GENEWISE: #35 Case Study: Leber's Hereditary Optic Neuropathy (LHON)

Leber hereditary optic neuropathy (LHON) is a rare mitochondrial disorder that typically affects young males with progressive visual loss due to optic neuropathy.

LHON was the first disease to be associated with mitochondrial DNA (mtDNA) point mutations and is, maternally inherited.

Whereas both the father and the mother contribute to the nuclear portion of the zygote, the mother's ovum is virtually the sole provider of the zygote's cytoplasmic contents which contains several hundred intracytoplasmic mitochondria. “Maternal inheritance” refers to the transmission of the mitochondrial genome from a mother to all her children, with no paternal (father’s) mtDNA contribution.

The mitochondria generate the cellular energy necessary for normal cellular function and maintenance thus those cells in tissues particularly reliant on mitochondrial energy production, such as the central nervous system, including the optic nerve, retinal pigment epithelium, and extraocular muscles contain more mitochondria. If a new mutation occurs in the mtDNA and the proportion of mutant mtDNA exceeds a certain tissue-specific threshold, however, the wild type mtDNA is no longer able to compensate to sustain normal cellular function, and the disease phenotype is expressed.

Other genetic factors may influence the phenotypic expression of LHON such as nuclear genes that regulate the expression of mitochondrial genes.

There could be differential diagnoses that include other optic neuropathies such as demyelinating optic neuritis, Neuromyelitis optica spectrum disease, Toxic optic neuropathy or Compressive optic neuropathy to consider in the diagnostic process.

Incidence:

Males are predominantly affected but the disorder may also be seen in females, though rarely (males-to-female ratio = 3:1). While the exact prevalence of LHON is not known, it was estimated to be 13.57 per 10,000 patients or 1:737 in a south Indian and 1 in 50,000 in a study group from northeast England.

Inheritance:

• All Mitochondria in an offspring are inherited from the mother.
• All offspring of an affected or carrier female are at risk of being affected.
• All daughters of an affected or carrier female are at risk of transmitting the condition.
• Affected males cannot pass the condition to any of their children.

Patient clinical history:

A 48 years old male, presented with progressive optic neuropathy (B/L) since 4 months. He was diagnosed with hypertension in September 2023. He had no past history of diabetes, thyroid disorders, Tuberculosis, or any other chronic illness. There was no other central nervous system deficit. Fundoscopy showed bilateral optic atrophy, Nerve Conduction Studies performed were suggestive of axonal symmetrical polyneuropathy, MRI brain revealed bilateral intraorbital optic nerve thinning, and BERA study was normal.

A suspicion of LHON needed to be ruled out / confirmed.

Family history and Pedigree:

There is no history of similar complaints in the family.

Mitochondrial genome sequencing and whole exome sequencing was performed:

• Mitochondrial sequencing reported a pathogenic variant in the MT-ND4 gene, confirming the diagnosis of LHON.
• Exome sequencing reported a heterozygous variant of uncertain significance in the ACO2 gene which corresponds with Optic Atrophy 9.

Discussion and Conclusion:

• Given the clinical indication, mitochondrial genome testing was performed and revealed a pathogenic variant in MT-ND4 which confirmed the diagnosis of Leber’s Congenital Optic Neuropathy.
• The maximum cases of LHON arise due to a pathogenic variant in?MT-ND4 (m.11778G>A).
• The proband was also found to have a missense variant in ACO2 gene which corresponds to the OMIM diagnosis of Optic Atrophy, 9. The reported variant is classified as a variant of uncertain significance (VUS) according to ACMG/AMP guidelines.
• Variations in a genetic sequence are classified as variants of uncertain significance (VUS) when the association with disease risk and the significance to function are unclear. These VUS are usually missense, silent, intronic variants, or in-frame deletions and insertions. They have an unknown effect on protein function based on current information.
• Segregation analysis of a variant of uncertain significance, i.e. testing for the same variant in the parents of the proband, confers the penetrance and susceptibility of a variant in a specific disease to establish a pathogenicity associated with the phenotype.

Management for LHON:

• As with the majority of mitochondrial disorders, the therapeutic options for LHON remain only supportive.
• It is essential to counsel patients about the deleterious effects of smoking, the consumption of large amounts of alcohol, and certain medications and toxins that can adversely affect mitochondrial function.
• Furthermore, low-vision rehabilitation and visual aids can be an option in patients with intact peripheral vision. Younger patients with the onset of disease at the age of less than 20 years have been reported to have a better visual prognosis.
• Idebenone, a ubiquinone analogue, has been found to be beneficial in promoting vision recovery in LHON patients, particularly in the early stages of the disease and in younger patients. However, treatment options must be carefully discussed with the treating physician.
• If a primary LHON variant is detected in the family, screening of other family members is advised to exclude the possibility of a de-novo variant.
• Given that LHON is maternally inherited, all males should be reassured that none of their offspring will inherit the mutation.
• Homoplasmic females, however, will pass on the mutation to all their offspring. In heteroplasmic mothers, however, varying levels of variant mtDNA is transferred to the offspring with approximately 60% variant mtDNA required as the threshold for disease manifestation.
• Children of homoplasmic mothers need to be aware that the penetrance of LHON is variable, and not all carriers develop the disease.?

Kindly note that the above information is only for the family to help understand the condition and may help make, informed healthcare decisions. Any / All final testing/ treatment/management decisions must be discussed and formulated with the primary treating physician.

References:

1.?Hage R, Vignal-Clermont C. Leber Hereditary Optic Neuropathy: Review of Treatment and Management. Front Neurol. 2021 May 26;12:651639. doi: 10.3389/fneur.2021.651639. PMID: 34122299; PMCID: PMC8187781.

2.?Esmaeil Ali, Ali Ali, Behbehani Raed, Leber’s hereditary optic neuropathy: Update on current diagnosis and treatment. Front. Ophthalmol., 11 January 2023, Volume 2 - 2022 |?https://doi.org/10.3389/fopht.2022.1077395

3.?Shemesh A, Sood G, Margolin E. Leber Hereditary Optic Neuropathy (LHON) [Updated 2022 Sep 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.?Available from: https://www.ncbi.nlm.nih.gov/books/NBK482499/

4.Yu-Wai-Man P, Chinnery PF. Leber Hereditary Optic Neuropathy. 2000 Oct 26 [Updated 2021 Mar 11]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews? [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.?Available from: https://www.ncbi.nlm.nih.gov/books/NBK1174/