The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease.

Childhood glaucoma encompasses congenital and juvenile primary glaucoma, which are heterogeneous, uncommon, and irreversible optic neuropathies leading to visual impairment with a poorly understood genetic basis. Our goal was to identify gene variants associated with these glaucoma types by assessing the mutational burden in 76 matrix metalloproteinase-related genes. We studied 101 childhood glaucoma patients with no identified monogenic alterations using next-generation sequencing. Gene expression was assessed through immunohistochemistry. Functional analysis of selected gene variants was conducted in cultured cells and in zebrafish. Patients presented a higher proportion of rare variants in four metalloproteinase-related genes, including CPAMD8 and ADAMTSL4, compared to controls. ADAMTSL4 protein expression was observed in the anterior segment of both the adult human and zebrafish larvae's eye, including tissues associated with glaucoma. In HEK-293T cells, expression of four ADAMTSL4 variants identified in this study showed that two variants (p.Arg774Trp and p.Arg98Trp) accumulated intracellularly, inducing endoplasmic reticulum stress. Additionally, overexpressing these ADAMTSL4 variants in zebrafish embryos confirmed partial loss-of-function effects for p.Ser719Leu and p.Arg1083His. Double heterozygous functional suppression of adamtsl4 and cpamd8 zebrafish orthologs resulted in reduced volume of both the anterior eye chamber and lens within the chamber, supporting a genetic interaction between these genes. Our findings suggest that accumulation of partial functional defects in matrix metalloproteinase-related genes may contribute to increased susceptibility to early-onset glaucoma and provide further evidence supporting the notion of a complex genetic inheritance pattern underlying the disease.

Preserflo TM MicroShunt implantation combined with Ologen TM in primary and secondary glaucoma patients in a clinical setting.

PURPOSE: This study aims to assess the effectiveness and safety of combining the Preserflo™ MicroShunt implant (MicroShunt) with a simultaneous Ologen™ implant in patients with glaucoma. METHODS: We conducted a retrospective study on consecutive patients with medically uncontrolled glaucoma who underwent MicroShunt + Ologen implantation as a standalone procedure or in combination with phacoemulsification (combined procedure). Success was defined as achieving an intraocular pressure (IOP) of 6-15 mmHg at 18 months post surgery, with a preoperative IOP reduction of at least 20%, and without (complete success) or with (qualified success) the need for antiglaucoma medications. The primary endpoint was the success rate. RESULTS: Forty-eight eyes from 47 patients were included, with 28 eyes (58.3%) undergoing the standalone procedure and 20 eyes (41.7%) undergoing the combined procedure. Overall, there was a significant reduction in preoperative IOP from 19.7 ± 5.8 mmHg to 11.4 ± 2.6 mmHg at 18 months ( P < 0.0001). In the standalone procedure group, preoperative IOP decreased from 21.5 ± 5.2 mmHg to 11.7 ± 2.5 mmHg ( P < 0.0001), and in the combined procedure group, preoperative IOP decreased from 17.1 ± 5.8 mmHg to 10.9 ± 2.7 mmHg ( P = 0.0002), with no significant difference between the two groups regarding final IOP. The mean number of antiglaucoma medications significantly decreased from 3.2 ± 1.1 to 0.3 ± 0.7 in the overall study population ( P < 0.0001). At 18 months, 40 eyes (83.3%) were classified as successful. Regarding safety, out of the total number of eyes, two (4.2%) experienced choroidal detachment without visual impairment, two (4.2%) had transient hyphema, one (2.1%) showed reactivation of a corneal herpetic ulcer, one (2.1%) had diplopia, and one (2.1%) exhibited a shallow anterior chamber during the first week. CONCLUSION: The combination of Ologen™ and Preserflo™ MicroShunt, either alone or in conjunction with phacoemulsification, demonstrated a favorable profile in terms of IOP reduction and safety.

Intraoperative OCT to check the correct postimplant position of PreserfloTM.

INTRODUCTION: This study was designed to examine the capacity of intraoperative optical coherence tomography (OCT) to predict the postimplant position of the glaucoma drainage device PreserfloTM. METHODS: 13 eyes (mean age 65.42 (14.89) years) underwent PreserfloTM (Santen, Osaka, Japan) placement. Before surgery, participants were subjected to a comprehensive ophthalmic examination (intraocular pressure (IOP), cup to disk ratio (C/D), visual field, OCT, endothelial cell count). Anterior segment OCT scans were obtained intraoperatively using a Rescan 700 OCT system (Carl Zeiss Meditec, Inc., Oberkochen, Germany). One day postsurgery, anterior segment OCT using the Spectralis OCT (Heidelberg Engineering GmbH) was performed in a sitting position to capture the same chamber cross-section as before. The main outcome variables were tube-endothelium distance (T-E) and tube length (TL) in the anterior chamber measured using both OCT systems. Correlation between intraoperative and office measurements was examined through Pearson correlation (r) and intraclass correlation coefficients (ICC). RESULTS: Mean intraoperative and in-office T-E were 625.26 (SD 366.60) versus 561.16 (SD 364.62) µm respectively (p = 0.540). Intraoperative and in-office anterior chamber TL were 1386 (SD 701.82) and 1433.91 (SD 713.55) µm, respectively (p = 0.029). Excellent correlation was observed between both sets of T-E (r = 0.992; p = 0.008) and TL (r = 0.984; p = 0.016) values. Both OCT systems showed good agreement yielding ICCs of 0.992 (p < 0.001) for T-E and 0.995 (p = 0.001) for TL. DISCUSSION: Excellent correlation was observed between our intraoperative and postoperative OCT measurements. These results support the usefulness of intraoperative OCT to confirm the correct position of an implanted PreserfloTM microshunt.

Effectiveness and safety of XEN63 in patients with primary-open-angle glaucoma.

This paper evaluates the effectiveness and safety of XEN63 stent, either standalone or in combination with phacoemulsification, in patients with primary open-angle glaucoma (POAG). Eighty eyes from 80 patients with medically uncontrolled POAG were assigned to undergo XEN63 implant. The primary outcome was the surgical success, defined as an intraocular pressure (IOP) lowering from preoperative values ≥ 20% and an IOP absolute value between 6 and 18 mmHg, with or without antiglaucoma medications. Forty-three (53.7%) eyes underwent XEN63-standalone and 37(46.2%) eyes a XEN63 + Phacoemulsification procedure. Success rate was 68.8% (55/80) eyes in the overall study sample, 69.8% (30/43) eyes in the XEN63-standalone group; and 67.6% (25/37) eyes in the XEN63 + Phaco group (p = 0.6133). Preoperative IOP was significantly lowered from 22.1 ± 4.9 mmHg and 19.8 ± 3.7 mmHg to 14.7 ± 5.3 mmHg and 13.8 ± 3.4 mmHg in the XEN63-standalone and XEN63 + Phaco groups, respectively (p < 0.0001 each, respectively); without significant differences between them at any of the time-points measured. Preoperative number of ocular-hypotensive drugs was significantly reduced from 2.3 ± 0.8 to 0.3 ± 0.7 drugs, from 2.5 ± 0.7 to 0.3 ± 0.7 drugs; and from 2.0 ± 0.8 to 0.3 ± 0.7 drugs, in the overall, XEN63-standalone, and XEN63 + Phaco groups, respectively. Regarding safety, 3(42.5%) eyes had transient hypotony at some point during the study, although only in one (1.2%) eye was clinically significant. Four (5.0%) eyes underwent a needling, 4 (5.0%) eyes underwent surgical-bleb-revision, 1 (1.2%) eye required a device replacement and 1 (1.2%) eye a device removal due to maculopathy. XEN63, either alone or in combination with phacoemulsification, significantly lowered IOP and reduced the number of ocular hypotensive medications. The rate of ocular hypotony was relatively high, although it was clinically relevant only in one eye.

Primary congenital glaucoma in two siblings with different compound heterozygous CYP1B1 genotypes.

OBJECTIVE: To describe the inheritance pattern and clinical variability of primary congenital glaucoma (PCG) in a family with two affected siblings. MATERIALS AND METHODS: Two sisters diagnosed at birth with bilateral PCG, whose father had bilateral PCG and mother had bilateral microphthalmus, were subjected to a familial genetic study and ophthalmologic follow-up including intraocular pressure (IOP) measurement, and collection of biometric and cup-to-disc ratio data. RESULTS: The inheritance pattern was autosomal recessive in compound heterozygosis. The sisters were found to be carriers of three pathogenic allele variants of the CYP1B1 gene: c.317C>A (p.Ala106Asp) and c.1345delG (p.Asp449MetfsTer8) in one patient (10 years) and c.1345delG (p.Asp449MetfsTer8) and c.202_209delCAGGCGGC (p.Gln68Serfs153Ter) in her older sister (12 years). Surgical histories included: three goniotomies and two Ahmed valves in each eye, and two trabeculectomies and a pupilloplasty in the right eye in the 10-year old; and one goniotomy, trabeculectomy and three Ahmed valves in each eye in the older sister. Currently, both sisters have a controlled intraocular pressure of 18-20 mmHg in both eyes. The father is blind in both eyes and carries two variants c.317C>A (p.Ala106Asp) and c.202_209delCAGGCGGC (p.Gln68Serfs153Ter). The mother with a single variant c.1345delG (p.Asp440MetfsTer8) has a prosthetic right eye and microphthalmus left eye. CONCLUSIONS: The sisters were found to show two different allelic CYP1B1 variants (compound heterozygosis) with different repercussions on the clinical severity of PCG. These findings highlight the importance of genetic screening of affected families.