A de novo deletion of 20q11.2-q12 in a boy presenting with abnormal hands and feet, retinal dysplasia, and intractable feeding difficulty.

Proximal interstitial deletions involving 20q11-q12 are very rare. Only two cases have been reported. We describe another patient with 20q11.21-q12 deletion. We precisely mapped the 6.5-Mb deletion and successfully determined the deletion landmarks at the nucleotide level. Common clinical features among the three cases include developmental delay, intractable feeding difficulties with gastroesophageal reflux, and facial dysmorphism including triangular face, hypertelorism, and hypoplastic alae nasi, indicating that the 20q11.2-q12 deletion can be a clinically recognizable syndrome. This is also supported by the fact that the three deletions overlap significantly. In addition, unique features such as arthrogryposis/fetal akinesia (hypokinesia) deformation and retinal dysplasia are recognized in the patient reported herein.

Selective photodynamic therapy by targeted verteporfin delivery to experimental choroidal neovascularization mediated by a homing peptide to vascular endothelial growth factor receptor-2.

OBJECTIVE: To evaluate the feasibility, efficacy, and selectivity of photodynamic therapy (PDT) using targeted delivery of verteporfin to choroidal neovascularization (CNV) in the rat laser-injury model of CNV. METHODS: We performed PDT in rat eyes on experimental CNV and normal retina and choroid using verteporfin conjugates. A targeted verteporfin conjugate was made by conjugating verteporfin (after isolation from its liposomal formulation) to a modified polyvinyl alcohol (PVA) polymer (verteporfin-PVA) followed by linkage to the peptide ATWLPPR known to bind the receptor for vascular endothelial growth factor, VEGFR2. The verteporfin-PVA conjugate served as a control. We performed fluorescent fundus angiography to determine the optimal timing of light application for PDT using the conjugates. Closure of CNV was assessed angiographically and graded in a masked standardized fashion. We used standardized histological grading to compare the effects on normal retina and choroid. RESULTS: The verteporfin-PVA conjugation ratio was on average 28:1. The conjugate retained typical emission/excitation spectra and photosensitizing activity and was as efficient as an equivalent amount of verteporfin. Peak intensity of targeted verteporfin in CNV was detected angiographically at 1 hour after intravenous injection. Photodynamic therapy using targeted verteporfin (3 or 4.5 mg/m2) with light application 1 hour after drug injection showed angiographic closure of all treated CNV (17/17) 1 day after treatment. Photodynamic therapy using verteporfin-PVA at the same drug dose achieved closure in 18 of 20 CNV. Histological examination after PDT of normal retina and choroid using targeted verteporfin and irradiation at 1 hour showed minimal effect on retinal pigment epithelium and no injury to photoreceptors, whereas PDT using verteporfin-PVA resulted in retinal pigment epithelium necrosis and mild damage to photoreceptors. CONCLUSIONS: Verteporfin bound to the targeting peptide, ATWLPPR, retained its spectral and photosensitizing properties. Angiography demonstrated localization of the targeted verteporfin 1 hour after injection. Photodynamic therapy using targeted verteporfin and the control conjugate were more effective in causing CNV closure than standard liposomal verteporfin. The targeted verteporfin resulted in more selective treatment than the control conjugate or standard verteporfin. These results suggest that targeted PDT strategies based on selective expression of receptors on CNV vasculature may improve current therapy. CLINICAL RELEVANCE: Targeted PDT for CNV is feasible and may offer a qualitative improvement in current treatments for patients with age-related macular degeneration. This study provides the basis for further preclinical studies of targeted PDT strategies and subsequent clinical trials.

Verteporfin photodynamic therapy in the rat model of choroidal neovascularization: angiographic and histologic characterization.

PURPOSE: To develop a model of verteporfin photodynamic therapy (PDT) for experimental choroidal neovascularization CNV in the rat. METHODS: A laser injury model was used to induce experimental CNV in rats. The transit and accumulation of the photosensitizer verteporfin was assessed angiographically in CNV lesions, to determine the optimal time for delivery of light energy. The CNV lesions were then treated with verteporfin PDT, with two doses of verteporfin (3.0 and 6.0 mg/m(2)) and four activating doses of light energy (10, 25, 50, and 100 J/cm(2)). Closure of the CNV was assessed both angiographically and histologically. Verteporfin PDT was also performed on areas of normal choroid and retina at the two verteporfin doses and four light energy doses. The effect of these treatments on these structures was also assessed angiographically and histologically. RESULTS: Peak verteporfin intensities in the CNV were detected at 15 to 20 minutes after intravenous injection. Rates of closure of the CNV varied as a function of the dose of verteporfin and of the activating light energy. Angiographic closure of the CNV correlated with damage to the neovascular complex, as seen with light and electron microscopy. Damage to areas of normal choroid and retina treated with verteporfin PDT also varied as a function of the verteporfin and light energy doses. CONCLUSIONS: Verteporfin PDT for experimental CNV in the rat is a feasible, effective, and reproducible model that can be used for testing the efficacy of adjunctive therapy to verteporfin PDT.

Novel splice variants of amphiphysin I are expressed in retina.

Using RT-PCR-based cDNA cloning, we identified novel splice variants of amphiphysin I, termed amph Ir, that are expressed specifically in retina. In comparison with the prototype amphiphysin I, amph Ir contained two novel insertions (inserts A and B) and one deletion. Insert A is only 9 bp in length but appears to be a determinant for the retina-specific expression. In contrast, insert B is a large domain of 1740 bp and two shorter transcripts with 3'-truncated insert B were also expressed. All the insert sequences were present as unidentified exons in the amphiphysin I gene on human chromosome 7. Western blot analysis of various rat tissues with anti-insert B antibody confirmed the presence and tissue specificity of the variant proteins.