Introduction

Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain [1]. Historically, these diseases were classified into distinct syndromes based on their clinical presentations. However, with developments in whole genome sequencing technology and increased availability of genetic testing in the past decade, in particular mitochondrial DNA (mtDNA) sequencing, it is now recognised that many of these classic syndromes are associated with multiple genes and genetic variants, including variants in the nuclear DNA (nDNA) (Table 1). Additionally, the same genetic variant may have different clinical presentations depending on the level of tissue mutation load, a unique characteristic of mitochondrial disease. Within a cell, pathogenic mtDNA mutations are frequently mixed with normal mtDNA, a state known as heteroplasmy (Fig. 1). As the percentage of mutant mtDNA (mutant load) increases, the bioenergetic defect becomes increasingly severe, leading to a continuum of clinical presentations [1]. In this review, we provide an update on the ophthalmic presentations of mitochondrial disease and review their management, including extraocular manifestations, retinopathy, optic neuropathy, and visual dysfunction arising from dysfunction of the retrochiasmal visual pathways.

Table 1 Summary of classic mitochondrial diseases with ophthalmic manifestations.
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Fig. 1: Overview of mitochondrial DNA (mtDNA) and heteroplasmy.
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A. The mitochondrial genome encodes 13 protein subunits, two ribosomal RNAs (rRNAs), and 22 transfer RNAs (tRNAs), organised in a circular structure. The 13 protein subunits instruct the cell to produce the protein subunits of the enzyme complexes of the mitochondrial respiratory chain, which is comprised of five enzyme complexes (I-V) and two mobile electron carriers, coenzyme Q10 (CoQ) and cytochrome c (Cyt c). mtDNA variants in genes encoding the protein subunits of the mitochondrial respiratory chain, may cause biochemical abnormalities that interfere with oxidative phosphorylation, thereby precipitating a bioenergetic defect and mitochondrial failure. Nuclear-encoded proteins (not depicted) also play an integral role in the replication, maintenance, transcription, and translation of mtDNA and mtDNA-encoded proteins. Variants in these genes can result in disturbed mtDNA integrity; defects in mtDNA replication and maintenance; defects in mitochondrial fusion and fission; and defects in nucleotide synthesis and salvage. B. Each human cell contains thousands of copies of mtDNA and they are usually all identical (homoplasmy). Individuals with mitochondrial diseases resulting from mutations in the mtDNA may harbour a mixture of normal and mutated mtDNA within each cell (heteroplasmy). As mutant load increases, the bioenergetic defect caused by biochemical abnormalities of mitochondrial respiration becomes increasingly severe, leading to a continuum of clinical presentations. Panel A adapted from ‘Human mtDNA Sequence Map’ and ‘Electron Transport Chain’, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates (accessed 15 January 2022).

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Extraocular manifestations

Given the high energy demand of muscle tissue, extraocular muscle dysfunction is one of the major clinical manifestations of mitochondrial disease. First described by Von Graefe in 1868 [2], the syndrome of progressive external ophthalmoplegia (often termed ‘chronic progressive external ophthalmoplegia’ or CPEO) is a constellation of clinical findings relating to myopathy of the extraocular muscles, including bilateral ptosis and symmetrical reduction in ocular movements due to myopathy and, in later stages, to fibrotic restriction (Fig. 2). Affecting ~3.4 people per 100,000, CPEO can present on a spectrum between an isolated CPEO phenotype and disorders where CPEO is one feature of a multisystem syndrome—as a group termed CPEO ‘plus’ (Table 1) [3].

Fig. 2: Overview of the ophthalmic manifestations of mitochondrial disease.
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A Mitochondrial dysfunction can affect many parts of the eye, resulting in multiple ophthalmic manifestations, including abnormalities of the cornea, lens, ciliary body, retina, and optic nerve. However, classic presentations of primary mitochondrial diseases typically affect: (1) extraocular muscles, resulting in ptosis and ophthalmoplegia; (2) outer retina, resulting in retinal pigmentary changes or macular pattern dystrophy; (3) inner retina, resulting in loss of retinal ganglion cells and optic atrophy; and (4) cerebral cortex and/or white matter, resulting in visual field defects and disorders of higher visual processing. B Features of CPEO including bilateral ptosis due to reduced levator palpebrae superioris function and diffuse ophthalmoparesis. C Axial T2-weighted MRI brain of a patient with MELAS due to the m.3243A>G mutation in MT-TL1 and left homonymous hemianopia, demonstrating a discrete right medial occipital cortical lesion with associated oedema. Optos wide-field fundus imaging (pseudocolour imaging on the left and fundus autofluorescence on the right) of individuals (right eye only) carrying pathogenic SSBP1 variants (D), PDSS1 (E), MT-TL1 (F), and MT-ATP6 (G) variants. Pseudocolor imaging demonstrates various degrees of retinal vessels attenuation, pigmentary changes mainly localised in the mid-peripheral retina in SSBP1- and PDSS1-associated retinopathy and widespread pigmentary changes in MT-ATP6-associated retinopathy with various degrees of retinal atrophy observed in all affected individuals. Characteristic features of foveopathy is observed in SSBP1 case; retinitis pigmentosa features with retinal vessels attenuation, pigmentary (bone spicule) changes in mid-periphery are seen in PDSS1 case; and pattern dystrophy in MIDD case. Fundus autofluorescence image indicates areas of retinal atrophy with patches of decreased autofluorescence and demonstrates hypoautofluorescence corresponding to mid-peripheral pigmentary changes with a hyperautofluorescence ring at the macula delineating the border between normal and abnormal retina. H Fundus photographs of a patient with LHON due to the m.11778G>A mutation in MT-ND4 experiencing acute onset vision loss in the left eye initially, followed 2 months later by vision loss in the right eye. The right optic nerve appears oedematous with hyperaemia and peripapillary telangiectasia. The left optic nerve appears pale temporally with resolving disc oedema. I Fundus photographs of a patient with DOA due to a pathogenic variant in OPA1. Both optic discs show temporal pallor and OCT (not shown) demonstrated diffuse loss of peripapillary RNFL with some nasal sparing and diffuse thinning of the GC-IPL. CPEO: chronic progressive external ophthalmoplegia; DOA: dominant optic atrophy; GC-IPL: ganglion cell-inner plexiform layer; LHON: Leber hereditary optic neuropathy; MELAS: mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes; MRI: magnetic resonance imaging; OCT: optical coherence tomography; RNFL: retinal nerve fibre layer. A created with BioRender.com. B adapted from Jain, S. Simplifying Strabismus: A Practical Approach to Diagnosis and Management. Cham: Springer International Publishing; 2019. Images D–G courtesy of Professor Andrew R. Webster and Dr. Neringa Jurkute (Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom).

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The onset of CPEO is often insidious and while it can occur at any age, it is often seen in young adults (mean age 29 years) presenting with bilateral symmetrical ptosis as the result of poor function of the levator palpebrae superioris [3,4,5]. Classically, diplopia was not considered a presenting feature: the symmetrical nature of the extraocular myopathy and the ptosis itself (and in many patients a degree of visual suppression) preventing diplopia in the early stages. However, several case series have reported diplopia in up to 50% of cases, and early oculomotor changes can often be seen on examination including slowed saccades before any deviation becomes manifest [6, 7].

Clinical spectrum of Chronic Progressive External Ophthalmoplegia (CPEO)

Several syndromes include a CPEO presentation (Table 1)—perhaps the most notable CPEO plus syndrome was described by Kearns and Sayre [8], in which CPEO is accompanied by pigmentary retinopathy (discussed in Retinal Manifestations below), cardiac conduction defects, raised cerebrospinal fluid protein levels, and cerebellar ataxia [9]. With a prevalence of ~1.5 per 100,000 in one study [10], the Kearns Sayre Syndrome (KSS) generally presents in young adults and represents an intermediate phenotype along the spectrum of disease severity. At the more severe end of this spectrum lies the Pearson Syndrome, where large-scale mitochondrial DNA deletions lead to respiratory chain dysfunction manifesting with sideroblastic anaemia, exocrine pancreatic dysfunction, and myopathy among other features usually leading to death in infancy [11, 12]. In patients with the Pearson Syndrome who survive infancy, CPEO often develops together with pigmentary retinopathy and Leigh-like Syndrome (discussed in ‘Retinal Manifestations’ below) in early life.

This spectrum of severity is reflected in the genetic heterogeneity underlying CPEO. While around half of solved cases are sporadic, 50% are inherited either in an autosomal fashion or maternally (Table 1) [7]. Like many mitochondrial disorders, there can be great variability in the phenotypes of patients with the same genetic diagnoses, which are thought to relate to the level of mitochondrial heteroplasmy or exposure to environmental mitochondrial toxins [13, 14].

Extraocular manifestations—management

Whilst the clinical diagnosis is often not in doubt, several conditions (Table 2) can present with some features common to CPEO and these should be excluded by appropriate examination or investigation, especially if genetic testing for a genetic variant associated with CPEO is uninformative. Additionally, all patients with CPEO should undergo a dilated fundus examination to visualise retinal abnormalities that might suggest KSS. If KSS is suspected clinically, neurological assessment and additional investigations such as cardiac assessment and lumbar puncture should be considered.

Table 2 Differential diagnoses of Chronic Progressive External Ophthalmoplegia.
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Management of ptosis

Ptosis associated with CPEO can be challenging both for the patient (who may adopt an altered head position, have their visual axis obscured or be troubled by poor cosmesis) and the surgeon (with continued progression, absent Bell’s reflex and poor residual levator palpebrae superioris function (LPF)). In early disease, where there is residual LPF, surgical approaches to augment this muscle can be useful [15]. However, as muscle function becomes impaired with progression of the disease, suspensory approaches with fascia lata or, more often, silicone are indicated [4, 16, 17]. Conservative measures such as ptosis props and scleral contact lenses have a role and, while they may be poorly tolerated early in disease, they may have an adjunctive role when surgical options have been exhausted or are not appropriate [15].

Management of ophthalmoplegia

Symptomatic ophthalmoplegia is managed with a combination of conservative approaches, botulinum toxin, and surgical interventions. The progressive, symmetrical nature of ophthalmoplegia may necessitate a nuanced discussion with patients regarding the need for repeated interventions over their lifetime and patients should be carefully consented for the high likelihood of multiple procedures, and the need for adjuncts as the disease progresses.

While occlusion will resolve diplopia, Fresnel prisms can be useful in managing a varying deviation as they can be easily adjusted over time. Prisms can also be helpful for small residual angles, particularly as there is suggestion that CPEO patients can have narrower fusional amplitudes [18]. Botulinum toxin alone, although insufficient for the larger exodeviations seen in CPEO, may be particularly useful for residual angles that may develop post-surgically [19, 20].

Strabismus surgery for CPEO should be carefully planned and patients informed that the deviation will invariably return given the progressive nature of the underlying cytopathy. Forced duction testing can be very useful, as under-action and failure of ipsilateral antagonist muscles to relax can both lead to deviations. It has been suggested that muscle resection can be more effective than recession [21]. However, one larger case series has suggested near-maximal horizontal surgery using adjustable sutures to be the most effective [20].

Retinal manifestations

Although primary retinal ganglion cell (RGC) loss involving the inner retina and optic atrophy are classical manifestations of mitochondrial disease (discussed in ‘Optic Neuropathy’ below), outer retinal involvement is also observed as part of the phenotype of several syndromic central nervous system diseases caused by mtDNA mutations. Additionally, pathogenic defects in nDNA have also been identified to cause combined optic atrophy and retinal dystrophy [22]. In the outer retina, the photoreceptors, retinal pigment epithelium (RPE), and Müller cells contain large numbers of mitochondria, making these cell populations vulnerable to mitochondria dysfunction and oxidative damage [23]. The retina can be involved as part of the phenotype of several mitochondrial syndromes including KSS; Neuropathy, Ataxia, Retinitis Pigmentosa (NARP); Maternally Inherited Leigh Syndrome (MILS); and Maternally Inherited Diabetes and Deafness (MIDD) (discussed in more detail below) [22]. Historically, various terms have been used to describe the retinal manifestations of mitochondrial disease, including ‘pigmentary degeneration’ and ‘salt and pepper retinopathy’ [9, 24]. Identification of these classic mitochondrial retinopathies may help facilitate the clinical and molecular diagnosis of specific mitochondrial diseases.

A recent classification system, based on multimodal imaging findings from 23 patients with retinopathy and genetically-defined mitochondrial disease, identified three distinct phenotypes of mitochondrial retinopathy [25]. Sporadic single large-scale mtDNA deletions, such as those associated with CPEO, exhibited either mild, focal pigmentary abnormalities on ophthalmoscopy (Type 1 mitochondrial retinopathy; usually visually asymptomatic), or widespread granular fundus alterations on ophthalmoscopy and autofluorescence (Type 3 mitochondrial retinopathy; frequently associated with nyctalopia and severe widespread visual dysfunction). Type 2 mitochondrial retinopathy was usually associated with the m.3243A>G mutation in MT-TL1 (the most common disease-causing mtDNA mutation with a carrier rate of ~1 in 400 people) [26] and displayed a spectrum of manifestations including multifocal white-yellowish subretinal deposits and pigmentary changes (limited to the posterior pole) or chorioretinal atrophy with or without foveal involvement. Patients frequently reported problems in dim light and, if they had chorioretinal atrophy, severe central vision loss.

Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) and Maternally Inherited Leigh Syndrome (MILS)

NARP is a progressive neurodegenerative disease that presents clinically with the features in its name and other associated findings, including seizures, cognitive impairment, and developmental delay [27]. The characteristic ocular finding is a salt and pepper retinopathy that appears early in the disease course and eventually progresses to retinitis pigmentosa [28]. Other visual symptoms include nyctalopia and constriction of visual fields.

NARP is primarily caused by the m.8993T>G/C mutation in MT-ATP6, leading to complex V dysfunction and impaired ATP production [27, 29]. This particular mtDNA variant is also the most common one associated with MILS, a severe multisystem mitochondrial disorder characterised by encephalopathy, lactic acidosis, cardiomyopathy, and respiratory dysfunction [30]. In contrast to NARP, which generally presents in childhood, the first signs of MILS are seen in infancy [31]. The heteroplasmy level of the mutant mtDNA species is helpful in determining the phenotypic expression of the mtDNA variant, with a high mutation load (>90%) causing the more severe MILS phenotype and a mutation load 60–90% causing NARP [32, 33].

Maternally Inherited Diabetes and Deafness (MIDD)

First described by Van den Ouweland et al. [34], MIDD is a multisystem disorder characterised by maternally transmitted diabetes mellitus and sensorineural hearing deafness. Most cases of MIDD are due to the aforementioned m.3243A>G mutation in MT-TL1, encoding a mitochondrial transfer RNA. It should be noted that the m.3243A>G mutation is clinically heterogeneous and, depending on mutant load and tissue level, can present as MIDD; Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like episodes (MELAS); CPEO; an overlap syndrome; or with a clinical phenotype that does not fall within the criteria for currently recognised mitochondrial syndromes [26].

Most patients with MIDD remain visually asymptomatic with good visual acuity. Despite diabetes mellitus being a defining feature, the prevalence of diabetic retinopathy is lower than those with type 2 diabetes mellitus of similar duration [35, 36]. Instead, the majority of patients with MIDD exhibit a specific macular pattern dystrophy (mean age at detection 46.5 years, range 27–71 years) [35, 36], characterised by RPE hyperpigmentation that surrounds the macula or is more extensive and encompasses the optic disc [35, 37, 38]. A unique feature of the macular pattern dystrophy in MIDD, that may help to distinguish it from other maculopathies, is the finding of occult RPE disruption seen on autofluorescence imaging as a diffuse speckled pattern, extending beyond the macular abnormalities seen on ophthalmoscopy [38, 39]. Autofluorescence imaging has been suggested as a useful marker of disease progression [40, 41]. As the disease progresses, areas of speckled pigments on autofluorescence evolve into areas of atrophy, with relative sparing of the fovea until the advanced stages of the disease.

Multimodal imaging, in particular, OCT and wide-field autofluorescence, should be performed as subtle outer retinal changes of mitochondrial retinopathies may not be obvious on ophthalmoscopy. Visual electrophysiology testing including visually-evoked potentials, pattern electroretinogram and full-field electroretinogram should also be considered, especially in subclinical forms of mitochondrial retinopathies as they may help to localise the abnormality and detect outer retinal dysfunction while there are no structural changes observed.

Retinal manifestations—management

Although genotype-phenotype correlations are not always clear-cut, the specific pattern of retinal abnormalities may be helpful in guiding genetic testing and subsequent management. Macular pattern dystrophy in association with hearing loss are defining features of MIDD and this combination should prompt testing for the m.3243A>G mutation in MT-TL1. As the m.3243A>G mutation is associated with both MIDD and MELAS, patients with this mutation should be referred for multidisciplinary investigations to identify other organ involvement, including sensorineural hearing loss, diabetes, cardiac conduction defects and kidney disease.

There are currently no specific pharmacological treatments for mitochondrial retinopathies. Those with advanced disease involving the fovea or with chorioretinal atrophy may benefit from supportive management, such as visual impairment registration and referral to a low vision clinic.

Optic neuropathies

Inherited optic neuropathies (IONs) are characterised by bilateral and progressive degeneration of the optic nerve secondary to a genetic variant which invariably affects mitochondrial function [42]. Clinically, they are characterised by loss of visual acuity/field and colour vision caused by RGC loss. The archetypical ION is an isolated bilateral optic neuropathy as seen in Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA). However, many IONs can present as part of a systemic syndrome such as Wolfram syndrome, where the optic atrophy is accompanied by diabetes insipidus, diabetes mellitus and sensorineural hearing loss. Furthermore, a subgroup of LHON and DOA can sometimes present with extraocular features referred to as LHON “plus” and DOA “plus”, respectively. It should be stressed, however, that establishing causation between these extraocular features and the underlying mtDNA or nDNA genetic variant is not always straightforward.

Leber Hereditary Optic Neuropathy (LHON)

Considered the prototype of mitochondrial disease, LHON is an important cause of inherited mitochondrial blindness, affecting ~ 1 in 30,000 individuals [43]. In most affected individuals (peak age 15–35 years), painless bilateral sequential vision loss is the only symptom of LHON, with an inter-eye delay of weeks to months. Visual acuity declines rapidly to 20/200 or less, reaching a nadir ~ 4–6 weeks after onset. Long-term visual prognosis is generally poor for most patients with visual acuity worse than 20/400 [44].

Three primary mtDNA point mutations (m.3460G>A in MT-ND1, m.11778G>A in MT-ND4 and m.14484T>C in MT-ND6) account for ∼ 90% of LHON cases globally [42]. These three mutations all involve genes encoding subunits of complex I, the first enzyme of the mitochondrial respiratory chain. In LHON, defective mitochondrial oxidative phosphorylation precipitates a bioenergetic crisis and elevated levels of reactive oxygen species (ROS), leading to RGC dysfunction and release of signalling factors that trigger cellular apoptosis [23]. The m.14484T>C mtDNA variant and onset of LHON before the age of 12 (childhood LHON) are associated with a relatively more favourable visual prognosis [45].

Not all individuals who carry a genetic mutation associated with LHON will experience visual loss. The penetrance of LHON has often be reported as being ~50% among male carriers and ~10% among female carriers, highlighting the marked sex bias. However, in a recent national Australian cohort, the penetrance of LHON was reported to be lower at 17.5% for male carriers and 5.4% for female carriers [46]. These differences could reflect other genetic and environmental influences with the latter possibly having changed over time e.g. smoking habits. This incomplete penetrance is not fully explained by mitochondrial heteroplasmy, as most LHON carriers are homoplasmic. External metabolic stressors, such as smoking, excessive alcohol consumption and certain toxins, have been identified as contributory factors leading to disease conversion [47]. Hormonal influences are also thought to modulate the risk of visual loss with oestrogens being protective for female LHON carriers [48, 49].

Dominant Optic Atrophy (DOA)

DOA is the most common ION with an estimated minimum prevalence of 1 in 25,000 [50]. Visual loss typically presents in the first two decades of life with the majority of patients declining steadily over time to reach the criteria for registration as visually impaired. OPA1 (3q21) is thought to be the causative gene in over 60–70% of DOA cases [51]. Over 450 pathogenic variants of OPA1 have been described with missense variants and variants located in the GTPase/dynamin domain associated with a worse ocular phenotype and a higher probability of DOA ‘plus’ [78].

Retrochiasmal vision loss—management

Managing the retrochiasmal manifestations of mitochondrial diseases is challenging. There are currently no licensed disease-modifying treatments. Medications that have been trialled to prevent or treat stroke-like episodes in MELAS include coenzyme-Q10, L-arginine, L-carnitine and high-dose taurine supplementation [79]. Treatment for MELAS is generally supportive and may include referral to low vision service for those with visual impairment; cochlear implantation for those with sensorineural hearing loss; anticonvulsant therapy for seizure prevention (avoiding sodium valproate), and screening for other organ involvement including cardiac conduction defects, diabetes, kidney disease, and other ocular manifestations.

Conclusion

Due to their predilection for metabolically active tissues, the eye is involved in over half of all patients with mitochondrial disease; affecting the extraocular muscles, retina and optic nerves. Although often considered as rare diseases with little or no effective treatments, significant progress has been made in the development of gene therapy and gene editing platforms, in particular for patients with mitochondrial optic neuropathies. A paradigm shift in therapy for mitochondrial disorders is underway and this must be reflected in a dramatic alternation in our clinical management of these patients: early and accurate molecular diagnosis must be the standard of care for these patients. In order to have access to nascent gene therapies and the exciting range of therapeutic trials underway in this traditionally underserved area of ophthalmology, patients need timely, expert neuro-ophthalmological evaluation and genetic testing.

Summary

  • Ophthalmic manifestations of mitochondrial disease include, but are not limited to, progressive external ophthalmoplegia, retinopathy, optic neuropathy, and deficiencies of the retrochiasmal visual pathways.

  • Although traditionally recognised by ‘classic’ presentations, genotype–phenotype correlations in mitochondrial disease are imprecise; all patients should have genetic testing even if the presentation is not ‘classic’.

  • Recent advancements in the development of gene therapy and gene editing techniques for mitochondrial diseases underscore the importance of timely neuro-ophthalmological evaluation and genetic testing.