The Prevalence and Natural History of Dominant Optic Atrophy Due to OPA1 Mutations

Abstract

Purpose-Autosomal dominant optic atrophy (DOA) is a major cause of visual impairment in young adults and it is characterized by selective retinal ganglion cell loss. In order to define the prevalence and natural history of this optic nerve disorder, we performed a population-based epidemiological and molecular study of presumed DOA cases in the north of England. Design-Case seriesParticipants-Seventy-six affected probands with a clinical diagnosis of DOA were identified from our neuro-ophthalmology and neurogenetics database.Methods-OPA1 genetic testing was performed using a PCR-based sequencing strategy. OPA1 negative cases were then screened for large-scale OPA1 re-arrangements and OPA3 mutations. Additional affected family members identified through contact tracing were examined and longitudinal visual data was analyzed.Main Outcome Measures-The prevalence and molecular characteristics of DOA in the north of England. Visual function and disease progression among patients with OPA1 positive mutations. Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsResults-The detection rate of OPA1 mutations was 57.6% among probands with a positive family history of optic atrophy (19/33) and 14.0% among singleton cases (6/43). About two-thirds of our DOA families harbored OPA1 mutations (14/22, 63.6%), and five novel OPA1 mutations were identified. Only one family carried a large-scale OPA1 rearrangement and no OPA3 mutations were found in our optic atrophy cohort. The minimum point prevalence of DOA in the north of England was 2.87 per 100,000 (95% CI 2.54-3.20), or 2.09 per 100,000 (95% CI 1.95-2.23) when only OPA1 positive cases were considered. Snellen visual acuity varied markedly between OPA1 positive cases with a mean of 20/173 (Range 20/20-hand movement), and visual function worsened in 67.4% of patients during follow-up. The mean rate of visual loss was 0.032 LogMAR/years but some patients experienced much faster visual decline (Range = 0-0.171 LogMAR/years). OPA1 missense mutations were associated with a significantly worse visual outcome compared to other mutational subtypes (P = 0.0001).Conclusions-DOA causes significant visual morbidity and affects at least 1 in 35,000 of the general population.

Pathological Confirmation of Optic Neuropathy in Familial Dysautonomia

“…This is because melanopsin retinal ganglion cells are more resistant to mitochondrial stress and neurodegeneration (17). The optic neuropathy observed in familial dysautonomia particularly resembles that seen in dominant optic atrophy, in which the optic nerve damage is present since childhood, even in visually asymptomatic patients, which can be proven by OCT (25). In both familial dysautonomia and dominant optic atrophy, the genetic defect is located at the nuclear DNA (IKBKAP gene in 9q31 in familial dysautonomia; and OPA1 gene in 3q28 in dominant optic atrophy) (1,25).…”

“…The optic neuropathy observed in familial dysautonomia particularly resembles that seen in dominant optic atrophy, in which the optic nerve damage is present since childhood, even in visually asymptomatic patients, which can be proven by OCT (25). In both familial dysautonomia and dominant optic atrophy, the genetic defect is located at the nuclear DNA (IKBKAP gene in 9q31 in familial dysautonomia; and OPA1 gene in 3q28 in dominant optic atrophy) (1,25). While the OPA1 gene in involved in mitochondrial membrane stabilization, COX function, and mitochondrial respiratory chain metabolism (26), the role of the IKBKAP gene in mitochondrial metabolism remains unexplored.…”

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

“…Autosomal dominant optic atrophy (DOA) is a disorder that results from the degeneration of the optic nerve fibers (1). 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).…”

“…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). Its prevalence is estimated to be 1 per 30,000 worldwide with higher frequencies in Denmark (1 per 10,000) due to a founder effect (3).…”

Multiethnic involvement in autosomal-dominant optic atrophy in Singapore

“…10 Severe syndromes affecting young children, due to recessive OPA1 inheritance, were also recently reported. 5,11,12 Although ADOA is an ubiquitous condition, [13][14][15][16][17][18] several studies have reported its possibly lower incidence in Asia. 19,20 Our aim was to investigate, for the first time, its occurrence in the multiethnic population of Singapore.…”