Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2.

Isolated strabismus affects 1-5% of the general population. Most forms of strabismus are multifactorial in origin; although there is probably an inherited component, the genetics of these disorders remain unclear. The congenital fibrosis syndromes (CFS) represent a subset of monogenic isolated strabismic disorders that are characterized by restrictive ophthalmoplegia, and include congenital fibrosis of the extraocular muscles (CFEOM) and Duane syndrome (DURS). Neuropathologic studies indicate that these disorders may result from the maldevelopment of the oculomotor (nIII), trochlear (nIV) and abducens (nVI) cranial nerve nuclei. To date, five CFS loci have been mapped (FEOM1, FEOM2, FEOM3, DURS1 and DURS2), but no genes have been identified. Here, we report three mutations in ARIX (also known as PHOX2A) in four CFEOM2 pedigrees. ARIX encodes a homeodomain transcription factor protein previously shown to be required for nIII/nIV development in mouse and zebrafish. Two of the mutations are predicted to disrupt splicing, whereas the third alters an amino acid within the conserved brachyury-like domain. These findings confirm the hypothesis that CFEOM2 results from the abnormal development of nIII/nIV (ref. 7) and emphasize a critical role for ARIX in the development of these midbrain motor nuclei.

Mouldable, thermoplastic, glue-on frog-supportive shoes change hoof kinetics in normal and obese Shetland ponies.

BACKGROUND: Obesity and hyperinsulinaemia are frequently encountered in the equine population and risk factors for the development of laminitis. There are many options for hoof support that claim a beneficial effect, but often the scientific evidence is scarce. OBJECTIVES: To quantify the effect of frog-supportive shoes on hoof kinetics in normal and obese ponies. STUDY DESIGN: Controlled in vivo trial. METHODS: Ten Shetland mares (n = 10) with a normal (n = 5) or obese (n = 5) body condition were led over a dynamically calibrated pressure plate before (T0), immediately after (T1) and 72 h (T2) after application of the shoes. The following locomotor variables were measured: stance duration (StDur), vertical impulse (VI), peak vertical force (PVF), time to PVF and time from PVF to lift off. The hoof print was divided into a toe and heel region and the StDur toe-heel index was calculated. The toe-heel hoof balance curves of the vertical force were plotted throughout the stance phase. RESULTS: The VI and PVF increased significantly 72 h after application of the shoes, when compared with T0 and T1. The StDur toe-heel index and toe-heel balance curves were significantly different between the normal and obese ponies. These variables became more comparable between the groups after application of the frog-supportive shoes. MAIN LIMITATIONS: It would have been interesting to measure the effect of the shoe in patients with acute laminitis. However, this would have had major welfare implications. CONCLUSIONS: The obese ponies moved more carefully than the normal group, demonstrated by a decreased loading of the toe area. The data illustrate that the ponies became more comfortable 72 h after application of the shoes, with a pronounced effect in the obese group. Thus, these results suggest that frog-supportive shoes could be beneficial, especially for obese ponies.

Distinct redox behaviour of prosthetic groups in ready and unready hydrogenase from Chromatium vinosum.

The redox behaviour of the Ni(III)/Ni(II) transition in hydrogenase from Chromatium vinosum is described and compared with the redox behaviour of the nickel ion in the F420-nonreducing hydrogenase from Methanobacterium thermoautotrophicum. Analogous to the situation in the oxidised hydrogenase of Desulfovibrio gigas (Fernandez, V.M., Hatchikian, E.C., Patil, D.S. and Cammack, R. (1986) Biochim. Biophys. Acta 883, 145-154), the C. vinosum enzyme can also exist in two forms: the 'unready' form (EPR characteristics of Ni(III): gx,y,z = 2.32, 2.24, 2.01) and the 'ready' form (EPR characteristics Ni(III): gx,y,z = 2.34, 2.16, 2.01). Like in the oxidised enzyme of M. thermoautotrophicum the Ni(III)/Ni(II) transition for the unready form titrated completely reversible (both at pH 6.0 and pH 8.0). In contrast, the reversibility of the Ni(III)/Ni(II) transition in the ready enzyme was strongly dependent on pH and temperature. At pH 6.0 and 2 degrees C reduction of Ni(III) in ready enzyme was completely irreversible, whereas at pH 8.0 and 30 degrees C Ni(III) in both ready and unready enzyme titrated with E0' = -115 mV (n = 1). Hampered redox equilibration between the ready enzyme and the mediating dyes is interpreted in terms of an obstruction of the electron transfer from nickel at the active site to the artificial electron acceptors in solution. The origin of this obstruction might be related to possible changes in the protein structure induced by the activation process. The E0'-value of the Ni(III)/Ni(II) equilibrium was pH sensitive (-60 mV/delta pH) indicating that reduction of nickel is coupled to a protonation. A similar pH-dependence was observed for the titration of the spin-spin interaction of Ni(III) and a special form of the [3Fe-4S]+ cluster (E0' = +150 mV, pH 8.0, 30 degrees C). Redox equilibration of this coupling was extremely sensitive to pH and temperature. The uncoupled [3Fe-4S]+ cluster titrated pH-independently with E0' = -10 mV (pH 8.0, 30 degrees C).

A procedure for selecting mammalian cells with an impairment in oxidative phosphorylation.

The mitochondrial encephalomyopathies in man are characterized by heterogeneous defects leading to an impairment in the pathway of aerobic energy production. As a means of investigating the molecular and genetic mechanisms underlying these disorders we have developed a procedure for selecting mammalian cell lines with features resembling the human pathological phenotypes. The principle of the selection is the use of a fluorescent amphiphilic dye, 2,4-(dimethylamino)-1-styrylmethylpyridiniumiodine, a cation showing two main features. Firstly, it is accumulated by mitochondria to an extent correlated with the magnitude of the electrochemical gradient of protons across the mitochondrial inner membrane. Secondly, upon irradiation with UV light, it gives rise to formation of free radicals, which inflict damage to the cell. Mutant cells with an impairment in oxidative phosphorylation will have more chance to survive than wild type cells. The selection procedure was applied to a stock of mutagenized Chinese hamster ovary cells. After subcloning of the cells which survived the selection procedure, twenty-six independent clones were isolated. Eighteen of the clones had a partial deficiency of cytochrome c oxidase ranging from 30 to 60% of the activity in control cells. The properties of two of the clones are described. One clone has been cultured under non-selective conditions for at least 12 months with retention of the partial deficiency of cytochrome c oxidase.

Effect of 17O2 and 13CO on EPR spectra of nickel in hydrogenase from Chromatium vinosum.

Oxygen, either molecular oxygen or a reduction adduct, can tightly bind in the vicinity of the two forms of trivalent nickel occurring in hydrogenase from Chromatium vinosum, as evident from studies with 17O-enriched O2. This oxygen is not in the first coordination sphere of nickel. As has been reported earlier for hydrogenase from Desulfovibrio gigas (Fernandez, V.M., Hatchikian, A.C., Patil, D.S. and Cammack, R. (1986) Biochim. Biophys. Acta 883, 145-154), also the relative activity of the C.vinosum enzyme correlates well with the presence of only one of the two Ni(III) forms in the oxidized preparation. These results make it less likely that a specific oxygenation of only one of the Ni(III) forms would be the reason for the reversible inactivation of nickel hydrogenases by oxygen. Reaction of H2-reduced enzyme with 13CO now demonstrated beyond doubt that: (i) One 13CO molecule is a direct ligand to nickel in axial position; and (ii) hydrogen binds at the same coordination site as CO. It can also be concluded that hydrogen is not bound as a hydride ion, but presumably as molecular hydrogen. A simple way to explain the EPR spectra from the 13CO-adduct of the enzyme is to assume a monovalent state for the nickel.

Correlation between surgical success rate and severity of congenital glaucoma.

AIM: To study the correlation between severity of primary congenital glaucoma (PCG) and success of three types of surgery. METHODS: This was a retrospective review of all records of patients diagnosed with PCG up to age 1 year who underwent goniotomy, trabeculotomy, or combined trabeculotomy-trabeculectomy with mitomycin C as initial procedure between 1982 and 2002 at the King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. 532 paediatric glaucoma patients below age 1 year (820 eyes) with a minimum 1 year follow up were identified. The main outcome measures used for the surgeries were postoperative intraocular pressure, stability of the corneal diameter, and maintenance of corneal clarity. Surgical success was defined as a postoperative intraocular pressure of < or = 21 mm Hg without additional medical or surgical therapy, and with decreased corneal oedema, stabilised corneal diameter, and no additional optic nerve damage for at least 1 year after surgery. Complications, time of surgical failure, and follow up were recorded. RESULTS: The eyes were grouped into mild (249), moderate (342), and severe (229) PCG, based on intraocular pressure, corneal diameter, and clarity. All three surgical procedures resulted in high success rates of 81-100% for the mild form of PCG. Eyes classified with moderate glaucoma had a 13%, 40%, and 80% success rate respectively for goniotomy, trabeculotomy, and combined trabeculotomy-trabeculectomy with mitomycin C. The success rate for severe PCG was 10% and 70% for trabeculotomy and combined surgery respectively. Goniotomy was never done for eyes with this condition. CONCLUSION: Clinical classification of PCG is helpful for surgical decision making. The mild form has a high surgical success regardless of the procedure chosen. Combined trabeculotomy-trabeculectomy with mitomycin C gave the best results for moderate and severe cases of PCG.

Melanin macroglobules as a cellular marker of neurofibromatosis: a quantitative study.

To investigate the usefulness of melanin macroglobules (MMG) as a cellular marker for neurofibromatosis, their density was quantified in biopsies of café-au-lait spots (macules) (CALM) from 22 patients with von Recklinghausen's neurofibromatosis, 6 patients with bilateral acoustic neurofibromatosis, and 19 controls. The density of MMG was significantly higher in biopsies of the CALM of patients with von Recklinghausen's neurofibromatosis than in patients with bilateral acoustic neurofibromatosis (p less than .01) or controls (p less than .0008). The mode of acquisition of von Recklinghausen's neurofibromatosis (inherited vs new mutation) was not related to the density of MMG. On light microscopy, 14/22 (64%) patients with von Recklinghausen's neurofibromatosis had 11 or more MMG per 5 high-power fields. In contrast, none of the other two groups had more than 10 MMG per 5 high-power fields.

Monovalent nickel in hydrogenase from Chromatium vinosum. Light sensitivity and evidence for direct interaction with hydrogen.

Redox titrations with hydrogenase from Chromatium vinosum show that its nickel ion can exist in 3, possibly 4, different redox states: the 3+, 2+, 1+ and possibly a zero valent state. The 1+ state is unstable: oxidation to Ni(II) occurs unless H2 gas is present. The Ni(I) coordination, but not that of Ni(III), is highly light sensitive. A photoreaction occurs on illumination. It is irreversible below 77 K, but reversible at 200 K. The rate of this photodissociation reaction in 2H2O is nearly 6-times slower than in H2O, indicating the breakage of a nickel-hydrogen bond. This forms the first evidence for an H atom in the direct coordination sphere of Ni in hydrogenase and for the involvement of this metal in the reaction with hydrogen.

Eye findings in patients with phenylketonuria.

Untreated phenylketonuria (PKU) is characterized by excretion of phenylpyruvic acid in the urine and mental retardation. Reported eye abnormalities include photophobia (probably due to the albinoid iris), cataracts, and corneal opacities. Eleven patients in an institutionalized population of approximately 1,000 mentally retarded patients had PKU. Cataracts were found in six patients. One patient had bilateral phthisis bulbi and one patient had monocular phthisis. No corneal opacities were found otherwise. All patients with cataracts were middle-aged or had a history of severe self-induced trauma or treatment with high dosages of thioridazine hydrochloride. Albinism is associated with anomalous chiasmal routing of optic fibers and abnormal, extraocular motility. The ocular hypopigmentation of patients with PKU did not have the same results; all seeing patients were orthophoric. Although eye abnormalities are common in PKU except for hypopigmentation, none can be considered a direct effect of the inborn error of metabolism.

Combined trabeculotomy and trabeculectomy as an initial procedure in uncomplicated congenital glaucoma.

OBJECTIVE: To review the results of combined trabeculotomy and trabeculectomy as a primary procedure in congenital glaucoma. METHODS: A retrospective review of 100 consecutive eyes in 60 children undergoing surgery from December 30, 1991, to April 17, 1996. Features at initial examination, ie, corneal size and clarity, presence or absence of anterior segment structural abnormalities, and intraocular pressure (IOP), were noted. Data pertaining to perioperative use of mitomycin and the occurrence of complications were collected. After surgery, all patients had IOP, corneal integrity, and any postoperative complication recorded under chloral hydrate sedation. RESULTS: Mean preoperative IOP was 31 mm Hg. Average horizontal corneal diameter was 12.60 mm. Ninety-five eyes had corneal opacification. Twenty-nine eyes had additional anterior segment anomalies, with ectropion uveae (n = 11), Peters anomaly (n = 9), and partial aniridia (n = 7) being the most common. Mitomycin (0.2 or 0.4 mg/mL) was used in 87 eyes. Eleven eyes sustained hyphemas during or just after surgery. Total average follow-up was 304 days. Eyes in which no coexistent anterior segment anomalies were present had a 78% (49 eyes) operative success (IOP, <21 mm Hg); however, in eyes with associated anterior segment anomalies, the success rate was much lower (45% [18 eyes]). The difference in success rates between both groups was statistically significant (P = .03, chi2 test). CONCLUSIONS: Primary combined trabeculotomy and trabeculectomy was a useful initial procedure in uncomplicated congenital glaucoma. This was particularly true where corneal opacification, as in nearly all our eyes, precluded goniotomy, however, where other stigmata of anterior segment dysgenesis coexisted, results were significantly poorer.

Psychophysical assessment of visual acuity in infants with visual disorders.

The measurement of visual acuity is an essential part of the eye examination of adults, but is rarely attempted in infants being examined for presumed or known eye disease. We have used a preferential looking technique to test visual acuity of infants attending a hospital eye clinic. Serial measurements of acuity of infants attending a hospital eye clinic. Serial measurements of acuity in infants with certain eye diseases can provide examples of the effects of visual deprivation on the developing human visual system. Amongst 14 cases of monocular visual form deprivation in early life, there were 9 infants who had monocular occlusion as therapy for esotropia; 3 infants who had unilateral opacities of the ocular media; and 2 infants who had unilateral eyelid closure from infection or burns. Despite differences in exact mode of deprivation, the effects on visual acuity were similar. There was a reduction of visual acuity in the deprived eye and a simultaneous increase in acuity of the non-deprived eye. These effects of monocular deprivation were not permanent. Recovery occurred with reverse deprivation or by simple cessation of the deprivation. Of 10 children with binocular visual form deprivation, there were 5 who had bilateral congenital cataracts and 5 who had bilateral uncorrected high refractive errors. Infants with cataract surgery before 2 months of age showed normal early development of visual acuity. A 4-6 month delay before treatment resulted in reduced acuity, but recovery subsequently occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Ocular abnormalities in mucolipidosis IV.

Systemic findings in a 23-year-old white man with mucolipidosis type IV included early delayed psychomotor development, mental retardation, and mild facial dysplasia. There was urinary excretion of chondroitin sulfate. Ophthalmologic examination showed corneal haze, pigmentary retinopathy, and severe optic atrophy. Light microscopy showed massively engorged superficial and intermediate epithelial cells of both the cornea and the conjunctiva. By transmission electron microscopy these contained fine granular material consistent with acid mucopolysaccharide and concentric lamellar bodies presumably representing phospholipids. This storage phenomenon was also found in macrophages, plasma cells, ciliary epithelial cells, Schwann cells, retinal ganglion cells, and vascular endothelial cells. Light microscopy also disclosed early cataract formation, marked outer retinal degeneration, and optic atrophy.

Secondary posterior chamber intraocular lens implantation in children.

BACKGROUND: Primary intraocular lens (IOL) implantation after cataract aspiration is a widely accepted means of correcting pediatric aphakia. However, little is available in the literature on secondary IOL implantation in children. We present our experience over the past 6 years. METHODS: The charts of 57 aphakic children (61 eyes) who underwent secondary posterior chamber IOL implantation between January 1989 and April 1996 were reviewed. In general, these children were either intolerant of or noncompliant with their contact lenses. An attempt was made to correlate visual outcome with patient variables. Evaluation of the ciliary sulcus structure was made in selected patients by ultrasonographic biomicroscopy to reveal any changes resulting from the presence of the IOL haptic in the sulcus. RESULTS: The age range at the time of surgery was 2 to 16 years (mean 8 y). Mean follow-up was 14 months (range 6 to 48 months). Forty-two percent of the patients had a best-corrected visual acuity of 20/40 or better and 78% saw better than 20/80. Posterior capsular opacification occurred in 10 eyes, 8 of which required neodymium:yttrium-aluminum-garnet laser capsulotomy. No major complications occurred. Ciliary sulcus evaluation by biomicroscopy did not reveal any significant ciliary body or scleral erosion. No changes were noted when the implanted sulcus was compared with the normal contralateral side. CONCLUSION: Although follow-up was short, this review suggests that secondary posterior chamber IOL implantation is a safe alternative when other methods of correcting pediatric aphakia fail.

Glaucoma in Sturge-Weber syndrome.

BACKGROUND: In glaucoma associated with Sturge-Weber syndrome (SWS), medical treatment often fails to control intraocular pressure, thus requiring surgical intervention that may result in serious complications. METHODS: Eighteen consecutive patients with SWS were reviewed retrospectively at the King Khaled Eye Specialist Hospital. An intraocular pressure less than 20 mm Hg, plus stable optic nerve cup-to-disc ratio and corneal diameter (or visual fields where appropriate), were parameters chosen to indicate that the glaucoma was being controlled. RESULTS: Glaucoma was found in 15 of 18 patients (22 eyes). The mean follow-up time was 62 months (range, 12 to 148 months). Medical treatment alone was successful in 5 patients (7 eyes); the remainder required surgical intervention. The initial surgical procedures included cyclocryotherapy, YAG laser goniotomy, surgical goniotomy, and trabeculotomy or trabeculectomy. Eight eyes required subsequent surgery, 5 with Molteno or Ahmed implants. Early postoperative choroidal effusion and hemorrhage occurred in 4 eyes and resolved spontaneously. Hemorrhagic choroidal detachment with total retinal detachment developed in 2 patients 3 to 5 months after surgery. In 1 patient a recurrent serous choroidal detachment after suture lysis was associated with total optic atrophy. CONCLUSIONS: Glaucoma in SWS is common. Control of glaucoma was successfully achieved with medical treatment in 7 of 22 eyes of our 15 SWS-glaucoma patients, and we consider it the initial treatment of choice. Of the 15 eyes that required surgery, late postoperative complications resulted in loss of vision as a result of persistent postoperative hypotony in 3 eyes that underwent surgical procedures.

Recognized globe perforation during strabismus surgery: incidence, risk factors, and sequelae.

BACKGROUND: Inadvertent perforation of the globe is a well-recognized complication of extraocular muscle surgery. We evaluated the incidence, risk factors, and sequelae of this complication at our institution. METHODS: Medical records of patients who underwent extraocular muscle surgery at King Khaled Eye Specialist Hospital, Saudi Arabia, between September 1983 and April 1997, were reviewed for the occurrence of globe perforation. We documented preoperative visual acuity and refraction, surgical procedure, how the perforation occurred, and immediate management, as well as the sequelae of the perforation, its management, and final outcome. RESULTS: Recognized perforations occurred in 15 of 4886 procedures, for an overall incidence rate of 3/1000. Perforations were 3 times more common in myopic eyes (>-6.00 D, P =.05) and 2 times more common in eyes with previous extraocular muscle surgery. Perforations occurred during muscle reattachment (5 cases), placement of traction sutures at the limbus (4 cases with transient hyphema), muscle disinsertion (3 cases), and placement of sutures at the muscle insertion before disinsertion (3 cases). One patient had a large scleral laceration with uveal prolapse, necessitating scleral patch graft at the time of surgery, and later had retinal detachment surgery with loss of 2 lines of visual acuity. Endophthalmitis, cataract, glaucoma, and phthisis bulbi were not encountered in our review. CONCLUSION: The current incidence of globe perforation is low and only rarely associated with serious sequelae.

Long-term outcome of neonatal macular hemorrhage.

BACKGROUND: We studied long-term visual acuity in children who had macular hemorrhages at birth. METHODS: Of 11 involved children, seven had eye examinations at about age 10. Two were contacted by telephone; two were lost to follow up. RESULTS: Of the seven examined children, six had normal visual acuities. One had reduced vision in the eye with the macular hemorrhage, possibly related to deprivation amblyopia secondary to slow resorption of the hemorrhage. The two patients contacted by telephone reported normal vision. CONCLUSION: Although macular hemorrhages generally resolve without any lasting damage, the outcome may be less favorable in some patients.

Pediatric IOL implantation: the KKESH experience.

BACKGROUND: Intraocular lens (IOL) implantation is increasingly accepted as a means of correcting pediatric aphakia. However, few large series have been reported. We present our experience over the past 6 years. METHODS: Charts were reviewed of 84 patients (88 eyes) 8 years old or younger who underwent IOL implantation at King Khaled Eye Specialist Hospital between January 1989 and March 1995. An attempt was made to correlate visual outcome with patient variables, and refractive outcome was assessed. RESULTS: Despite a high percentage of patients with penetrating trauma (24%) and a significant level of poor compliance with amblyopia treatment (33%), one third of patients saw 20/40 or better, and 60% had at least 20/80 acuity. Improved visual outcome correlated with later onset and shorter duration of opacity and compliance with occlusion therapy. The posterior capsule was left intact in the majority of cases; opacification occurred in 47 eyes, 25 of which required Nd:YAG capsulotomy. No unexpected complications occurred. Prediction of postoperative pseudophakic refraction was within 2 diopters (D) in 70% of patients. CONCLUSION: IOL implantation in appropriate children can be used as a safe alternative to other methods of correcting pediatric aphakia. Visual outcome often depends on amblyopia management. These patients are appropriately followed by ophthalmologists who are experienced in managing amblyopia and pediatric pseudophakia.

Strabismus induced by radial keratotomy.

The history of a woman who developed diplopia after radial keratotomy is reported. Examination showed that this was the result of the appearance of accommodative esotropia. Some complications of refractive surgery reported in the literature were reviewed. It is the current policy of the U.S. military services to disquality an applicant for entry who has undergone refractive surgery. Based on this review of complications it is argued that this is still the correct policy.

Eye injuries during training exercises with paint balls.

The use of paint balls, increasingly popular for war games and survival games, has recently been introduced for certain military training exercises. We treated two soldiers who had severe permanent ocular damage after being hit by these balls. Both removed their goggles after their vision was obscured with paint from a hit on these protective lenses. They were then hit for a second time, resulting in the eye injury. Based on these cases and on a literature review, we conclude that protective eye gear should be mandatory when paint pellets are used. It is essential that service members participating in such exercises be instructed not to remove their protective goggles under any circumstances.

The anatomy of probing and irrigation for congenital nasolacrimal duct obstruction.

In this study, an easily palpable landmark, the supraorbital notch or foramen, was used to simplify the localization of the nasolacrimal duct during the probing procedure. The notch was palpated in 50 patients of a pediatric clinic. The topographic anatomy of the notch in relation to the lacrimal drainage system was studied in 10 skulls. The supraorbital notch is a convenient landmark for the guidance of a probe into the nasolacrimal canal. This technique should reduce the failure rate of probing without the need for infracturing of the lower turbinate or silicone intubation.