Electrodiagnostic tests of the visual pathway and applications in neuro-ophthalmology.

This article describes the main visual electrodiagnostic tests relevant to neuro-ophthalmology practice, including the visual evoked potential (VEP), and the full-field, pattern and multifocal electroretinograms (ffERG; PERG; mfERG). The principles of electrophysiological interpretation are illustrated with reference to acquired and inherited optic neuropathies, and retinal disorders that may masquerade as optic neuropathy, including ffERG and PERG findings in cone and macular dystrophies, paraneoplastic and vascular retinopathies. Complementary VEP and PERG recordings are illustrated in demyelinating, ischaemic, nutritional (B12), and toxic (mercury, cobalt, and ethambutol-related) optic neuropathies and inherited disorders affecting mitochondrial function such as Leber hereditary optic neuropathy and dominant optic atrophy. The value of comprehensive electrophysiological phenotyping in syndromic diseases is highlighted in cases of SSBP1-related disease and ROSAH (Retinal dystrophy, Optic nerve oedema, Splenomegaly, Anhidrosis and Headache). The review highlights the value of different electrophysiological techniques, for the purposes of differential diagnosis and objective functional phenotyping.

Dominant ACO2 mutations are a frequent cause of isolated optic atrophy.

Biallelic mutations in ACO2, encoding the mitochondrial aconitase 2, have been identified in individuals with neurodegenerative syndromes, including infantile cerebellar retinal degeneration and recessive optic neuropathies (locus OPA9). By screening European cohorts of individuals with genetically unsolved inherited optic neuropathies, we identified 61 cases harbouring variants in ACO2, among whom 50 carried dominant mutations, emphasizing for the first time the important contribution of ACO2 monoallelic pathogenic variants to dominant optic atrophy. Analysis of the ophthalmological and clinical data revealed that recessive cases are affected more severely than dominant cases, while not significantly earlier. In addition, 27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy. In silico analyses of ACO2 variants predicted their deleterious impacts on ACO2 biophysical properties. Skin derived fibroblasts from patients harbouring dominant and recessive ACO2 mutations revealed a reduction of ACO2 abundance and enzymatic activity, and the impairment of the mitochondrial respiration using citrate and pyruvate as substrates, while the addition of other Krebs cycle intermediates restored a normal respiration, suggesting a possible short-cut adaptation of the tricarboxylic citric acid cycle. Analysis of the mitochondrial genome abundance disclosed a significant reduction of the mitochondrial DNA amount in all ACO2 fibroblasts. Overall, our data position ACO2 as the third most frequently mutated gene in autosomal inherited optic neuropathies, after OPA1 and WFS1, and emphasize the crucial involvement of the first steps of the Krebs cycle in the maintenance and survival of retinal ganglion cells.

Electrophysiology in neuro-ophthalmology.

This chapter reviews common applications of visual electrophysiology relevant to neuro-ophthalmology practice. The use of standard tests and extended protocols are described including the cortical visual evoked potential and pattern and full-field electroretinogram (PERG; ERG) methods, the latter including the photopic negative response. Abnormalities of these recordings are rarely specific but provide valuable diagnostic guidance and an objective measure of visual pathway function, difficult or impossible to infer by other methods. The electrophysiological phenotypes associated with Leber hereditary optic neuropathy, OPA1- and SSBP1-associated dominant optic atrophy, and WFS1-related syndromes are described. Typical changes in retinal and optic nerve function tests associated with acquired disease are highlighted, including those related to demyelination, ischemic, compressive, nutritional and toxic, and nonorganic etiologies. The importance of complementary testing using different electrophysiological techniques is emphasized, for the purposes of differential diagnosis and in disorders that may masquerade as optic nerve pathology.

Leber Hereditary Optic Neuropathy-Light at the End of the Tunnel?

Leber hereditary optic neuropathy (LHON) is an important cause of mitochondrial blindness. The majority of patients harbor one of three mitochondrial DNA (mtDNA) point mutations, m.3460G>A, m.11778G>A, and m.14484T>C, which all affect complex I subunits of the mitochondrial respiratory chain. The loss of retinal ganglion cells in LHON is thought to arise from a combination of impaired mitochondrial oxidative phosphorylation resulting in decreased adenosine triphosphate (ATP) production and increased levels of reactive oxygen species. Treatment options for LHON remain limited, but major advances in mitochondrial neuroprotection, gene therapy, and the prevention of transmission of pathogenic mtDNA mutations will hopefully translate into tangible benefits for patients affected by this condition and their families.

Leber hereditary optic neuropathy: bridging the translational gap.

PURPOSE OF REVIEW: Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) genetic disorder in the population. We address the clinical evolution of the disease, the secondary etiological factors that could contribute to visual loss, and the challenging task of developing effective treatments. RECENT FINDINGS: LHON is characterized by a preclinical phase that reflects retinal ganglion cell (RGC) dysfunction before rapid visual deterioration ensues. Children can present atypically with slowly progressive visual loss or an insidious/subclinical onset that frequently results in considerable diagnostic delays. The LHON mtDNA mutation is not sufficient on its own to precipitate RGC loss and the current body of evidence supports a role for smoking and estrogen levels influencing disease conversion. Clinical trials are currently investigating the efficacy of adeno-associated viral vectors-based gene therapy approaches for patients carrying the m.11778G>A mutation. Mitochondrial replacement therapy is being developed as a reproductive option to prevent the maternal transmission of pathogenic mtDNA mutations. SUMMARY: LHON is phenotypically more heterogeneous than previously considered and a complex interplay of genetic, environmental and hormonal factors modulates the risk of a LHON carrier losing vision. Advances in disease modelling, drug screening and genetic engineering offer promising avenues for therapeutic breakthroughs in LHON.