Genotypic and phenotypic characterisation of RP2- and RPGR-associated X-linked inherited retinal dystrophy, including female manifestations.

BACKGROUND: With the promise of gene replacement therapy, eligible males and females with X-linked inherited retinal dystrophy (XL-IRD) should be identified. METHODS: Retrospective observational cohort study to establish the phenotypic and genotypic spectrum of XL-IRD within New Zealand (NZ). Thirty-two probands, including 9 females, with molecularly proven XL-IRD due to RP2 or RPGR mutations, and 72 family members, of which 43 were affected, were identified from the NZ IRD Database. Comprehensive ophthalmic phenotyping, familial cosegregation, genotyping, and bioinformatics were undertaken. Main outcome measures were: RP2 and RPGR pathogenic variant spectrum, phenotype in males and females (symptoms, age of onset, visual acuity, refraction, electrophysiology, autofluorescence, retinal appearance), and genotype-phenotype correlation. RESULTS: For 32 families, 26 unique pathogenic variants were identified; in RP2 (n = 6, 21.9% of all families), RPGR exons 1-14 (n = 10, 43.75%), and RPGR-ORF15 (n = 10, 34.3%). Three RP2 and 8 RPGR exons 1-14 variants are novel, rare, and cosegregate. Thirty-one percent of carrier females were significantly affected, with 18.5% of families initially classified as autosomal dominant. Of five Polynesian families, 80% had novel disease-causing variants. One Maori family showed keratoconus segregating with an ORF15 variant. CONCLUSIONS: Significant disease was present in 31% of genetically proven female carriers, often leading to an erroneous presumption of the inheritance pattern. Pathogenic variants in 44% of the families were in exon 1-14 of RPGR, more frequent than usually described, which may inform the gene testing algorithm. Proving cosegregation in families for novel variants and identifying affected females and males translates to optimised clinical care and potential for gene therapy.

Incomplete peripheral retinal vascularisation in retinopathy of prematurity: is it the consequence of changing oxygen saturation?

Background: We wish to determine the prevalence and risk factors of incomplete peripheral avascular retina (IPAR) in children screened for retinopathy of prematurity (ROP) and its association with oxygen saturation (SpO2) targets. Methods: A retrospective review of retinal images of premature infants born and screened for ROP in Auckland Region, New Zealand, between January 2013 and December 2017 was conducted. Images were reviewed to determine if avascular retina was present at their final ROP screening. The prevalence of peripheral avascular retina was compared among infants born prior to (Group 1) and after (Group 2) 2015 when the SpO2 target was increased. Infants with any concurrent ocular pathology or who had received ROP treatment were excluded. Results: In total, 62 (12.8%) of the total of 486 infants (247 in Group 1; 239 in Group 2) were found to have IPAR at their last ROP screening. Group 1 had more statistically significant infants with IPAR compared to Group 2 (39/247 infants and 23/239 infants respectively; p = 0.043). Conclusions: Incomplete peripheral retinal vascularisation occurred at a prevalence of 12.8% in infants at risk of ROP. Higher SpO2 targets did not increase the prevalence of incomplete peripheral retinal vascularisation. Low gestational age and low birth weight are likely risk factors for the development of avascular retina. Further research into the risk factors associated with incomplete peripheral retinal vascularisation and the associated long-term outcomes is needed.

Regulation of connexin43 gap junction protein triggers vascular recovery and healing in human ocular persistent epithelial defect wounds.

Transiently blocking the expression of the gap junction protein connexin43 using antisense oligodeoxynucleotides or blocking hemichannels with connexin mimetic peptides has been shown to significantly improve outcomes in a range of acute wound models. Less is known about their likely effects in nonhealing wounds. In the eye, prolonged inflammation and lack of epithelial recovery in nonhealing corneal epithelial wounds may lead to corneal opacity, blindness or enucleation. We report here the first human applications of antisense oligodeoxynucleotides that transiently block translation of connexin43 in a prospective study of five eyes with severe ocular surface burns (persistent epithelial defects), which were unresponsive to established therapy for 7 days to 8 weeks prior to treatment. Connexin43-specific antisense oligodeoxynucleotide was delivered in cold, thermoreversible Poloxamer407 gel under either an amniotic membrane graft or a bandage contact lens. The connexin43-specific antisense application reduced inflammation within 1-2 days, and in all five eyes complete and stable corneal reepithelialization was obtained. Recovery of the vascular bed and limbal reperfusion appeared to precede corneal epithelial recovery. We conclude that connexin modulation provides a number of benefits for nonhealing ocular burn wounds, one of which is to promote vascular recovery.

Persistent Avascular Retina in Infants With a History of Type 2 Retinopathy of Prematurity: To Treat or Not to Treat?

PURPOSE: To investigate persistent avascular retina in infants with type 2 retinopathy of permaturity (ROP) that persisted after 45 weeks' post-menstrual age when regular ROP screening ceased. METHODS: A prospective observational study where fundus fluorescein angiography (FFA) was completed on consecutive infants who had a history of type 2 ROP and avascular retina during ROP screening that persisted after 45 weeks' post-menstrual age. RESULTS: FFA was completed on 72 eyes of 36 infants (53% male), with a mean gestational age of 26.0 ± 2.2 weeks and a mean birth weight of 834.6 ± 216.3 grams. The mean age at discharge from ROP screening was 47.6 weeks' post-menstrual age. All patients had type 2 ROP at the worst stage of their disease, with predominantly stage 2 disease. FFA was performed at a mean age of 18.8 ± 10.3 months post-menstrual age. All patients had detectable avascular retina in peripheral zone II or III on FFA. Peripheral vessel leakage was present in 3 eyes of 2 infants (5.5%), who both subsequently received peripheral laser treatment. CONCLUSIONS: Premature infants with type 2 ROP may have persistent peripheral avascular retina with unknown long-term ocular complications, which can present management dilemmas. Retinal FFA is recommended to determine retinal ischemia and aid decision making for treatment in these cases. [J Pediatr Ophthalmol Strabismus. 2019;56(4):222-228.].

Informed consent for strabismus surgery: the importance of patient information sheets.

PURPOSE: To analyze the additive effect of supplementing verbal consent with written patient information sheets in optimizing patients' and families' understanding of strabismus surgery. METHODS: A prospective randomized study was conducted with 28 patients for strabismus surgery randomized into two groups: group 1 with standardized oral informed consent, and group 2 with standardized oral consent and a written information sheet. A confidential questionnaire with 13 questions was completed by patients and families before surgery. RESULTS: A total of 7 adults and 21 children were included in the study. The mean score (number of correct answers) for group 1 was 4.14 ± 1.99; for group 2, 5.79 ± 2.12 (P = 0.044), indicating that patients and families in group 2 understood their strabismus surgery better than those in group 1. Areas needing more emphasis during the consent process were identified, including risk of under- or overcorrection or repeat surgery and use of eyedrops postoperatively. CONCLUSIONS: In this study, patient information sheets seemed to help patients and families better understand information about their surgery. Patient recall of information provided is poorly reliable and must be considered in decision making for medicolegal cases.

ADAMTSL4 assessment in ectopia lentis reveals a recurrent founder mutation in Polynesians.

BACKGROUND: To clinically characterize a cohort of patients with ectopia lentis (EL), or Marfanoid features in whom a definite genetic diagnosis of Marfan syndrome (MFS) had been excluded (atypical MFS), and to evaluate the contribution of mutations in ADAMTSL4 (OMIM * 610113), and P3H2 (LEPREL1; OMIM * 610341) to disease in this population. MATERIALS AND METHODS: Subjects underwent comprehensive ophthalmic examination, including keratometry. Mutational analysis of ADAMTSL4 and P3H2 was undertaken using PCR, high resolution melting analysis, and sequencing. The frequency of c.2237G>A; p.(Arg746His) was determined in an unaffected Polynesian cohort. Haplotype analysis used tagged single nucleotide polymorphic markers. RESULTS: Mutational analysis of ADAMTSL4 identified two pathogenic variants in ADAMTSL4 in 11/31 (35%) probands, consistent with the autosomal recessive EL phenotype. A recurrent, rare missense variant in ADAMTSL4, c.2237G>A; p.(Arg746His), was present in 10 probands -(8 homozygotes), predominantly of Polynesian descent, and all shared the same haplotype. p.(Arg746His) affects the Thrombospondin1 (TSP1) domain of the protein and is predicted to be pathogenic. No pathogenic variants in P3H2 were identified. CONCLUSION: A recurrent pathogenic ADAMTSL4 variant is a major cause of early onset autosomal recessive EL in a Cook Island Maori population and associated with a common haplotype, suggesting a founder effect. Children presenting under the age of 5 years, particularly of Cook Island or New Zealand Maori descent, with isolated ectopia lentis, should in the first instance be tested for this single variant.

Outcomes of scleral-sutured conventional and aniridia intraocular lens implantation performed in a university hospital setting.

PURPOSE: To evaluate the outcomes of transscleral sutured posterior chamber intraocular lens (PC IOL) implantation. SETTING: Public university hospital, Auckland, New Zealand. DESIGN: Retrospective case series. METHODS: A modified no-touch transscleral sutured PC IOL implantation technique with a 1-piece monofocal IOL (Alcon CZ70BD) or an aniridia IOL (type 67G, Morcher) was assessed. RESULTS: Seventy-eight cases (80.8% men; 53.9% aphakic) were identified. The mean follow-up was 35.5 months and the mean age at surgery, 41 years±21 (SD). The preoperative corrected distance visual acuity (CDVA) was worse than 6/30 in 66.7%. Indications included ocular trauma (46.2%), nontraumatic crystalline lens subluxation (16.7%), post-complicated cataract surgery (10.3%), idiopathic IOL dislocation (10.3%), and congenital cataract/aphakia (10.3%). An aniridia IOL was required in 39.7% of eyes. There were no significant intraoperative complications in 74.4% of eyes. Postoperative complications included transient corneal edema (15.4%), wound leak requiring resuturing (7.7%), retinal detachment (7.7%), and cystoid macular edema (6.4%). One eye (1.3%) developed suture breakage-related late IOL dislocation. Overall, 91.3% of eyes had improved visual acuity or were within 1 line of the presenting CDVA. In eyes with a guarded prognosis, 34.8% achieved a CDVA of 6/12 or better and 43.5% a CDVA of 6/15 to 6/48. In the better prognosis group, 73.9% achieved a CDVA of better than 6/12 and all achieved better than 6/30. CONCLUSIONS: Scleral-sutured IOLs achieved good visual outcomes in a public hospital setting. The rate of complications was moderate in this series with a high proportion of severe ocular trauma and a large percentage of aniridia IOLs. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Alström syndrome--an uncommon cause of early childhood retinal dystrophy.

Alström syndrome (AS) is a ciliopathy and an uncommon cause of syndromic retinal dystrophy. This case reports findings in a 5-year-old boy with severe early onset retinal dystrophy, and how the recognition of extraocular features with genetic analysis led to the correct diagnosis of AS after 4 years of investigation.