Extensive macular atrophy with pseudodrusen-like appearance: a new clinical entity.

PURPOSE: To describe a previously unreported clinical entity of progressive extensive macular atrophy and pseudodrusen-like appearance in middle-aged patients. DESIGN: Clinical, electrophysiologic, and molecular retrospective study. METHODS: The database of an outpatient clinic unit for genetic sensory diseases was screened for patients older than 40 years with uncharacterized macular dystrophy. Patients with extensive macular atrophy and pseudodrusen-like appearance were included. RESULTS: Eighteen patients of 45 records (40%) matched the inclusion criteria. Bilateral polycyclic well-delineated chorioretinal atrophy extending to the temporal vascular arcades, with a larger vertical axis and without sparing of the fovea featured the macular lesion. The pseudodrusen-like appearance was widespread throughout the posterior pole and the peripheral retina. In the extreme periphery, paving stone lesions were located mostly in the inferior quadrants. In contrast to age-related macular degeneration, a rapid progression of the atrophy was observed with an early involvement of the foveal zone, thus leading to a severe visual loss. All the patients except 2 were legally blind at the end of the follow-up. Unlike age-related macular degeneration, in none of these patients did choroidal neovascularization develop. In all patients, the scotopic and photopic electroretinography responses were reduced. CONCLUSIONS: Extensive macular atrophy with pseudodrusen should be considered as a possible pattern of severe macular dystrophy occurring in the middle-aged adult.

Novel KCNV2 mutations in cone dystrophy with supernormal rod electroretinogram.

PURPOSE: To describe patients with cone dystrophy and supernormal rod electroretinogram (ERG) and search for mutations in the recently described KCNV2 gene. DESIGN: Clinical and molecular study. METHODS: Patients from three families originating from France, Morocco, and Algeria had standard ophthalmologic examination and color vision analysis, Goldmann perimetry, International Society for Clinical Electrophysiology of Vision (ISCEV) protocol in accordance with ERG testing, autofluorescence evaluation, and optical coherence tomography 3 scanning. The two coding exons of KCNV2 were polymerase chain reaction amplified and sequenced. RESULTS: All patients had the characteristic features of supernormal, delayed rod ERG responses at the highest levels of stimulation and markedly reduced cone responses. In the French family, two affected sisters were compound heterozygotes for the recurrent c.1381G>A (Gly461Arg) mutation and for a novel c.442G>T (Glu148Stop) mutation. In the Moroccan family, affected members were homozygotes for the novel c.1404delC mutation (His468fsX503) and in the Algerian family, the proband was homozygote for the novel c.1001delC mutation (Ala334fsX453). In the three families, parents were unaffected heterozygote carriers. None of the mutations were present in 50 control chromosomes. CONCLUSIONS: The three novel truncative mutations are likely to be null mutations leading to loss of function, with no difference in the phenotype presentation. Amino acid changes are found exclusively in the N-terminal fragment of the protein and in the P-loop, indicating the importance of those regions for the function of the KCNV2 protein.

Molecular and in silico analyses of the full-length isoform of usherin identify new pathogenic alleles in Usher type II patients.

The usherin gene (USH2A) has been screened for mutations causing Usher syndrome type II (USH2). Two protein isoforms have been identified: a short isoform of 1,546 amino acids and a more recently recognized isoform extending to 5,202 amino acids. We have screened the full length by genomic sequencing. We confirm that many mutations occur in the exons contributing solely to the longer form. USH2 is an autosomal recessive disorder and, in contrast to previous studies, both mutations were identified in 23 patients and a single mutation in 2 out of 33 patients. A total of 34 distinct mutated alleles were identified, including one complex allele with three variants and another with two. A total of 27 of these are novel, confirming that most mutations in usherin are private. Many of the mutations will lead to prematurely truncated protein but as there are a substantial number of missense variants, we have used in silico analysis to assess their pathogenicity. Evidence that they are disease-causing has been produced by protein alignments and three-dimensional (3D) structural predictions when possible. We have identified a previously unrecognized cysteine rich structural domain, containing 12 dicysteine repeats, and show that three missense mutations result in the loss of one of a pair of the defining cysteine-cysteine pairs.