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Inherited Optic Neuropathies: Genetics and New Directions for Diagnosis and Therapy

Bao Jian Fan, MD, PhD

The inherited optic neuropathies are a group of genetically heterogeneous disorders that typically manifest as bilaterally central visual loss and optic atrophy. The two most common inherited optic neuropathies are Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA). LHON is caused by point mutations in mitochondrial DNA (mtDNA), whereas DOA is caused by mutations in nuclear genes [1,2]. Mitochondrial dysfunction and selective apoptosis of retinal ganglion cells (RGCs) are characteristic pathological features shared by LHON and DOA, resulting in progressive optic nerve degeneration and visual loss [3–6]. Some patients with hereditary neurodegenerative diseases and syndromes may also exhibit optic neuropathies; these include Wolfram syndrome, Mohr–Tranebjaerg syndrome, Friedreich ataxia, Charcot–Marie–Tooth disease, familial dysautonomia, and myotonic dystrophy, among others. Various neurological and systemic abnormalities, such as deafness and diabetes mellitus, are regularly observed in these patients [2].

The inherited optic neuropathies may be sporadic or familial. The mode of inheritance in families affected by these disorders can be autosomal dominant, autosomal recessive, X-linked recessive, or maternal (mitochondrial). However, clinical variability owing to reduced penetrance and variable expressivity often makes recognition of the patterns of inheritance problematic [2]. Genetic analysis can be helpful to tackle these problems, and greatly improves the diagnosis of these disorders. Effective treatments for the inherited optic neuropathies are limited. Among the treatment options available, idebenone has been suggested to be one of the most promising for LHON and DOA [2,6]. However, additional clinical evidence for the efficacy of idebenone in these diseases is needed before broad clinical use. During the past 2 decades, our understanding of the clinical features, genetics, and pathogenesis of the inherited optic neuropathies has been greatly advanced. New forms of genetic diagnostic testing and promising gene therapies are emerging. In this article, recent advances in our understanding of the molecular basis of LHON and DOA will be reviewed, and new genetic testing and emerging gene therapies will be discussed.

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