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

P Yu-Wai-Man,M Votruba,P F Chinnery,A T Moore

doi:10.1038/eye.2014.37

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.

Highlights

Hereditary optic nerve disorders result in significant chronic visual morbidity, and the minimum prevalence of affected individuals in the population has been estimated at 1 in 10 000.1 Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA) are the two classical paradigms for this group of disorders, and they account for most of the inherited optic atrophy cases seen in clinical practice
LHON is caused by mitochondrial DNA point mutations, whereas, in DOA, the majority of cases are due to pathogenic mutations in the OPA1 gene, which codes for an inner mitochondrial membrane protein.[1,2]
The ability to rescue retinal ganglion cell (RGC) and improve visual function was subsequently confirmed in vivo by two independent research groups working on LHON rodent models expressing mutated ND4 (m.11778G4A) complex I subunits.[85,86]

Summary

Introduction

Hereditary optic nerve disorders result in significant chronic visual morbidity, and the minimum prevalence of affected individuals in the population has been estimated at 1 in 10 000.1 Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA) are the two classical paradigms for this group of disorders, and they account for most of the inherited optic atrophy cases seen in clinical practice. Mitochondria have limited autonomy and they rely heavily on the nuclear genome for the vast majority of proteins required for mtDNA replication, transcription, and translation.[4,5] In 1988, two seminal papers were published linking for the first time specific mtDNA mutations with human disease: large-scale single mtDNA deletions in patients with mitochondrial myopathies and the m.11778G4A point mutation in families with LHON.[8,9] Families segregating classical mitochondrial phenotypes in a clear-cut Mendelian pattern of inheritance were subsequently reported, and the existence of nuclear genetic defects disrupting mitochondrial proteins was widely suspected This hypothesis was confirmed in 2001, when mutations in the nuclear genes, POLG and PEO1, were identified in families with autosomal dominant chronic progressive external ophthalmoplegia (CPEO).[10] The pathological hallmark of all these nuclear mitochondrial disorders is mtDNA instability, which can be quantitative in nature with a reduction in mtDNA copy number (depletion) or qualitative with the accumulation of high levels of somatic mtDNA mutations (predominantly deletions) in affected tissues. Visual recovery is usually heralded by the appearance of small islands of vision in the central visual field and, as the scotoma

29 T N 58 Quadrants 56 N T 40

Findings

Conclusion