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Retinitis pigmentosa (RP) ranks first in the structure of hereditary retinal diseases. Vasoconstriction is one of the main ophthalmoscopic indications of PR. Laser speckle flowgraphy (LSFG) is a new non-invasive method that allows quantitative assessment of blood flow in the posterior pole of the eye.Purpose: to evaluate changes in blood flow as determined by the LSFG method in the area of the optic nerve head (ONH) and the macular area in PR patients.Material and methods. The study included 16 patients with PR aged 25 to 70 years. The control group consisted of 40 healthy volunteers, comparable in gender and age. Blood flow was determined using an LSFG-RetFlow device (Nidek), the main indicator of blood flow determined was MBR (Mean Blur Rate), which was measured for the entire study area, as well as separately for large vessels, and for the microvasculature. A wide range of pulse wave parameters determined by the tool instrument was also analyzed.Results. This study revealed a significant decrease in blood flow in PR patients compared with healthy individuals in different age groups and at different stages of the disease (p d 0.05). In patients with low visual acuity, the deficit of blood flow in the macular area was found to be more pronounced.Conclusion. LSFG is an effective method for determining ocular blood flow in PR patients. The data may indicate that a decrease in blood flow is an independent pathogenetic factor in the development of PD. In the future, the method can be used to assess the effectiveness of therapy of patients with PR.

Purpose: to evaluate the results of gene therapy by the recombinant adeno-associated viral vector voretigene neparvovec (VN) in children with follow-up periods of 1, 3, 6, and 12 months.Material and methods. The study included 6 children (12 eyes) aged 5 to 15 with a confirmed biallelic mutation in the RPE65 gene, treated with VN (Luxturna, USA). Treatment efficacy was assessed by surveying which included questions on spatial orientation under various types of illumination, Goldman perimetry, microperimetry, best corrected visual acuity (BCVA), electroretinogram (ERG), and visual evoked potentials (VEP). To assess the structure of the retina, the central retinal thickness (CRT) was evaluated by optical coherence tomography.Results. All children showed subjective changes in visual perception, including improved orientation in the dark and twilight, and improved contrast. In one case, the child with initially low visual acuity showed improved visual fixation. In 4 patients out of 6 (8 eyes), an expansion of the visual fields was noted, including 2 cases who displayed significant expansion thereof. In 2 patients (4 eyes), the visual fields were not narrowed and remained so throughout the entire observation period. Mean light sensitivity of the retina in 3 patients and fixation indices in 1 patient improved significantly as shown by microperimetry. BCVA remained stable throughout the study or changed insignificantly. Initially, ERG could not be detected in 8 eyes, but after an VN injection, 6 eyes demonstrated a partial recovery at different times — from 1 to 12 months. An increase in the amplitude of the P1 component to pattern VEP and P2 component to flash VEP was observed in all patients, which indicates an enhanced activity in the projection of the visual cortex after the restoration of the visual cycle. No significant changes were revealed in CRT (p = 0.9). Complications and adverse events were noted in 9 eyes (75 %): chorioretinal dystrophy at the injection site in 3 patients (5 eyes), multifocal nummular dystrophy in 2 patients (4 eyes), local episcleritis in 1 eye, transient increase in intraocular pressure in 2 patients (3 eyes).Conclusion. The results of a one-year post VN treatment follow-up of Russian patients with RPE65-associated inherited retinal disease demonstrate stabilization and improvement of visual functions, which is especially important for otherwise incurable patients with a progressive course of the disease.

Purpose. To develop a new method of amblyopia treatment in children with unstable central and eccentric fixation by centralizing visual fixation and increasing retinal photosensitivity in the macular region using biofeedback. Material and methods. The study included 27 patients (27 eyes) with amblyopia of various origins, aged 5 to 17 (averagely 9.15 ± 3.19 years), who were able to perform training sessions on the MP-3 Nidek microperimeter (Japan). In addition to standard examination, all patients underwent binocular status assessment using a four-point test, macular electroretinography, microperimetry, optical coherence tomography (OCT). The treatment, carried out on the microperimeter using visual (flickering checkerboard pattern) and sound signal biofeedback, consisted of 10—15 sessions, 10—12 minutes each. All patients were examined before treatment cycle, immediately upon the end of the cycle, and also 1 and 3 months after it. Results. Preliminary results showed an increase in best corrected visual acuity (BCVA) from 0.41 ± 0.24 to 0.68 ± 0.27 (33.9 %), the photosensitivity of the retina in the fovea increased from 27.07 ± 3.90 to 29.8 ± 3.3 dB (10 %), fixation density in the central region from 59.80 ± 31.08 to 72.05 ± 34.5 %(20.4 %) with its amplitude decreased by more than two times. After treatment, unstable central fixation changed to stable central fixation in all cases. With eccentric fixation, the fixation point shifted closer to the central region, and fixation characteristics improved in 75 % of cases. The obtained results retained throughout the observation period which lasted up to 3 months. Conclusion. The proposed new treatment method of amblyopia with impaired fixation of various degrees proved to be effective and safe and can be recommended for use in pediatric patients.

Familial exudative vitreoretinopathy (FEVR)is a rare genetically heterogeneous disease with multiple types of inheritance (autosomal dominant, autosomal recessive, X-linked) and widely varying clinical features. Up to 40 % of cases of FEVR are associated with mutations of the FZD4 gene.Purpose: to investigate the clinical manifestations of FEVR in children with nucleotide sequence alterations in the FZD4 gene. Material and methods. The Helmholtz National Medical ResearchCenter of Eye Diseases and the ResearchCentre for MedicalGenetics conducted a joint in-depth ophthalmological examination of 18 patients aged from 3 weeks to 17 years with a diagnosis of FEVR, which included a detailed ophthalmoscopy under drug mydriasis, ultrasound and electrophysiological examination, photographic recording of fundus changes using RetCam and Fundus Foto. Molecular genetic examination was carried out by direct sequencing according to Sanger. Results. Nucleotide sequence alterations in the FZD4 gene were detected in 3 patients(16.7 %)from two unrelated families. In one family, a 12-year-old girl wasfound to display the firstsymptoms of ophthalmic pathology (reduced vision, strabismus) at the age of 3.5 years. In another family, the clinical manifestations of FZD4 gene mutations were observed in two children during the first year of life (at the age of 5 and 11 months).Conclusions. The clinical picture of 3 patients with detected changes in the nucleotide sequence of the FZD4 gene is characterized by early manifestation and bilateral asymmetric ophthalmoscopic damage. The results of the study indicate the need for a timely diagnosis of FEVR in young children, recommend an interdisciplinary approach to the study of the disease, which should contribute to a better understanding of pathogenesis, and the development of an effective diagnostic, treatment and rehabilitation algorithm.

Aim: to study genotype-phenotype correlations in patients with inherited retinal diseases with mutations in ABCA4 gene in Russian Federation.Patients and methods. 21 patients from Russian population aged from 7 to 51 years old (mean age 20 ± 11 years with best-corrected visual acuity from 0,02 to 0,6 (0,14 ± 0,11) with ABCA4-associated retinopathy, verified by molecular genetics methods. All patients besides standard ophthalmic examination and photodocumentation were performed Spectral-Domain OCT and fundus autofluorescence on Spectralis ®HRA+OCT (Heidelberg Engineering, Germany). Full-field electroretinogram (ERG), 30-Hz flicker ERG and macular chromatic ERG (MERG) to red stimulus were recorded on electroretinographic system MBN (MBN, Russia). (Russia) Molecular genetic studies were performed using Next Generation Sequencing (NGS) and Sandger direct sequencing. Results: In ABCA4-associated Stargardt disease 1 type (STGD1) genotype [p.L541P, p.A1038V] of «frequent» mutations was revealed in 9 patients, in 2 cases in was associated another “frequent” mutation p.G1961E. In 4 patients with genotype [p.L541P, p.A1038V] “severe” phenotype of Stargardt disease was found: with large defect of the ellipsoid zone and large zone of central reduced autofluorescence, severely subnormal macular ERG (MERG) to red stimulus and subnormal 30 Hz flicker and full-field maximal ERG. In one patient with these mutations in homozygous state ABCA4-associated cone-rod dystrophy (CORD3, clinically looking alike secondary retinal dystrophy is diagnosed. In 2 patients with genotype [p.L541P, p.A1038V] and mutation p.G1961E was found mild phenotype. One patient with homozygous mutation p.R653C autosomal recessive ABCA4-associated retinitis pigmentosa (RP19) was diagnosed. Clinical picture and autofluorescence were polymorphic in all patients.Conclusions. Our study with ophthalmological, molecular genetics and instrumental methods widens the spectrum of clinical signs of inherited eye diseases associated with mutations in АВСА4 gene, widens the spectrum mutations in Russian Federation and reveals clinicо-genetic genotype-phenotype correlations.

Inherited retinal dystrophies (IRD) is an extensive group of genetically heterogeneous diseases with significant clinical polymorphism. With the development of gene therapy, a new era in the treatment of hereditary human diseases has opened. To date, clinical studies of a number of gene medications are performed the world over, including those intended for the treatment of hereditary eye diseases (Leber congenital amaurosis (LCA), retinitis pigmentosa, achromatopsia, Stargardt's disease, choroideremia, etc.). The varieties of two former conditions, specifically LCA type 2 and retinitis pigmentosa (RP) type 20 with biallelic mutations in the RPE65 gene belong to IRD. Epidemiological studies indicate the rarity of these diseases, which explains why IRD caused by biallelic mutations in the RPE65 gene are included into the list of rare (orphan) diseases of the Russian Ministry of Health. For these IRDs, a gene replacement therapy has been developed: voretigen neparvovek, which must only be applied once. Currently, the Medical Genetic Research Center and Helmholtz National Medical Research Center of Eye Diseases have identified a group of patients who meet the criteria for genetic therapy. In 2021, а specialized gene therapy center has been established at the Helmholtz Research Center, which was certified by the Ministry of Health. A group of leading experts in the field of inherited retinal diseases and medical genetics developed and approved at professional workshops a number of measures that promote the introduction into clinical practice of the voretigen neparvovek as a gene replacement therapy for the treatment of RPE65-related IRD in the Russian Federation.

The purpose: to describe clinical cases of oculodental-digital dysplasia (ODDD, OMIM #164200) with mutation in GJA1 (OMIM 121014) with molecular genetic verification of the diagnosis.Methods. The article describes the clinical case of oculodental-digital dysplasia in a 51 years old patient. Patient underwent full ophthalmic examination including autorefractometry, visual acuity testing with full correction, tonometry, biomicroscopy, fundus examination and photo as well as kinetic perimetry, autofluorescence and optical coherence tomography (OCT) of macula and optic disk were performed. Electrophysiological examination included Visual Evoked Potentials (VEP) to flash and pattern stimulation, ISCEV standard electroretinograms (ERG) and macular ERG. For the verification of the diagnosis and pathologic gene molecular genetic examination was performed with family anamnesis previously attained.Results. The patient was complaining the deterioration of vision, hearing loss and the sense of smell. Visual deterioration was associated with nyctalopia. Natural history revealed glaucoma 2а which was diagnosed when he was 48 years old. Best corrected visual acuity was 1,0. Peripheral visual field defects were revealed bilaterally. High visual acuity correlated with normal foveal structure on OCTs the retinal nerve fiber layer (RNFL) was thinner than normal in temporal half; deep excavation was visualized in both eyes. Normal MERG and bilateral decrease of scotopic, maximal full-field ERG was recorded which correlated with nyctalopia, as well as subnormal photopic responses indicating cone system involvement. The genetics revealed characteristic features of the face: a small nose with hypoplasia of the wings of the nose, unfolded nostrils and a wide bridge of the nose (pseudohypertelorism). On right-wing the ear sink was detected 2 antitraguses. Changes fingers upper extremities — operated syndactyly IV and V on the background of brachydactyly of the fingers. On the legs on both sides — syndactyly III–IV. 10 years the sense of smell has been dereriorated. In the study of DNA in proband in direct Sanger sequencing of all exons 1–2 and regions of exon-intron compounds of gene GJA1, was found the pathogenic variant in second exon c.412G>A (p.Gly138Ser) in heterozygous state. Was established autosomal dominant type of disease.Conclusion. We are the first to describe rod-cone dystrophy in oculodental-digital dysplasia.

This literature review offers a detailed description of the genes and proteins involved in pathophysiological processes in isolated retinitis pigmentosa (RP). To date, 84 genes and 7 candidate genes have been described for non-syndromic RP. Each of these genes encodes a protein that plays a role in vital processes in the retina and / or retinal pigment epithelium, including the cascade of phototransduction (transmission of the visual signal), the visual cycle, ciliary transport, the environment of photoreceptor cilia and the interphotoreceptor matrix. The identification and study of pathophysiological pathways affected in non-syndromic RP is important for understanding the main pathogenic ways and developing approaches to target treatment.

Multimodal visualization data of inherited retinal degeneration (IRD) on a Mirante platform (Nidek, Japan), used in a number of clinical cases, is compared with the data obtained by electrophysiological diagnostic methods. 4 patients with varying IRD were examined: adult-onset foveomacular vitelliform dystrophy, Stargardt disease, including those with fundus flavimaculatus, and retinitis pigmentosa. Multimodal imaging includes: colour fundus imaging, fundus autofluorescence, retro mode, and optical coherence tomography. Electroretinography was performed using an MBN electroretinograph (Russia), and electrooculography was performed using a RETIscan Science system (Roland Consult, Germany). Using non-invasive retinal imaging methods, specific patterns of inherited dystrophies were shown, which correlated well with the data of electrophysiological research methods. The combination of multimodal imaging on the Mirante platform (Nidek, Japan) in combination with electrophysiological diagnostic methods can be successfully used in complex diagnostics, monitoring of the progression, and evaluation of the results of IRD treatment.

Purpose: to assess the inner retinal layer’s changes of the central retina in comparison with bioelectrical activity of macula assessed by MERG and with thickness of photoreceptor retinal layers in patients with retinitis pigmentosa.Patients and methods: 10 patients (20 phakic eyes) with RP were examined. Mean age was 27.0 ± 18.5 years. Mean best corrected visual acuity was 0.38 ± 0.22. The fundus photography electrophysiological studies were performed besides standard ophthalmological examination. Maximal electroretinogram (ERG) or cone-rod response, ERG to 30 Hz flicker and macular ERG were registered with electroretinograph MBN (Russia). Images were acquired using the protocol of scanning Macula radial (12 lines 9 mm long, each radial image is the average out of 50 scans) with settings ultrafine with automatic segmentation of the retina and calculation thickness. Retinal segmentation with the following calculation of different retinal layers was performed on SD-OCT RS-3000 Advance (Nidek, Japan) with obtainment of the map with 6 mm in diameter in accordance with the Early Treatment Diabetic Retinopathy Study (ETDRS).Results. We revealed increased thickness of retinal nerve fiber layer (RNFL), decrease of thickness of ganglion cell layer (GCL) (p < 0,05) and normal (p > 0,05) inner nuclear layer (INL) thickness. These structural changes are associated with the decrease of bioelectric macula’s activity measured by MERG (decrease of α- and β-wave amplitude) and decrease the thickness of photoreceptor layers in all zones according to EDTRS.Conclusion. Increase of thickness RNFL, decrease of GCL’s thickness and normal INL in patients with RP is associated with decrease of thickness of photoreceptor layers in EDTRS zones and decrease of amplitude of MERG.

Achromatopsia (ACHM) is a rare autosomal recessive disease. Its mutation spectrum is well described in other populations, but the data on ACHM prevalence and features in Russia are insufficient. Purpose. To describe clinically and genetically the Russian cohort of AHCM for the potential use of targeted treatment approaches, including gene therapy. Material and methods. Out of 18 patients with clinical manifestations of ACHM, 10 patients were chosen (6 with no kinship relatedness and 4 with kinship relatedness) aged 12.3 ± 5.8 years. These patients underwent standard ophthalmologic examination: visometry, perimetry, biomicroscopy, ophthalmoscopy, as well as optical coherence tomography, electroretinography, and color test on distinguishing color shades, in order to determine the clinical characteristics of ACHM. Molecular genetic confirmation of the clinical diagnosis was performed by high-performance parallel DNA sequencing. An in silico analysis of pathogenetic pathways of the clinical picture in 10 patients with confirmed ACHM was performed. Results. In the examined Russian patients, previously determined mutations in the CNGA3 and CNGB3 genes were confirmed. The most common mutation was a single nucleotide deletion with a reading frame shift in the 10th exon of the CNGB3 gene; a missense mutation in the 8th exon of the CNGA3 gene was second frequent. One patient had mutations in the CNGA3 and CNGB3 genes. Segregation analysis confirms the autosomal recessive nature of disease inheritance. Mutations in the CNGB3 gene have been observed to lead to more serious clinical manifestations than mutations in CNGA3. Conclusions. The analysis of the Russian ACHM cohort shows that mutations in the CNGA3 and CNGB3 genes are the main cause of the development of the disease. A complete molecular genetic confirmation of the clinical diagnosis has been obtained, which is necessary for prescribing targeted treatment to patients, including gene therapy.

The complete form of X-linked congenital stationary night blindness (CSNB) is a rare genetic disease caused by a mutation in the NYX gene. CSNB is associated with the mutations taking place in 17 genes, whilst its CSNB1A form is caused by the mutations in the NYX gene, which were characterized earlier, although nothing had been reported so far about the Russian founder principle. The paper analyzes the pathogenetic mechanisms in a family with diagnosed CSNB1A and a new genetically confirmed mutation in the NYX gene in four members of one Russian family. Two brothers of the four siblings (two boys, two girls) with congenital stationary night blindness, diagnosed in early childhood, and high myopia underwent a standard ophthalmic examination, supplemented with OCT, electroretinography and color blind test with tables by Rabkin and Farnsworth test, whereupon they were sent to molecular genetics confirmation of the diagnosis by whole exome sequencing with subsequent Sanger sequencing confirmation of the detected mutation in the proband and proband’s relatives. In members of the family with clinical features of CSNB1A the reading frame shift mutation was genetically confirmed in the NYX gene (c.283delC, p.His95fs, NM_022567.2). This mutation is inherited in X-linked form. This is the first report of a case with a novel and probable founder mutation from Russia associated with CSNB1A. Since the mRNA of a NYX gene consists of only 2696 base pairs, a gene replacement therapy, or CRISPR-based gene editing, or a similar approach may be envisaged for the correction of frameshift in His95fs position.

The purpose: to describe clinical cases of choroideremia with mutation in CHM gene with molecular genetic verification of the diagnosis. Methods. Two relatives: a patient aged 33 and his mother’s sibs aged 39 with a rare hereditary retinal disease — choroideremia were examined. Patients’ full ophthalmic examination including autorefractometry, visual acuity testing with full correction, tonometry, biomicroscopy, fundus examination and photo as well as kinetic perimetry were performed. Electrophysiological examination included maximal electroretinogram (ERG), ERG to 30 Hz flicker and macular ERG (MERG) that were registered with electroretinograph MBN (Russia). Family anamnesis was studied. Genetic examination was performed for the verification of the diagnosis and pathologic gene molecular. Results. In 33-year-old patient advanced stage was diagnosed: best corrected visual acuity (BCVA) was OU 0,9, visual field was constricted to 10 degrees in both eyes. High BCVA and subnormal MERG correlated with comparatively preserved foveal structure on OCT. There was the terminal stage of choroideremia: In 39 years old his mother’s sibs BCVA was 0,1 OU, constricted to 5 degrees in both eyes. Maximal ERG and ERG to 30 Hz flicker were nonrecordable. Low BCVA and nonrecordable MERG correlated with defected retinal layers and cystoids macular edema on OCT. In both patients we revealed previously described pathogenic variant of nucleotic sequence in 6 exon of CHM gene (chrX:85213886 G>A), causing nonsense-mutation (p.Arg267*, NM_000390.2) in hemizygous state. Conclusion. Etiopathogenetic approach in choroideremia diagnostics allows providing correct diagnosis, prevention and developing of new treatment methods considering etiological factor.

The paper is aimed at studying the bioelectrical activity of macula, light sensitivity and macular structure in retinitis pigmentosa (RP) with cystoid macular oedema (CMO) and atrophic maculopathy. 29 patients (58 phakic eyes), aged 16 to 40 (the average age 28.4 ± 8.2 years) with retinitis pigmentosa (RP) were divided into two groups: patients with foveal atrophy (30 eyes) and CMO (28 eyes). The control group involved 29 healthy subjects of the same age. The total ERG, the 30 Hz flicker ERG and macular ERG (MERG) were determined. The amplitude and latency of a- and b-waves were assessed. Light sensitivity and perimetric indices were estimated with automatic computer perimetry. Spectral ocular coherent tomography (OCT) was performed. In atrophic maculopathy and CMO, the decrease of the amplitude of a- and b-waves of MERG and a prolonged implicit time of the a-wave were found. The increased implicit time of the b-wave was found only in patients with CMO and it correlates with intraretinal cystoid changes in the inner nuclear and outer plexiform layers of the retina. A significant positive correlation between the amplitude of the a-wave of maximal ERG and mean sensitivity (MS), and a significant negative correlation between the a-wave amplitude and mean deviation (MD) indices of automatic perimetry were found. Thus, the prolonged implicit time of the b-wave of MERG is a specific sign of CMO. Perimetric indices are additional diagnostic criteria and may be used together with electroretinography to diagnose RP and assess its progression // Russian Ophthalmological Journal, 2016; 1: 12-18.