Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease.

Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we refined the position of the disease locus (MCOP6) in an interval of 250 kb in chromosome 2q37.1 in two large Faroese families. We detected three different mutations in PRSS56. Patients of the Faroese families were either homozygous for c.926G>C (p.Trp309Ser) or compound heterozygous for c.926G>C and c.526C>G (p.Arg176Gly), whereas a homozygous 1 bp duplication (c.1066dupC) was identified in five patients with arMCOP from a consanguineous Tunisian family. In one patient with MCOP from the Faroe Islands and in another one from Turkey, no PRSS56 mutation was detected, suggesting nonallelic heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603 amino acid long secreted trypsin-like serine peptidase. The c.1066dupC is likely to result in a functional null allele, whereas the two point mutations predict the replacement of evolutionary conserved and functionally important residues. Molecular modeling of the p.Trp309Ser mutant suggests that both the affinity and reactivity of the enzyme toward in vivo protein substrates are likely to be substantially reduced.

Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene.

Complete achromatopsia is a rare autosomal recessive disease associated with CNGA3, CNGB3, GNAT2 and PDE6C mutations. This retinal disorder is characterized by complete loss of color discrimination due to the absence or alteration of the cones function. The purpose of the present study was the clinical and the genetic characterization of achromatopsia in a large consanguineous Tunisian family. Ophthalmic evaluation included a full clinical examination, color vision testing and electroretinography. Linkage analysis using microsatellite markers flanking CNGA3, CNGB3, GNAT2 and PDE6C genes was performed. Mutations were screened by direct sequencing. A total of 12 individuals were diagnosed with congenital complete achromatopsia. They are members of six nuclear consanguineous families belonging to the same large consanguineous family. Linkage analysis revealed linkage to GNAT2. Mutational screening of GNAT2 revealed three intronic variations c.119-69G>C, c.161+66A>T and c.875-31G>C that co-segregated with a novel mutation p.R313X. An identical GNAT2 haplotype segregating with this mutation was identified, indicating a founder mutation. All patients were homozygous for the p.R313X mutation. This is the first report of the clinical and genetic investigation of complete achromatopsia in North Africa and the largest family with recessive achromatopsia involving GNAT2; thus, providing a unique opportunity for genotype-phenotype correlation for this extremely rare condition.

Intravitreal injection of triamcinolone combined with bevacizumab for choroidal neovascularization associated with large retinal pigment epithelial detachment in age-related macular degeneration.

PURPOSE: To discuss the effect and outcome of a combined intravitreal triamcinolone acetonide (IVTA) injection with intravitreal bevacizumab (IVB) in treating choroidal neovascularization (CNV) associated with large retinal pigment epithelial detachment (PED) in age-related macular degeneration (AMD). DESIGN: Prospective, consecutive, observational case series. METHODS: Seven eyes (five patients) with CNV associated with large PED in AMD were treated by IVTA (4 mg/ 0.1 ml), followed by a IVB (1.25 mg/0.05 ml) 1 week later. Patients were evaluated for best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) at baseline, at 1 week and every 6 weeks. Fluorescein angiography (FA) and indocyanine green angiography (ICG) were performed at baseline and every 3 months afterwards. Indications for retreatment by combined injection were defined as persistent PED with subretinal and/or intraretinal fluid on OCT. Patients with flattening of the PED and activity leakage demonstrated by OCT underwent subsequent IVB. RESULTS: The mean duration of follow-up was 11 months (range 9-14 months). BCVA at baseline averaged 20/125, and 20/80 at the end of follow-up. FA showed no leakage from the lesion in four eyes at the end of follow-up, and three eyes showed a decrease in leakage. Average central foveal thickness was (CFT) 325.7 microns at baseline and 209.2 microns at the end. The average size of the PED was 2.34 disk diameters (range 1.33-3.25) at baseline, and the PED disappeared in four eyes, while it decreased in size at the end in the remaining three. The subretinal fluid disappeared in all patients at the end. The combined treatment (IVTA with IVB 1 week later) was repeated in four eyes, and the number of IVB after combined injection ranged from one to three. No RPE tear appeared during follow-up. Two eyes developed glaucoma controlled by topical medication. There were no other ocular or systemic complications CONCLUSION: Combined IVB and IVTA therapy seems to be an effective and safe procedure to treat CNV associated with large PED in AMD.