Comprehensive Genotyping and Phenotyping Analysis of GUCY2D-Associated Rod- and Cone-Dominated Dystrophies.

PURPOSE: To describe the genetic and clinical spectrum of GUCY2D-associated retinopathies and to accurately establish their prevalence in a large cohort of patients. DESIGN: Retrospective case series. METHODS: Institutional study of 47 patients from 27 unrelated families with retinal dystrophies carrying disease-causing GUCY2D variants from the Fundación Jiménez Díaz hospital dataset of 8000 patients. Patients underwent ophthalmological examination and molecular testing by Sanger or exome sequencing approaches. Statistical and principal component analyses were performed to determine genotype-phenotype correlations. RESULTS: Four clinically different associated phenotypes were identified: 66.7% of families with cone/cone-rod dystrophy, 22.2% with Leber congenital amaurosis, 7.4% with early-onset retinitis pigmentosa, and 3.7% with congenital night blindness. Twenty-three disease-causing GUCY2D variants were identified, including 6 novel variants. Biallelic variants accounted for 28% of patients, whereas most carried dominant alleles associated with cone/cone-rod dystrophy. The disease onset had statistically significant differences according to the functional variant effect. Patients carrying GUCY2D variants were projected into 3 subgroups by allelic combination, disease onset, and presence of nystagmus or night blindness. In contrast to patients with the most severe phenotype of Leber congenital amaurosis, 7 patients with biallelic GUCY2D had a later and milder rod form with night blindness in infancy as the first symptom. CONCLUSIONS: This study represents the largest GUCY2D cohort in which 4 distinctly different phenotypes were identified, including rare intermediate presentations of rod-dominated retinopathies. We established that GUCY2D is linked to about 1% of approximately 3000 molecularly characterized families of our cohort. All of these findings are critical for defining cohorts for inclusion in future clinical trials.

Generation of the induced pluripotent stem cell line SFMUi001-A from a patient with usher syndrome type 2 caused by biallelic variants in the USH2A gene.

Biallelic variants in the USH2A gene cause Usher syndrome type 2 (USH2), in which patients' symptoms are progressive night blindness, reduced visual field, decreased central vision and sensorineural hearing impairment. There is currently no effective drug for USH2. In this study, we isolated peripheral blood mononuclear cells from a patient with USH2. The pluripotency of induced cells was verified by the presence of cell surface markers, the expression of pluripotent genes, and the formation of teratomas. The generation of this induced pluripotent stem cell line provides an effective way to study USH2, such as disease modeling and drug screening. Usher syndrome type 2 (USH2) is a genetic disease mainly caused by biallelic variants in the USH2A gene. Patients usually present with progressive night blindness, reduced visual field, and then reduced central vision. Patients with USH2 also have sensorineural hearing impairment. There is currently no effective treatment for USH2, and the pathogenesis is still unclear. Therefore, it is of great significance to study the pathogenic mechanism of USH2A gene variants for the study of therapeutic targets. In this study, we obtained induced pluripotent stem cell (iPSC) line containing USH2A gene variants. We isolated mononuclear cells from the peripheral blood of patient and established iPSCs by reprogramming with nonintegrating vectors. We then confirmed the pluripotency of our generated iPSCs through the detection of multiple cell surface markers, the expression of pluripotency-related genes, and the ability to form teratomas with three germ layer structures in vivo. The generation of this cell line will facilitate research on USH2 disease and will play a role that cannot be underestimated in future organoid generation, drug screening, and research on drug targets as well as mechanisms.

Extended functional rescue following AAV gene therapy in a canine model of LRIT3-congenital stationary night blindness.

Congenital stationary night blindness (CSNB) is a group of inherited retinal diseases in which either rod-to-ON-bipolar cell (ON-BC) signaling, or rod function is affected leading to impaired vision under low light conditions. One type of CSNB is associated with defects in genes (NYX, GRM6, TRPM1, GPR179, and LRIT3) involved in the mGluR6 signaling cascade at the ON-BC dendritic tips. We have previously characterized a canine model of LRIT3-CSNB and demonstrated short-term safety and efficacy of an ON-BC targeting AAV-LRIT3 (AAVK9#4-shGRM6-cLRIT3-WPRE) gene therapy. Herein, we demonstrate long-term functional recovery and molecular restoration following subretinal injection of the ON-BC targeting AAV-LRIT3 vector in all eight treated eyes for up to 32 months. Following subretinal administration of the therapeutic vector, expression of the LRIT3 transgene, as well as restoration of mGluR6 signaling cascade member TRPM1, were confirmed in the outer plexiform layer (OPL) of the treated area. However, further investigation of the transgene LRIT3 transcript expression by RNA in situ hybridization (RNA-ISH) revealed off-target expression in non-BCs including the photoreceptors, inner nuclear, and ganglion cell layers, despite the use of a mutant AAVK9#4 capsid and an improved mGluR6 promoter designed to specifically transduce and promote expression in ON-BCs. While the long-term therapeutic potential of AAVK9#4-shGRM6-cLRIT3-WPRE is promising, we highlight the necessity for further optimization of AAV-LRIT3 therapy in the canine CSNB model prior to its clinical application.

Birt-Hogg-Dubé syndrome associated with chorioretinopathy and nyctalopia: a case report and review of the literature.

PURPOSE: To report a rare case of Birt-Hogg-Dubé Syndrome (BHD) with progressive chorioretinopathy. METHODS: Case report. RESULTS: A 55-year-old woman presented with longstanding nyctalopia attributed to a congenital retinal dystrophy, but no prior genetic testing. Her posterior pole examination demonstrated retinal pigment epithelium (RPE) mottling with extensive macular drusen and paracentral chorioretinal atrophy, consistent with a fleck retinopathy. Her past medical history was remarkable for nephrectomy for unilateral renal malignancy, parotid tumors and thyroid nodules. Dark adaptation time was prolonged, and electroretinography (ERG) revealed abnormal waveforms with depressed amplitudes. Genetic testing confirmed a deletion mutation in the folliculin (FLCN) gene and was negative for other relevant mutations, including EFEMP1 responsible for autosomal dominant macular and peripapillary drusen in Doyne honeycomb retinal dystrophy and TIMP3 responsible for Sorsby Fundus Dystrophy. CONCLUSION: BHD is a rare autosomal-dominant disorder with multi-systemic clinical manifestations caused by a mutation in the FLCN gene. Affected individuals are prone to renal and pulmonary cysts, renal cancer, and fibrofolliculomas. Reports on ocular manifestations of BHD include eyelid fibrofolliculomas, flecked chorioretinopathy, choroidal melanoma, choroidal melanoma with sector melanocytosis, and retinal pigment epithelial micro-detachments. In this case of BHD, we note a fleck retinopathy with bilateral chorioretinal atrophy, displaying a phenotype of extensive chorioretinopathy associated with impaired dark adaptation and ERG abnormalities. ABBREVIATIONS: BHD: Birt-Hogg-Dubé syndrome; FLCN: Folliculin. RPE: retinal pigment epithelium; OD: Oculus dexter (right eye); OS: Oculus sinister (left eye). OU: Oculus uterque (both eyes); ERG: electroretinogram; mfERG: multifocal electroretinography. ffERG: full-field electroretinography; FAF: fundus autofluorescence; OCT: optical coherence tomography; FA: fluorescein angiography; DA: dark-adapted; LA: light-adapted; mTOR: mammalian target of rapamycin; EFEMP1: epithelial growth factor-containing fibulin-like extracellular matrix protein 1; VPS13B: Vacuolar Protein Sorting 13 Homolog B; AGBL5: AATP/GTP-Binding Protein Like 5; ALMS1: Alstrom Syndrome 1; COL1BA1: Collagen Type I Beta, Alpha Chain 1; PDE6A: Rod Phosphodiesterase 6-alpha; USH2A: Usherin 2a; VCAN: Versican; RP: Retinitis pigmentosa; AR: Autosomal recessive.

A MIDDLE-AGED PATIENT WITH BILATERAL VISION LOSS AND NYCTALOPIA.

PURPOSE: To report a case of nonparaneoplastic autoimmune retinopathy in a patient with a diagnosis of Lambert-Eaton myasthenic syndrome. METHODS: Case report. Main outcome measures included findings on retinal examination and analysis of fundus autofluorescence, spectral-domain optical coherence tomography, and full-field electroretinogram. Vitamin A levels and results of antiretinal antibody testing and paraneoplastic workup are also presented. RESULTS: A 47-year-old male presented with a 1-year history of bilateral vision loss and nyctalopia. Past medical history was significant for Lambert-Eaton myasthenic syndrome, confirmed by positive voltage-gated calcium channel antibodies, and thymectomy reported as thymic follicular hyperplasia. Optical coherence tomography showed bilateral diffuse outer retinal atrophy and ellipsoid zone loss. Fundus autofluorescence displayed a bull's pattern of hyperautofluorescence around each fovea. Full-field electroretinogram showed an extinguished rod response and a severely depressed cone response in each eye. CONCLUSION: We describe a case of nonparaneoplastic autoimmune retinopathy in a patient with Lambert-Eaton myasthenic syndrome. Multimodal retinal imaging and electroretinogram confirmed the presence of autoimmune retinopathy with severe rod-cone degeneration. The association of this myasthenic syndrome with AIR is novel.

Unilateral cataract and congenital stationary night blindness in a child with novel variants in TRPM1.

Unilateral cataract can cause pediatric vision impairment. Although the majority of unilateral cataracts are idiopathic in nature, genetic causes have been reported. We present the case of a 4-week-old child of nonconsanguineous parents who was affected with unilateral cataract. Whole-genome sequencing using DNA extracted from blood and the lens epithelial cells following cataract surgery revealed two presumed pathogenic variants in the TRPM1 gene, the founding member of the melanoma-related transient receptor potential (TRPM) subfamily. TRPM1 is responsible for regulating cation influx to hyperpolarized retinal ON bipolar cells, and mutations in this gene are a major cause of autosomal recessive congenital stationary night blindness (CSNB). Electroretinography revealed findings consistent with CSNB, a phenotype that was not initially suspected, and which would likely have been missed without genome sequencing. It remains unclear whether the TRPM1 variants are associated with the cataract phenotype.

Mutation analysis reveals novel and known mutations in SAG gene in first two Egyptian families with Oguchi disease.

BACKGROUND: Oguchi disease is a rare type of congenital stationary night blindness associated with an abnormal fundus appearance. It is inherited in an autosomal recessive manner where two types exist according to the gene affected; type 1 associated with S-antigen (SAG) gene mutations and type 2 associated with rhodopsin kinase (GRK1) gene mutations. PURPOSE: The aim of this work was to describe the clinical and genetic findings of the first two reported families of Oguchi disease in Egypt and African region. METHODS: Four members of two consanguineous Egyptian families with history of night blindness since childhood underwent complete ophthalmological examination, standard automated static perimetry, fundus color photography, fundus autofluorescence (FAF), fundus fluorescein angiography (FFA) in light-adapted state and spectral-domain optical coherence tomography (SD-OCT) of both the macula and the optic nerve head as well as central corneal thickness with repeated fundus photography following prolonged dark adaptation. Mutation screening of 7 coding exons of GRK1 gene and 15 coding exons of SAG gene as well as some flanking regions were performed using Sanger sequencing technique. The variants were tested for pathogenicity using different in silico functional analysis tools. RESULTS: The clinical examination and investigations confirmed Oguchi disease phenotype. One patient showed p.R193* (c.577C > T) which is a previously reported SAG gene mutation in a homozygous form. The other three patients from a different family showed (c.649-1 G > C), a novel canonical splice site SAG gene mutation in a homozygous form. CONCLUSION: The identification of the novel canonical splice site SAG gene variant in three members of the same family with clinically confirmed Oguchi disease reinforces its pathogenicity. A fourth patient from another family carried a previously reported mutation in the same gene. SAG gene variants may be the underlying genetic cause for Oguchi disease in Egypt. Our findings have expanded the spectrum of Oguchi disease-associated mutations in SAG gene and may serve as a basis for genetic diagnosis for Oguchi disease.

Targeting ON-bipolar cells by AAV gene therapy stably reverses LRIT3-congenital stationary night blindness.

SignificanceCanine models of inherited retinal diseases have helped advance adeno-associated virus (AAV)-based gene therapies targeting specific cells in the outer retina for treating blinding diseases in patients. However, therapeutic targeting of diseases such as congenital stationary night blindness (CSNB) that exhibit defects in ON-bipolar cells (ON-BCs) of the midretina remains underdeveloped. Using a leucine-rich repeat, immunoglobulin-like and transmembrane domain 3 (LRIT3) mutant canine model of CSNB exhibiting ON-BC dysfunction, we tested the ability of cell-specific AAV capsids and promotors to specifically target ON-BCs for gene delivery. Subretinal injection of one vector demonstrated safety and efficacy with robust and stable rescue of electroretinography signals and night vision up to 1 y, paving the way for clinical trials in patients.

Electronegative electroretinogram in the modern multimodal imaging era.

BACKGROUND: The electronegative electroretinogram (ERG) reflecting inner retinal dysfunction can assist as a diagnostic tool to determine the anatomical location in eye disease. The aim of this study is to determine the frequency and aetiology of electronegative ERG in a tertiary ophthalmology centre and to develop a clinical algorithm to assist patient management. METHODS: Retrospective review of ERGs performed at the Save Sight Institute from January 2011 to December 2020. ERGs were performed according to ISCEV standard. The b:a ratio was analysed in dark adapted (DA) 3.0 or 12.0 recordings. Patients with ratio of ≤1.0 were included. RESULTS: A total of 4421 patients had ERGs performed during study period, of which 139 patients (3.1%) had electronegative ERG. The electronegative ERG patients' median age at referral time was 37 (0.7-90.6) years. The causative aetiologies were photoreceptor dystrophy (48, 34.5%), Congenital Stationary Night Blindness (CSNB) (33, 23.7%), retinal ischemia (18, 12.9%), retinoschisis (15, 10.8%), paraneoplastic autoimmune retinopathy (PAIR) and nonPAIR (14, 10.1%), batten disease (4, 2.9%), and inflammatory retinopathy (4, 2.9%). There were three patients with an unclassified diagnosis. Thirty-two patients (23%) had good vision and a normal fundus appearance. Eleven patients (7.9%) had good vision and normal results in all multimodal imaging. CONCLUSIONS: The frequency of electronegative ERG in our referral centre was 3.1% with photoreceptor dystrophy as the main aetiology. A significant number of the cases had good vision with normal fundus or normal multimodal imaging. This further highlights the value of an ERG in this modern multimodal imaging era.

Vitamin A retinopathy secondary to Billroth II anastomosis triggered after the beginning of dialysis.

PURPOSE: To report a case of vitamin A retinopathy secondary to Billroth II anastomosis triggered after the beginning of dialysis in a patient with a chronic renal failure. CASE REPORT: A 73-year-old male complained of nyctalopia that had started 9 months ago, coinciding with the beginning of dialysis. His medical history is remarkable for hepatic cirrhosis and Billroth II anastomosis 20 years ago. Best-corrected visual acuity (BCVA) was 60 letters in both eyes. Dilated fundus examination showed faint white-yellowish dots. Optical coherence tomography (OCT) illustrated hyperreflective dots and small hyporreflective cavities between the retinal pigment epithelium (RPE) and the ellipsoid zone (EZ). En face OCT showed multiple hyperreflective dots that coincide with white-yellowish dots of the fundus, and multiple hyporreflective defects which correspond to hyporreflective cavities seen in the OCT. Visual field examination showed concentric narrowing of the visual field. A diagnosis of vitamin A deficiency was confirmed and oral vitamin A supplementation was initiated. One month after treatment, the patient reported a subjective improvement of nyctalopia, and BCVA ameliorated up to 80 and 85 letters. Fundus examination, OCT, and en face OCT showed a diminution of the observed lesions. Moreover, visual field improved. CONCLUSION: Early diagnosis of vitamin A deficiency can prevent irreversible visual sequelae. This highlights the crucial role of ophthalmologists in the prompt detection of this condition. A lifelong monitoring should be needed in patients undergoing biliopancreatic diversion surgery. Furthermore, OCT and en face OCT becomes a main tool in the diagnosis and monitor response to treatment.

Influenza-associated thrombotic thrombocytopenic purpura: A report of two cases and a brief review of the literature.

BACKGROUND AND OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) is often preceded by a recent history of an acute infection and influenza is the most implicated virus. MATERIALS AND METHODS: We identified two cases of TTP, which were preceded by influenza between 2010 and 2021. In one patient, we epitope mapped the binding specificity of antibodies using an overlapping peptide approach of the stalk protein of Influenza B and the cysteine-rich spacer domain (CRSD) of ADAMTS13. A literature search was performed for reports of influenza-associated TTP over the period 1980-2021. RESULTS: Two patients were identified in which TTP was preceded by influenza, one Influenza A and the other Influenza B. Epitope mapping of the latter's plasma identified target epitopes in both the stalk protein of Influenza B and CRSD of ADAMTS13. The literature review revealed only seven case reports, all but one from Europe or Asia and associated with Influenza A. Severe ADAMTS13 deficiency was demonstrated in only four cases. CONCLUSION: We report the first small case series of influenza-associated TTP. Moreover, it is the first case implicating Influenza B and a mechanism favouring polyclonal B-cell proliferation rather than molecular mimicry as the stimulus to form anti-ADAMTS13 auto-antibodies is suggested.

Negative electroretinograms: genetic and acquired causes, diagnostic approaches and physiological insights.

The dark-adapted human electroretinogram (ERG) response to a standard bright flash includes a negative-going a-wave followed by a positive-going b-wave that crosses the baseline. An electronegative waveform (or negative ERG) results when the b-wave is selectively reduced such that the ERG fails to cross the baseline following the a-wave. In the context of a normally sized a-wave, it indicates a site of retinal dysfunction occurring after phototransduction (commonly at the photoreceptor to bipolar cell synapse). This is an important finding. In genetic disease, the pattern of ERG abnormality can point to variants in a small group of genes (frequently those associated with congenital stationary night blindness and X-linked retinoschisis, but negative ERGs can also be seen in other conditions including syndromic disease). In acquired disease, there are numerous causes, but specific features may point to melanoma-associated retinopathy (MAR). In some cases, the visual symptoms precede the diagnosis of the melanoma and so the ERG findings can initiate investigations facilitating early detection and treatment. Negative ERGs can occur in other paraneoplastic conditions, and in a range of other diseases. This review will outline the physiological basis for the negative ERG, report prevalences in the literature from different cohorts, discuss the range of causes, displaying examples of a number of ERG phenotypes, highlight features of a clinical approach to patients, and briefly discuss further insights relating to current flows shaping the a-wave trough and from single-cell transcriptome analysis.

Restoration of mGluR6 Localization Following AAV-Mediated Delivery in a Mouse Model of Congenital Stationary Night Blindness.

Purpose: Complete congenital stationary night blindness (cCSNB) is an incurable inherited retinal disorder characterized by an ON-bipolar cell (ON-BC) defect. GRM6 mutations are the third most prevalent cause of cCSNB. The Grm6-/- mouse model mimics the human phenotype, showing no b-wave in the electroretinogram (ERG) and a loss of mGluR6 and other proteins of the same cascade at the outer plexiform layer (OPL). Our aim was to restore protein localization and function in Grm6-/- adult mice targeting specifically ON-BCs or the whole retina. Methods: Adeno-associated virus-encoding Grm6 under two different promoters (GRM6-Grm6 and CAG-Grm6) were injected intravitreally in P15 Grm6-/- mice. ERG recordings at 2 and 4 months were performed in Grm6+/+, untreated and treated Grm6-/- mice. Similarly, immunolocalization studies were performed on retinal slices before or after treatment using antibodies against mGluR6, TRPM1, GPR179, RGS7, RGS11, Gß5, and dystrophin. Results: Following treatment, mGluR6 was localized to the dendritic tips of ON-BCs when expressed with either promoter. The relocalization efficiency in mGluR6-transduced retinas at the OPL was 2.5% versus 11% when the GRM6-Grm6 and CAG-Grm6 were used, respectively. Albeit no functional rescue was seen in ERGs, relocalization of TRPM1, GPR179, and Gß5 was also noted using both constructs. The restoration of the localization of RGS7, RGS11, and dystrophin was more obvious in retinas treated with GRM6-Grm6 than in retinas treated with CAG-Grm6. Conclusions: Our findings show the potential of treating cCSNB with GRM6 mutations; however, it appears that the transduction rate must be improved to restore visual function.

Clinical and genetic investigations of three Moroccan families with retinitis pigmentosa phenotypes.

Purpose: Progressive inherited retinal dystrophies, characterized by degeneration of rod photoreceptors and then cone photoreceptors, are known as retinitis pigmentosa (RP), for which 89 genes have been identified. Today, only five Moroccan families with RP with a genetic diagnosis have been reported, justifying our investment in providing further clinical and genetic investigations of families with RP in Morocco. Methods: The clinical diagnosis based on a combination of a history of night blindness, abnormal rod or rod-cone responses in electroretinography (ERG), and constricted visual field or difficulty perceiving side objects identified three Moroccan families with an RP phenotype. Probands of these families underwent whole exome sequencing (WES), and candidate variants were evaluated for their segregation within family members. Results: All patients had a history of night blindness and unrecordable rod and cone ERG traces. In addition, one patient had cystoid macular edema, and another had discrete autofluorescence abnormalities, in addition to ellipsoid zone disorganization and narrowed retinal vessels. WES sequencing revealed heterozygous compound mutations in CRB1:c.1690G>T//c.1913C>T and in ABCA4:c.5908C>T//c.6148G>C and a homozygous PDE6B splice mutation c.1920+2T>C. Conclusions: We provide the first description of Moroccan patients with the RP phenotype harboring pathogenic mutations in the CRB1 and ABCA4 genes and the second description of an individual with RP with a PDE6B mutation, associated with cystoid macular edema. These data contribute to expand the genetic diagnosis of RP phenotypes in Morocco.

Bi-Allelic Pathogenic Variations in MERTK Including Deletions Are Associated with an Early Onset Progressive Form of Retinitis Pigmentosa.

Bi-allelic pathogenic variants in MERTK cause retinitis pigmentosa (RP). Since deletions of more than one exon have been reported repeatedly for MERTK, CNV (copy number variation) analysis of next-generation sequencing (NGS) data has proven important in molecular genetic diagnostics of MERTK. CNV analysis was performed on NGS data of 677 individuals with inherited retinal diseases (IRD) and confirmed by quantitative RT-PCR analysis. Clinical evaluation was based on retrospective records. Clinical re-examination included visual field examination, dark adaption, scotopic and photopic full-field electroretinograms (ffERG), multifocal ERG (mfERG) and optic coherence tomography (OCT). Fourteen variants were detected in MERTK in six individuals, three of which were deletions of more than one exon. Clinical examinations of five out of six individuals revealed a severe phenotype with early-onset generalized retinal dystrophy with night blindness and progressive visual field loss; however, one individual had a milder phenotype. Three individuals had hearing impairments. We show that deletions represent a substantial part of the causative variants in MERTK and emphasize that CNV analysis should be included in the molecular genetic diagnostics of IRDs.

Serum concentration of vitamin A and its relationship with body adiposity, oxidative stress, and cardiovascular risk in women with recommended dietary intake of vitamin A.

INTRODUCTION: Background: evidence indicates a role of vitamin A in the regulation of fat mass influencing obesity and cardiovascular diseases. Material and methods: a cross-sectional study in 200 women, paired by age and by the recommended dietary intake of vitamin A. Subjects were divided into four groups according to body mass index (BMI): 80 eutrophic (E), 40 overweight (OW), 40 class I obesity (OI) and 40 class II obesity (OII). Lipid and glycemic profiles were measured and oxidative stress was evaluated through serum concentrations of uric acid, glutathione peroxidase (GSH-Px), and thiobarbituric acid reactive substances (TBARS). Results: the cutoff points for deficiency of serum retinol and ß-carotene levels were < 1.05 µmol/L and 40 µg/dL, respectively. For the recommended dietary intake of vitamin A it was 700 µg/day. Retinol and ß-carotene deficiency was found in the E group at 5 % and 15 %, respectively, reaching 77.5 % and 82.5 % in the OII group. Conclusions: a correlation was observed between serum concentrations of retinol and ß-carotene and glycemic, lipid, and markers of oxidative stress profiles in the groups studied. It was observed that OI and OII subjects who had retinol and ß-carotene deficiency presented a risk that was 16 and 20.7 times greater, respectively, of having a diagnosis with DM2 as compared to E subjects with adequate concentrations of vitamin A. Increased demand of vitamin A may be related to increased BMI, body adiposity, and oxidative stress even when a recommended intake of vitamin A is reached.

INTRODUCCIÓN: Introducción: la evidencia indica un papel de la vitamina A en la regulación de la masa grasa que influye en la obesidad y las enfermedades cardiovasculares. Material y métodos: estudio transversal con 200 mujeres emparejadas por edad y por la ingesta dietética de vitamina A recomendada. Se dividieron en cuatro grupos según el índice de masa corporal (IMC): 80 eutróficas (E), 40 con sobrepeso (OW), 40 con obesidad de clase I (OI) y 40 con obesidad de clase II (OII). Se midieron los perfiles lipídicos y glucémicos y se evaluó el estrés oxidativo a través de las concentraciones séricas de ácido úrico, glutatión-peroxidasa (GSH-Px) y sustancias reactivas del ácido tiobarbitúrico (TBARS). Resultados: los puntos de corte para la deficiencia de las concentraciones séricas de retinol y caroteno fueron de 1,05 µmol/L y 40 g/dL, respectivamente. Para la ingesta dietética recomendada de vitamina A fue de 700 g/día. Se encontró deficiencia de retinol y caroteno en el grupo E, del 5 % y 15 %, respectivamente, alcanzando un 77,5 % y 82,5 % en el grupo OII. Conclusiones: se observó correlación entre las concentraciones séricas de retinol y caroteno y los perfiles glucémico, lipídico y de marcadores de perfiles de estrés oxidativo en los grupos estudiados. Se observó que los sujetos con OI y OII que tenían deficiencia de retinol y caroteno presentaban un riesgo 16 y 20,7 veces mayor, respectivamente, de ser diagnosticados de DM2 en comparación con los E con concentraciones adecuadas de vitamina A. El aumento de la demanda de vitamina A puede estar relacionado con el aumento del IMC, la adiposidad corporal y el estrés oxidativo, incluso cuando se alcanza la ingesta recomendada de vitamina A.

Unique combination of clinical features in a large cohort of 100 patients with retinitis pigmentosa caused by FAM161A mutations.

FAM161A mutations are the most common cause of autosomal recessive retinitis pigmentosa in the Israeli-Jewish population. We aimed to characterize the spectrum of FAM161A-associated phenotypes and identify characteristic clinical features. We identified 114 bi-allelic FAM161A patients and obtained clinical records of 100 of these patients. The most frequent initial symptom was night blindness. Best-corrected visual acuity was largely preserved through the first three decades of life and severely deteriorated during the 4th-5th decades. Most patients manifest moderate-high myopia. Visual fields were markedly constricted from early ages, but maintained for decades. Bone spicule-like pigmentary changes appeared relatively late, accompanied by nummular pigmentation. Full-field electroretinography responses were usually non-detectable at first testing. Fundus autofluorescence showed a hyper-autofluorescent ring around the fovea in all patients already at young ages. Macular ocular coherence tomography showed relative preservation of the outer nuclear layer and ellipsoid zone in the fovea, and frank cystoid macular changes were very rare. Interestingly, patients with a homozygous nonsense mutation manifest somewhat more severe disease. Our clinical analysis is one of the largest ever reported for RP caused by a single gene allowing identification of characteristic clinical features and may be relevant for future application of novel therapies.

Sensing through Non-Sensing Ocular Ion Channels.

Ion channels are membrane-spanning integral proteins expressed in multiple organs, including the eye. In the eye, ion channels are involved in various physiological processes, like signal transmission and visual processing. A wide range of mutations have been reported in the corresponding genes and their interacting subunit coding genes, which contribute significantly to an array of blindness, termed ocular channelopathies. These mutations result in either a loss- or gain-of channel functions affecting the structure, assembly, trafficking, and localization of channel proteins. A dominant-negative effect is caused in a few channels formed by the assembly of several subunits that exist as homo- or heteromeric proteins. Here, we review the role of different mutations in switching a "sensing" ion channel to "non-sensing," leading to ocular channelopathies like Leber's congenital amaurosis 16 (LCA16), cone dystrophy, congenital stationary night blindness (CSNB), achromatopsia, bestrophinopathies, retinitis pigmentosa, etc. We also discuss the various in vitro and in vivo disease models available to investigate the impact of mutations on channel properties, to dissect the disease mechanism, and understand the pathophysiology. Innovating the potential pharmacological and therapeutic approaches and their efficient delivery to the eye for reversing a "non-sensing" channel to "sensing" would be life-changing.

Coroideremia familiar: reporte de caso con énfasis en la evolución clínica y adquisición de discapacidad visual / Familiar choroideremia: case report with emphasis on clinical evolution and acquisition of visual impairment

Resumen La coroideremia es una enfermedad retiniana hereditaria que se caracteriza por la degeneración progresiva coriocapilar de coroides y retina; esta tiene la capacidad de limitar el funcionamiento y generar discapacidad, afectando el desempeño de la persona en el ámbito familiar, social y profesional, al producir dificultades en la comunicación, la movilidad, el desplazamiento y la gestión de su diario vivir. Esta condición de salud ocular se origina por una mutación del gen que codifica la proteína RabEscort-1, ubicada en el cromosoma Xq21. Su fisiopatología no es clara, y los reportes de caso de coroideremia familiar son escasos en Latinoamérica. Se reporta el caso de un hombre de 54 años con nictalopía y pérdida progresiva de agudeza visual, con un hermano menor con coroideremia y primo materno con sospecha de dicha enfermedad, con énfasis en evolución clínica, hallazgos al fondo de ojo y progresión a discapacidad categoría visual, tipo baja visión. MÉD.UIS. 2020;33(2):109-115.

Abstract Choroideremia is a hereditary retinal disease characterized by progressive choroidal and retinal choriocapillary degeneration, it has the ability to limit functioning and generate disability, affecting the persons performance in the family, social and professional environment, by causing difficulties in communication, mobility, displacement and management of your daily life. This eye health condition is caused by a mutation of the gene that encodes the RabEscort-1 protein, located on the Xq21 chromosome. His pathophysiology is not clear, and case reports of familial choroideremia are sparse in Latin America. The case of a 54-year-old man with night blindness and progressive loss of visual acuity is reported, with a younger brother with choroideremia and maternal cousin with suspected disease, with emphasis on clinical evolution, fundus findings and progression to disability category visual, low vision type. MÉD.UIS. 2020;33(2):109-115.