Treatment strategies for inherited optic neuropathies: past, present and future

Abstract

Bilateral visual loss secondary to inherited optic neuropathies is an important cause of registrable blindness among children and young adults. The two prototypal disorders seen in clinical practice are Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). About 90% of LHON cases are due to one of three mitochondrial DNA (mtDNA) point mutations: m.3460G>A, m.11778G>A, and m.14484T>C, which affect critical complex I subunits of the mitochondrial respiratory chain. The majority of patients with DOA harbour pathogenic mutations within OPA1, a nuclear gene that codes for a multifunctional inner mitochondrial membrane protein. Despite their contrasting genetic basis, LHON and DOA share overlapping pathological and clinical features that serve to highlight the striking tissue-specific vulnerability of the retinal ganglion cell (RGC) layer to disturbed mitochondrial function. In addition to severe visual loss secondary to progressive optic nerve degeneration, a subgroup of patients will also develop a more aggressive syndromic phenotype marked by significant neurological deficits. The management of LHON and DOA remains largely supportive, but major advances in our understanding of the mechanisms underpinning RGC loss in these two disorders are paving the way for novel forms of treatment aimed at halting or reversing visual deterioration at different stages of the disease process. In addition to neuroprotective strategies for rescuing RGCs from irreversible cell death, innovative in vitro fertilisation techniques are providing the tantalising prospect of preventing the germline transmission of pathogenic mtDNA mutations, eradicating in so doing the risk of disease in future generations.

Figure 1

The prevalence of inherited optic neuropathies in the North of the United Kingdom. *Includes patients with LHON and DOA.

Figure 2

(a) Fundal abnormalities in Leber hereditary optic neuropathy. This m.11778G>A male carrier experienced visual loss in his right eye initially, followed 8 months later by his left eye. The fundus pictures were taken 1 month after the left eye had become affected. Best-corrected visual acuities at that point were counting fingers in the right eye and 6/36 in the left eye. There is temporal pallor of the right optic disc, whereas the left optic disc is still hyperaemic consistent with the more recent disease onset. Vascular tortuosity of the central retinal vessels can also be observed in both eyes. L, left eye; R, right eye; T, temporal papillomacular bundle. (b) Pattern of retinal ganglion cell loss in autosomal dominant optic atrophy. The patient harbours a pathogenic OPA1 nonsense mutation within exon 27 (c.2713C>T, p.R905X). Pallor of the optic nerve head is more pronounced temporally and optical coherence tomography (OCT) imaging shows relative sparing of the nasal peripapillary retinal nerve fibre layer (RNFL). OCT measurements were obtained with the spectral-domain Cirrus platform (Carl Zeiss Meditec, Dublin, CA, USA). In addition to the average thickness, RNFL values are shown for each individual quadrant and each clock hour. The analysis software automatically selects the appropriate age-corrected normative range for the patient, and the RNFL measurements (dark traces) are represented within colour-coded distribution centiles: (i) red<1%, (ii) yellow 1–5%, and (iii) green 5–95%.