone maximal surgical recessions186. Ptosis management in CPEO is difficult due to the fact that there is poor levator function and a poor Bell reflex. Thus, procedures to lift ptotic lids have a higher risk of producing dry eye, exposure keratopathy, and corneal ulcers. These risks have to be balanced with the debilitating effect of the ptosis as individuals may adopt extreme chin-up head postures to achieve functional vision. The ptosis can be observed until the marginal reflex distance is less than 2mm or the lid causes visual field changes within 30 degrees of fixation on visual field testing122. Noninvasive techniques such as lid taping or lid crutches are usually poorly tolerated and not widely used. Another possible option for improving ptosis is to use scleral contact lenses that can increase palpebral fissures and marginal reflex distance94. Anterior levator resections and advancements can be considered if there is adequate levator function. The amount of residual levator function before surgery is considered is somewhat

controversial with different authors suggesting anywhere from 5 to 8mm of levator excursion as a threshold for surgery avoid any exposure complications39. In cases of inadequate levator function, silicone frontalis slings are recommended, as silicone slings have more potential for post-operative adjustments compared to fascia lata or Gore-Tex materials199. If there is overcorrection with corneal exposure after surgical repair, the lagophthalmos can be managed conservatively with lubricating drops and ointments, reversing the procedure (if silicone rods were used in a frontalis sling procedure), or procedures to repair lower lid laxity (lateral tarsal strips or wedge resections). Kearns-Sayre Syndrome Kearns-Sayre Syndrome (KSS) is a CPEO-plus syndrome first described by Kearns and Sayre in 1958 when they reported two cases of young men with CPEO, pigmentary retinopathy, and complete heart block97 .Kearns later described additional clinical features including weakness of orbicularis oculi, facial, and peripheral muscles, deafness, small stature, abnormal EEG findings, and increased protein content of the cerebrospinal fluid96. The current clinical diagnostic criteria define KSS as CPEO and pigmentary retinopathy with the onset before the age of 20 and at least one of the following features: cardiac conduction block, cerebrospinal protein concentration greater than 0.1g/L, or cerebral ataxia148. Genetic testing and muscle biopsies for histopathology and biochemical analysis demonstrate overlap within the spectrum of CPEO-plus syndromes, but are important for confirmation of the diagnosis and counselling of patients with KSS. Epidemiology KSS affects individuals under the age of 20 and has no predilection for sex or race. The prevalence of KSS is estimated to be 1-3/100,000 based on population studies of large scale mtDNA deletions.30; 153; 168 Etiology and Genetics Unlike CPEO, which has a high proportion of familial single nucleotide mutations, KSS is sporadic in 90% of cases and associated with large scale mtDNA deletions. The only maternal factor associated with de novo mtDNA deletions in children is the mother harboring a mtDNA deletion herself, which confers a 4% risk of KSS in her offspring.29 The most common deletion found in KSS is a 4977 base pair deletion, but single nucleotide deletions or even autosomal gene deletions can cause KSS.148; 201; 212 There is overlap in the CPEO and CPEO-plus syndromes (including KSS) caused by common mtDNA deletions, postulated to be the result of differing heteroplasmy in the various tissues. The timing of the mtDNA deletion during development is thought to play an important role in the tissue distribution of the affected mitochondria: the deletion causing KSS occurs earlier than in CPEO and affects more organ systems as a result.112 Clinical manifestations The diagnosis of KSS requires patients to present with both CPEO and pigmentary retinopathy before the age of 20 years, as well as at least one additional feature (cardiac conduction block, cerebrospinal protein concentration greater than 0.1g/L, or cerebral ataxia). While the

ophthalmoplegia of KSS is functionally and biochemically indistinguishable from isolated CPEO which is reviewed above, the KSS clinical phenotype is much broader than these defining features and requires a multidisciplinary approach to appropriately diagnose and manage its multiorgan manifestations140. The retinal degeneration found in KSS is best described as a pigmentary or salt-and-pepper retinopathy rather than an ‘atypical retinitis pigmentosa’ as KSS and RP have several important differentiating features. The salt-and-pepper retinopathy of KSS is most noticeable in the posterior pole or peripapillary retina rather than mid-peripheral retina where RP degeneration occurs128. Further, the pigmentary changes in KSS give the retina a mottled appearance and bone spicules are rarely seen in KSS. RPE atrophy can reveal underlying choroidal vasculature described as ‘choroidal sclerosis’42Histopathologic studies suggest that RPE dysfunction is the causative mechanism for the retinal degradation41 Uncommonly, KSS can be associated with subretinal fibrosis, macular holes, or vitelliform-like retinal lesions5; 107. Electroretinography can vary from normal to severely depressed, but abnormalities are usually mild compared to the severe rod-cone dystrophy pattern seen in RP15. Approximately 50% of patients with KSS will have visual complaints such as decreased visual acuity or nyctalopia, but their impairment is usually mild16. Cardiac disease is present in up to 2/3 of patients with KSS and can present with a range of symptoms including fatigue, syncope, bradycardia, and sudden cardiac death90. First- and second-degree AV blocks can progress to complete third-degree AV block, but serious cardiac arrhythmias, including ventricular tachycardia and Torsades de Pointes can also develop. Importantly, these potentially fatal arrhythmias or heart blocks can occur without any preceding symptoms or ECG changes and frequent ECGs are recommended with a low threshold for installing implantable permanent pacemakers90. The elevated CSF protein found in KSS reflects a dysfunction in the active transport and clearance of CSF proteins by the choroid plexus182. Choroid plexus dysfunction is also thought to contribute to the low levels of CSF 5-methyltetrahydrofolate (5-MTFH) relative to serum, as 5MTFH is actively transported into the CSF via the choroid plexus171; 178. CSF 5-MTFH levels are correlated with both age and characteristic white matter changes on MRI. KSS patients develop white-matter lesions on T2-weighted sequences in subcortical white matter, brain stem, globus pallidus, thalamus and cerebellum160; 190; 213. These white matter changes are also associated with restricted diffusion on DWI and ADC sequences. These abnormalities on neuro-imaging correspond to ‘status spongiosus’, where spongiform vacuolization can be found in white matter of the cerebrum and cerebellum, as well as brain stem gray matter177. It is postulated that these spongiform changes, particularly within the dentate nucleus, result in disconnection of Purkinje cell dendrites and underlie the cerebellar ataxia in KSS181. Cognitive impairments and dementia, aggravated by sensorineural hearing loss, are also present in many patients with KSS22; 106. Beyond the central nervous system findings, peripheral motor and sensory neuropathies have also been reported, as well as atrophy of striated skeletal muscle18; 170; 211. KSS is also associated with a variety of endocrinopathies and metabolic dysfunctions underlying the short stature that is commonly seen in KSS31; 70. There is a high prevalence of diabetes

mellitus, abnormal growth hormone, hypogonadism, hypothyroidism, and hypoparathyroidism in KSS52; 66. Treatment The management of KSS requires a multidisciplinary approach to successfully diagnose and manage the varied symptoms and morbidity associated with KSS140. The ophthalmoplegia can be managed in a similar fashion to isolated CPEO and is described above. The visual impairment associated with the pigmentary retinopathy is usually mild, and treatments should be directed to optimizing residual vision. Evaluation and follow-up with a cardiologist for conduction blocks, dysrhythmias, or cardiomyopathies are essential to avoid sudden cardiac death, as individuals may be asymptomatic prior to catastrophic or fatal cardiac events98. Implantable pacemakers should be considered in all patients with KSS to prevent morbidity or mortality from severe heart block. There is evidence to support the use of implantable defibrillators to treat potentially fatal arrhythmias that can occur even in the presence of a functioning pacemaker, however this is not a routine practice82. Likewise, routine monitoring for endocrinopathies is required in KSS with replacement therapy as indicated 92. Patients respond well to growth hormone supplementation and have improvement in their final height as mature adults.150 The diabetes associated with KSS typically presents with insulin resistance rather than islet cell failure and can initially be managed with oral agents, though 45% will require insulin within the first two years.93 Supplementation with oral folic acid (1-3mg/kg) has been shown to improve neurological symptoms scores and white matter lesions on neuroimaging.149 Supplementation with coenzyme Q10 has also be reported to have improvement in cardiac conduction, ocular motility, neurological symptoms, and corneal edema. A single clinical trial evaluating creatine monohydrate, coenzyme Q10, and α-lipoic acid showed benefit in surrogate markers of oxidative stress in mitochondrial diseases; nutraceutical therapy should be offered to patients with KSS.183 A Phase II clinical trial (ClinicalTrials.gov #NCT01370447) is in progress evaluating a vitamin E derived coenzyme Q10 analogue, EPI743, in end-stage mitochondrial diseases. There are case reports that a low-carbohydrate and high-fat diet (e.g., the Atkin’s diet) can also improve symptoms in mitochondrial diseases such as KSS and this diet is being studied in another clinical trial (ClinicalTrials.gov #NCT02385565).1; 17 MELAS Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome was first described in 1984141 and the first pathogenic mtDNA mutation, m.3243A>G, was discovered in 199061. As the name suggests, the clinical diagnosis of MELAS syndrome depends on three cardinal features: 1) encephalopathy with seizures and/or dementia, 2) mitochondrial myopathy characterized by lactic acidosis at rest and/or ragged red fibers on muscle biopsy and 3) stroke-like episodes causing transient hemiparesis or cortical blindness, particularly before age 40. MELAS is considered to be the most common maternally inherited mitochondrial disorder with a minimum prevalence of 0.18/100,000 in Japan204. The m.3243A>G mutation is much

more common in the population but the wide spectrum of phenotypes makes detection more elusive129. Several studies showed a minimum prevalence of the m.3243A>G mutation carriers to be between 7.69-236/100,000 48; 116; 117; 168. Clinical presentation and diagnosis Symptom onset occurs early in life as most patients present prior to age 10 and 99% of patients present before age 40158. Presenting symptoms most commonly include seizures, stroke like episodes, cortical blindness, muscle weakness, short stature, recurrent vomiting or recurrent headaches158. Morbidity and mortality are increased in MELAS syndrome with a median survival of 16.9 years from onset of symptoms95. Cause of death is frequently cardiomyopathy, status epilepticus and stroke95; 214. Juvenile onset of symptoms carries a worse prognosis204. Clinical testing can support the diagnosis and direct symptomatic treatment efforts. MRI brain imaging during a stroke-like episodes demonstrates hyperintense T2 signal that does not correspond to any vascular territory and demonstrates minimally decreased or even increased diffusion on DWI suggesting vasogenic edema80. Lactic acidosis, although nonspecific, is a common manifestation and elevated lactate levels can be detect in blood and CSF141. Muscle biopsy reveals ragged red fibers with Gomori trichrome stain which are characteristic of many mitochondrial disorders. These fibers also are positive for succinate dehydrogenase (SDH) stain and in the case of MELAS syndrome most RRFs stain positive for cytochrome oxidase (COX)44. Definitive diagnosis requires mtDNA testing to find one of the pathogenic mutations. Clinical manifestations of MELAS syndrome include cardiac, endocrine, muscloskeletal, neurologic and psychiatric symptoms, among others, which are beyond the scope of this review. Specifically to the eye, MELAS patients as well as m.3243A>G carriers have been reported to present with retinal dystrophy, pigmentary retinopathy, ptosis, ophthalmoplegia and optic atrophy53; 54; 91; 109; 215 . Corneal polymegathism with normal corneal thickness and endothelial cell count has also been reported but it’s clinical significance is unclear8. Cortical blindness as a result of stroke-like episodes affecting the occipital cortex or other parts of the visual pathway are also important to consider. Two diagnostic frameworks have been developed to diagnose patients with MELAS syndrome. The original criteria, developed by Hirano and coworkers included the three cardinal symptoms of: (1) stroke-like episode before age 40 yr; (2) encephalopathy characterized by seizures and/or dementia and (3) lactic acidosis and/or ragged-red fibers . Two of the following three criteria help confirm the diagnosis: normal early psychomotor development, recurrent vomiting or recurrent headaches76. The MELAS group in Japan published a second set of criteria that supports the diagnosis if patients fulfill two category A and two category B criteria (Table 1)204. Category A • Headaches with vomiting • Seizures • Hemiplegia • Cortical Blindness • Acute focal lesions on neuroimaging

Category B • High plasma or CSF lactate • Mitochondrial abnormality on muscle biopsy • Pathogenic mutation related to MELAS

Genetics and pathophysiology Since the m.3243A>G mutation in MT-TL1 was first described, more than 30 pathogenic mutations for MELAS syndrome have been found but the m.3243A>G mutation still accounts for 78-80% of cases158; 204. Interestingly, the m.3243A>G mutation phenotype has large variations in penetrance and expressivity as many mutation carriers show only isolated symptoms including diabetes mellitus or sensorineural hearing loss while others present with syndromes such as myoclonic epilepsy with ragged red fibers (MERRF), Chornic external ophthalmoplegia (CPEO) or Leigh syndrome129. MT-TL1 encodes for the mitochondrial leucine tRNALeu (UUR) and mutations invariably affect the function of all 13 mitochondrially encoded proteins involved in oxidative phosphorylation. Mutations in components of complex 1 are also associated with MELAS, specifically mutations in MT-ND1, one of the most common sites of pathogenic mutations for LHON100. This gives rise to overlap syndromes between LHON and MELAS20. Interestingly, ophthalmological findings in MELAS syndrome are varied and present in <25% of patients as opposed to LHON where optic atrophy is the defining feature. Differences in clinical features can be partially attributed to mitochondrial copy number differences and heteroplasmy as well as downstream genetic effects but the entire pathogenesis is incompletely understood62. The pathophysiology of MELAS is attributed to decreased protein translation leading to deficient electron transport chain function and an energy deficit in metabolically active tissues99. Energy deficiency in turn promotes mitochondrial proliferation that can lead to angiopathy that contributes to ischemia during stroke-like episodes71. An important pathological process in MELAS and one targeted for therapy is a relative deficiency of nitric oxide (NO). NO is important for vascular smooth muscle relaxation to allow for vasodilation under increasing oxygen demands. NO deficiency is multifactorial and occurs due to decreased availability of NO precursors, citrulline and arginine, impaired production in vascular endothelial cells, increased sequestration by COX and shunting to reactive nitrogen species45. Supplementation of arginine and citrulline for the treatment of MELAS syndrome is one of the only widespread treatment modalities used. Treatment The mainstay of treatment for MELAS is supportive and requires a multidisciplinary approach. Consensus statement developed by the mitochondrial medicine society provides a framework for management140. A comprehensive evaluation at the time of diagnosis and in regular intervals should be used to screen for the cardiac, renal, endocrine, ophthalmologic, auditory and psychiatric manifestations. Management of ophthalmic complications should be tailored to the patients needs and preferences and should follow standard of practice with support from low vision specialists169. The standard of care management of diabetes, cardiomyopathy, seizures and other clinical manifestations applies to MELAS patients with several important caveats. Certain agents that can induce lactic acidosis or mitochondrial toxins such as aminoglycoside antibiotics, metformin and valproic acid should be avoided in MELAS7; 44. An important addition to the

standard of care management of stroke is the use of arginine supplementation. Administration of intravenous arginine is recommended within 3 hours of onset of stroke-like episodes103. Administration of oral arginine during the interictal phase helps reduce the number of stroke like episodes104. A 9-year follow up of an open label multicenter clinical trial of IV arginine in the acute setting and oral arginine in interictal periods showed trends towards improvement in symptoms and disability scores105. Citrulline, a precursor of arginine increases serum NO levels to a larger extent than arginine supplementation but no clinical trials have been conducted yet to show symptomatic relief46. Nutrition supplementation is commonly suggested for mitochondrial disorders with a goal of reducing reactive oxygen species and supplementing the mitochondrial ETC. Coenzyme Q10, vitamins B,C and E and Idebenone, an anti-oxidant and electron donor used for LHON have been proposed but their efficacy has not been shown167. Strategies aimed at compensatory mechanisms of the mitochondria have been investigated including ketogenic diets, aimed at increasing mtDNA and improvement of complex 1 function as well as pharmacological activation of mitochondrial biogenesis via NAD donors or poly-ADP ribose polymerase inhibitors. A more direct strategy in the form of molecular genetics using endonucleases targeted at the MT-TL1 gene aims to excise the mutated gene from the mtDNA, therefore preferentially increasing survival of wildtype mitochondria in the cell152; 202. The ultimate goal of a true cure in the form of genetic engineering is enticing but has not been shown in humans yet. Risks, including failure to correct the phenotype, cell death and metaplasmic transformation, are large hurdles in the quest for genetic cure.

Mitochondrial disorders often involve the eye either as the primary manifestation of disease or as part of a constellation of symptoms. Increased awareness and improved diagnostic capabilities are allowing for better understanding of the manifestations of mitochondrial dysfunctions and diagnosis of disease. The unique metabolic nature of ocular tissues make ophthalmologists key players in diagnosis and management of patients with mitochondrial disorders. As therapeutic technology develops, ophthalmologists will also be indispensable for delivery of therapies locally to the eye and to monitor it's effect.

Insert 1 Legend: 19-year-old man presented with 2 days history of sudden loss of vision in the right eye. Best corrected central acuity was 20/200 and 20/20. There was no relative afferent puillary defect. Fundoscopy demonstrated mild right optic nerve head hyperemia (Figure 1). 2 months later he re-presented with decreased vision in the left eye. Vision was now 20/200 and 20/100 with minimal right RAPD and mild pallor of the right optic nerve and slightly hyperemic appearance of the left nerve. This case demonstrates typical presentation of a patient with LHON: sudden visual loss in a young male with vision in the range of 20/100-20/400, with minimal or no RAPD and only mild hyperemia of the

optic nerve on examination. This is usually followed by the visual loss in the fellow eye several months later. Eventually bilateral optic nerve pallor ensues.

Insert 2 Legend: A 48-year-old man was referred for evaluation of glaucomatous optic neuropathy by his optometrist. Best corrected central visual acuity was 20/30 in each eye, there was no relative afferent pupillary defect, fundus examination revealed mild optic cupping but more importantly very symmetric temporal optic nerve pallor. Formal visual field testing demonstrated central scotomas in each eye. There was thinning on peripapillary ocular coherence tomography testing in each eye. Ganglion cell analysis of the macular complex demonstrated diffuse thinning bilaterally (Figure 2). This case demonstrates a typical patinet with dominant optic atrophy who is often asymptomatic with mildly reduced central acuities in each eye and very symmetric temporal optic nerve pallor often present along with mild cupping which is often mistaken for glaucomatous optic neuropathy. There is characteristic central or cecocentral scotomas on visual field testing demonstrating involvement of the papillo-macular bundle.

Literature search Literature search was conducted using PubMed for the years 1966 to 2018. Keywords included “mitochondrial” “mitochondria”, “mitochondrion”, “Leber’s Hereditary Optic Neuropathy”, “LHON”, “kjer-type”, “autosomal dominant optic atrophy”, “dominant optic atrophy”, “ADOA”, “DOA”, “MELAS” “mitochondrial encephalopathy, lactic acidosis and stroke”, “CPEO”, “Chronic progressive external ophthalmoplegia”, “Progressive external ophthalmoplegia”, “PEO”, “Red ragged fibres”, “RRF”, “Ophthalmoplegia”, “Kearns-Sayer”, “KSS”. English language articles and those with English abstracts were included. Relevant references within publications and historical references were included. EndNote Software was used to format the references. REFERENCES:

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Disorder LHON

MELAS

CPEO

KSS

Ocular manifestation Iris

Abnormality Pupil dysfunction

Reference Bremner 1999

Lens

Cataract

Lachmund 2006

Retina

Retinal dystrophy

Gronlund 2010

Optic nerve

Optic Neuropathy

Bird 1949

Glaucoma

Elevated IOP

Inagaki 2006

Motility

Nystagmus

Nakaso 2012

Iris

Atrophy

Rummelt 1993

Lens

Cataract Refractive error

Bene 2003 Gronlund 2010

Retina

Pigmentary retinopathy Macular degeneration Retinal dystrophy

Isashiki 1998 Rath 2008 Gronlund 2010

Choroid

Atrophy

Rummelt 1993

Optic nerve

Atrophy

Motility

Nystagmus Progressive external ophthalmoplegia

Shinmei 2007

Extraocular muscles

Ptosis

Gronlund 2010

Lens

Cataract

Van Hove 2009

Motility

Progressive external ophthalmoplegia

Von graefe 1868

Extraocular muscles

Ptosis

Conjunctiva

Conjunctivitis

Schmitz 2003

Cornea

Endothelial dysfunction Keratitis

Lee 2012 Schmitz 2003

Lens

Refractive error

Gronlund 2010

Retina

Pigmentary retinopathy Retinal dystrophy Macular degeneration

Isashiki 1998 Gronlund 2010

Motility

DOA

Carelli 2009

Progressive external ophthalmoplegia

Kearns 1958

Lens

Cataract

Grau 2013

Optic nerve

Atrophy

Glaucoma

Elevated IOP

Yu-Wai-Man 2010

Motility

Nystagmus Progressive external ophtahlmoplegia

Liskova 2013 Kuncl RW 1999

Delettre-Cribaille 2007

Extraocular muscles

Ptosis

Figure 1. Ocular manifestations of mitochondrial disorders. Multiple mitochondrial disorders are defined by their ocular manifestations but other, lesser known, pathological changes can be seen in multiple structures of the eye. LHON- Leber’s Hereditary Optic Neuropathy, MELAS- Mitochhondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes, CPEO- Chronic Progressive External Ophthalmoplegia, KSS- Kearns Sayre Syndrome, DOA- Dominant Optic Atrophy.