NMNAT1-ASSOCIATED CONE–ROD DYSTROPHY: EVIDENCE FOR A SPECTRUM OF FOVEAL MALDEVELOPMENT

Purpose: To describe in detail the phenotype of two siblings with biallelic NMNAT1 mutations. Methods: A 4-year-old male patient (P1) and his 7-year-old sister (P2), product of a nonconsanguineous union of Egyptian ancestry, underwent a comprehensive ophthalmic examination, retinal imaging with spectral domain optical coherence tomography and near infrared (NIR) fundus autofluorescence (FAF), and full-field electroretinograms (ERG). Results: Patients had blurred vision and nystagmus at ∼3 years of age. P2 was hyperopic (+6D). Visual acuity in P1 was 20/100 at age 3 and remained at ∼20/125 at age 4; P2 visual acuity was 20/70 at age 4 and declined to ∼20/200 at age 7. ERGs recorded in P1 showed relatively large rod-mediated responses but nearly undetectable cone signals. There was foveal/parafoveal depigmentation. Spectral domain optical coherence tomography showed hypoplastic foveas, a thin outer nuclear layer centrally but normal thickness beyond the vascular arcades. At the foveal center, cone outer segments were absent and the outer nuclear layer was further hyporreflective. The inner retina was mostly within normal limits. There was central depigmentation on near infrared fundus autofluorescence. Biallelic mutations were identified in NMNAT1 : One was previously reported (c.769 G>A; pGlu257Lys), and the other one (c.245T>C; pVal82Ala) was novel. Conclusion: NMNAT1 mutations cause a consistent phenotype characterized by early-onset, progressive, cone>rod retinawide dysfunction and predominantly central abnormalities ranging from a hypoplastic to an atrophic fovea, supporting a critical role for NMNAT1 in central retinal development and maintenance. Relatively preserved inner retina and detectable photoreceptors may become therapeutic targets.