Long-term follow-up of a patient with JAG1-associated retinopathy.

PURPOSE: To report the long-term structural and functional changes in the posterior segments of an adult with an unusual retinal dystrophy caused by a novel mutation in JAG1. METHODS: A 33-year-old female underwent comprehensive ophthalmic examination, including best corrected visual acuity (BCVA) measurement, dilated fundus imaging (wide-angle fundus colour and short wavelength autofluorescence imaging), macular and peripheral spectral-domain optical coherence tomography (SD-OCT) and electroretinography (ERG) at baseline and 10 years later at the age of 43. The patient also underwent systemic review with detailed cardiac, brain and renal investigations. During follow-up, genetic analysis using whole-exome sequencing was performed on the patient and her parents to identify disease-causing variants. RESULTS: The patient's main complaint was of a recent onset of bilateral photophobia and blurred vision in the left eye. On examination, the most striking retinal finding was of bilateral well-demarcated, anterior circumferential chorioretinal atrophy with scattered pigment clumping from the mid periphery to the ora. In addition, she had posterior pole RPE hypopigmentation, peripapillary chorioretinal atrophy, left macular choroidal folds and retinal vasculature tortuosity with atypical branching. Her retinal electrophysiology was consistent with a cone rod photoreceptor dystrophy and left macular dysfunction. Ten years later, her BCVA, the anterior circumferential chorioretinal atrophy and her visual field constriction all remained stable. Her retinal electrophysiology demonstrated deterioration of left rod function, while cone dysfunction remained stable. Macular function deteriorated in both eyes. During follow-up, she was also noted to have progressive aortic root dilatation, posterior embryotoxon and an x ray diagnosis of butterfly vertebrae. Whole-exome sequencing revealed a novel c.2412C > A p.(Tyr804Ter) truncating mutation in JAG1 that was predicted to be pathogenic and suggested a diagnosis of Alagille syndrome. CONCLUSION: This is the first report of the long-term detailed follow-up of a patient with Alagille syndrome whose most striking ophthalmic finding was bilateral well-demarcated, anterior circumferential chorioretinal atrophy. During follow-up, this finding remained stable, suggesting that this may be developmental in origin. This is in contrast with the progressive deterioration in the posterior pole retinal and macular function.

The prevalence and natural history of dominant optic atrophy due to OPA1 mutations.

PURPOSE: 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. DESIGN: Case series. PARTICIPANTS: 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. 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. 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.