Extraocular features of Leber hereditary optic neuropathy: A scoping review

Leber hereditary optic neuropathy (LHON) is a rare inherited mitochondrial disease that leads to mitochondrial dysfunction, resulting in optic nerve damage and vision loss. Systemic involvement has been reported in several LHON cases, referred to as LHON+ disorders. However, the causes and presentations of such conditions have been poorly studied. It is suggested that 90% of mitochondrial dysfunction is caused by one of three primary point mutations in mitochondrial DNA that affect respiratory complex I (referred to as mtDNA LHON), with unresolved cases of LHON being caused by other variants, known as autosomal recessive LHON. The cardiac, musculoskeletal, neurological, and auditory systems are commonly affected in LHON. For example, hypertrophic cardiomyopathy and sudden cardiac death have been linked to specific mutations. Neurological effects - such as dystonia, epilepsy, polyneuropathy, and ataxia - as well as hearing loss, have also been observed in patients with specific mitochondrial mutations. These findings highlight the need for a more comprehensive evaluation beyond standard ophthalmic assessments. LHON is typically diagnosed based on a combination of ophthalmic imaging, patient age and gender, clinical course (bilateral, rapidly progressive, and sequential visual loss), family history, maternal inheritance, and fundus appearance. However, the advent of genetic testing has significantly expanded the recognized phenotype. In terms of treatment, idebenone is the only FDA-approved therapy for LHON; however, intravitreal gene therapy yields promising improvement, especially for the most common m.11778G>A mutation, which accounts for 70% of causative mutations. At present, these therapies are confined to ocular treatment.

This review highlights the importance of recognizing systemic manifestations of LHON, which are frequently overlooked in clinical practice.

Early detection of these systemic manifestations, especially in cardiac and neurological systems, could help with prompt intervention and improve patient outcomes. Further research into gene therapy and mitochondrial replacement techniques holds promising potential for developing more effective treatment strategies.