DLG2 intragenic exonic deletions reinforce the link to neurodevelopmental disorders and suggest a potential association with congenital anomalies and dysmorphism.

PURPOSE: Multiple studies suggest an association between DLG2 and neurodevelopmental disorders and indicate the haploinsufficiency of this gene; however, few cases have been thoroughly described. We performed additional studies to confirm this clinical association and DLG2 haploinsufficiency. METHODS: Chromosomal microarray analysis was performed on 11,107 patients at the Cytogenetics Laboratory at the University of Alabama at Birmingham. The Database of Genomic Variants-Gold Standard Variants and the Genome Aggregation Database were selected for the association analysis. Fifty-nine patients from the literature and DECIPHER, all having DLG2 intragenic deletions, were included for comprehensive analysis of the distribution of these deletions. RESULTS: A total of 13 patients with DLG2 intragenic deletions, from 10 families in our cohort, were identified. Nine of 10 probands presented with clinical features of neurodevelopmental disorders. Congenital anomalies and dysmorphism were common in our cohort of patients. Association analysis showed that the frequency of DLG2 deletions in our cohort is significantly higher than those in the Database of Genomic Variants-Gold Standard Variants and the Genome Aggregation Database. Most of DLG2 intragenic deletions identified in 69 unrelated patients from our cohort, the literature, and DECIPHER map to the 5' region of the gene, with a hotspot centered around HPin7, exon 8, and HPin8. CONCLUSION: Our findings reinforce the link between DLG2 intragenic deletions and neurodevelopmental disorders, strongly support the haploinsufficiency of this gene, and indicate that these deletions might also have an association with congenital anomalies and dysmorphism.

Mitochondrial genome variant m.3250T>C as a possible risk factor for mitochondrial cardiomyopathy.

The MT-TL1 gene codes for the mitochondrial leucine transfer RNA (tRNALeu(UUR) ) necessary for mitochondrial translation. Pathogenic variants in the MT-TL1 gene result in mitochondriopathy in humans. The m.3250T>C variant in the MT-TL1 gene has been previously associated with exercise intolerance and mitochondrial myopathy, yet disease classification for this variant has not been consistently reported. Molecular studies suggest the m.3250T>C variant does not alter tRNALeu(UUR) structure but may have a modest impact on aminoacylation capacity. However, functional studies are limited. Our study aimed to further define the clinical presentation, inheritance pattern, and molecular pathology of the m.3250T>C variant. Families with the m.3250T>C variant were recruited from the Mitochondrial Disease Clinic at Cincinnati Children's Hospital Medical Center and GeneDx laboratory database. Affected individuals most frequently presented with cardiac findings, exercise intolerance, and muscle weakness. Hypertrophic cardiomyopathy was the most frequent cardiac finding. Many asymptomatic individuals had homoplasmic or near homoplasmic levels of the m.3250T>C variant, suggesting the penetrance is incomplete. Patient-derived fibroblasts demonstrated lowered ATP production and increased levels of reactive oxygen species. Our results demonstrate that the m.3250T>C variant exhibits incomplete penetrance and may be a possible cause of cardiomyopathy by impacting cellular respiration in mitochondria.

The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction.

PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. METHODS: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. RESULTS: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. CONCLUSION: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.

Fragile Bones Secondary to SMURF1 Gene Duplication.

Studies on mice have shown that the Smad Ubiquitin Regulatory Factor-1 (SMURF1) gene negatively regulates osteoblast function and the response to bone morphogenetic protein in a dose-dependent fashion (Chan et al. in Mol Cell Biol 27(16):5776-5789, https://doi.org/10.1128/MCB.00218-07, 2007; Yamashita et al. in Cell 121(1):101-113, https://doi.org/10.1016/j.cell.2005.01.035, 2005). In addition, a tumorigenic role for SMURF1 has been implicated due to the interference with apoptosis signals (Nie et al. in J Biol Chem 285(30):22818-22830, https://doi.org/10.1074/jbc.M110.126920, 2010; Wang et al. in Nat Commun 5:4901, https://doi.org/10.1038/ncomms5901, 2014). A 10-year-old girl with a history of severe developmental delay, infantile seizures, and B-cell lymphoma, in remission for approximately 3.5 years, was referred to the metabolic bone clinic for fractures and low bone mineral density. Array comparative genomic hybridization revealed a pathogenic microduplication in chromosome 7 at bands 7q21.3q22.1 that encompasses the SMURF1 gene. The clinical features of this child are congruous with the phenotype as ascribed excess Smurf1 mutations in mice. This is the first case description of osteoporosis in a child secondary to a microduplication involving SMURF1 gene.

Haptic Amputation Under Endoscopic Guidance in Uveitis-Glaucoma-Hyphema Syndrome: A Case Report.

Uveitis-glaucoma-hyphema (UGH) syndrome is a rare ophthalmic postoperative complication in which the intraocular implants or devices like intraocular lenses (IOLs) produce chronic mechanical chaffing to the adjacent uveal tissues and/or trabecular meshwork (TM) resulting in a wide spectrum of clinical ophthalmic manifestations ranging from chronic uveitis to secondary pigment dispersion, iris defects, hyphema, macular oedema, or spiked intraocular pressure (IOP). Spiked IOP is a result of direct damage to the TM, hyphema, pigment dispersion, or recurrent intraocular inflammation. UGH syndrome generally develops over a time course, varying from weeks to several years postoperatively. Conservative treatment with anti-inflammatory and ocular hypotensive agents might be sufficient in mild to moderate UGH cases but surgical intervention with implant repositioning, exchange, or explantation might be necessary in more advanced situations. Here, we report our challenge in managing a one-eyed 79-year-old male patient with UGH secondary to migrated haptic, which was successfully managed by intraoperative IOL haptic amputation under endoscopic guidance.

An Adoptive Threshold-Based Multi-Level Deep Convolutional Neural Network for Glaucoma Eye Disease Detection and Classification.

Glaucoma, an eye disease, occurs due to Retinal damages and it is an ordinary cause of blindness. Most of the available examining procedures are too long and require manual instructions to use them. In this work, we proposed a multi-level deep convolutional neural network (ML-DCNN) architecture on retinal fundus images to diagnose glaucoma. We collected a retinal fundus images database from the local hospital. The fundus images are pre-processed by an adaptive histogram equalizer to reduce the noise of images. The ML-DCNN architecture is used for features extraction and classification into two phases, one for glaucoma detection known as detection-net and the second one is classification-net used for classification of affected retinal glaucoma images into three different categories: Advanced, Moderate and Early. The proposed model is tested on 1338 retinal glaucoma images and performance is measured in the form of different statistical terms known as sensitivity (SE), specificity (SP), accuracy (ACC), and precision (PRE). On average, SE of 97.04%, SP of 98.99%, ACC of 99.39%, and PRC of 98.2% are achieved. The obtained outcomes are comparable to the state-of-the-art systems and achieved competitive results to solve the glaucoma eye disease problems for complex glaucoma eye disease cases.

Retinal Detachment After Cyclophotocoagulation in a Child with Knobloch Syndrome.

Knobloch syndrome (KS) is typically characterized by high myopia, vitreoretinal degeneration, retinal detachment, and macular abnormalities. We report a case of glaucoma in KS, which represents the fourth reported case and the first description of the retinal events after the glaucoma procedure. Retinal detachment followed standard cyclophotocoagulation procedure for glaucoma in a 2-month-old boy. Ophthalmologists should be aware of the possibility of retinal detachment from any ocular intervention in patients with KS.

Overhanging-Dissecting Blebs: Immunohistochemical Characterization.

PURPOSE: The purpose of this study was to determine if glaucoma filtering blebs migrate over or under the cornea epithelium using histopathologic and immunohistochemical techniques to evaluate the likely origin of the surface epithelium and bleb matrix. METHODS: Histologic and immunohistochemical evaluations were performed of normal conjunctiva (n=4), corneal overhanging-dissecting blebs (n=4), and leaking blebs over the scleral surface (n=6). Antibodies were used against epithelial [cytokeratin 3 (CK3)+12, CK13] and extracellular matrix [decorin and keratan sulfate (KS)] antigens. Labeling was graded in a semiquantitative manner. RESULT: The epithelium of dissecting (over cornea) blebs was labeled primarily with CK3+12 antibody. KS staining was faint and comparable in normal conjunctiva, and the stroma of dissecting and leaking blebs (P=0.12). Decorin staining in the normal conjunctival stroma was of moderate intensity and comparable with the dissecting bleb staining and; significantly greater than that in the leaking blebs (P=0.02). CONCLUSIONS: Histology and ICH indicate that the epithelium of the dissecting blebs has a corneal epithelial phenotype. The extracellular matrix immunophenotype was similar to the normal conjunctival stroma suggesting that dissecting blebs migrate under the corneal epithelium.

Short and long-term outcomes of angle supported phakic intraocular lens implantation in high myopic eyes.

This cohort study included 36 eyes of 21 patients with high myopia treated with angle supported phakic intraocular lens (pIOL). Endothelial cell density (ECD) at baseline, 6mo and 3y were 3017±296, 2775±265 and 2558±299 cells/mm2 respectively. ECD loss at 6mo was 7.2% and annual ECD loss was 3% over 36mo. Corrected distance visual acuity at 36mo was 0.4 logMAR or better in 32 (88.9%) eyes. Intraocular pressure did not change (P=0.9). No eyes developed cataract, retinal detachment or pupillary distortion. Angle supported pIOL gives good visual outcome. Endothelial cell loss should be monitored.

Indications and techniques employed for keratoplasty in the Eastern province of Saudi Arabia: 6 years of experience.

BACKGROUND AND OBJECTIVES: Keratoplasty services in Saudi Arabia have progressed steadily in the past few decades. We sought to identify the leading indications and types of keratoplasty performed in the Eastern Province of Saudi Arabia over a six-year period and to compare these indications with published data. DESIGN AND SETTING: This was a retrospective descriptive analysis of the records of patients who underwent keratoplasty at four ophthalmology centers in the Eastern Province between 2008 and 2013. PATIENTS AND METHODS: All keratoplasty procedures were included in the analysis. The primary surgical indication and type of surgery were identified for each case. RESULTS: Keratoplasties included 570 penetrating keratoplasty, 217 deep lamellar keratoplasty, 80 triple procedures, 24 descemet stripping automated endothelial keratoplasty and 12 Boston keratoprosthesis implantations. The mean age of all patients was 28.8 years (range 14-72 years), and 58.9% of the patient were males. The lead.ing indication for keratoplasty was keratoconus 53.10%, bullous keratopathy 13.80%, corneal scarring 10.7%, regrafts 9.1%, and stromal dystrophies 4.9%. CONCLUSIONS: In this study, the leading indications for keratoplasty were keratoconus, bullous keratopathy, corneal scarring, regrafts and stromal dystrophies. A significant increasing trend for descemet's stripping automated endothelial keratoplasty surgeries was observed in spite of the number of cases.