Leber hereditary optic neuropathy (LHON)

LHON manifests as bilateral, painless, subacute central visual loss. Peak onset is in the second and third decades, and 95% of those who lose vision do so before age 50. Blurring begins in the central field of one eye; the fellow eye follows within weeks to months, with at least 97% bilateral within one year, and in 25% to 50% the loss is bilateral at onset. An enlarging central or centrocaecal scotoma is the characteristic field defect, with acuity deteriorating to counting fingers or worse. Optic atrophy follows, typically within six weeks, together with marked retinal nerve fibre layer thinning.

Visual recovery is usually incomplete and varies by variant: reported in 14% with m.11778G>A, 15% to 25% with m.3460G>A and 37% to 64% with m.14484T>C, although the ranges reflect differing definitions of recovery and m.3460G>A is regarded as carrying the worst outcome. Most affected individuals remain severely visually impaired, with a lasting effect on everyday functioning and quality of life. Postural tremor, peripheral neuropathy, non-specific myopathy, movement disorders and a multiple-sclerosis-like illness have also been reported.

Northern European surveys reported disease prevalence of 1 in 31,000 in north-east England, 1 in 39,000 in the Netherlands and 1 in 50,000 in Finland. A registry-based Spanish study, which ascertained diagnosed cases rather than surveying a population, gives a correspondingly lower 0.55 per 100,000 inhabitants, or 0.79 after capture-recapture correction.

The proportion carrying a pathogenic variant is far higher than the proportion who lose vision: in the same north-east England survey, 1 in 8,500 carried a primary LHON variant while 1 in 31,000 had lost vision. This gap reflects the markedly incomplete penetrance described below.

LHON is caused by pathogenic variants in mitochondrial DNA. The three primary variants affect subunits of complex I of the respiratory chain: m.11778G>A in MT-ND4, accounting for 60% to 70% of cases in northern European populations, m.14484T>C in MT-ND6, and m.3460G>A in MT-ND1; together they account for approximately 90% of affected individuals. Rarer variants occur in further complex I subunit genes, among them MT-ND2, MT-ND3, MT-ND4L and MT-ND5, and beyond complex I in MT-ATP6, MT-CO3 and MT-CYB. At the cellular level, impaired oxidative phosphorylation and increased reactive oxygen species trigger apoptotic death of retinal ganglion cells.

This panel analyses the complete mitochondrial genome, that is all 37 mitochondrial genes, so that rare and secondary variants outside the three primary positions are also detected.

Variants are typically homoplasmic but show markedly incomplete penetrance: the lifetime risk of visual loss is approximately 32% to 51% in male carriers and 8% to 28% in female carriers, depending on the variant, and males are four to five times more frequently affected. The mother usually carries the variant herself, whether or not she has lost vision; up to 40% of affected individuals have no known family history, so an unremarkable family history does not argue against the diagnosis, while in about 60% of families, visual loss among maternal relatives is known. The factors underlying reduced penetrance are only partly understood; tobacco smoking and heavy alcohol consumption are recognised triggers of manifestation.

LHON shows mitochondrial, that is matrilineal, inheritance. A female carrying a pathogenic mitochondrial DNA variant transmits it to all of her offspring; affected or carrier males do not transmit it.

Heteroplasmy, a mixture of mutated and wild type mitochondrial DNA, is present in about 10% to 15% of individuals with LHON. It does not compromise detection, because affected individuals generally carry more than 70% mutated mitochondrial DNA in leukocytes, but a heteroplasmic mother may transmit a lower mutant load and a correspondingly lower risk. Because penetrance is incomplete and sex-biased, carrier status must be distinguished from disease status in counselling.

The diagnosis is established by molecular genetic testing. No consensus clinical criteria exist: the characteristic picture raises suspicion, but molecular confirmation establishes the diagnosis. In the great majority the causative variant lies in mitochondrial DNA and is detected by this panel. A minority carry biallelic variants in nuclear genes, causing autosomal recessive LHON; these are not detected by this panel and require separate nuclear gene analysis. Optical coherence tomography of the retinal nerve fibre layer and visual field-testing document the stage and extent of involvement.

Main differential diagnoses include:

• Autosomal recessive LHON (arLHON), not covered by this panel: a clinical picture indistinguishable from mitochondrial LHON, caused by biallelic variants in nuclear genes encoding complex I subunits and assembly factors, among them DNAJC30, NDUFS2, NDUFA12 and MCAT. These lie in the nuclear genome and are not analysed here: a normal mitochondrial result does not exclude LHON. Where suspicion persists, particularly with consanguinity or affected siblings without maternal transmission, nuclear gene analysis should follow; DNAJC30, NDUFA12 and MCAT are covered by our optic atrophy panel. Inheritance is autosomal recessive, so the sibling recurrence risk is 25% and counselling differs fundamentally from the matrilineal pattern.
• Autosomal dominant (DOA): insidious bilateral central visual loss, usually from childhood or early adulthood, with slower progression and temporal optic disc pallor; OPA1, autosomal dominant. Not on this panel, but on our panel.
• Demyelinating optic neuritis, including multiple-sclerosis-associated forms: usually unilateral and painful with substantial spontaneous recovery, unlike the bilateral painless loss of LHON; periventricular demyelination on MRI and unmatched oligoclonal bands in cerebrospinal fluid. A demyelinating picture does not exclude LHON, since some affected individuals, usually women, develop a multiple-sclerosis-like illness.
• Toxic and nutritional optic neuropathy: bilateral painless centrocaecal loss attributable to tobacco, alcohol, methanol or ethambutol, or to vitamin B12 or folate deficiency; often reversible once the cause is removed or the deficiency corrected.

• Genetic testing establishes the diagnosis by identifying the causative mitochondrial variant and provides the basis for genetic counselling. A confirmed result supports condition-specific management and surveillance, and identifies the variant on which therapeutic eligibility depends.
• Once the familial variant is known, maternal relatives can clarify their carrier status within genetic counselling, taking into account the incomplete and sex-biased penetrance.

• Yu-Wai-Man P, Chinnery PF. Leber hereditary optic neuropathy. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: .
• Moster ML, Sergott RC, Newman NJ, Yu-Wai-Man P, Carelli V, Bryan MS, et al. Cross-sectional analysis of baseline visual parameters in subjects recruited into the RESCUE and REVERSE ND4-LHON gene therapy studies. J Neuroophthalmol. 2021;41(3):298-308. PMID: .
• Bušányová B, Vajter M, Kelifová S, Lišková P, Miková H, Breciková K, et al. Leber hereditary optic neuropathy in Czechia and Slovakia: quality of life and costs from patient perspective. Heliyon. 2024;10(11). PMID: .
• Esmaeil A, Ali A, Behbehani R. Leber’s hereditary optic neuropathy: update on current diagnosis and treatment. Front Ophthalmol. 2022;2:1077395. PMID: .
• Esteban-Vasallo MD, Domínguez-Berjón MF, Chalco-Orrego JP, González Martín-Moro J. Prevalence of Leber hereditary optic neuropathy in the Community of Madrid (Spain), estimation with a capture-recapture method. Orphanet J Rare Dis. 2024;19(1):220. PMID: .
• Lenaers G, Beaulieu C, Charif M, Gerber S, Kaplan J, Rozet JM. Autosomal recessive Leber hereditary optic neuropathy, a new neuro-ophthalmo-genetic paradigm. Brain. 2023;146(8):3156-3161. PMID: .
• Carelli V, Carbonelli M, de Coo IF, Kawasaki A, Klopstock T, Lagrèze WA, et al. International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy. J Neuroophthalmol. 2017;37(4):371-381. PMID: .