scholarly journals Progressive cone and cone-rod dystrophies: clinical features, molecular genetics and prospects for therapy

2019 ◽  
Vol 103 (5) ◽  
pp. 711-720 ◽  
Author(s):  
Jasdeep S Gill ◽  
Michalis Georgiou ◽  
Angelos Kalitzeos ◽  
Anthony T Moore ◽  
Michel Michaelides
Keyword(s):  
Molecular Genetics ◽  
Common Disease ◽  
Retinal Diseases ◽  
Rod Photoreceptor ◽  
Cone Photoreceptor ◽  
Current Management ◽  
Imaging Characteristics ◽  
Disease Associated Genes ◽  
Vision Disturbance ◽  
Made In

Progressive cone and cone-rod dystrophies are a clinically and genetically heterogeneous group of inherited retinal diseases characterised by cone photoreceptor degeneration, which may be followed by subsequent rod photoreceptor loss. These disorders typically present with progressive loss of central vision, colour vision disturbance and photophobia. Considerable progress has been made in elucidating the molecular genetics and genotype–phenotype correlations associated with these dystrophies, with mutations in at least 30 genes implicated in this group of disorders. We discuss the genetics, and clinical, psychophysical, electrophysiological and retinal imaging characteristics of cone and cone-rod dystrophies, focusing particularly on four of the most common disease-associated genes: GUCA1A, PRPH2, ABCA4 and RPGR. Additionally, we briefly review the current management of these disorders and the prospects for novel therapies.

scholarly journals Targeting of the NRL Pathway as a Therapeutic Strategy to Treat Retinitis Pigmentosa

2020 ◽  
Vol 9 (7) ◽  
pp. 2224 ◽  
Author(s):  
Spencer M. Moore ◽  
Dorota Skowronska-Krawczyk ◽  
Daniel L. Chao
Keyword(s):  
Retinitis Pigmentosa ◽  
Autosomal Recessive ◽  
Therapeutic Strategy ◽  
Leucine Zipper ◽  
Retinal Dystrophy ◽  
Rod Photoreceptor ◽  
Cone Photoreceptor ◽  
Future Directions ◽  
Inherited Retinal Dystrophy ◽  
Visual Acuity Loss

Retinitis pigmentosa (RP) is an inherited retinal dystrophy (IRD) with a prevalence of 1:4000, characterized by initial rod photoreceptor loss and subsequent cone photoreceptor loss with accompanying nyctalopia, visual field deficits, and visual acuity loss. A diversity of causative mutations have been described with autosomal dominant, autosomal recessive, and X-linked inheritance and sporadic mutations. The diversity of mutations makes gene therapy challenging, highlighting the need for mutation-agnostic treatments. Neural leucine zipper (NRL) and NR2E3 are factors important for rod photoreceptor cell differentiation and homeostasis. Germline mutations in NRL or NR2E3 leads to a loss of rods and an increased number of cones with short wavelength opsin in both rodents and humans. Multiple groups have demonstrated that inhibition of NRL or NR2E3 activity in the mature retina could endow rods with certain properties of cones, which prevents cell death in multiple rodent RP models with diverse mutations. In this review, we summarize the literature on NRL and NR2E3, therapeutic strategies of NRL/NR2E3 modulation in preclinical RP models, as well as future directions of research. In summary, inhibition of the NRL/NR2E3 pathway represents an intriguing mutation agnostic and disease-modifying target for the treatment of RP.

scholarly journals Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1120
Author(s):  
Fay Newton ◽  
Roly Megaw
Keyword(s):  
Retinitis Pigmentosa ◽  
Apoptotic Cell ◽  
Gene Replacement ◽  
Innate Immune ◽  
Cone Photoreceptor ◽  
Cell Death Pathways ◽  
Retinal Photoreceptors ◽  
Photoreceptor Death ◽  
Made In

Retinitis pigmentosa (RP) is the most common cause of inherited blindness and is characterised by the progressive loss of retinal photoreceptors. However, RP is a highly heterogeneous disease and, while much progress has been made in developing gene replacement and gene editing treatments for RP, it is also necessary to develop treatments that are applicable to all causative mutations. Further understanding of the mechanisms leading to photoreceptor death is essential for the development of these treatments. Recent work has therefore focused on the role of apoptotic and non-apoptotic cell death pathways in RP and the various mechanisms that trigger these pathways in degenerating photoreceptors. In particular, several recent studies have begun to elucidate the role of microglia and innate immune response in the progression of RP. Here, we discuss some of the recent progress in understanding mechanisms of rod and cone photoreceptor death in RP and summarise recent clinical trials targeting these pathways.

Probing inner retinal circuits in the rod pathway: A comparison of c-fos activation in mutant mice

2004 ◽  
Vol 21 (6) ◽  
pp. 873-881 ◽  
Author(s):  
BRETT W. HANZLICEK ◽  
NEAL S. PEACHEY ◽  
CHRISTIAN GRIMM ◽  
STEPHANIE A. HAGSTROM ◽  
SHERRY L. BALL
Keyword(s):  
Light Exposure ◽  
Amacrine Cells ◽  
Bipolar Cells ◽  
Early Gene ◽  
Rod Photoreceptor ◽  
Cone Photoreceptor ◽  
Outer Retina ◽  
Inner Retina ◽  
Double Labeling ◽  
Immunohistochemical Studies

We have used wild-type mice and mice possessing defects in specific retinal circuits in order to more clearly define functional circuits of the inner retina. The retina of the nob mouse lacks communication between photoreceptors and depolarizing bipolar cells (DBCs). Thus, all light driven activity in the nob mouse is mediated via remaining hyperpolarizing bipolar cell (HBC) circuits. Transducin null (Trα−/−) mice lack rod photoreceptor activity and thus remaining retinal circuits are solely generated via cone photoreceptor activity. Activation in inner retinal circuits in each of these mice was identified by monitoring light-induced expression of an immediate early gene, c-fos. The number of cells expressing c-fos in the inner retina was dependent upon stimulus intensity and was altered in a systematic fashion in mice with known retinal mutations. To determine whether c-fos is activated via circuits other than photoreceptors in the outer retina, we examined c-fos expression in tulp1−/− mice that lack photoreceptors in the outer retina; these mice showed virtually no c-fos activity following light exposure. Double-labeling immunohistochemical studies were carried out to more clearly define the population of c-fos expressing amacrine cells. Our results indicate that c-fos may be used to map functional circuits in the retina.

scholarly journals 1403. Tuberculous sacroiliitis: Clinical and Imaging Characteristics

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S786-S786
Author(s):  
Fatma Hammami ◽  
Makram Koubaa ◽  
Amal Chakroun ◽  
Chakib Marrakchi ◽  
Fatma Smaoui ◽  
...  
Keyword(s):  
Sacroiliac Joint ◽  
Soft Tissues ◽  
Clinical Laboratory ◽  
Diagnostic Delay ◽  
Joint Space ◽  
Antitubercular Therapy ◽  
Common Disease ◽  
Osteoarticular Tuberculosis ◽  
Imaging Characteristics ◽  
Imaging Results

Abstract Background Osteoarticular tuberculosis remains a common disease among which the spine is the most affected site. Less frequently, sacroiliac joint is involved. Its diagnosis is often delayed due to misleading and varied symptoms. The aim of this work was to study the clinical features and the contribution of imaging results in the diagnosis of tuberculous sacroiliitis. Methods We conducted a retrospective study including all patients hospitalized in the infectious disease department for tuberculous sacroiliitis. The diagnosis was based on clinical, laboratory and radiological features. Results In total, we encountered 12 women with a median age of 51 [39-63] years. Three patients had a family history of tuberculosis (25%). The median diagnostic delay was 155 [48-331] days. The revealing symptoms were lower back pain (75%) and hip pain (25%) associated with fever (83.3%) and weight loss (75%). Reduced mobility was noted in 3 cases (25%). Pulmonary tuberculosis and tuberculous spondylodiscitis were associated with tuberculous sacroiliitis in 5 cases (41.7%) and 4 cases (33.3%), respectively. Tuberculin skin test was positive in 6 cases (50%). Laboratory investigations revealed elevated C-reactive protein levels in 11 cases (91.6%) and accelerated erythrocyte sedimentation rates in 9 cases (75%). Needle biopsy of the sacroiliac joint (41.7%) and soft tissues abscess puncture (16.6%) were performed. Computed tomography scan revealed joint space widening (83.3%), peripheral joint erosions (83.3%) and osteolysis (58.3%). Soft tissue abscesses were noted in 66.7% of the cases. Magnetic resonance imaging was performed in 4 cases (33.3%). Sacroiliac joint was hypointense in T1-weighted images (75%), hyperintense in T2 weighted images (50%) and in STIR images (50%). Bone scintigraphy, performed in 5 cases, revealed hyperfixation of the sacroiliac area (100%). All patients received antitubercular therapy. Percutaneous abscess drainage was indicated in 4 cases (33.3%). Conclusion Because of its deep localization, the diagnosis of tuberculous sacroiliitis is mainly based on imaging results associated with epidemiological, clinical and laboratory features. Antitubercular therapy initiated promptly leads to recovery. Disclosures All Authors: No reported disclosures

scholarly journals Retinoic acid signaling mediates peripheral cone photoreceptor survival in a mouse model of retina degeneration

2021 ◽  
Author(s):  
Ryoji Amamoto ◽  
Grace K Wallick ◽  
Constance Cepko
Keyword(s):  
Retinoic Acid ◽  
Mouse Model ◽  
Color Vision ◽  
Mouse Models ◽  
Night Vision ◽  
Conditional Knockout ◽  
Peripheral Retina ◽  
Rod Photoreceptor ◽  
Cone Photoreceptor

Retinitis Pigmentosa (RP) is a wide array of progressive, debilitating visual disorders caused by mutations in a diverse set of genes. In both human patients and mouse models of RP, rod photoreceptor dysfunction leads to loss of night vision, and is followed by secondary cone photoreceptor dysfunction and degeneration, leading to loss of daylight color vision. A strategy to prevent secondary cone death could provide a generalized RP therapy to preserve daylight color vision regardless of the underlying mutation. In mouse models of RP, cones in the far peripheral retina survive long-term, despite complete rod loss. The mechanism for such peripheral cone survival had not been explored. Here, we found that active retinoic acid (RA) signaling in peripheral Muller glia is both sufficient and necessary for the extended cone survival. RA depletion by conditional knockout of RA synthesis enzymes, or overexpression of an RA degradation enzyme, abrogated peripheral cone survival. Conversely, constitutive activation of RA signaling in the central retina promoted long-term cone survival. These results indicate that RA signaling mediates the prolonged peripheral cone survival in the rd1 mouse model of retinal degeneration, and provide a basis for a generic strategy for cone survival in the many diseases that lead to loss of cone-mediated vision.

scholarly journals Correction of NR2E3 Associated Enhanced S-cone Syndrome Patient-specific iPSCs using CRISPR-Cas9

Genes ◽  
2019 ◽  
Vol 10 (4) ◽  
pp. 278 ◽  
Author(s):  
Laura Bohrer ◽  
Luke Wiley ◽  
Erin Burnight ◽  
Jessica Cooke ◽  
Joseph Giacalone ◽  
...  
Keyword(s):  
Photoreceptor Cell ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Model Systems ◽  
Patient Specific ◽  
Rod Photoreceptor ◽  
Cone Photoreceptor ◽  
Retinal Cells ◽  
Enhanced S Cone Syndrome

Enhanced S-cone syndrome (ESCS) is caused by recessive mutations in the photoreceptor cell transcription factor NR2E3. Loss of NR2E3 is characterized by repression of rod photoreceptor cell gene expression, over-expansion of the S-cone photoreceptor cell population, and varying degrees of M- and L-cone photoreceptor cell development. In this study, we developed a CRISPR-based homology-directed repair strategy and corrected two different disease-causing NR2E3 mutations in patient-derived induced pluripotent stem cells (iPSCs) generated from two affected individuals. In addition, one patient’s iPSCs were differentiated into retinal cells and NR2E3 transcription was evaluated in CRISPR corrected and uncorrected clones. The patient’s c.119-2A>C mutation caused the inclusion of a portion of intron 1, the creation of a frame shift, and generation of a premature stop codon. In summary, we used a single set of CRISPR reagents to correct different mutations in iPSCs generated from two individuals with ESCS. In doing so we demonstrate the advantage of using retinal cells derived from affected patients over artificial in vitro model systems when attempting to demonstrate pathophysiologic mechanisms of specific mutations.

scholarly journals Molecular genetics of oligodendrogliomas: a model for improved clinical management in the field of neurooncology

2005 ◽  
Vol 19 (5) ◽  
pp. 1-9 ◽  
Author(s):  
Catherine L. Nutt
Keyword(s):  
Molecular Genetics ◽  
Clinical Management ◽  
Molecular Genetic ◽  
Genetic Alterations ◽  
Homozygous Deletion ◽  
Molecular Genetic Study ◽  
Positive Role ◽  
Oligodendroglial Tumors ◽  
Imaging Characteristics ◽  
Astrocytic Gliomas

Over the last several years, oligodendroglial tumors have become a model for the positive role of molecular genetics in improved treatment of patients with brain tumors. Oligodendrogliomas, in contrast to astrocytic gliomas, frequently respond to chemotherapy and have a better overall prognosis. Combined loss of chromosomes 1p and 19q has proven to be a powerful predictor of chemotherapeutic response and survival in oligodendrogliomas. In contrast, other genetic alterations, such as TP53 and PTEN mutations, EGFR amplification, and homozygous deletion of CDKN2A have been correlated with worse outcome in these tumors. Furthermore, 1p/19q loss has been shown to correlate with unequivocal oligodendroglial tumor histology, location and growth pattern of tumors within the brain, and magnetic resonance imaging characteristics. Although much is also known about the molecular pathological characteristics of astrocytic gliomas, the significance of this information to clinical management in patients with these tumors has not been as striking as has been the case for oligodendrogliomas; possible reasons for this are discussed. In this paper the author will summarize these advances, thus attempting to highlight the molecular genetic study of oligodendrogliomas as a model for improved clinical management in the field of neurooncology.

scholarly journals Shortwave infrared otoscopy for diagnosis of middle ear effusions: a machine-learning-based approach

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rustin G. Kashani ◽  
Marcel C. Młyńczak ◽  
David Zarabanda ◽  
Paola Solis-Pazmino ◽  
David M. Huland ◽  
...  
Keyword(s):  
Machine Learning ◽  
Otitis Media ◽  
Middle Ear ◽  
Infrared Region ◽  
Common Disease ◽  
Specificity And Sensitivity ◽  
Traditional Approaches ◽  
Shortwave Infrared ◽  
Made In

AbstractOtitis media, a common disease marked by the presence of fluid within the middle ear space, imparts a significant global health and economic burden. Identifying an effusion through the tympanic membrane is critical to diagnostic success but remains challenging due to the inherent limitations of visible light otoscopy and user interpretation. Here we describe a powerful diagnostic approach to otitis media utilizing advancements in otoscopy and machine learning. We developed an otoscope that visualizes middle ear structures and fluid in the shortwave infrared region, holding several advantages over traditional approaches. Images were captured in vivo and then processed by a novel machine learning based algorithm. The model predicts the presence of effusions with greater accuracy than current techniques, offering specificity and sensitivity over 90%. This platform has the potential to reduce costs and resources associated with otitis media, especially as improvements are made in shortwave imaging and machine learning.

scholarly journals Inflammasomes in the urinary tract: a disease-based review

2016 ◽  
Vol 311 (4) ◽  
pp. F653-F662 ◽  
Author(s):  
J. Todd Purves ◽  
F. Monty Hughes
Keyword(s):  
Urinary Tract ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Common Disease ◽  
Disease States ◽  
Tract Infections ◽  
Molecular Patterns ◽  
Made In ◽  
Lower Urinary

Inflammasomes are supramolecular structures that sense molecular patterns from pathogenic organisms or damaged cells and trigger an innate immune response, most commonly through production of the proinflammatory cytokines IL-1β and IL-18, but also through less understood mechanisms independent of these cytokines. Great strides have been made in understanding these structures and their dysfunction in various inflammatory diseases, lending new insights into urological and renal problems. From a clinical perspective, benign urinary pathology almost universally involves the inflammatory process, and understanding how inflammasomes translate etiological conditions (diabetes, obstruction, stones, urinary tract infections, etc.) into acute and chronic inflammatory responses is critical to understanding these diseases at a molecular level. To date, inflammasome components have been found in the bladder, prostate, and kidney and have been shown to be activated in response to several infectious and noninfectious insults. In this review, we summarize what is known regarding inflammasomes in both the upper and lower urinary tract and describe several common disease states where they potentially play critical roles.

Sign in / Sign up

Export Citation Format

Share Document