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Leber Hereditary Optic Neuropathy

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Description: Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disorder that primarily affects the optic nerves, leading to sudden, painless vision loss typically in young adults.
Type: Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disorder. It is transmitted through maternal inheritance, meaning it is passed down from the mother to her offspring through the mitochondrial DNA (mtDNA).
Signs And Symptoms: Clinically, there is an acute onset of visual loss, first in one eye, and then a few weeks to months later in the other. Onset is usually young adulthood, but age range at onset from 7-75 is reported. The age of onset is slightly higher in females (range 19–55 years: mean 31.3 years) than males (range 15–53 years: mean 24.3). The male-to-female ratio varies between mutations: 3:1 for 3460 G>A, 6:1 for 11778 G>A and 8:1 for 14484 T>C.This typically evolves to very severe optic atrophy and a permanent decrease of visual acuity. Both eyes become affected either simultaneously (25% of cases) or sequentially (75% of cases) with a median inter-eye delay of 8 weeks. Rarely, only one eye is affected. In the acute stage, lasting a few weeks, the affected eye demonstrates an oedematous appearance of the nerve fiber layer, especially in the arcuate bundles and enlarged or telangiectatic and tortuous peripapillary vessels (microangiopathy). The main features are seen on fundus examination, just before or after the onset of visual loss. A pupillary defect may be visible in the acute stage as well. Examination reveals decreased visual acuity, loss of color vision and a cecocentral scotoma on visual field examination.
Prognosis: Leber Hereditary Optic Neuropathy (LHON) prognosis generally involves progressive vision loss, primarily in young adults. The condition often leads to central vision loss in both eyes, usually starting in one eye and then affecting the other after some time. The severity of vision loss can vary, but many patients become legally blind. There is currently no cure, though some treatments and lifestyle changes might help manage the condition and potentially improve outcomes. Early diagnosis and genetic counseling are essential for patient management.
Onset: Leber hereditary optic neuropathy (LHON) typically has an onset in young adulthood, most commonly between the ages of 15 and 35. However, cases have been reported in individuals as young as 2 and as old as 87.
Prevalence: Leber Hereditary Optic Neuropathy (LHON) is a rare mitochondrial genetic disorder. Its prevalence is estimated at approximately 1 in 30,000 to 50,000 individuals.
Epidemiology: In Northern European populations about one in 9,000 people carries one of the three primary LHON mutations. There is a prevalence of between 1:30,000 to 1:50,000 in Europe.
The LHON ND4 G11778A mutation is the primary mutation in most of the world, with 70% of Northern European cases and 90% of Asian cases. Due to a Founder effect, the LHON ND6 T14484C mutation accounts for 86% of LHON cases in Quebec, Canada.More than 50% of males with a mutation and more than 85% of females with a mutation never experience vision loss or related medical problems. The particular mutation type may predict the likelihood of penetrance, severity of illness and probability of vision recovery in the affected. As a rule of thumb, a woman who harbors a homoplasmic primary LHON mutation has a ~40% risk of having an affected son and a ~10% risk of having an affected daughter.Additional factors may determine whether a person develops the signs and symptoms of this disorder. Environmental factors such as smoking and alcohol use may be involved, though studies of these factors have produced conflicting results. Researchers are also investigating whether changes in additional genes, particularly genes on the X chromosome, contribute to the development of signs and symptoms. The degree of heteroplasmy, the percentage of mitochondria that have mutant alleles, may play a role. Patterns of mitochondrial alleles called haplogroup may also affect expression of mutations.
Intractability: Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disorder that typically leads to sudden vision loss. There are currently no guaranteed cures or universally effective treatments, making the disease largely intractable. Some therapies and lifestyle changes might provide some benefit or slow progression in certain cases, but overall, managing LHON remains challenging.
Disease Severity: Leber Hereditary Optic Neuropathy (LHON) typically leads to severe vision loss or blindness, predominantly affecting central vision. The severity can vary, with some individuals experiencing partial vision recovery, although this is rare. The condition is generally considered serious due to its significant impact on visual acuity and quality of life.
Healthcare Professionals: Disease Ontology ID - DOID:705
Pathophysiology: The eye pathology is limited to the retinal ganglion cell layer, especially the maculopapillary bundle. Degeneration is evident from the retinal ganglion cell bodies to the axonal pathways leading to the lateral geniculate nuclei. Experimental evidence reveals impaired glutamate transport and increased reactive oxygen species (ROS) causing apoptosis of retinal ganglion cells. Also, experiments suggest that normal, non-LHON-affected retinal ganglion cells produce less of the potent superoxide radical than other normal central nervous system neurons. Viral vector experiments that augment superoxide dismutase 2 in LHON cybrids or LHON animal models or use of exogenous glutathione in LHON cybrids have been shown to rescue LHON-affected retinal ganglion cells from apoptotic death. These experiments may in part explain the death of LHON-affected retinal ganglion cells in preference to other central nervous system neurons that also carry LHON-affected mitochondria.
Carrier Status: Leber Hereditary Optic Neuropathy (LHON) is typically inherited in a mitochondrial manner. Carrier status refers to individuals who carry mutations in their mitochondrial DNA but may not necessarily exhibit symptoms. Since mitochondrial DNA is inherited solely from the mother, both males and females can be carriers, but only females can pass the condition on to their offspring.

The likelihood of being a carrier and later developing symptoms can be influenced by various factors, including genetic background and environmental factors. Carriers may remain asymptomatic throughout their lives, but they still have the potential to transmit the mutation to their children.
Mechanism: Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disorder that primarily affects the optic nerves, leading to acute or subacute loss of central vision.

**Mechanism:**
LHON is caused by mutations in the mitochondrial DNA (mtDNA), which are maternally inherited. The condition primarily affects young adult males but can also occur in females.

**Molecular Mechanisms:**
1. **mtDNA Mutations:** The most common mutations linked to LHON occur in the genes encoding components of Complex I (NADH dehydrogenase) in the mitochondrial electron transport chain. These include ND1, ND4, and ND6 genes.

2. **Impaired Complex I Activity:** The mutations lead to a defective Complex I, which disrupts normal oxidative phosphorylation. This impairs ATP production and increases the generation of reactive oxygen species (ROS).

3. **Oxidative Stress:** Elevated ROS levels cause oxidative damage to mitochondrial and cellular components. Neurons, particularly the retinal ganglion cells, are highly susceptible to this oxidative stress.

4. **Apoptosis:** The damaged retinal ganglion cells undergo apoptosis (programmed cell death), leading to the degeneration of the optic nerve and consequent vision loss.

These molecular mechanisms contribute to the characteristic pattern of optic nerve damage observed in LHON.
Treatment: The prognosis for those left untreated is almost always continued significant visual loss in both eyes. Regular corrected visual acuity and perimetry checks are advised for affected people. There is beneficial treatment for some cases of LHON, especially for early-onset disease, and experimental treatment protocols are in progress. Genetic counseling should be offered. Health and lifestyle choices should be reassessed, particularly in light of toxic and nutritional theories of gene expression. Vision aids assistance and work rehabilitation should be used to assist in maintaining employment.For those who carry a LHON mutation, preclinical markers may be used to monitor progress. For example, fundus photography can monitor nerve fiber layer swelling. Optical coherence tomography can be used for more detailed study of retinal nerve fiber layer thickness. Red green color vision testing may detect losses. Contrast sensitivity may be diminished. There could be an abnormal electroretinogram or visual evoked potentials. Neuron-specific enolase and axonal heavy chain neurofilament blood markers may predict conversion to affected status.Cyanocobalamin (a form of B12) should be avoided as it may lead to blindness in LHON patients.Avoiding optic nerve toxins is generally advised, especially tobacco and alcohol. Certain prescription drugs are potential risks, so all drugs should be treated with suspicion and checked before use by those at risk. Ethambutol, in particular, has been implicated as triggering visual loss in carriers of LHON. In fact, toxic and nutritional optic neuropathies may have overlaps with LHON in symptoms, mitochondrial mechanisms of disease and management. And when a patient with LHON or toxic/nutritional optic neuropathy has a hypertensive crisis as a possible complication of the disease process, nitroprusside (trade name: Nipride) should not be used, due to increased risk of optic nerve ischemia in response to this anti-hypertensive.Idebenone has been shown in a small placebo-controlled trial to have modest benefit in about half of patients. People most likely to respond best were those treated early in onset.
α-Tocotrienol-quinone, a vitamin E metabolite, has had some success in small open-label trials in reversing early onset vision loss.Various treatment approaches have had early trials or been proposed, but so far none with convincing evidence of usefulness or safety for treatment or prevention, including brimonidine, minocycline,curcumin, glutathione, near infrared light treatment, and viral vector techniques."Three person in vitro fertilization" is a proof-of-concept research technique for preventing mitochondrial disease in developing human fetuses. So far, viable macaque monkeys have been produced. But ethical and knowledge hurdles remain before use of the technique in humans is established.
Compassionate Use Treatment: Leber Hereditary Optic Neuropathy (LHON) is a mitochondrial genetic disorder that primarily affects vision. Here are some details regarding compassionate use treatments and off-label or experimental treatments:

1. **Compassionate Use Treatment:**
- **Idebenone**: Idebenone is an antioxidant that has been granted orphan drug status for LHON in various regions, including Europe. It is available through compassionate use programs in certain countries, allowing patients access outside of clinical trials.

2. **Off-Label or Experimental Treatments:**
- **Gene Therapy**: Several experimental gene therapy approaches, such as the GS010 (Lenadogene nolparvovec) treatment, are being studied to introduce or correct the defective ND4 gene associated with LHON.
- **Mitochondrial-Targeted Antioxidants**: Various antioxidants targeting mitochondria to reduce oxidative stress, such as EPI-743 (Vatiquinone), are being investigated.
- **Nutritional Supplements**: High doses of certain vitamins and cofactors like B-complex vitamins, vitamin C, Coenzyme Q10, and creatine may be used off-label with the aim of supporting mitochondrial function, although their efficacy is not well-established.

These treatments are typically considered in a clinical trial setting or under special access programs due to the rare and severe nature of LHON.
Lifestyle Recommendations: For Leber Hereditary Optic Neuropathy (LHON), lifestyle recommendations typically focus on mitigating risk factors that may exacerbate the condition. Key recommendations include:

1. **Avoid Smoking**: Smoking is known to increase the risk of vision loss in individuals with LHON. It is strongly advised to cease smoking if you have LHON or are at risk.
2. **Limit Alcohol Consumption**: Excessive alcohol can also negatively impact optic nerve health. Moderation or avoidance is recommended.
3. **Balanced Diet**: A nutritious diet that supports overall health can be beneficial. Ensure adequate intake of vitamins and nutrients.
4. **Regular Exercise**: Engage in regular physical activity to maintain overall health and wellbeing.
5. **Avoid Certain Drugs**: Some medications might exacerbate symptoms, so it's important to inform your healthcare provider about your condition when being prescribed new medications.

It is also advisable to regularly consult with a healthcare provider, preferably one who specializes in genetic conditions or neurology, to manage the disease effectively.
Medication: Leber Hereditary Optic Neuropathy (LHON) currently has no approved medications specifically for its treatment. However, idebenone has shown some promise in improving visual outcomes and is sometimes used off-label. Additionally, genetic counseling and supportive care, such as visual aids and occupational therapy, are important aspects of managing the condition.
Repurposable Drugs: Leber Hereditary Optic Neuropathy (LHON) is a rare mitochondrial genetic disorder leading to central vision loss. While specific treatments are limited, some drugs being investigated for repurposing include:

1. **Idebenone**: An antioxidant that has shown some promise in clinical trials for improving visual function in LHON patients.
2. **EPI-743**: A synthetic analog of coenzyme Q10, aimed at reducing oxidative stress in mitochondrial disorders.

Clinical efficacy can vary, and ongoing research aims to find more effective treatments.
Metabolites: Leber Hereditary Optic Neuropathy (LHON) is primarily associated with defects in mitochondrial DNA that affect the normal function of the mitochondria. Patients with LHON often exhibit disrupted oxidative phosphorylation leading to impaired ATP production and increased reactive oxygen species. Metabolites involved in mitochondrial function, such as NADH, ATP, and various intermediates of the citric acid cycle, can be affected in this condition. Specific altered metabolites have not been universally identified due to variability in presentations and genetic backgrounds of affected individuals.
Nutraceuticals: Leber Hereditary Optic Neuropathy (LHON) is a mitochondrial genetic disorder that primarily affects the optic nerves, leading to loss of central vision. Regarding nutraceuticals, idebenone has been investigated as a potential treatment. Idebenone is an antioxidant that may help protect the optic nerve cells from oxidative stress, which is believed to play a role in LHON. Currently, there is no universal cure, and treatment mainly focuses on supportive care and symptom management. Consult with a healthcare provider for personalized advice and potential treatment options.
Peptides: Leber Hereditary Optic Neuropathy (LHON) is a genetic disorder that leads to sudden, painless vision loss due to optic nerve dysfunction. Current research into treatments includes evaluating peptides and nanotechnology-based approaches, but no definitive treatments using these methods are widely accepted as of now. Peptides may offer potential benefits by targeting mitochondrial dysfunction, while nanotechnology could provide innovative delivery systems for these therapeutic agents. However, these approaches are still largely experimental and require more clinical validation.