WFS1 in Optic Neuropathies: Mutation Findings in Nonsyndromic Optic Atrophy and Assessment of Clinical Severity.

PURPOSE: To search for WFS1 mutations in patients with optic atrophy (OA) and assess visual impairment. DESIGN: Retrospective molecular genetic and clinical study. PARTICIPANTS: Patients with OA followed at a national referral center specialized in genetic sensory diseases. METHODS: Mutation screening in WFS1 was performed by Sanger sequencing. WFS1-positive patients were evaluated on visual acuity (VA) and retinal nerve fiber layer (RNFL) thickness using time-domain (TD) or spectral-domain (SD) optical coherence tomography (OCT). Statistical analysis was performed. MAIN OUTCOME MEASURES: Mutation identification, VA values, and RNFL thickness in sectors. RESULTS: Biallelic WFS1 mutations were found in 3 of 24 unrelated patients (15%) with autosomal recessive nonsyndromic optic atrophy (arNSOA) and in 8 patients with autosomal recessive Wolfram syndrome (arWS) associated with diabetes mellitus and OA. Heterozygous mutations were found in 4 of 20 unrelated patients (20%) with autosomal dominant OA. The 4 WFS1-mutated patients of this latter group with hearing loss were diagnosed with autosomal dominant Wolfram-like syndrome (adWLS). Most patients had VA decrease, with logarithm of the minimum angle of resolution (logMAR) values lower in arWS than in arNSOA (1.530 vs. 0.440; P = 0.026) or adWLS (0.240; P = 0.006) but not differing between arNSOA and adWLS (P = 0.879). All patients had decreased RNFL thickness that was worse in arWS than in arNSOA (SD OCT, 35.50 vs. 53.80 µm; P = 0.018) or adWLS (TD-OCT, 45.84 vs. 59.33 µm; P = 0.049). The greatest difference was found in the inferior bundle. Visual acuity was negatively correlated with RNFL thickness (r = -0.89; P = 0.003 in SD OCT and r = -0.75; P = 0.01 in TD-OCT). CONCLUSIONS: WFS1 is a gene causing arNSOA. Patients with this condition had significantly less visual impairment than those with arWS. Thus systematic screening of WFS1 must be performed in isolated, sporadic, or familial optic atrophies.

Relative frequencies of inherited retinal dystrophies and optic neuropathies in Southern France: assessment of 21-year data management.

PURPOSE: Inherited retinal dystrophies (IRDs) and inherited optic neuropathies (IONs) are rare diseases defined by specific clinical and molecular features. The relative prevalence of these conditions was determined in Southern France. METHODS: Patients recruited from a specialized outpatient clinic over a 21-year period underwent extensive clinical investigations and 107 genes were screened by polymerase chain reaction/sequencing. RESULTS: There were 1957 IRD cases (1481 families) distributed in 70% of pigmentary retinopathy cases (56% non-syndromic, 14% syndromic), 20% maculopathies and 7% stationary conditions. Patients with retinitis pigmentosa were the most frequent (47%) followed by Usher syndrome (10.8%). Among non-syndromic pigmentary retinopathy patients, 84% had rod-cone dystrophy, 8% cone-rod dystrophy and 5% Leber congenital amaurosis. Macular dystrophies were encountered in 398 cases (30% had Stargardt disease and 11% had Best disease). There were 184 ION cases (127 families) distributed in 51% with dominant optic neuropathies, 33% with recessive/sporadic forms and 16% with Leber hereditary optic neuropathy. Positive molecular results were obtained in 417/609 families with IRDs (68.5%) and in 27/58 with IONs (46.5%). The sequencing of 5 genes (ABCA4, USH2A, MYO7A, RPGR and PRPH2) provided a positive molecular result in 48% of 417 families with IRDs. Except for autosomal retinitis pigmentosa, in which less than half the families had positive molecular results, about 75% of families with other forms of retinal conditions had a positive molecular diagnosis. CONCLUSIONS: Although gene discovery considerably improved molecular diagnosis in many subgroups of IRDs and IONs, retinitis pigmentosa, accounting for almost half of IRDs, remains only partly molecularly defined.