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.

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.

Pattern electroretinogram and spatial contrast sensitivity in primary congenital glaucoma.

OBJECTIVE: The authors investigated the temporal and spatial characteristics of pattern electroretinogram (PERG) and spatial contrast sensitivity (CS) in primary congenital glaucoma (PCG) to determine whether the PERG and CS could be useful tools in the diagnosis of childhood glaucoma, especially PCG. PARTICIPANTS: The PERGs were evaluated in eyes from ten patients with PCG and nine age-matched visually normal subjects. INTERVENTION: All patients received complete ophthalmologic evaluations including visual field testing. MAIN OUTCOME MEASURES: The PERGs were recorded using phase-alternating (2, 4, and 16 reversals per second [rps]) checkerboard patterns (30' and 60' checks). RESULTS: The patients with PCG exhibited decreased CS when compared with that of control subjects. Significant PERG deficits also were detected in these patients. However, PERG amplitude in patients with PCG almost reached control subject levels at high (16 rps) temporal frequency. This was true for both 30' and 60' checks. Taken together, these observations on PERG amplitude suggest a more important deficiency of the neural response of the retinal cells at lower temporal frequency (rps) in patients with PCG. This is unlike primary open-angle glaucoma (POAG) in which significant PERG deficits are observed at high temporal frequencies. CONCLUSIONS: The PERG amplitude is reduced in patients with PCG, and this is consistent with a loss of CS and visual field changes in these patients. However, the spatiotemporal characteristics of the PERG deficits in PCG differ from those of POAG. This could suggest a difference in the mechanisms mediating retinal ganglion cell dysfunction in the two types of glaucoma.

Recombinant interferon alfa-2b in the treatment of vision-threatening capillary hemangiomas in childhood.

INTRODUCTION: Hemangiomas of the orbit and eyelids may cause serious ocular problems usually related to amblyopia and astigmatism. Steroids have become the accepted treatment. However, some hemangiomas are resistant to steroids or require prolonged use,with unacceptable side effects. Interferon alfa-2b, an antiangiogenic protein, was used in this prospective study to treat visually threatening hemangiomas that were unresponsive to oral or intralesional steroid treatment. METHODS: Forty patients aged 2 to 36 months with life- or organ-threatening hemangiomas were prospectively enrolled to evaluate the efficacy and safety of interferon alfa treatment for hemangiomas. Sixteen of these 40 patients had hemangiomas causing serious ocular dysfunction. The patients were treated with 3 x 10(6) U/m2 interferon alfa-2b subcutaneously daily for 3 months; treatment was then tapered or retreated according to response and protocol. Therapeutic responses were documented. RESULTS: Fifteen patients with ocular hemangiomas have finished treatment. The pretreatment volume measured by computed axial tomographywas an average of 22.3 cm3. Clinical response with eye opening was observed at an average of 6 weeks. There was a significant regression of the hemangioma in all patients, with an average 82% reduction in volume. Patients were treated with glasses and occlusion therapy as appropriate. Final visual acuities with a follow-up averaging 14 months after cessation of interferon treatment were normal, except that five of 15 patients had amblyopia; one of these patients had 20/40, two had 20/60, and two had 20/70. There were no major illnesses or serious adverse side effects. CONCLUSION: Interferon alfa-2b treatment resulted in good to excellent regression of all the hemangiomas. This regression was clinically significant,with patients able to open the affected eye an average of 6 weeks into treatment. Visual results were good, with moderate amblyopia occurring only in patients treated at a later age. Interferon alfa-2b was well tolerated by these young patients, and no significant illness or side effect has occurred.

A second locus (GLC3B) for primary congenital glaucoma (Buphthalmos) maps to the 1p36 region.

Primary congenital glaucoma (gene symbol: GLC3) is an ocular disorder that occurs for 0.01-0.04% of blind people. In the majority of familial cases reported so far, this condition is inherited as an autosomal recessive trait. We have recently used a group of 17 GLC3 families with a minimum of two affected offspring and consanguinity in most of the parental generation and mapped the first GLC3 locus (GLC3A) to the 2p21 region. Six families did not show any linkage to the GLC3A locus and thus provided evidence for genetic heterogeneity of this disorder. A total of eight families unlinked to the 2p21 region were used to search for the chromosomal location of the second GLC3 locus. Herein, we describe mapping of a new locus (designated GLC3B) for primary congenital glaucoma to the short arm of chromosome 1 (1p36.2-36.1) that is situated centromeric to the neuroblastoma and Charcot-Marie-Tooth type 2A (CMT2A) loci. A total of 17 DNA markers were genotyped from this region of chromosome 1. Four families showed no recombination with the two markers D1S2834 and D1S402 with a maximum lod score of 4.510 and 4.157 respectively. Pairwise and multipoint linkage analysis and inspection of the haplotypes revealed that the remaining four families are not linked to this part of chromosome 1, thus providing further evidence that at least one more locus for the autosomal recessive form of GLC3 must exist in the genome. Based on the recombination events, the overall linkage map of this region is: tel-D1S1192-D1S1635-D1S1193 - (D1S1597/-D1S489/D1S228)- [GLC3B/D1S2834/D1S402] - (D1S1176/D1S507/D1S407) - D1S2728-(MFAP2/D1S170) - D1S1368 - D1S436-D1S1592-cen.

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 elctroretinogram 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 off-response 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.

Assignment of a locus (GLC3A) for primary congenital glaucoma (Buphthalmos) to 2p21 and evidence for genetic heterogeneity.

Primary congenital glaucoma (GLC3) is an inherited eye disorder that accounts for 0.01-0.04% of total blindness. Although a large number of chromosomal abnormalities have already been reported in patients with congenital glaucoma, the precise location and pathogenesis of this condition remain elusive. By using a group of 17 GLC3 families and a combination of both candidate regional and general positional mapping strategies, we have mapped a locus for GLC3 to the short arm of chromosome 2. Eleven families showed no recombination with 3 tightly linked markers of D2S177 (Z = 9.40), D2S1346 (Z = 8.83), and D2S1348 (Z = 8.90) with a combined haplotype lod score of 11.50. Haplotype and multipoint linkage analyses of 14 DNA markers from 2p indicated that the disease gene is located in the 2p21 region and is flanked by DNA markers D2S1788/D2S1325 (theta = 0.03; Z = 5.42) and D2S1356 (theta = 0.05; Z = 4.69). Inspection of haplotype and heterogeneity analysis confirmed that 6 families are not linked to the 2p21 region, thus providing the first proof of genetic heterogeneity for this phenotype. We therefore designated the locus on 2p21 GLC3A and positioned it in the overall linkage map of Tel-D2S405-D2S367-(D2S1788/D2S1325)-[(GLC3A++ +, D2S177)/(D2S1346/D2S1348)]-D2S1356-D2S119- D2S1761-D2S1248-D2S1352-D2S406- D2S441-Cen. Of the seven genes mapping to the 2p21 region, CAD, CALM2, and LHCGR are centromeric to D2S119 and can be excluded as a candidate for GLC3A, but mutations in PRKR, TIK, SOS1, or SPTBN1 may still be accountable for this phenotype. As human 2p21 shows homology with mouse chromosomes 11 and 17, the homolog of GLC3A is expected to reside on one of these two chromosomes.

Maturation of binocular pattern visual evoked potentials in normal full-term and preterm infants from 1 to 6 months of age.

The purpose of this study was to evaluate the visual development of preterm infants from 1 to 6 mo of age, using the pattern visual evoked potentials (VEP) in response to three check sizes: 60, 30, and 15 min of arc. Pattern VEP were recorded in 24 full-term and 24 preterm infants (26-36 wk of gestation). The results showed a rapid visual maturation between 1 and 3 mo, followed by a slower progression over the next 3 mo, in both groups. The implicit time of the P100 wave of the pattern VEP was also found to shorten with increasing check sizes. The maturation of pattern VEP in preterm infants was shown to be related to their gestational (or corrected) age rather than their postnatal age. The pattern VEP obtained in response to a 60-min check size in preterm infants aged between 1.5 and 2.5 mo (corrected age) showed a tendency for a faster maturation than those of full-term infants. Our results suggest that within the first 6 mo of age, pattern VEP response is useful to monitor visual development in full-term infants as well as in preterm infants using corrected age.

Ocular findings and visual evoked potential response in the Prader-Willi syndrome.

It has recently been suggested that aberrant misrouting of retino-geniculate-cortical (RGC) projections, a finding previously noted only in albinism, may be an additional feature of the Prader-Willi syndrome. To determine the prevalence of ocular abnormalities in patients with the syndrome and to look for evidence of misrouted RGC projections by means of testing of the pattern-onset visual evoked potential (VEP) response, we examined 12 patients with Prader-Willi syndrome, 8 albino subjects and 5 healthy control subjects. Ocular findings in the first group included telecanthus (in five subjects), strabismus, nystagmus, foveal hypoplasia, visual field defects and cataract. However, the VEP asymmetry typically seen in albinism was not noted in any of the patients with Prader-Willi syndrome. Our findings do not support previous claims of abnormal optic nerve fibre decussation in Prader-Willi syndrome.

Peters' anomaly. The spectrum of associated ocular and systemic malformations.

The cases of Peters' anomaly seen over the past decade, at Hospital Ste-Justine in Montreal, are reviewed. Associated ocular anomalies were observed in 50% of cases while 60% of patients presented with associated systemic defects. It is clear, from these patients and those reported in the literature, that Peters' anomaly can be an isolated condition, or part of distinct syndromes: the Krause-Kivlin syndrome or the Peters'-plus syndrome. The authors emphasize the importance for the ophthalmologist to recognize these possibilities if proper management is to be provided.

Bimedial rectus recession measured from the limbus for congenital esotropia.

We reviewed the surgical results of bimedial rectus muscle recession measured from the limbus in 34 patients with congenital esotropia less than 1 year of age. The mean amount of recession was 10.8 mm. The procedure was successful (10 delta or less of horizontal deviation at 6 months) in 23 patients (68%). In all but one case failure was due to undercorrection. The success rate was 81% in the small-angle deviation group, compared with 29% in the large-angle deviation group (p less than 0.01). The average amount of deviation before surgery was 54.4 delta in the surgical success group and 65.0 delta in the undercorrection group (p less than 0.02). More surgery should be done in patients with larger deviations. Prospective randomized studies are needed to evaluate the efficacy of recession from the limbus versus recession from the insertion site.

First cytogenetic evidence of homozygosity for the retinoblastoma deletion in chromosome 13.

Retinoblastoma (Rb) provided the first model in which both normal alleles of a recessive gene had to be lost as a prerequisite for tumorigenicity. However, region q14 of chromosome 13 appears cytogenetically normal in the majority of Rb tumors, and no homozygotic deletion had previously been observed. High-resolution cytogenetics of an Rb tumor revealed a homozygotic deletion in bands q13.3-14.2 of chromosomes 13 in 35% of the cells and a heterozygotic deletion, involving the same region, in 17%. In one third of the cells, although random chromosome loss occasionally occurred, no specific anomaly was detected. The remaining cells showed either monosomy 13, tetraploidy, or an i(1p). Revealing a homozygotic deletion in subbands 14.1 and 14.2 of chromosomes 13 provides the first cytogenetic evidence of the two somatic mutations considered essential to inactivate the Rb gene. These results allow insight into the succession of events necessary for tumor development.

Inferior oblique myositis presenting as superior oblique muscle palsy.

A 14-year-old girl presented with progressive vertical strabismus simulating superior oblique muscle palsy. However, because of the presence of limitation of infraduction, computed tomography was done; it showed a large mass in the region of the right inferior oblique muscle. A biopsy specimen of the enlarged muscle showed mainly degenerative and some regenerative changes. The diagnosis was orbital myositis, which should be considered in the differential diagnosis of strabismus, especially if the clinical findings are atypical of strabismus.

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.

Nonteratoid medulloepithelioma of the ciliary body.

A 34-month-old girl was treated for anterior uveitis, a superiorly subluxated cataract, rubeosis iridis and secondary glaucoma of the right eye of 3 months duration. She was diagnosed as having medulloepithelioma only after a mass was subsequently identified on the anterior surface of the iris. A low grade malignant nonteratoid medulloepithelioma was found to involve the ciliary surface throughout the circumference of the enucleated right globe. These tumors are generally associated with a good prognosis for survival, but are potentially lethal when they extend extrasclerally.