The prevalence and natural history of dominant optic atrophy due to OPA1 mutations.
OBJECTIVE
Autosomal dominant optic atrophy (DOA) is a major cause of visual impairment in young adults that is characterized by selective retinal ganglion cell loss. To define the prevalence and natural history of this optic nerve disorder, we performed a population-based epidemiologic and molecular study of presumed DOA cases in the north of England.


METHODS
Case series.


METHODS
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 polymerase chain reaction-based sequencing strategy. OPA1-negative cases were then screened for large-scale OPA1 rearrangements and OPA3 mutations. Additional affected family members identified through contact tracing were examined, and longitudinal visual data were analyzed.


METHODS
The prevalence and molecular characteristics of DOA in the north of England. Visual function and disease progression among patients with OPA1-positive mutations.


RESULTS
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). Approximately two thirds of our families with DOA harbored OPA1 mutations (14/22, 63.6%), and 5 novel OPA1 mutations were identified. Only 1 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% confidence interval [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 to hand movements), and visual function worsened in 67.4% of patients during follow-up. The mean rate of visual loss was 0.032 logarithm of the minimum angle of resolution per year, but some patients experienced faster visual decline (range = 0-0.171 logarithm of the minimum angle of resolution/year). OPA1 missense mutations were associated with a significantly worse visual outcome compared with other mutational subtypes (P=0.0001).


CONCLUSIONS
Dominant optic atrophy causes significant visual morbidity and affects at least 1 in 35,000 of the general population.
Yu-Wai-Man
Patrick
P
Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, UK. Patrick.Yu-Wai-Man@ncl.ac.uk
Griffiths
Philip G
PG
Burke
Ailbhe
A
Sellar
Peter W
PW
Clarke
Michael P
MP
Gnanaraj
Lawrence
L
Ah-Kine
Desiree
D
Hudson
Gavin
G
Czermin
Birgit
B
Taylor
Robert W
RW
Horvath
Rita
R
Chinnery
Patrick F
PF
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D004739:England / Q000453:epidemiology; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D009154:Mutation; D029241:Optic Atrophy, Autosomal Dominant / Q000453:epidemiology* / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D015995:Prevalence; D011506:Proteins / Q000235:genetics; D014786:Vision Disorders / Q000453:epidemiology / Q000235:genetics; D014792:Visual Acuity / Q000502:physiology; D055815:Young Adult
C443108:OPA3 protein, human; D011506:Proteins; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human