Hereditary Optic Neuropathy

Inherited disorders causing degeneration of retinal ganglion cells and optic nerve axons, with progressive bilateral visual loss. Prevalence about 1 in 10,000 to 1 in 12,000 for the two commonest forms.

• Leber hereditary optic neuropathy: maternally inherited mitochondrial DNA point mutations affecting complex I (11778 in about 70 percent, 3460 in 15 percent, 14484 in 10 percent). Males are affected more than females (about 80 to 90 percent of visual loss in males), with onset typically at 15 to 35 years. Incomplete penetrance (males about 50 percent, females about 10 percent) and triggers include smoking, alcohol, and toxins.
• Dominant optic atrophy: autosomal dominant mutations of OPA1 (mitochondrial fusion), onset in the first decade, slowly progressive.
• Others: Wolfram syndrome (WFS1: diabetes insipidus, diabetes mellitus, optic atrophy, deafness), OPA3 (Costeff syndrome), Behr syndrome, hereditary spastic paraplegia with optic atrophy, and OPA1-plus phenotypes.

• Leber hereditary optic neuropathy: acute or subacute, painless central visual loss in one eye, followed by the fellow eye within weeks to months (median 2 to 3 months, bilateral at presentation in 25 percent); central or cecocentral scotomas; dyschromatopsia; acuity usually falls below 6/60. Acute phase: hyperaemic disc, peripapillary telangiectatic microangiopathy, vascular tortuosity, swelling of the nerve fibre layer without fluorescein leakage (pseudo-oedema); later temporal pallor and optic atrophy. Spontaneous partial recovery in 14484 mutation (up to 50 to 60 percent), 3460 (about 20 percent), and 11778 (about 4 percent). Associated cardiac conduction defects (pre-excitation) and neurological features (multiple-sclerosis-like illness) in some.
• Dominant optic atrophy: insidious bilateral visual loss in childhood with mild to moderate acuity loss (6/12 to 6/60), temporal pallor with a triangular excavation of the disc, central or cecocentral scotoma, and blue-yellow colour defect (tritanopia); deafness and ophthalmoplegia in plus forms.
• Wolfram syndrome: childhood diabetes mellitus, optic atrophy, diabetes insipidus, sensorineural deafness, urinary tract dilation, and psychiatric symptoms.

• Detailed pedigree (maternal transmission for Leber), exposure history (tobacco, alcohol, drugs), visual acuity, colour vision, central fields (cecocentral scotoma), pupils, dilated fundus examination, and optical coherence tomography (thickened nerve fibre layer in the acute phase, then thinning of the papillomacular bundle).
• Molecular genetic testing: a mitochondrial panel for the three common mutations (blood), then full mitochondrial genome sequencing when negative; OPA1 sequencing and deletion analysis; WFS1 testing.
• Visual evoked potentials (delayed or reduced amplitude) and electroretinogram (normal, excludes retinal disease).
• MRI of the brain and orbits with contrast to exclude compressive, inflammatory and demyelinating causes (including aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies), and ECG for conduction defects.
• Screening for diabetes and hearing for Wolfram syndrome, and for associated systemic features of mitochondrial disease.

• Counselling and avoidance: stop smoking, avoid heavy alcohol intake, avoid mitochondrial toxins (ethambutol, linezolid, chloramphenicol, aminoglycosides, antiretrovirals such as zidovudine, amiodarone), and treat head injury and nutritional deficiency.
• Idebenone (short-chain quinone analogue of coenzyme Q10): 900 mg daily (300 mg three times daily with food) for Leber hereditary optic neuropathy, started as soon as possible and continued for at least 12 months (benefit is greater in patients treated within 12 months of onset; improves colour vision and visual recovery). Monitor liver function.
• Gene therapy: intravitreal lenadogene nolparvovec (ND4 gene, 9 x 10^10 genomes per eye) for the 11778 mutation, available in some regions.
• Cardiology review (ECG) for pre-excitation, and neurology review for associated neurological disease.
• Dominant optic atrophy: no proven treatment; supportive care, avoidance of toxins, regular review, and genetic counselling.
• Wolfram syndrome: insulin for diabetes, desmopressin for diabetes insipidus, hearing aids or cochlear implants, urological care, and multidisciplinary follow-up.
• Low-vision rehabilitation, school and workplace adaptations, certification and registration of visual impairment, and psychological support.
• Genetic counselling: maternal relatives are at risk (all children of an affected mother carry the mutation; sons about 40 to 50 percent develop disease and daughters about 10 to 15 percent); reproductive options.
• Follow-up every 6 to 12 months and sooner for new symptoms.