Genotypes Predispose Phenotypes—Clinical Features and Genetic Spectrum of ABCA4-Associated Retinal Dystrophies

The ABCA4 gene is one of the most common disease-causing genes of inherited retinal degeneration. In this study, we report different phenotypes of ABCA4-associated retinal dystrophies in the Taiwanese population, its clinical progression, and its relationship with genetic characteristics. Thirty-seven subjects were recruited and all patients underwent serial ophthalmic examinations at a single medical center. Fundus autofluorescence (FAF) images were quantified for clinical evaluation, and panel-based next-generation sequencing testing was performed for genetic diagnosis. Visual preservation, disease progression, and genotype–phenotype correlation were analyzed. In this cohort, ABCA4-associated retinal degeneration presented as Stargardt disease 1 (STGD1, 62.16%), retinitis pigmentosa (32.43%), and cone-rod dystrophy (5.41%). STGD1 could be further divided into central and dispersed types. In each phenotype, the lesion areas quantified by FAF increased with age (p < 0.01) and correlated with poorer visual acuity. However, three patients had the foveal sparing phenotype and had relatively preserved visual acuity. Forty-two ABCA4 variants were identified as disease-causing, with c.1804C>T (p.Arg602Trp) the most frequent (37.84%). Patients with a combination of severe/null variants could have more extensive phenotypes, such as arRP and dispersed STGD1. This is the first cohort study of ABCA4-associated retinal degeneration in Taiwan with wide spectrums of both genotypic and phenotypic characteristics. An extremely high prevalence of c.1804C>T, which has not been reported in East Asia before, was noted. The extensiveness of retinal involvement might be regarded as a spectrum of ABCA4-associated retinal dystrophies. Different types of genetic variations could lead to distinctive phenotypes, according to the coding impact of variants.

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Spontaneous Regression of Choroidal Neovascularization in a Patient with Pattern Dystrophy

Case Reports in Ophthalmological Medicine ◽

10.1155/2016/9685290 ◽

2016 ◽

Vol 2016 ◽

pp. 1-5

Author(s):

Anastasios Anastasakis ◽

Flamur Goleni ◽

Gerasimos Livir-Rallatos ◽

Charalampos Livir-Rallatos ◽

Panagiotis Zafirakis ◽

...

Keyword(s):

Visual Acuity ◽

Choroidal Neovascularization ◽

Spontaneous Regression ◽

Fundus Autofluorescence ◽

Subretinal Fluid ◽

Autofluorescence Imaging ◽

Choroidal Neovascular Membrane ◽

Pattern Dystrophy ◽

Retinal Dystrophies

Purpose. To present a case of a patient with pattern dystrophy (PD) associated choroidal neovascularization (CNV) that resolved spontaneously without treatment.Methods. A 69-year-old male patient was referred to our unit, for evaluation of a recent visual loss (metamorphopsias) in his left eye. Fundus examination, fundus autofluorescence imaging, and fluorescein angiography showed a choroidal neovascular membrane in his left eye. Since visual acuity was satisfactory the patient elected observation. Clinical examination and OCT testing were repeated at 6 and 12 months after presentation.Results. Visual acuity remained stable at the level of 0.9 (baseline BCVA) during the follow-up period (12 months). Repeat OCT testing showed complete spontaneous regression of the choroidal neovascular membrane without evidence of intra- or subretinal fluid in both follow-up visits.Conclusions. Spontaneous regression of choroidal neovascularization can occur in patients with retinal dystrophies and associated choroidal neovascular membranes. The decision to treat or observe these patients relies strongly on the presenting visual acuity, since, in isolated instances, spontaneous resolution of choroidal neovascularization may occur.

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Novel mutation in the choroideremia gene and multi-Mendelian phenotypes in Spanish families

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2017-311427 ◽

2018 ◽

Vol 102 (10) ◽

pp. 1378-1386 ◽

Cited By ~ 6

Author(s):

Marta de Castro-Miró ◽

Raul Tonda ◽

Gemma Marfany ◽

Ricardo P Casaroli-Marano ◽

Roser Gonzàlez-Duarte

Keyword(s):

Novel Mutation ◽

Imaging Techniques ◽

Fundus Autofluorescence ◽

Genetic Diagnosis ◽

Swept Source ◽

Non Invasive ◽

Efficient Management ◽

Retinal Dystrophies ◽

Whole Exome ◽

Massive Sequencing

AimsWe aimed to accurately diagnose several retinitis pigmentosa (RP) patients with complex ocular phenotypes by combining massive sequencing genetic diagnosis and powerful clinical imaging techniques.MethodsWhole-exome sequencing (WES) of selected patients from two RP families was undertaken. The variants identified were validated by Sanger sequencing and cosegregation analysis. Accurate clinical re-evaluation was performed using electrophysiological and visual field records as well as non-invasive imaging techniques, such as swept-source optical coherence tomography and fundus autofluorescence.ResultsThe WES results highlighted one novel and one reported causative mutations in the X-linked choroideremia gene (CHM), which challenged the initial RP diagnosis. Subsequent clinical re-evaluation confirmed the choroideremia diagnosis. Carrier females showed different degrees of affectation, even between twin sisters, probably due to lyonization. A severe multi-Mendelian phenotype was associated with coincidental dominant pathogenic mutations in two additional genes: PAX6 and PDE6B.ConclusionsGenetic diagnosis via massive sequencing is instrumental in identifying causative mutations in retinal dystrophies and additional genetic variants with an impact on the phenotype. Multi-Mendelian phenotypes previously ascribed to rare syndromes can thus be dissected and molecularly diagnosed. Overall, the combination of powerful genetic diagnosis and clinical non-invasive imaging techniques enables efficient management of patients and their prioritisation for gene-specific therapies.

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Clinical and anamnestic characteristics of patients with adenomyosis, accompanied by pelvic pain syndrome

GYNECOLOGY ◽

10.26442/20795696.2018.6.180132 ◽

2018 ◽

Vol 20 (6) ◽

pp. 77-80

Author(s):

M R Orazov ◽

V E Radzinsky ◽

M B Khamoshina ◽

A O Dukhin ◽

L R Toktar ◽

...

Keyword(s):

Pelvic Pain ◽

Chronic Pelvic Pain Syndrome ◽

Pain Syndrome ◽

Reproductive Age ◽

Pelvic Pain Syndrome ◽

Common Disease ◽

Contributing Factors ◽

High Prevalence ◽

Inflammatory Processes ◽

History Of

Pelvic pain syndrome associated with adenomyosis is a common disease in women of reproductive age. Frequency of detection in the population varies from 10 to 53%. The aim - to study the clinical and anamnestic risk factors of pelvic pain, with adenomiose. Materials and methods. The study included 120 (n=120) patients with diffuse adenomyosis with pain and painless form of the disease who underwent examination and treatment in the gynecological Department of the Central clinical hospital №6 of Russian Railways in Moscow. Each patient was provided with an individual card, which was encrypted 171 sign. The studied parameters reflected the passport and anthropometric data, information about education, social status, presence of occupational hazards, complaints, illness. Results. Burdened gynecological and somatic histories, manifested a low health index, a more pronounced hereditary a family history of neoplastic diseases are contributing factors, and high prevalence of postponed surgeries, chronic, long-term ongoing inflammatory processes of the pelvic organs to create a favorable background for the further progression of chronic pelvic pain syndrome in adenomiose.

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Clinical Phenotype of PDE6B-Associated Retinitis Pigmentosa

International Journal of Molecular Sciences ◽

10.3390/ijms22052374 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2374

Author(s):

Laura Kuehlewein ◽

Ditta Zobor ◽

Katarina Stingl ◽

Melanie Kempf ◽

Fadi Nasser ◽

...

Keyword(s):

Visual Acuity ◽

Genetic Testing ◽

Retinitis Pigmentosa ◽

Fundus Autofluorescence ◽

Retinal Disease ◽

New Drugs ◽

Autofluorescence Imaging ◽

Full Field ◽

Tertiary Referral Center ◽

The Right

In this retrospective, longitudinal, observational cohort study, we investigated the phenotypic and genotypic features of retinitis pigmentosa associated with variants in the PDE6B gene. Patients underwent clinical examination and genetic testing at a single tertiary referral center, including best-corrected visual acuity (BCVA), kinetic visual field (VF), full-field electroretinography, full-field stimulus threshold, spectral domain optical coherence tomography, and fundus autofluorescence imaging. The genetic testing comprised candidate gene sequencing, inherited retinal disease gene panel sequencing, whole-genome sequencing, and testing for familial variants by Sanger sequencing. Twenty-four patients with mutations in PDE6B from 21 families were included in the study (mean age at the first visit: 32.1 ± 13.5 years). The majority of variants were putative splicing defects (8/23) and missense (7/23) mutations. Seventy-nine percent (38/48) of eyes had no visual acuity impairment at the first visit. Visual acuity impairment was mild in 4% (2/48), moderate in 13% (6/48), and severe in 4% (2/48). BCVA was symmetrical in the right and left eyes. The kinetic VF measurements were highly symmetrical in the right and left eyes, as was the horizontal ellipsoid zone (EZ) width. Regarding the genetic findings, 43% of the PDE6B variants found in our patients were novel. Thus, this study contributed substantially to the PDE6B mutation spectrum. The visual acuity impairment was mild in 83% of eyes, providing a window of opportunity for investigational new drugs. The EZ width was reduced in all patients and was highly symmetric between the eyes, making it a promising outcome measure. We expect these findings to have implications on the design of future PDE6B-related retinitis pigmentosa (RP) clinical trials.

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Nutraceutical Supplementation Ameliorates Visual Function, Retinal Degeneration, and Redox Status in rd10 Mice

Antioxidants ◽

10.3390/antiox10071033 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1033

Author(s):

Lorena Olivares-González ◽

Sheyla Velasco ◽

Isabel Campillo ◽

David Salom ◽

Emilio González-García ◽

...

Keyword(s):

Oxidative Stress ◽

Retinal Degeneration ◽

Antioxidant Properties ◽

Photoreceptor Cells ◽

Redox Status ◽

Inherited Retinal Dystrophies ◽

Stress Markers ◽

Retinal Dystrophies ◽

Progressive Degeneration ◽

Light Stimuli

Background: Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive degeneration of photoreceptor cells. Ocular redox status is altered in RP suggesting oxidative stress could contribute to their progression. In this study, we investigated the effect of a mixture of nutraceuticals with antioxidant properties (NUT) on retinal degeneration in rd10 mice, a model of RP. Methods: NUT was orally administered to rd10 mice from postnatal day (PD) 9 to PD18. At PD18 retinal function and morphology were examined by electroretinography (ERG) and histology including TUNEL assay, immunolabeling of microglia, Müller cells, and poly ADP ribose polymers. Retinal redox status was determined by measuring the activity of antioxidant enzymes and some oxidative stress markers. Gene expression of the cytokines IL-6, TNFα, and IL-1β was assessed by real-time PCR. Results: NUT treatment delayed the loss of photoreceptors in rd10 mice partially preserving their electrical responses to light stimuli. Moreover, it ameliorated redox status and reduced inflammation including microglia activation, upregulation of cytokines, reactive gliosis, and PARP overactivation. Conclusions: NUT ameliorated retinal functionality and morphology at early stages of RP in rd10 mice. This formulation could be useful as a neuroprotective approach for patients with RP in the future.

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Local Laboratory Testing of Germline BRCA Mutations vs. Myriad: A Single-Institution Experience in Korea

Diagnostics ◽

10.3390/diagnostics11020370 ◽

2021 ◽

Vol 11 (2) ◽

pp. 370

Author(s):

Joohyun Hong ◽

Jiyun Lee ◽

Minsuk Kwon ◽

Ji-Yeon Kim ◽

Jong-Won Kim ◽

...

Keyword(s):

Genetic Testing ◽

High Risk ◽

Salt Lake ◽

Medical Center ◽

Brca Mutation ◽

Genetic Diagnosis ◽

Metastatic Breast ◽

Breast Cancer Patients ◽

Brca 1 ◽

Local Laboratory

Genetic diagnosis for human epidermal growth factor receptor 2-negative metastatic breast cancer patients with the germline BRCA (gBRCA) mutation has been emphasized since the development of polyadenosine diphosphate-ribose polymerase inhibitors. Myriad Genetics, Inc.’s (Salt Lake City, UT, USA) companion diagnostics service is almost exclusively used for genetic testing. The aim of this study was to compare the results of germline BRCA mutation tests returned by a local laboratory and those performed by Myriad. Between April 2014 and February 2018, 31 patients with gBRCA 1/2 mutation test results from both Samsung Medical Center (Seoul, Korea) and Myriad were enrolled. “Discordant: Opposite classification” was observed for only one among 27 (3.7%). This discrepancy was due to the detection of a deleterious large genomic rearrangement of BRCA 1 by Myriad. Samsung Medical Center performed multiple ligation-dependent probe amplifications (MLPA) to detect large genomic rearrangements only in high-risk patients. This one case was not suspected as high risk and MLPA was not performed. The concordant rate was 74.1% for all 27 patients. “Discordant: Laboratory’s uncertain classification” was found in 22.2% of the sample (six patients). All discrepancies were generated during interpretation of BRCA 2 gene sequencing. Further studies and standardization of genetic testing for BRCA 1/2 genes are required.

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Nature and nurture: overcoming constraints on immunity

Parasitology ◽

10.1017/s0031182000083396 ◽

1989 ◽

Vol 99 (S1) ◽

pp. S21-S35 ◽

Cited By ~ 20

Author(s):

D. Wakelin

Keyword(s):

Cell Function ◽

Climatic Factors ◽

Epidemiological Studies ◽

Parasitic Infections ◽

Helminth Parasites ◽

Genetic Characteristics ◽

Development Of Resistance ◽

High Prevalence ◽

Genetically Determined ◽

Induced Immunity

SUMMARYParasitic infections in man and domestic animals exhibit two striking characteristics (a) their prevalence is high, but infections are unequally distributed among individuals within populations and (b) immunity is often slow to develop and appears, at best, only partially effective. Recent immunological and epidemiological studies suggest that effective immunity can develop, but that high prevalence within populations reflects the operation, not only of socio-economic and climatic factors, or husbandry practices, but also of powerful environmentally induced constraints upon the development of resistance. Immunogenetic studies suggest the operation of additional constraints which reflect individual genetic characteristics, and which influence the ability to develop and express effective immunity. A full understanding of all constraints is necessary before levels of population and individual resistance to infection can be increased; the need for such understanding has become more pressing with the prospect that anti-parasite vaccines may become available. Two aspects of environmentally induced constraints are considered, those arising from nutritional inadequacies and those resulting from exposure to infection in early life. Both are discussed primarily in terms of helminth parasites. Genetically determined constraints are discussed with reference to MHC-restricted recognition of malarial peptide vaccines and in terms of Class II molecule-directed control of T-cell function inLeishmaniainfections. Genetic influences are also considered from the standpoint of inflammatory cell function, in immunity against intestinal nematodes and in vaccine-induced immunity againstSchistosoma. Finally, parasite-induced constraints, particularly those which down-regulate protective responses are discussed briefly.

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Gambaran Kualitas Hidup pada Pasien Diabetik Retinopati Berdasarkan Tingkat Keparahan Visus

JURNAL MANAJEMEN DAN PELAYANAN FARMASI (Journal of Management and Pharmacy Practice) ◽

10.22146/jmpf.44456 ◽

2020 ◽

Vol 10 (2) ◽

pp. 105

Author(s):

Novita Dhewi Ikakusumawati ◽

Dewi Magistasari ◽

Novena Adi Yuhara ◽

Tri Murti Andayani ◽

Supanji Supanji ◽

...

Keyword(s):

Quality Of Life ◽

Visual Acuity ◽

Diabetic Retinopathy ◽

Utility Score ◽

Microvascular Complications ◽

Cross Sectional ◽

Number Of Patients ◽

High Prevalence ◽

Anxiety Depression

Diabetic retinopathy (DR) is one of the microvascular complications of diabetes mellitus (DM) which incidence increases with the high prevalence of DM. The presence of these complications will affect quality of life, especially vision-related. The purpose of this study was to determine the quality of life in RD patients assessed using the VFQ-25 and EQ-5D questionnaires, and to determine the of quality of life based on the visual acuity (VA) severity. This study was an observational study in outpatient with diabetic retinopathy during October 2018 – Januari 2019 period, in RSUP dr. Sardjito and RS Mata Dr. YAP, Yogyakarta. The design of this study was cross sectional which observed quality of life and vision. Quality of life was measured by specific for vision instrument (NEI-VFQ-25) and generic instrument (EQ-5D-5L). The number of patients in this study were 100 patients with an average age of 55 years, the most frequent type of RD was 84% proliferative RD. The average quality of life scores in RD patients measured using the VFQ-25 and EQ-5D utility questionnaires were 64.1 ± 16.2 and 0.61 ± 0.24, respectively. Based on VFQ-25, the most affected subscales were driving, dependence, and role difficulties subscale. Meanwhile, domains that have the most problems with the EQ-5D were pain / discomfort and anxiety / depression (78%). The total VFQ-25 score decreased with increasing visual severity, i.e. normal / mild (n = 19) 73.50 ± 15.08; moderate (n = 15) 68.14 ± 15.33; and severe (n = 66) 60.48 ± 15.64. The EQ-5D utility score showed a similar pattern, with scores of 0.66 ± 0.27 (normal / mild); 0.65 ± 0.22 (medium); and 0.59 ± 0.24 (severe); respectively. The higher severity of visual acuity so the quality of life become lower.

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