Mitochondria and the eye-manifestations of mitochondrial diseases and their management

Abstract

Historically, distinct mitochondrial syndromes were recognised clinically by their ocular features. Due to their predilection for metabolically active tissue, mitochondrial diseases frequently involve the eye, resulting in a range of ophthalmic manifestations including progressive external ophthalmoplegia, retinopathy and optic neuropathy, as well as deficiencies of the retrochiasmal visual pathway. With the wider availability of genetic testing in clinical practice, it is now recognised that genotype-phenotype correlations in mitochondrial diseases can be imprecise: many classic syndromes can be associated with multiple genes and genetic variants, and the same genetic variant can have multiple clinical presentations, including subclinical ophthalmic manifestations in individuals who are otherwise asymptomatic. Previously considered rare diseases with no effective treatments, considerable progress has been made in our understanding of mitochondrial diseases with new therapies emerging, in particular, gene therapy for inherited optic neuropathies.

Fig. 1. Overview of mitochondrial DNA (mtDNA) and heteroplasmy.

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).

Fig. 2. Overview of the ophthalmic manifestations of mitochondrial disease.

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).