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Sequence Analysis and Homology Modeling Suggest That Primary Congenital Glaucoma on 2p21 Results from Mutations Disrupting Either the Hinge Region or the Conserved Core Structures of Cytochrome P4501B1

We recently reported three truncating mutations of the cytochrome P4501B1 gene (CYP1B1) in five families with primary congenital glaucoma (PCG) linked to the GLC3A locus on chromosome 2p21. This could be the first direct evidence supporting the hypothesis that members of the cytochrome P450 superfamily may control the processes of growth and differentiation. We present a comprehensive sequence analysis of the translated regions of the CYP1B1 gene in 22 PCG families and 100 randomly selected normal individuals. Sixteen mutations and six polymorphisms were identified, illustrating an extensive allelic heterogeneity. The positions affected by these changes were evaluated by building a three-dimensional homology model of the conserved C-terminal half of CYP1B1. These mutations may interfere with heme incorporation, by affecting the hinge region and/or the conserved core structures (CCS) that determine the proper folding and heme-binding ability of P450 molecules. In contrast, all polymorphic sites were poorly conserved and located outside the CCS. Northern hybridization analysis showed strong expression of CYP1B1 in the anterior uveal tract, which is involved in secretion of the aqueous humor and in regulation of outflow facility, processes that could contribute to the elevated intraocular pressure characteristic of PCG.

Novel TIGR/MYOC mutations in families with juvenile onset primary open angle glaucoma.

Mutations in the trabecular meshwork induced glucocorticoid response protein (TIGR) or myocilin (MYOC) has recently been shown to cause juvenile onset primary open angle glaucoma (JOAG). In this study, we identified two new mutations (Asp380Ala and Ser502Pro) in two British families and another (Pro370Leu) in a French-Canadian family. These mutations were not present in a total of 106 normal chromosomes. In another Turkish family with JOAG, we also detected a sequence variant that was proven to be an amino acid polymorphism (Arg76Lys). No other sequence changes were found in the entire coding region and splice junctions of the TIGR/MYOC gene in this family. However, it is still possible that mutations either in the TIGR promoter or in another neighbouring gene could cause glaucoma in this JOAG family. Our results confirm the role of the TIGR/MYOC gene in the aetiology of the JOAG phenotype.

Incidence and Prognosis of Childhood Glaucoma: A Study of 63 Cases

Sixty-three consecutive cases (95 eyes) of glaucoma in children were studied. Glaucoma associated with congenital anomalies (group II) formed the largest group in this study. This accounted for 46% of the cases compared to primary congenital glaucoma (group I) that accounted for 22.2%. Secondary glaucoma (group III) occurred in 31.8%. The presenting signs and symptoms in group I were tearing and corneal edema. In 50% of the cases in groups II and III, diagnosis was made on a routine ophthalmologic examination. Surgery was performed in 95.8% of eyes in group I, 53.2% in group II, and 54.2% in group III. The best visual prognosis occurred in group I where 77.3% of affected eyes had visual acuity equal to or better than 20/50 with good pressure control in all. This was followed by group II where 41.5% had vision equal to or better than 20/50 and 41.4% had 20/200 vision or less. Intraocular pressure remained uncontrolled in 19.1% of this group. The worst prognosis and morbidity was found in group III where 30.5% of eyes had 20/50 vision or better and 47.8% had 20/200 vision or less. In group III, 33.3% had uncontrolled intraocular pressure.

Treatment of Periocular Infantile Hemangiomas with Propranolol: Case Series of 18 Children

PURPOSE To study the efficacy of propranolol in the treatment of periocular infantile hemangiomas (IHs). DESIGN Retrospective interventional case series. PARTICIPANTS Eighteen children presenting periocular IH with occlusion of the pupil, anisometropic astigmatism, proliferating eyelid IH, or cosmetically disfiguring periocular IH. METHODS All patients received treatment with propranolol started at 0.5 mg/kg/day with an incremental increase by 0.5 mg/kg/day every 4 days, up to a maximum of 2 to 3 mg/kg/day. Complete eye examinations and serial photographs were obtained before, during, and after treatment. Doppler ultrasound and magnetic resonance imaging performed pre- and post-treatment were compared when available. MAIN OUTCOME MEASURES Evolution of the treated IH was evaluated with respect to astigmatism, amblyopia, and size of the lesion. RESULTS The IH size decreased in 17 of 18 patients. We noted a greater reduction when treatment was administered during the proliferative phase of growth of IHs. At the conclusion of treatment, none of our patients had amblyopia. The mean value of amblyogenic astigmatism (n = 7) decreased from 2.71 diopters (D) pretreatment to 1.03 D post-treatment. On radiology, 8 patients had significant regression of the lesion size of their IH and 1 patient had a limited progression. Propranolol had to be temporarily discontinued in only 1 patient because of symptomatic hypotension. CONCLUSIONS Propranolol seems to be an effective modality of treatment for periocular IH. It seems to be most efficacious when initiated in the proliferative phase of IH but may be beneficial even in the later stage. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

On- and off-responses in the photopic electroretinogram in complete-type congenital stationary night blindness.

We examined the on- and off-responses of the photopic electroretinogram in patients with complete congenital stationary night blindness. Standard flash electroretinograms as well as those produced in a ganzfeld modified for long-duration light stimuli (500 msec) permitted the separation of on- and off-responses in four patients and four normal subjects. The amplitude and latency of the electroretinogram on- response (a- and b-waves) and off-response (d-wave) in addition to the oscillatory potentials of the off-response in normal subjects and patients were compared. The abnormal on-response was demonstrated in all the patients, and the offresponse with its oscillatory potentials were preserved. We showed that the second portion of the off-response (of inner retinal origin) is normal. If congenital stationary night blindness is a defect of depolarizing bipolar cells, these results preclude input of the depolarizing bipolar cells and support the hyperpolarizing bipolar cells as the cellular origin of the off-response electroretinogram.

Clinical evaluation of aminocaproic acid for managing traumatic hyphema in children.

PURPOSE The purpose of this study is to determine the incidence of secondary hemorrhage after traumatic hyphema in children and to evaluate the efficacy of epsilon aminocaproic acid in reducing this incidence. METHODS In a prospective, randomized, double-blind study performed between November 1987 and February 1994, 94 children admitted for traumatic hyphema were assigned to receive either aminocaproic acid (n = 48) (100 mg/kg every 4 hours; maximum, 30 g daily) or placebo (n = 46) for 5 days. Patients who had ingested aspirin in the week preceding admission were excluded from the study. RESULTS Mean age of the patients was 9.4 years. Black patients comprised 4% of the study population. Secondary hemorrhage occurred in only three patients (3.2%), two from the placebo group and one from the aminocaproic acid group, none of whom had any complications. The duration of hospital stay and the clot resorption times were increased significantly in the aminocaproic acid group (P < 0.001). CONCLUSIONS The authors report a very low incidence of secondary hemorrhage compared with most previous studies. This difference is likely related to the small proportion of black patients in our study and to the exclusion of patients having ingested aspirin, two factors that seem to be associated with higher rates of rebleeding. The efficacy of aminocaproic acid could not be determined due to the low incidence of hemorrhage. The results of this study, however, suggest that the incidence of secondary hemorrhage in white patients without prior ingestion of aspirin is insufficient to justify routine use of aminocaproic acid in managing traumatic hyphema. Rather, an individualized decision based on the risk factors of each patient would seem more appropriate to avoid a slower clot resorption time and possible side effects of this medication.

Exclusion of primary congenital glaucoma (buphthalmos) from two candidate regions of chromosome arm 6p and chromosome 11

Primary congenital glaucoma (gene symbol: GLC3) is characterized by an improper development of the aqueous outflow system. The reduced outflow of fluid results in an increased intraocular pressure leading to buphthalmos, optic nerve damage, and eventual visual impairment. GLC3 is a heterogeneous condition with an estimated incidence of 1:2,500 in Middle Eastern and 1:10,000 in Western countries. In many families, GLC3 is an autosomal recessive trait with presentation of an earlier age-of-onset, high intraocular pressure, enlarged cloudy cornea, buphthalmos, and a more aggressive course. The pathogenesis of GLC3 remains elusive despite extensive histologic efforts to identify a single anatomic defect. Recent advances in positional mapping and cloning of human disorders provided an opportunity to identify chromosome locations of the GLC3 phenotype. Our laboratory is currently involved in the mapping of this condition by using a combination of candidate chromosome regions associated with the GLC3 phenotype and by a general positional mapping strategy. 16 refs., 3 tabs.