Mutations in TUBB4B Cause a Distinctive Sensorineural Disease.

Leber congenital amaurosis (LCA) is a neurodegenerative disease of photoreceptor cells that causes blindness within the first year of life. It occasionally occurs in syndromic metabolic diseases and plurisystemic ciliopathies. Using exome sequencing in a multiplex family and three simplex case subjects with an atypical association of LCA with early-onset hearing loss, we identified two heterozygous mutations affecting Arg391 in ß-tubulin 4B isotype-encoding (TUBB4B). Inspection of the atomic structure of the microtubule (MT) protofilament reveals that the ß-tubulin Arg391 residue contributes to a binding pocket that interacts with α-tubulin contained in the longitudinally adjacent αß-heterodimer, consistent with a role in maintaining MT stability. Functional analysis in cultured cells overexpressing FLAG-tagged wild-type or mutant TUBB4B as well as in primary skin-derived fibroblasts showed that the mutant TUBB4B is able to fold, form αß-heterodimers, and co-assemble into the endogenous MT lattice. However, the dynamics of growing MTs were consistently altered, showing that the mutations have a significant dampening impact on normal MT growth. Our findings provide a link between sensorineural disease and anomalies in MT behavior and describe a syndromic LCA unrelated to ciliary dysfunction.

Martinique (West Indies) crinkled retinal pigment epitheliopathy: clinical description.

PURPOSE: To report a previously undescribed pattern of crinkled retinal pigment epithelium (RPE), observed in a family of black patients originating from Martinique, an island in the French West Indies. METHODS: Three generations were examined by visual acuity measurement and fundus photography. Autofluorescence photography, fluorescein and indocyanine green angiography, visual field testing, electrophysiology, and spectral domain optical coherence tomography were performed in certain patients. RESULTS: One 86-year-old grandmother, her 7 children, her nephew, and 18 of her 22 grandchildren were examined. Nine patients were affected: five children, one nephew, and three grandchildren. An unrelated patient originating from the same area was also affected. In the third generation, fundus findings were whitish deep lines located in the posterior pole. Optical coherence tomography showed a crinkled pattern of a slightly elevated RPE. In the second generation, a scalloped crinkled RPE was observed in the posterior pole and midperiphery, giving an image of dry desert land in fluorescein and indocyanine green angiography. Optical coherence tomography showed that the RPE formed ripples, giving it a crinkled appearance. Complications were observed in six cases: they included RPE atrophy (one case), subretinal and sub-RPE hemorrhages because of polypoidal choroidal vasculopathy (four cases), and fibrovascular scarring (one case). The grandmother's fundi were characterized by peripheral pigmentary changes, with severe visual loss. CONCLUSION: The observed pattern appeared different from previously described dystrophies and could be referred to as Martinique crinkled retinal pigment epitheliopathy.

Ultrasound assessment of short-term ocular vascular effects of intravitreal injection of bevacizumab (Avastin(®) ) in neovascular age-related macular degeneration.

PURPOSE: Angiogenic inhibitors, alone or combined with other therapies, are believed to represent a promising treatment for neovascularization in age-related macular degeneration (wet AMD). They can maintain or improve visual acuity (VA), at least for the first 2years. However, evolution to retinal atrophy cannot be ruled out and it may be useful to assess the effects of antiangiogenic therapy on retinal and choroidal circulation. METHODS: We carried out a pilot study in 15 patients with wet AMD. Time-averaged mean blood flow velocities (BFVs) in the central retinal, temporal posterior ciliary and ophthalmic arteries (CRA, TPCA and OA) were measured by ultrasound imaging before and 4weeks after a single intravitreal injection of 1.25mg bevacizumab in 0.05ml. Patients underwent two ophthalmic examinations, before and 4weeks after injection, including VA measurement and optical coherence tomography (OCT3) examination. RESULTS: In treated eyes, bevacizumab injection was followed by a significant improvement in VA (from 20/125 to 20/80; p=0.0214), and a decrease in mean central macular thickness (from 392±96µm to 271±50µm; p=0.0038). Mean BFV decreased by 10% in the CRA (p=0.0226), 20% in the TPCA (p=0.0026) and 20% in the OA (p=0.0003). No effect was observed in fellow eyes. CONCLUSIONS: Intravitreal bevacizumab acutely improved VA and reduced central macular thickness in wet AMD. Ultrasound imaging revealed that BFVs decreased in all retrobulbar arteries, suggesting that after local diffusion, bevacizumab exerts a short-term regional effect. Bevacizumab might therefore induce hypoperfusion of the whole eye, which may correspond to a vascular side-effect.