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Leber hereditary optic neuropathy
LHON is a mitochondrial genetic condition leading to progressive loss of central vision, most commonly affecting young adult males. It is caused by specific changes in mitochondrial DNA that impair energy production in retinal cells.
Overview
Leber hereditary optic neuropathy (LHON) is a maternally inherited genetic condition that primarily affects the optic nerve, which transmits visual information from the eye to the brain. This condition typically leads to rapid and painless loss of central vision, usually in one eye first, followed by the other eye weeks or months later [PMID:33653133]. While vision loss is the most prominent feature, some individuals may experience other symptoms, though these are less common.
LHON is a rare condition, with an estimated prevalence of approximately 1 in 30,000 to 1 in 50,000 individuals. Although it can affect people of any age, it most commonly manifests in young adults, particularly males between 15 and 35 years old. Women can also be affected, though typically less frequently and sometimes with a later onset or milder course.
Symptoms & clinical features
The hallmark symptom of LHON is a sudden, painless blurring and loss of central vision. This often begins in one eye and progresses over several weeks or months to affect the other eye. The visual impairment can range from moderately severe to profound blindness in the central field of vision, making activities like reading, driving, and recognising faces difficult. Peripheral vision, which is used for side vision and navigation, is generally preserved.
Beyond vision loss, some individuals with LHON may experience other neurological features, though these are less common. These can include mild tremors, changes in muscle tone (dystonia), or issues with nerve function outside the brain and spinal cord (peripheral neuropathy) [PMID:27051287]. Heart rhythm abnormalities have also been reported in a small number of cases, although these are typically not severe.
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Affected organs
The primary organ affected in LHON is the eye, specifically the optic nerve. The optic nerve is responsible for carrying visual signals from the retina to the brain. In LHON, the retinal ganglion cells, which are part of the retina and form the optic nerve, degenerate. This leads to atrophy (wasting away) of the optic nerve, impairing its ability to transmit visual information effectively.
While the eye is the main organ impacted, the condition originates from issues within mitochondria, which are found in almost all cells of the body. In rare instances, this widespread mitochondrial dysfunction may contribute to the less common neurological or cardiac symptoms observed in some individuals.
Risks & severity
The severity of vision loss in LHON can vary between individuals, even within the same family. Most affected individuals experience severe and permanent central vision loss. While spontaneous recovery of vision is rare, some individuals, particularly those with certain genetic changes, may experience a partial improvement in vision over time, though this is uncommon.
Males are significantly more likely to develop vision loss than females, even if they carry the same genetic change. The exact reasons for this difference are not fully understood, but it is thought that environmental factors, such as smoking or heavy alcohol consumption, or other genetic factors, may play a role in triggering the onset of symptoms [PMID:25725520]. The typical age of onset for vision loss is between 15 and 35 years, but it can occur in childhood or later adulthood.
Genetic causes
Leber hereditary optic neuropathy is caused by specific changes (pathogenic variants) in mitochondrial DNA (mtDNA). Mitochondria are often called the 'powerhouses' of the cell because they generate most of the energy needed for cellular function. Mitochondrial DNA is distinct from the DNA found in the cell's nucleus and is inherited exclusively from the mother.
Several specific mtDNA variants are known to cause LHON, with three being most common: m.3460G>A, m.11778G>A, and m.14484T>C. These variants affect genes that are crucial for the proper functioning of the mitochondrial respiratory chain, a process essential for producing energy (ATP) within cells. When these genes are altered, the cells, particularly the highly energy-dependent retinal ganglion cells, do not receive enough energy, leading to their dysfunction and eventual degeneration.
Inheritance pattern
LHON follows a mitochondrial inheritance pattern. This means that the genetic changes causing the condition are located in the mitochondrial DNA, which is passed down exclusively from the mother to all her children (both sons and daughters). Fathers do not pass on mitochondrial DNA to their children.
If a mother has a pathogenic variant in her mitochondrial DNA, all of her children will inherit that variant. However, not everyone who inherits the variant will develop symptoms. This is known as incomplete penetrance, and it is more pronounced in females; women carrying the variant are less likely to develop vision loss compared to men carrying the same variant. Daughters who inherit the variant can pass it on to their own children, while sons who inherit the variant cannot pass it on to their children.
Diagnosis & testing
The diagnosis of LHON is typically suspected based on the characteristic pattern of sudden, painless central vision loss, especially in young adults. An ophthalmologist will perform a thorough eye examination, which may show swelling of the optic nerve head in the acute phase, followed by optic atrophy in later stages. Visual field testing will confirm central vision loss.
Confirmation of LHON requires genetic testing to identify the specific pathogenic variants in mitochondrial DNA. This can be done using a blood sample. In the UK, genetic testing for LHON is available through the NHS Genomic Medicine Service (GMS). Referral to a clinical geneticist or neuro-ophthalmologist is often the pathway to accessing this specialised testing. The relevant NHS National Genomic Test Directory R-codes for optic neuropathies, which include LHON, would guide the specific tests offered.
Management & lifestyle
Currently, there is no cure for LHON, but management focuses on supporting individuals and managing symptoms. Medical treatments are available, such as idebenone, which may improve visual outcomes in some individuals, particularly if started early in the disease course [PMID:25725520]. This treatment is typically initiated under the guidance of a specialist.
Lifestyle advice includes avoiding factors that may exacerbate mitochondrial dysfunction, such as smoking and excessive alcohol consumption. Regular follow-up with an ophthalmologist is important to monitor vision changes and to offer low vision aids and support services. Genetic counselling is also recommended for affected individuals and their families to understand the inheritance pattern and implications for other family members.
UK care pathway
In the UK, individuals suspected of having LHON would typically be referred by their GP or ophthalmologist to a neuro-ophthalmologist or a clinical genetics service. These specialists can assess symptoms, arrange necessary investigations, and provide a definitive diagnosis. Genetic testing is usually performed through the NHS Genomic Medicine Service, adhering to the National Genomic Test Directory guidelines, which outlines specific R-codes for optic neuropathies. Genetic counsellors play a crucial role in explaining the condition, its inheritance, and implications for family planning and testing for at-risk relatives.
Frequently asked questions
Can women get Leber hereditary optic neuropathy?
Yes, women can develop LHON, although it is less common than in men. Women who carry the mitochondrial DNA variant are less likely to develop vision loss compared to men who carry the same variant. However, women who have the variant will pass it on to all of their children.
Is there a cure for LHON?
Currently, there is no definitive cure for LHON. However, treatments like idebenone may be offered and can help improve visual outcomes for some individuals, particularly if started early. Management also includes supportive care and avoiding certain lifestyle factors.
How quickly does vision loss occur in LHON?
Vision loss in LHON typically occurs suddenly and painlessly, often affecting one eye first, followed by the other eye within weeks or months. The central vision then progressively declines over several weeks or months.
If my mother has LHON, will I definitely get it?
If your mother has LHON, you will inherit the mitochondrial DNA variant that causes the condition, as mitochondrial DNA is passed from mother to all her children. However, inheriting the variant does not mean you will definitely develop vision loss; this is known as incomplete penetrance. Your risk of developing symptoms depends on your sex and other factors.
What kind of specialist should I see if I suspect LHON?
If you suspect LHON, you should initially see your GP or an ophthalmologist. They can then refer you to a neuro-ophthalmologist or a clinical genetics service for specialist assessment, diagnosis, and management.
References
- Yu-Wai-Man P, Carelli V, Newman NJ. Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial. Cell reports. Medicine. 2024. PMID: 38428428
- Jankauskaitė E, Bartnik E, Kodroń A. Investigating Leber's hereditary optic neuropathy: Cell models and future perspectives. Mitochondrion. 2017. PMID: 27847334
- Newman NJ. Leber hereditary optic neuropathy: some new observations. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society. 2011. PMID: 21317730
- Wilhelm H. Leber's hereditary optic neuropathy and the pupil. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2005. PMID: 16041586
- Battista M, Carelli V, Bottazzi L. Gene therapy for Leber hereditary optic neuropathy. Expert opinion on biological therapy. 2024. PMID: 38939999
- Chi SC, Cheng HC, Wang AG. Leber Hereditary Optic Neuropathy: Molecular Pathophysiology and Updates on Gene Therapy. Biomedicines. 2022. PMID: 36009477
- Ma Q, Sun Y, Lei K. Progress in diagnosis and treatment of Leber's hereditary optic neuropathy. Journal of molecular medicine (Berlin, Germany). 2024. PMID: 37982904
- Meyerson C, Van Stavern G, McClelland C. Leber hereditary optic neuropathy: current perspectives. Clinical ophthalmology (Auckland, N.Z.). 2015. PMID: 26170609