Dominant optic atrophy

Abstract

Definition of the diseaseDominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain.EpidemiologyThe prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world.Clinical descriptionDOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts.AetiologyTwo genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis.DiagnosisPatients are usually diagnosed during their early childhood, because of bilateral, mild, otherwise unexplained visual loss related to optic discs pallor or atrophy, and typically occurring in the context of a family history of DOA. Optical Coherence Tomography further discloses non-specific thinning of retinal nerve fiber layer, but a normal morphology of the photoreceptors layers. Abnormal visual evoked potentials and pattern ERG may also reflect the dysfunction of the RGCs and their axons. Molecular diagnosis is provided by the identification of a mutation in the OPA1 gene (75% of DOA patients) or in the OPA3 gene (1% of patients).PrognosisVisual loss in DOA may progress during puberty until adulthood, with very slow subsequent chronic progression in most of the cases. On the opposite, in DOA patients with associated extra-ocular features, the visual loss may be more severe over time.ManagementTo date, there is no preventative or curative treatment in DOA; severely visually impaired patients may benefit from low vision aids. Genetic counseling is commonly offered and patients are advised to avoid alcohol and tobacco consumption, as well as the use of me...

Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene

“…Current diagnostic genetic testing approaches in DOA searches for mutations in OPA1, OPA3, ACO2 and TMEM126A, with a diagnostic success rate estimated to be ~70% (2). Gene sequencing is either performed by conventional methods, such as Sanger sequencing or by targeted capture NGS protocols.…”

“…It is one of the most prevalent forms of inherited optic neuropathies, which are genetic conditions affecting the retinal ganglion cells whose axons constitute the optic nerve (2). DOA is an important cause of inherited visual failure and occurs equally among males and females (1).…”

“…The majority of DOA cases (80%) are isolated (non-syndromic) while the remaining (20%) are syndromic (2). DOA that presents clinically as an isolated optic neuropathy is caused by mutations in OPA1, mitochondrial dynamin like GTPase (OPA1) (4), OPA3, outer mitochondrial membrane lipid metabolism regulator (OPA3; also associated with cataracts) (5), aconitase 2 (ACO2) (6) and transmembrane protein 126A (TMEM126A) (7) genes, while syndromic DOA forms show greater genetic heterogeneity (8).…”

Mitochondrial dynamics in neuronal injury, development and plasticity

“…In addition to the diagnostic peripheral neuropathy associated with CMT2A, some patients also experience sensorineural hearing loss, impaired vision and encephalopathy (Stuppia et al, 2015). Similarly, although ADOA is clinically characterized by degeneration of the optic nerve, ∼20% of patients present with extraocular phenotypes, such as peripheral neuropathy and sensorineural hearing loss (Lenaers et al, 2012). Although very rare, de novo hypomorphic mutations in DNM1L, the gene encoding Drp1, are equally devastating and can cause severely impaired development of the nervous system, which leads to epileptic encephalopathy, development delay, pain insensitivity and evendepending on the mutation -early postnatal death (Fahrner et al, 2016;Sheffer et al, 2016;Waterham et al, 2007).…”

A 56‐Year‐Old Man With Visual Changes and Arthralgias

“…It is the most common inherited optic neuropathy. About 20% of patients have associated extraocular manifestations, such as neurosensory hearing loss (7). Wolfram syndrome is a rare autosomal-recessive genetic disorder characterized by juvenile-onset diabetes mellitus, diabetes insipidus, optic nerve atrophy, sensorineural deafness, and neurodegeneration.…”