Retinal disease course in Usher syndrome 1B due to MYO7A mutations.

The understanding of mechanisms underlying Usher syndrome(USH) has increased in recent years with the identification of the molecular bases of the diseases (reviewed in Refs. 1–3). The original clinical subcategories are now known to be caused by many different genes, and most of the gene products are postulated to play roles in an Usher protein network located in the region of the connecting ciliumof the photoreceptor.3–5 All forms of USH, by definition, lead to retinal degeneration, although some of the USH-causing genes can also cause nonsyndromic deafness.1 USH1B, the most common form of USH1, is caused by mutations in MYO7A(myosin 7A). Like most of the other forms of USH, there is no murine model with a retinal degenerationphenotype.1,6,7 The onus is thus placed on noninvasive human studies in patients with clarified genotypes to help define the retinal degenerative disease component of the syndrome. Given the prospect of therapy for USH1B,8 we have initiated studies to characterize in detail the retinal phenotype of USH patients with known genotypes. We first inquired in USH1B and in other USH genotypes about the earliest detectable site of disease and concluded that it was the photoreceptor.9 Then, we explored the microstructure of the central retina of USH1B patients using high-resolution optical coherence tomography.10 An unexpected result was that many patients showed a wide central region of structurally (and functionally) normal retina. This observation led to suggestions about candidate sites for treatment as well as retinal sites that would be ill-advised to treat in early safety trials. The finding of normal central retina in syndromic recessive retinal degenerationswas extended recently to include USH1C11 and nonsyndromic retinitis pigmentosa.12 Patterns of visual function have been published for various USH clinical and molecular subtypes (for example, Refs. 13–19). In the only previous study of USH1B, cross-sectional and longitudinal data for functional vision scores were analyzed, and deterioration rates were compared with those from USH2A.17 To increase the knowledge base of the USH1B phenotype in anticipation of clinical trials, we studied visual acuities, kinetic and chromatic static perimetry, and retinal imaging in a molecularly clarified group of USH1 patients with MYO7Amutations to determine the patterns of central, peripheral, and rod- and cone-based visual disturbances. A recent report of visual cycle abnormalities in Myo7a-deficient mice20 also prompted us to study the kinetics of dark adaptation in some USH1B patients with preserved rod function. Once it became clear that there were milder as well as more severe phenotypes, we inquired whether the genotypes of the different phenotypes could help to explain the variation in disease expression among patients.