Clinical, histopathological, and in silico pathogenicity analyses in a pedigree with familial amyloidosis of the Finnish type (Meretoja syndrome) caused by a novel gelsolin mutation.

Purpose: Familial amyloidosis of the Finnish type (FAF) is an inherited amyloidosis arising from mutations in the gelsolin protein (GSN). The disease includes facial paralysis, loose skin, and lattice corneal dystrophy. To date, FAF has been invariably associated with substitution of Asp214 in GSN. We describe the clinical, histopathological, and genetic features of a family with FAF due to a novel GSN mutation. Methods: Five affected adult individuals in a three-generation FAF pedigree were included in the study. Histopathological analysis was performed on an eyelid skin biopsy from one patient. Genetic analysis included next-generation sequencing (NGS) and Sanger sequencing for confirmation of the GSN variant. Several tools for in silico analysis of pathogenicity for the novel variant and to predict the effect of the amino acid replacement on protein stability were used. Results: Three older adult affected patients exhibited corneal lattice dystrophy, cutis laxa, and facultative peripheral neuropathy. Two younger adult individuals presented only with corneal amyloid deposits. NGS identified a heterozygous GSN c.1631T>G transversion, predicting a novel p.Met544Arg mutation. All in silico tools indicated that p.Met544Arg is deleterious for GSN functionality or stability. Conclusions: The results expand the molecular spectrum of GSN-linked systemic amyloidosis. The novel p.Met544Arg pathogenic variant is predicted to affect gelsolin function, presumably by impairing a potential calcium-sensitive, actin-binding region.

Clinical and Genetic Findings in Mexican Patients with Duane Anomaly and Radial Ray Malformations/Okihiro Syndrome.

BACKGROUND: Okihiro syndrome is an autosomal-dominant condition characterized by radial ray malformations associated with Duane anomaly and other clinical characteristics. SALL4 mutations have been identified in 80-90% of patients with Duane- Radial ray defects/Okihiro syndrome. We report the clinical findings and results of SALL4 sequencing from a group of Mexican patients with this disorder. OBJECTIVE: Clinical description and identification of SALL4 mutations in Mexican subjects with radial defects and Duane anomaly. MATERIALS AND METHODS: Five unrelated index cases were studied. Complete ophthalmologic and general physical examination was performed in all patients. Polymerase chain reaction amplification and automated nucleotide sequencing of coding exons and intron-exon junctions of SALL4 gene were carried out in genomic DNA. RESULTS: A novel heterozygous deletion was identified in one patient. Intragenic heterozygous single nucleotide polymorphisms on SALL4 gene ruled out deletions of some exons in other affected patients in whom non-pathogenic variants were identified by Sanger sequencing. Likewise, multiplex ligation-dependent probe amplification analysis ruled out large deletions in this gene. CONCLUSION: We observed a low frequency of SALL4 mutations in Mexican patients with clinical criteria of Okihiro syndrome.

Association study of multiple gene polymorphisms with the risk of adult-onset primary open-angle glaucoma in a Mexican population.

The aim of this study was to investigate the association of multiple primary open-angle glaucoma (POAG)-risk alleles in a Mexican population for the first time. Genotyping was performed for a total of 26 previously associated alleles located in 11 different genes, including MYOC, CYP1B1, OPTN, IL1A, TNF, OPA1, EDNRA, AGTR2, MTHFR, GSTM1, and GSTT1. The frequencies of these variants were compared in a group of 218 individuals (118 with POAG and 100 adult controls without the disease). Genomic DNA was extracted from blood leukocytes, and genotyping was performed using PCR followed by direct sequencing. GSTM1 and GSTT1 deletion variants were screened by agarose gel analysis. Individual SNP analysis showed that no specific variants conferred an elevated risk for developing POAG. However, the CG genotype for rs5335 polymorphism in EDNRA showed a protective effect against the development of POAG, as it provides an estimated odds ratio of 0.5 (95% CI, 0.3-0.9; p = 0.03). Moreover, one haplotype consisting of rs1056827 and rs100012 in CYP1B1 gene was significantly associated with a protective effect against POAG (p = 0.0045; OR = 0.3; 95% CI, 0.1-0.7). This is the first case-control investigation of POAG-risk alleles in multiple genes in a Latino population. Although our results support that the analyzed variants are not major risk factors for POAG in this ethnic group, they also point toward a protective effect conferred by EDNRA rs5335, as well as by a CYP1B1 haplotype consisting of rs1056827 and rs100012. Our study emphasizes the importance of genotyping ethnic groups with a complex admixture of ancestral populations for contributing to dissecting the genetics of POAG.

Combined Bacterial and Herpes Simplex Virus Keratitis following Small-Incision Lenticule Extraction for the Correction of Myopia.

A 28-year-old male presented unilateral visual loss, intense ocular pain, redness and intraocular hypertension in his right eye 2 days after undergoing small-incision lenticule extraction (SMILE) in both eyes. Initial examination of the affected eye revealed the presence of white infiltrates within the corneal interface, as well as a central epithelial defect. The patient was diagnosed with infectious keratitis, posteriorly the eye was irrigated with balanced saline solution and treatment was initiated with hourly moxifloxacin 0.5%. Since this approach failed to resolve symptoms, a sample from the interface was obtained for PCR assay, which revealed the presence of herpes simplex virus DNA, confirming the cause of the infection. The patient was prescribed a regimen of oral acyclovir, topical ganciclovir and prednisolone. Clinical improvement following resolution of the epithelial defect was observed. Although rare, herpetic keratitis following SMILE is best managed via early diagnosis and initiation of appropriate anti-herpetic treatment.

Pressure-induced stromal keratopathy after laser in situ keratomileusis: Acute and late-onset presentations.

We present a series of 4 cases of pressure-induced stromal keratopathy after laser in situ keratomileusis (LASIK). Four patients (5 eyes) with previous LASIK presented for poor visual acuity and ocular pain because of ocular hypertension. At examination, all cases revealed corneal haze and a space filled with fluid between the surgical flap and the residual stroma. All cases were managed with topical hypotensive treatment and one of them was also treated with a valve drainage device. Topical steroids restriction was indicated in all cases. Intraocular pressure (IOP) was normalized in all cases with subsequent interface fluid resolution and significant improvement of vision in most cases. Early recognition and appropriate treatment for pressure-induced stromal keratopathy is essential to avoid complications associated with prolonged elevated IOP. It is extremely important to measure the IOP in the peripheral cornea because IOP in the central cornea can be incorrectly measured with the characteristic interface fluid developed in this entity.

Familial Gelatinous Drop-Like Corneal Dystrophy Caused by a Novel Nonsense TACSTD2 Mutation.

PURPOSE: To describe the clinical findings and results of molecular analysis in a Mexican family diagnosed with gelatinous drop-like corneal dystrophy (GDLD). METHODS: Ophthalmological examination was performed in 1 unaffected and 4 affected relatives. Molecular analysis included polymerase chain reaction amplification and direct nucleotide sequencing of the entire TACSTD2 gene-coding region in genomic DNA. RESULTS: The corneal phenotype in adult patients was characterized by white-yellow nodular lesions on the corneal surface and stromal neovascularization. Lesions were incipient in an affected relative aged 14 years. Nucleotide sequencing of the TACSTD2 gene demonstrated a homozygous c.331G>T transversion, which predicts a novel p.(E111*) nonsense mutation, in DNA of all 4 GDLD relatives. CONCLUSIONS: Our results expand the mutational spectrum of TACSTD2 in patients with GDLD. To the best of our knowledge, this is the first clinical and molecular description of patients with GDLD from Latin America.

Scheimpflug and Optical Coherence Tomography Analysis of Posterior Keratoconus.

PURPOSE: To report a case series of 7 eyes of 6 patients with posterior keratoconus, evaluating corneal Scheimpflug tomographic changes and anterior-segment optical coherence tomography (OCT). METHODS: In our descriptive study, 6 patients were diagnosed with posterior keratoconus: 5 unilateral (7-, 33-, and 42-year-old males and 64- and 60-year-old female) and 1 bilateral (45-year-old female). Patients were diagnosed with slit-lamp examination, which revealed corneal opacity with an underlying posterior corneal depression. Additional analysis with anterior-segment OCT and Scheimpflug tomography evaluation was performed. RESULTS: Localized paracentral posterior keratoconus was diagnosed in 7 eyes. Scheimpflug images demonstrated posterior corneal depression. Clinical findings were examined by OCT. Genetic analysis revealed no alterations or associated syndromes. All patients were amblyopic in the affected eye, and no surgery was offered to improve their visual acuity. CONCLUSIONS: Posterior keratoconus is a rare noninflammatory condition usually present at birth and sometimes related to developmental abnormalities. Posterior keratoconus is usually unilateral and can present as a generalized or localized change in posterior corneal curvature.

Combined small-incision lenticule extraction and intrastromal corneal collagen crosslinking to treat mild keratoconus: Long-term follow-up.

PURPOSE: To report visual, refractive, and topographic outcomes of sequential, same-day small-incision lenticule extraction and intrastromal corneal collagen crosslinking (CXL) in eyes with mild keratoconus. SETTING: Institute of Ophthalmology Conde de Valenciana, Mexico City, Mexico. DESIGN: Prospective interventional case series. METHODS: Fifteen eyes with forme fruste keratoconus and/or irregular corneas, corrected distance visual acuity 20/40 or better, stable refraction of at least 1 year, age 18 years or older, and residual corneal thickness of greater tan 400 µm before performing collagen crosslinking were studied. Patients were treated with small-incision lenticule extraction followed by intrastromal injection of riboflavin inside the pocket. Ultraviolet A light with a wavelength of 370 nm to 3 mW/cm(2) was applied for 30 minutes. Follow-up was done at 1 day, at 1 week, and at 1, 3, 6, 12, 18, and 24 months. RESULTS: Eight patients were included in the study. The mean age was 29.5 years ± 5.5 (SD) (range 20 to 36 years). Twenty-four months of follow-up were completed in 13 eyes, and 12 months were completed in 2 eyes. Preoperative uncorrected distance visual acuity improved from 1.6 ± 0.3 LogMAR (Snellen 20/796) to postoperative 0.12 ± 0.20 LogMAR (Snellen 20/26) and was statistically significant (P < .001). Best-corrected distance visual acuity did not change significantly (P = .186), from 0.006 ± 0.02 LogMAR (Snellen 20/20) preoperatively to 0.04 ± 0.05 LogMAR (Snellen 20/21) postoperatively, and spherical equivalent improved from -4.3 ± 1.02 preoperatively to 0.2 ± 0.66 (P < .001). CONCLUSION: Although further follow-up and larger samples are needed to fully confirm these findings, the results suggest that combined small-incision lenticule extraction and intrastromal corneal collagen crosslinking are a promising treatment option for patients for whom conventional laser refractive surgery is contraindicated. FINANCIAL DISCLOSURE: Drs. Ramirez-Miranda and Navas are consultants to Carl Zeiss Meditec. No other author has a financial or proprietary interest in any material or method mentioned.

Rhodopsin p.N78I dominant mutation causing sectorial retinitis pigmentosa in a pedigree with intrafamilial clinical heterogeneity.

OBJECTIVE: The purpose of this study was to determine the molecular basis of retinitis pigmentosa (RP) in a 4 affected sib-family segregating this retinal phenotype. METHODS: Affected sibs underwent complete ophthalmologic examination including funduscopic inspection, electroretinogram, fluorescein angiography, visual field measurement, and optical coherence tomography. Both parents were deceased after their sixties and were reported with no visual handicap. Molecular analysis included direct nucleotide sequencing of the rhodopsin gene (RHO), at chromosome 3q21-q24, in DNA from a total of 4 affected sibs. A total of 200 ethnically matched alleles were included as mutation controls. RESULTS: Sector RP was clinically documented in this family. Wide phenotypic variability was observed with visual acuities ranging from 20/20 to 20/200 and variable funduscopic appearance. Molecular analysis disclosed a c.233A>T mutation at RHO exon 1, predicting a missense p.N78I substitution. CONCLUSIONS: Even though RP can be caused by mutations in a variety of genes, the RHO gene was chosen to be investigated in this RP family since it has been previously associated to sector disease. This case exemplifies the value of guiding RP molecular analysis based on funduscopic features.