Bilateral ocular hypertension with rapidly progressive optic neuropathy in a teen.

PURPOSE: We report a rare case of bilateral juvenile open-angle glaucoma (JOAG), with discussion of current understanding of its pathogenesis, differential diagnosis, genetics, and management. The importance of tonometry and dilated fundus examination as essential parts of a complete ocular examination, regardless of patient age, is emphasized. CASE REPORT: A Hispanic female teenager presented for an updated eye examination as a requirement before joining military boot camp. Chief concern was blurry vision at distance, with no other reported ocular or systemic problems. She manifested simple myopia in both eyes and was correctable to 20/20 in each eye with glasses. However, intraocular pressure (IOP) in each eye was measured above 40 mm Hg. Subsequent automated perimetry showed significant visual field defects, and laser polarimetry analysis of the optic nerve fibers corresponded with the visual field loss pattern. Maximal medical therapy was administered to lower the IOP, with minimal success. Subsequent incisional trabeculectomy with topical antimetabolite were performed in both eyes to achieve adequate control of her IOPs. CONCLUSIONS: Juvenile-onset Open Angle Glaucoma (JOAG) has been proposed to be a small subset of Primary Open Angle Glaucoma (POAG) and on a continual spectrum of Primary Open Angle Glaucoma. Because most patients with JOAG are asymptomatic, tonometry and optic nerve analysis are crucial in early detection and, thus, must be performed on all patients, young and old. JOAG has a variable onset, with rapidly progressive neuropathy that does not respond well to medical therapy alone, and surgical intervention is often the eventual treatment of choice. Mutations in the myocillin gene have been strongly linked to the disease. JOAG follows an autosomal dominant inheritance with relatively high penetrance. As such, close monitoring, genetics screening, and/or early medical management to prevent irreversible optic neuropathy and blindness should be considered as well for presymptomatic family members.

Paralogous murine Nudt10 and Nudt11 genes have differential expression patterns but encode identical proteins that are physiologically competent diphosphoinositol polyphosphate phosphohydrolases.

We previously described paralogous human genes [NUDT10 and NUDT11 [where NUDT is (nucleoside diphosphate attached moiety 'X')-type motif, also known as the 'nudix'-type motif]] encoding type 3 diphosphoinositol polyphosphate phosphohydrolases (DIPP3) [Hidaka, Caffrey, Hua, Zhang, Falck, Nickel, Carrel, Barnes and Shears (2002) J. Biol. Chem. 277, 32730-32738]. Normally, gene duplication is redundant, and lacks biological significance. Is this true for the DIPP3 genes? We address this question by characterizing highly-conserved murine Nudt10 and Nudt11 homologues of the human genes. Thus these genes must have been duplicated prior to the divergence of primates and sciurognath rodents, approx. 115 million years ago, greatly exceeding the 4 million year half-life for inactivation of redundant paralogues; our data therefore indicate that the DIPP3 duplication is unusual in being physiologically significant. One possible functional consequence is gene neofunctionalization, but we exclude that, since Nudt10 and Nudt11 encode identical proteins. Another possibility is gene subfunctionalization, which we studied by conducting the first quantitative expression analysis of these genes. We demonstrated high Nudt10 expression in liver, kidney and testis; Nudt11 expression is primarily restricted to the brain. This differential, but complementary, expression pattern indicates that subfunctionalization is the evolutionary consequence of DIPP3 gene duplication. Our kinetic data argue that diphosphoinositol polyphosphates are more physiologically relevant substrates for DIPP3 than are either diadenosine hexaphosphate or 5-phosphoribosyl 1-pyrophosphate. Thus the significance of the Nudt10/Nudt11 duplication is specific hydrolysis of diphosphoinositol polyphosphates in a tissue-dependent manner.