[Hereditary optic neuropathy associated with demyelinating diseases of the central nervous system]. / Nasledstvennaya opticheskaya neiropatiya v sochetanii s demieliniziruyushchimi zabolevaniyami tsentral'noi nervnoi sistemy.

Demyelinating optic neuritis and hereditary optic neuropathy (HON) take a leading place among the diseases, the leading clinical syndrome of which is bilateral optic neuropathy with a simultaneous or sequential significant decrease in visual acuity. Optic neuritis can occur at the onset or be one of the syndromes within multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD). HON are a group of neurodegenerative diseases, among which the most common variants are Leber's hereditary optic neuropathy (LHON), associated with mitochondrial DNA (mtDNA) mutations, and autosomal recessive optic neuropathy (ARON), caused by nuclear DNA (nDNA) mutations in DNAJC30. There are phenotypes of LHON «plus¼, one of which is the association of HON and CNS demyelination in the same patient. In such cases, the diagnosis of each of these diseases causes significant difficulties, due to the fact that in some cases there are clinical and radiological coincidences between demyelinating and hereditary mitochondrial diseases.

[Multifocal electroretinography in assessment of the functional state of the central retina in patients with retinitis pigmentosa]. / Mul'tifokal'naya elektroretinografiya v otsenke funktsional'nogo sostoyaniya tsentral'noi zony setchatki pri pigmentnom retinite.

Retinitis pigmentosa (RP) is an inherited disease associated with various genetic mutations. Developments in the field of genetic engineering give relevance to the search for methods of studying retinal function, which can prove informative in the selection of patients for treatment. PURPOSE: To evaluate the information content of multifocal electroretinography (mfERG) in the diagnostics of the functional state of the central retina in retinitis pigmentosa (RP). MATERIAL AND METHODS: The study included 115 patients (228 eyes) with PR and 15 people (30 eyes) who comprised the control group. All subjects underwent standard ophthalmological examination, computer perimetry, color vision study, retinal spectral optical coherence tomography, ganzfeld electroretinography (gERG) and mfERG. The relationship between mfERG parameters and the degree of gERG changes, as well as various functional and morphological parameters of the retina was assessed. RESULTS: Visual acuity and perimetry indices varied over a wide range. GERG was unrecordable in 50.4% of cases. MfERG was registered in 214 (98.3%) eyes with varying degrees of change in visual acuity, visual field and gERG parameters. A medium degree positive relationship was revealed between the biopotential density of the retina in the foveal and parafoveal zones and visual acuity (rs=0.68; 0.63), a high degree - between the density of ttotal biopotential of the central retina (DValue) and the average light sensitivity (rs=0.9), a weak degree - between DValue and the thickness and volume of the peripheral retina (rs=0.37; 0.42), a medium negative correlation was found between the average defect in light sensitivity and the biopotential density in the periphery (Rings 4-5) on mfERG, DValue (rs= -0.67; -0.65; -0.69). CONCLUSION: MfERG detects retinal dysfunctions at an early stage of RP, in eyes with high visual acuity, normal parameters of the central visual field and gERG, as well as in low visual acuity, a pronounced decrease in light sensitivity, unrecordable gERG. MfERG can be informative in the selection of patients with RP for gene therapy.

[Bilateral vision loss on programmed hemodialysis (clinical observation)]. / Dvustoronnyaya poterya zreniya na fone programmnogo gemodializa (klinicheskoe nablyudenie).

The most common complication of hemodialysis is blood pressure decrease, which is an ischemic optic neuropathy risk factor. The article presents a case study of sequential bilateral ischemic optic neuropathy with the development of amaurosis as a result of arterial hypotension against the background of programmed hemodialysis. Differential diagnosis in bilateral visual impairment is discussed.

[Metabolic disorders in hereditary optic neuropathies]. / Metabolicheskie narusheniya pri nasledstvennykh opticheskikh neiropatiyakh.

Folate metabolism disorders are known to have a potential involvement in the pathophysiology of mitochondrial diseases. Many researchers suggest that profound systemic folate deficiency may contribute to mitochondrial folate deficiency. Folic acid metabolism is closely related to vitamin B12 and homocysteine. Considering that hereditary optic neuropathies (HON) are mitochondrial diseases, it is important to study the folate status, the content of vitamin B12 and homocysteine in patients with this pathology. OBJECTIVE: To compare the content of folic acid, vitamin B12 and homocysteine in the blood serum of patients with Leber's hereditary optic neuropathy (LHON) and autosomal recessive optic neuropathy (ARON), optic neuropathy of other genesis, and the comparison group. MATERIAL AND METHODS: The study involved 58 patients with LHON and ARON, the control group of 49 patients with ischemic, inflammatory, traumatic and compressive optic neuropathies, and the comparison group of 20 healthy volunteers. RESULTS: A decrease in blood folic acid levels was revealed (4.0±1.6 ng/mL) in patients with HON compared to the control group (p=1.3·10-8) and the comparison group (p=1·10-17). The content of vitamin B12 in patients with HON was 380.8±168.1 pg/mL, which was significantly lower than in the comparison group (p=0.0001). The homocysteine content was 14.1±5.6 µmol/L in patients with HON, which was significantly higher than in the control group (p=0.0007) and the comparison group (p=0.000003). At the same time, an increase in homocysteine level of more than 10 µmol/L was revealed in 75% of patients with HON. Similar metabolic disorders were found in groups with various mutations in mitochondrial and nuclear DNA. CONCLUSION: Patients with HON showed marked decrease in the levels of folic acid and vitamin B12, as well as hyperhomocysteinemia. It is very important to identify the causes of metabolic disorders in order to determine the role of folate deficiency in the development of HON, as well as the possibility of its pharmacological treatment.

[Electrophysiological and psychophysical studies in assessment of visual functions in patients with hereditary optic neuropathy]. / Elektrofiziologicheskie i psikhofizicheskie issledovaniya v otsenke zritel'nykh funktsii pri nasledstvennoi opticheskoi neiropatii.

PURPOSE: To study the capabilities of electrophysiological and psychophysical examination methods for assessment of the functional state of ganglion cells, retina and optic nerve in patients with hereditary optic neuropathy (HON). MATERIAL AND METHODS: The study included 60 patients (118 eyes) with a genetically confirmed diagnosis of HON. All study patients underwent visual field test (VFT), spectral optical coherence tomography (OCT), flash and pattern visual evoked potentials (VEP) (Flash-VEP, FVEP; Pattern-VEP, PVEP), photopic electroretinography with photonegative response (PhNR) registration and the color vision test. In 24 patients (46 eyes), these parameters were assessed before the start of treatment and one year later. The treatment involved the mitochondria-targeted antioxidant SkQ1 - plastoquinonyl-decyl-triphenylphosphonium bromide (PDTP) in the form of eye drops. RESULTS: The main PVEP components for 1.0° and 0.3° were registered in 20% and in 14% of patient eyes with HON and high visual functions, respectively. After one year of PDTP use, a significant decrease in P100 peak latency was found only in the group with disease duration of ≤1.5 years as of the time of treatment start (p<0.05). Significant differences were observed in the PhNR amplitude (p<0.004) between patients of the main and the control groups, as well as in the PhNR amplitude between patients with visual acuity of ≤0.1 and ≥0.13 (p<0.01). Patients with high visual functions were found to have a correlation between the PhNR amplitude, GCC thickness and the global loss index (GLV). CONCLUSION: Along with VFT, OCT and color vision tests, electrophysiological studies are one of the main methods of examining patients with HON. After one year of PDTP use, there was a significant decrease in the FVEP P2 peak latency in the group with a disease duration of ≤1.5 years as of the time of treatment start. The PhNR amplitude in patients with high visual functions was found to correlate with structural changes in the ganglion cell layer and the retinal nerve fiber layer.

[Poppers maculopathy (case study)]. / Poppers-makulopatiya (klinicheskoe nablyudenie).

The article presents a clinical case of poppers-associated maculopathy - a maculopathy of toxic genesis, insufficiently represented in Russian scientific literature. The diagnosis was based on anamnestic data (long-term use of poppers), specific structural disorders of the outer layers of the retina in the foveolar zone according to spectral optical coherence tomography, as well as changes in multifocal and ganzfeld electroretinography readings. The main strategy for patients with this disorder is complete rejection of poppers.

[Asymmetric form of pigmentary retinopathy (case study)]. / Asimmetrichnaya forma pigmentnoi retinopatii (klinicheskoe nablyudenie).

Unilateral pigmentary retinopathy (PR) is a rare, atypical form of hereditary retinal pathology. Different types of secondary retinopathy associated with various non-hereditary diseases, trauma or intoxication can imitate unilateral PR. Therefore, it is important to determine the cause of visual disorders and differentiate between unilateral and asymmetric PR. The article presents an example of using modern structural and functional diagnostic methods that helped diagnose the asymmetric form of the disease in a patient with suspected unilateral PR.

[Characteristics of changes in retinal and optic nerve microvascularisature in Leber hereditary optic neuropathy patients seen with optical coherence tomography angiography]. / Osobennosti mikrososudistykh izmenenii setchatki i zritel'nogo nerva u patsientov s nasledstvennoi opticheskoi neiropatiei po dannym opticheskoi kogerentnoi tomografii-angiografii.

PURPOSE: To investigate the features of various parameters of the density of retinal blood vessels, optic nerve head (ONH) and peripapillary region in hereditary optic neuropathy (HON) patients revealed with optical coherence tomography angiography (OCTA). MATERIAL AND METHODS: The study included 29 HON patients divided into three groups based on symptoms duration (less than 1 year; 1-5 years, more than 5 years) and visual acuity (0.5-1.0; 0.04-0.4; 0.03 and lower). Relative macular, optic disc and peripapillary vessel density (VD, %) was assessed by OCTA (xR Avanti, Optovue Inc., USA). RESULTS: Significant progressive VD reduction in superficial capillary plexus (SCP) was detected in all parafovea sectors and in the temporal sector of perifovea over the course of disease progression. No significant differences of these parameters were found in correlation with visual acuity. Patients with VA of 0.5-1.0 turned out to have greater VD in deep capillary plexus (DCP), whereas no differences were found in relation to the duration of HON. A strong significant correlation between the SCP and DCP VD only in central foveal area was revealed in all groups depending on the VA and symptoms duration. Over the course of HON progression, VD in the temporal sector and in temporal segments of superior and inferior sectors has gradually reduced. In patients with VA of 0.5-1.0, the retinal nerve fibers layer (RNFL) thickness in the temporal sector and optic nerve VD was notably greater compared to patients with lower VA. The most significant correlation was established between VA and structural changes (K=0.75, p<0.001) and VD in the temporal sector (K=0.57-0.61, p<0.001). CONCLUSION: The obtained data suggest that derivative microvascular changes play an active role in the clinical progression of the disease.

[Morphological and functional indicators of retinal pigment epithelium and photoreceptor apparatus in inherited retinal diseases]. / Morfofunktsional'nye pokazateli retinal'nogo pigmentnogo epiteliya i fotoretseptornogo apparata pri nasledstvennykh zabolevaniyakh setchatki.

PURPOSE: To evaluate the relationship between the morphological and functional parameters of retinal pigment epithelium (RPE) and photoreceptors (PR) in inherited retinal diseases (IRD). MATERIAL AND METHODS: The study included 52 patients (104 eyes), 23 of them with Stargardt Disease (STGD), 19 with cone-rod dystrophy (CRD), 10 with retinitis pigmentosa/pigmentary abiotrophy (RP) of comparable disease durations. All patients underwent standard and additional ophthalmological examination: fundus autofluorescence (AF), spectral optical coherence tomography (OCT), computer perimetry (CP), electro-oculography (EOG), Ganzfeld electroretinography (gERG). RESULTS: Comparison of the groups of IRD patients and groups according to the degree of RPE damage with the control group revealed an increase in differences in the EOG and gERG indicators as the area and depth of damage to the RPE and PR progressed. The patterns of changes in RPE and PR, the frequency of their occurrence with IRD in this patient sample are described. A moderate correlation was found between the amount of RPE loss and EOG light rise, as well as between the defect of the ellipsoid zone and the amplitude of α- and ß-waves, the latency of ß-wave of the gERG. Some patients showed a mismatch between a small defect of the ellipsoid zone and RPE with significant damage to the visual field and reduction of the EOG and gERG indicators. The obtained electrophysiological indicators revealed pathological changes in RPE and PR, more significant and widespread in some cases than it was shown with visualization methods. Weak and moderate correlations between visual acuity, and RPE damage and light sensitivity index with loss of ellipsoid zone were calculated. CONCLUSIONS: Modern methods of retinal examination can help obtain complete and versatile picture of morphological and functional state of the retina in IDR that supplement each other. EOG and gERG have capability to determine the degree of RPE and PR functions impairment including those cases when morphological studies are not sufficiently informative.

[Structural and functional changes in the retina and optic nerve in patients with toxic optic neuropathy caused by acute methanol poisoning]. / Osobennosti strukturnykh i funktsional'nykh izmenenii setchatki i zritel'nogo nerva u patsientov s toksicheskoi opticheskoi neiropatiei na fone otravleniya metanolom.

PURPOSE: To identify the specifics of structural and functional changes in patients with toxic optical neuropathy caused by acute methanol poisoning. MATERIAL AND METHODS: One female patient with toxic optic neuropathy (TON), 2 male patients with partial optic atrophy caused by methanol poisoning, and 1 male patient with methanol intoxication after ethanol containing alcohol use were examined with kinetic perimetry and optical coherence tomography. RESULTS: Patients with TON caused by acute methanol poisoning were observed to have decreasing visual acuity to the extent of complete blindness. OCT follow-up studies revealed thinning of the retinal nerve fiber layer (RNFL) as well as formation of microcysts in the inner retinal layers, destruction of ellipsoid zone and outer segments of photoreceptors. The patient with methanol intoxication after use of ethanol containing alcohol had retained his visual functions; he was found to have microcysts and RNFL thinning during the first few months after the intoxication, but they were within normal range of OCT parameters. CONCLUSION: Patients with TON caused by acute methanol poisoning are common to have optic atrophy with either residual visual functions or complete blindness as well as microcysts formation, structural changes and destruction of the ellipsoid zone and outer segments of photoreceptors. In patient with methanol intoxication after use of ethanol, which is known to be an antidote, complete visual recovery was observed, although some microcystic changes and ganglion cells layer thinning were noted.

[New possibilities in the treatment of Stargardt disease]. / Novye vozmozhnosti terapii bolezni Shtargardta.

Stargardt disease is a hereditary retinal dystrophy associated with mutations in the ABCA4 gene. Currently, no etiopathogenetic drugs nor treatment methods for Stargardt disease have completely passed clinical trials. The review summarizes experimental and clinical studies of drugs aimed at reducing the accumulation of vitamin A dimers, lipofuscin, complement inhibition and RPE regeneration by stem cell transplantation, as well as gene therapy studies with intravitreal vector injection of the ABCA4 functional gene.

[Efficacy of transethmoidal orbital decompression in patients with dysthyroid optic neuropathy]. / Effektivnost' transetmoidal'noi dekompressii orbity u patsientov s opticheskoi neiropatiei pri endokrinnoi oftal'mopatii.

OBJECTIVES: To estimate efficacy and safety of endoscopic orbital decompression in patients with dysthyroid optic neuropathy (DON). MATERIAL AND METHODS: 19 patients aged 54.8±7.1 y.o. with DON were enrolled into the study. RESULTS: Visual acuity was from counting fingers till 0.9 (0.4±0.28) before surgery, it increased till 0.7±0.2 (p<0.05) after surgery. The amount of correct Ishihara plates increased from 5.8±7 till 13.3±7.6 (p<0.05). Exophthalmos reduced by 1.7 mm (p<0.05). Significant reduce of orbital inflammation was noted as well. CONCLUSIONS: This study is the first study of this kind in Russian Federation. Obtained results showed high efficacy and safety of endoscopic orbital decompression in patients with DON.

[Phenotype-genotype correlations in patients with inherited retinal diseases with p.G1961E mutation in the ABCA4 gene]. / Kliniko-geneticheskie korreliatsii u patsientov s nasledstvennymi zabolevaniiami setchatki pri mutatsii p.G1961E v gene AVSA4.

PURPOSE: To evaluate phenotype-genotype correlations in patients with inherited retinal diseases (IRD) with mutation p.G1961E in the ABCA4 gene. MATERIAL AND METHODS: The study included 20 patients with p.G1961E mutation in the heterozygous state in the ABCA4 gene who underwent complete ophthalmic examination, as well as high-performance parallel sequencing of the coding sequences and adjacent areas of the introns of the ABCA4, ELOVL4, PROM1, CNGB3 genes. RESULTS: The p.G1961E mutation was detected in heterozygous state with missense mutations, splice site mutations, a frameshift duplication, and a nonsense mutation in 18 patients, a second mutation was not detected in 2 patients. The duration of the disease in 4 patients was 2-5 years, which made it impossible to assess the morphofunctional changes in dynamics. In 13 of the 16 patients with IRD duration of 29±14 years and p.G1961E mutation in the ABCA4 gene the course of the disease was relatively mild: visual acuity of 0.15±0.07, loss of visual acuity averaging 0.037±0.019 per year, absolute/relative scotoma within 5-20°, and 3.52±1.21 mm loss of ellipsoid photoreceptor zone in the macular area according to OCT. In 3 patients, including one without a second mutation in the ABCA4 gene, better pronounced changes were revealed. Multifocal electroretinogram was altered in all 20 cases. In 7 of the 8 patients with p.G1961E in the heterozygous state in combination with complex mutation p.[L541P;A1038V], as well as in 2 patients without a second mutation, full-field electroretinography (Ganzfeld; ffERG) had changes (abnormalities) of varying intensity. CONCLUSION: A frequent mutation in the ABCA4 gene - p.G1961E - is associated with a relatively mild course of IRD in 81% of cases, even in the presence of a second, severe mutation. However, in rare cases a more severe phenotype of the IRD in patients with p.G1961E mutation can be observed, which may be associated with other genetic factors. In patients with the p.G1961E mutation in heterozygous state with p.[L541P;A1038V], ffERG changes (abnormalities) were revealed.

[Inherited retinal diseases in patients with ABCA4 gene mutations]. / Nasledstvennye zabolevaniia setchatki pri mutatsiiakh gena ABCA4.

ABCA4 is one of the main genes which mutations are associated with various inherited retinal diseases (IRD) such as Stargardt disease, cone dystrophy, cone-rod dystrophy, and retinitis pigmentosa. Wide prevalence of IRD, high heterogeneity of ABCA4 gene mutations that lead to impaired function of the protein with varying expressiveness make studying of the clinical and genetic characteristics of retinal diseases relevant for further investigations into pathogenesis, prognosis and outcome of the disease. This article reviews the literature on incidence of IRD caused by mutations in the ABCA4 gene and characteristics of the clinical progression of retinal diseases associated with various types of mutations, and presents analysis of clinical and genetic correlations in terms of the effect the mutation has on the structure or function of the protein.

[Clinical polymorphism of splice site mutations in the ABCA4 gene]. / Polimorfizm klinicheskikh proiavlenii pri mutatsiiakh saita splaisinga v gene AVSA4.

ABCA4 is one of the main genes whose mutations are associated with various inherited retinal diseases (IRD) such as Stargardt disease, cone dystrophy, cone-rod dystrophy, and retinitis pigmentosa. The severity of retinal dystrophy phenotype may be related to the degree of mutation pathogenicity, which depends on the localization in various regulatory regions of the gene and the effect on the amino acid composition of the protein molecule. The article describes two clinical cases of patients with splice site mutations in the compound heterozygous state with missense mutations in the ABCA4 gene with various phenotypic manifestations, which demonstrate the importance of molecular genetic analysis in patients with IRD. Such analysis allows determination and accumulation of data on phenotype-genotype correlations that can help predict the disease course.

[Torpedo macu-lopathy (clinical case)]. / Makulopatiia 'torpedo' (klinicheskii sluchai).

The article presents a clinical case of torpedo maculopathy. This congenital disorder is most likely to be caused by changes in the retinal pigment epithelium (RPE) during retinal fissure closure. Visual function is usually unaffected and the condition is revealed at routine ophthalmic examination in children and teens. Optical coherence tomography showed the absence of RPE, photoreceptor damage, and massive thinning of the outer nuclear layer at the diseased site without a significant change in the total retinal thickness. RPE involvement was also evidenced by changes in fundus autofluorescence.

[Molecular genetic diagnosis of Stargardt disease]. / Molekuliarno-geneticheskaia diagnostika bolezni Shtargardta.

AIM: To comparatively evaluate the efficacy of genetic screening in patients with Stargardt disease (SD) by using an express panel of 5 most common ABCA4 mutations and performing massive parallel sequencing of all coding regions of the ABCA4, ELOVL4, PROM1, and CNGB3 genes. MATERIAL AND METHODS: MLPA analysis for 5 ABCA4 mutations, namely p.G863A, p.L541P, p.A1038V, p.G1961E, and p.P1380L, was done in 54 patients with SD. In 25 patients, massive parallel sequencing of coding regions (exons) and neighboring introns of the ABCA4, ELOVL4, PROM1, and CNGB3 genes was also performed. RESULTS: Gene testing for 5 ABCA4 mutations showed that 50% of patients (27 patients) harbored one mutation and 13% - two mutations. At massive parallel sequencing (25 patients), two pathogenic alleles were found in 21 patients (84%), one mutation - in 23 patients (91.7%). The majority of mutations was accounted for by the ABCA4 gene (83% of all mutation-positive patients). CONCLUSION: Sequencing of exons and neighboring introns of the ABCA4, ELOVL4, PROM1, and CNGB3 genes with the new molecular genetic diagnostic system enabled confirmation of the diagnosis of SD in 84% of patients. High prevalence of p.L541P, p.A1038V, and p.G1961E mutations of the ABCA4 gene has been established.

Previously Unclassified Mutation of mtDNA m.3472T>C: Evidence of Pathogenicity in Leber's Hereditary Optic Neuropathy.

Leber's hereditary optic neuropathy (LHON) refers to a group of mitochondrial diseases and is characterized by defects of the mitochondrial electron transport chain and decreased level of oxidative phosphorylation. The list of LHON primary mtDNA mutations is regularly updated. In this study, we describe the homoplasmic nucleotide substitution m.3472T>C in the MT-ND1 (NADH-ubiquinone oxidoreductase chain 1) gene and specific changes in cell metabolism in a patient with LHON and his asymptomatic sister. To confirm the presence of mutation-related mitochondrial dysfunction, respiration of skin fibroblasts and platelets from the patient and his sister was studied, as well as the mitochondrial potential and production of reactive oxygen species in the skin fibroblasts. In addition, based on characteristics of the toxic effect of paraquat, a new approach was developed for detecting the functional activity of complex I of the mitochondrial respiratory chain.

[Relationship between structural and functional changes in retina in Stargardt disease]. / Vzaimosvyaz' strukturnykh i funktsional'nykh izmenenii setchatki pri bolezni Shtargardta.

AIM: To assess the relationship between structural abnormalities of the junction of the internal and external segments of photoreceptors (IS/OS junction) and functional changes. MATERIAL AND METHODS: The study enrolled 45 patients (90 eyes) with Stargardt disease, of them 22 women and 23 men. Ophthalmic examination included color vision test, static perimetry with a 60° field of view, electrophysiological studies, namely, ganzfeld and multifocal electroretinography (gERG and mfERG), autofluorescence, and optical coherence tomography (OCT). RESULTS: For analysis, the patients were divided into 3 groups depending on whether or not the structure of the IS/OS junction was damaged at OCT. A strong correlation has been found between the level of IS/OS damage and the MD index. There were no differences in foveal, perifoveal, or parafoveal retinal thicknesses. Retinal volumes within the 1-, 3- and 6-mm ring-shaped zones were also similar. All three groups showed a reduction in amplitudes of the major gERG waves and mfERG changes of different severity. The most frequent defect seen in all groups and the ring-shaped zones was a reduction in the amplitude and density of retinal biopotential (P1µv and P1 nv/deg2). CONCLUSION: A direct correlation exists between the extent and severity of structural changes in the IS/OS junction at OCT, visual functions assessed with perimetry, and disturbance of electrogenesis detected by mfERG and gERG.

[Stargardt's disease and abiotrophy of Franceschetti (fundus flavimaculatus): pathogenetic, clinical, and molecular genetic characteristics].

The article presents a review of literature on Stargardt's disease and abiotrophy of Franceschetti. Etiopathogenetic, clinical and molecular genetic characteristics are covered. Clinical and genetic classifications of the diseases are provided.