Introduction:
Leber hereditary optic neuropathy (LHON) is a congenital vision loss. It is an inherited mitochondrial disease that is a maternally transmitted genetic disorder. The condition is usually seen in the early adolescence period. Early childhood or adulthood cases are very rarely seen. It has a male predilection over females.
Patients may complain of blurred and clouded vision as the initial symptoms. It may affect one eye or both eyes simultaneously. The condition typically starts as a unilateral progressive optic neuropathy with sequential involvement of the other eye. As the condition worsens, bilateral vision loss, loss of visual acuity, and color vision are also observed. The condition affects central vision, which is required for detailed tasks like reading, driving, and recognizing faces. In addition, the death of nerve cells causes visual loss responsible for relaying visual information from the eyes to the brain.
In most cases, the vision loss is profound and permanent, and very rarely, central vision may improve. Therefore, treatment options are limited, and they include antioxidant supplements. Gene therapy trials are currently underway.
What Are the Signs and Symptoms of LHON?
The most common symptom of this disease is the loss of vision. The other features that can be seen are LHON plus, which includes:
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Movement disorders.
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Dystonia.
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Tremors.
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Abnormal cardiac conductions.
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Multiple sclerosis-like features involve muscle wastage, poor coordination, and numbness.
Some patients have entirely normal disks. Typical cases may have:
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Disc hyperemia with obscured disc margins and dilated capillaries on the disc surface is known as telangiectatic microangiopathy. Telangiectatic microangiopathy may be present in asymptomatic female relatives.
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Swelling of the peripapillary retinal nerve fiber layer (RNFL) or pseudo-edema.
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Dilatation and tortuosity of posterior pole vasculature.
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Subsequently, the vessels and pseudo edema regress, and severe optic atrophy supervene, with RNFL dropout most pronounced in the papillomacular bundle.
What Is the Cause of LHON?
Retinal ganglion cells (RGC) are the neurons present in the inner aspect of the retina. The axons of these neurons bundle around the optic disc, and as they travel through the lamina cribrosa, they form the optic nerve. These axons divide into a non-myelinated prelaminar part with high energy requirements and hence, contain a maximum number of mitochondria and a myelinated post-laminar part. RGC derives its energy through oxidative phosphorylation (OXPHOS) of nutrients in the mitochondria and produces adenosine triphosphate (ATP). OXPHOS involves several enzymes, including the nicotinamide adenine dinucleotide (NADH) - ubiquinone oxidoreductase, NADH dehydrogenase, or complex I is composed of several subunits.
The most common cause behind LHON syndrome is the point mutation of mitochondrial genome coding for NADH-ubiquinone oxidoreductase chains such as MT-ND1, MT-ND4, MT-ND4L, or MT-ND6 gene. These genes are located in the deoxyribose nucleic acid (DNA) of cellular structures known as mitochondria, which convert the energy formed from food into a form that cells can utilize. Although DNA is packaged in chromosomes within the nucleus, mitochondria can sometimes have a small amount of their DNA called mitochondrial DNA (mt DNA).
The genes associated with LHON create a protein with normal mitochondrial function. These proteins help convert oxygen, fats, and simple sugars to energy. Mutations of these genes interrupt the entire process. The mutations are clinically silent until and unless an unknown trigger induces respiratory chain dysfunction in the retinal ganglion cells. These mutations impair glutamate transport and increase the production of reactive oxygen species. This leads to retinal ganglion cell damage. However, it is still unclear how these genetic changes can cause the death of the optic nerve and lead to the specific features of LHON syndrome.
What Are the Investigations to Be Carried Out?
The investigations to be carried out are:
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Physical Examination: LHON syndrome is a mitochondrial disease; hence, a well-detailed history of mitochondrial disease can provide a family history.
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An increasing number of inherited neurological conditions can now be diagnosed by DNA analysis.
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Genetic testing is under active investigation, which can easily detect mitochondrial DNA defects. Gene therapy aims to deliver a functional protein to the target cell. It uses viral markers to deliver the desired gene to the target cell.
What Is the Prognosis and Treatment of LHON?
The prognosis is poor since most patients suffer permanent bilateral visual loss with a final visual acuity (VA) of 6/60 or less. There is no particular treatment for the disorder. Dietary deficiencies should be avoided, particularly B12. Cyanocobalamin form of vitamin B12 has been reported to worsen the condition. Smoking and excessive alcohol consumption should be avoided to minimize mitochondrial stress, as they can worsen visual functions. Nowadays, the quinone analog, Idebenone, a short-chain benzoquinone, is the only disease-specific drug approved and used to treat visual impairment in adolescents and adults. It has antioxidant properties and can act as a mitochondrial electron carrier. If the disorder is not treated, patients with LHON will develop optic atrophy, which is retinal ganglion cell death. It is the end stage of the disease, resulting in complete blindness. There is no such treatment for optic atrophy; hence, early detection and intervention are required to detect the underlying cause of atrophy can help prevent further damage from the disease.
What Is the Differential Diagnosis of LHON?
The differential diagnosis includes:
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Demyelinating optic neuritis.
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Neuromyelitis optica spectrum disease.
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Toxic optic neuropathy.
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Compressive optic neuropathy.
Conclusion:
Leber hereditary optic neuropathy is a genetic disease with varying clinical features based on the type of mutation, environmental factors, and exposure to toxins. When a patient has been diagnosed with LHON, other family members can be given genetic counseling and testing to determine whether they also inherit the same proband. In addition, all maternally related relatives should be screened for the disease. The disorder can be best managed by interprofessional teamwork. Treatment options are limited, and they include antioxidant supplements. Gene therapy trials are currently underway. Lifestyle modifications, along with vitamin supplements, are also recommended.
