[Long-term changes in morphological and functional parameters of the optic nerve in patients with various genetic variants of hereditary optic neuropathies]. / Dolgosrochnaya dinamika morfofunktsional'nykh pokazatelei zritel'nogo nerva u patsientov s razlichnymi geneticheskimi variantami nasledstvennykh opticheskikh neiropatii.

Leber's hereditary optic neuropathy (LHON) and autosomal recessive optic neuropathy (ARON) are degenerative diseases of the optic nerve caused by mutations in nuclear or mitochondrial DNA (nDNA, mtDNA). The clinical picture of these diseases is similar, but there are some differences in how the visual functions change in patients with different molecular genetic variants of hereditary optic neuropathies (HON). PURPOSE: This study evaluates the long-term changes in morphological and functional parameters in patients with different genetic variants of HON. MATERIAL AND METHODS: The study included 84 patients (165 eyes) with a genetically confirmed LHON or ARON diagnosis. The patients underwent best-corrected visual acuity (VA) test, color vision (CV) examination, computerized perimetry using the program for low vision assessment, optical coherence tomography (OCT). RESULTS: Over the course of the follow-up (60 months or longer) HON patients were revealed to have higher VA in c.152A>G and m.14484T>C mutations compared to mutations m.11778G>A and m.3460G>A. The final VA 0.5 or higher in patients with c.152A>G and m.14484T>C mutations in 54 and 71% of cases, and only in 6 and 13% of cases - with m.11778G>A and m.3460G>A mutations. Direct correlation was determined between minimal VA in the first year after disease onset and the final VA (K=0.67; p<0.001). In all patients with the investigated mutations CV recovered slightly quicker than VA. CONCLUSION: HON associated with c.152A>G and m.14484T>C mutations have better prognosis compared to LHON caused by m.11778G>A and m.3460G>A mutations. Vision recovery prognosis is worse in patients who had significant decrease of visual acuity at the disease onset. OCT findings reveal preservation of visual functions in all mutations.

[Rare pathogenic nucleotide variants of mitochondrial DNA associated with Leber's hereditary optic neuropathy]. / Redkie patogennye nukleotidnye varianty mitokhondrial'noi DNK, assotsiirovannye s nasledstvennoi opticheskoi neiropatiei Lebera.

Patients with Leber Hereditary Optic Neuropathy (LHON) in most cases have one of the three most common mutations: m.11778G>A in the ND4 gene, m.3460G>A in the ND1 gene, or m.14484T>C in the ND6 gene. According to the international Mitomap database, in addition to these three most common mutations, there are 16 other primary mutations that are even more rare. There are nucleotide substitutions that are classified as candidate or conditionally pathogenic mutations. Their involvement in the disease development is not proven due to insufficient research. Moreover, in many publications, the authors describe new primary and potential mitochondrial DNA mutations associated with LHON, which are not yet included in the genetic data bases. This makes it possible to expand the diagnostic spectrum during genetic testing in the future. The advancements in genetic diagnostic technologies allow confirmation of the clinical diagnosis of LHON. The importance of genetic verification of the disease is determined by the existing problem of differential diagnosis of hereditary optic neuropathies with optic neuropathies of a different origin.

[Optic neuropathies as an interdisciplinary subject of research]. / Opticheskie neiropatii kak predmet mezhdistsiplinarnogo izucheniya.

Despite the wide range of clinical, instrumental and laboratory methods used in modern ophthalmology, the problem of diagnosing optic neuropathy and identifying its etiology remains relevant. A complex multidisciplinary approach involving various specialists is required in the differential diagnosis of immune-mediated optic neuritis, for example in multiple sclerosis, neuromyelitis optica spectrum disorder, and MOG-associated diseases. Of special interest is differential diagnosis of optic neuropathy in demyelinating diseases of the central nervous system, hereditary optic neuropathies and ischemic optic neuropathy. The article presents a summary of scientific and practical results of differential diagnosis of optic neuropathies with various etiologies. Timely diagnosis and early therapy start reduces the degree of disability in patients with optic neuropathies of different etiologies.

[Masks hiding mitochondrial neurogastrointestinal encephalomyopathy. Case report].

The first documented case of mitochondrial neurogastrointestinal encephalomyopathy was described in 1962 by R. Luft. The variety and am-biguity of the clinical manifestations of the disease complicate its early diagnosis and treatment. The first clinical manifestations of the disease are associated with the pathology of the gastrointestinal tract. Low alertness and insufficient awareness of doctors delays the timely diagnosis of mitochondrial neurogastrointestinal encephalomyopathy. The aim of the work is to increase the alertness and awareness of narrow specialties about the possibility of differential diagnosis of an extremely rare detected disease on the base of our clinical observation.

[Autosomal recessive optic neuropathies: genetic variants, clinical manifestations]. / Autosomno-retsessivnye opticheskie neiropatii: geneticheskie varianty, klinicheskie proyavleniya.

Hereditary optic neuropathies (HON) - a group of neurodegenerative diseases characterized by primary loss of structure and function of the retinal ganglion cells and subsequent death of their axons, development of partial optic nerve atrophy. Autosomal dominant optic neuropathy and Leber`s hereditary optic neuropathy until recently were considered the most common genetic hereditary optic neuropathies, while autosomal recessive optic neuropathies (ARON) were described as rare types of HON, usually accompanying severe syndromic pathologies. In the 2000s it has become clear that ARON occur significantly more often, are underestimated, and their clinical variability is poorly studied. Despite the fact that non-syndromic ARON are less common than syndromic optic neuropathies, their contribution to the development of isolated hereditary optic neuropathies should be considered. This article presents a literature review on non-syndromic ARON developing as a result of mutations in the ACO2, MCAT, WFS1, RTN4IP1, TMEM126A, NDUFS2, DNAJC30 genes.

[Leber's hereditary optic neuropathy clinical features in patients with mitochondrial DNA m.13513G>A candidate mutation]. / Klinicheskie osobennosti nasledstvennoi opticheskoi neiropatii Lebera u patsientov s kandidatnoi mutatsiei m.13513G>A v mitokhondrial'noi DNK.

Leber's hereditary optic neuropathy (LHON) is caused by primary mtDNA by both primary mtDNA mutations and new mtDNA mutations. The last ones, when detected in several independent LHON families, receive candidate status. The description of new LHON-associated mtDNA mutation is relevant. PURPOSE: To determine the LHON clinical features in patients with the m.13513G>A mutation and to estimate the patients' proportion with this pathogenic variant in the LHON patients' sample. MATERIAL AND METHODS: The study included 5 LHON patients, associated with m.13513G>A mutation in the ND5 gene in the heteroplasmic state. A standard examination was performed, including color blindness test, visual fields test, spectral optical coherence tomography. RESULTS: LHON, associated with m.13513G>A in the heteroplasmic state in the range of 25-60%, is characterized by visual impairment without additional neurological or other extraocular symptoms. Visual recovery to 0.3-1.0 presents in all patients; the visual recovery onset occurs between 12 and 20 months from the disease manifestation. The decrease of the central scotoma size and its density and the color vision improvement are also observed as well as the average retinal nerve fibers layer and ganglion cell complex thickness decrease. The m.13513G>A mutation frequency is 5% in 100 LHON patients' sample and 22.5% in 22 LHON patients with rare and candidate mtDNA mutations. CONCLUSION: The m.13513G>A mutation can be considered as primary LHON mutation. The list of pathogenic variants recommended for testing LHON can include this mutation. The m.13513 G>A mutation determines the mild LHON course and good visual functions prognosis in these patients.

[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.

[New possibilities in diagnosis of hereditary optic neuropathies]. / Novye vozmozhnosti diagnostiki nasledstvennykh opticheskikh neiropatii.

The study analyses data from clinical and genetic examination of 114 patients, as well as examination of cytological skin fibroblasts of 20 patients with hereditary optic neuropathy (HON). The clinical examination revealed HON symptoms in all study patients, primary damage of the retinal ganglion cells accompanied by swelling of the peripapillary retinal nerve fiber layer (RNFL) in the acute stage of the disease was observed in 47% of cases. MtDNA mutations that cause the development of Leber hereditary optic neuropathy (LHON) were detected in 73% of cases, including three frequent mutations in 59% of cases, rare and candidate mutations - in 14% of cases; nDNA mutations associated with autosomal dominant optic neuropathy (ADON) - in 6.1% of cases; mutations in the DNAJC30 nDNA gene that caused autosomal recessive optic neuropathy (ARON) - in 21% of cases. Among patients with a clinical picture of LHON, mtDNA mutations were found in 77.6% of cases, while mutations of the DNAJC30 gene of nDNA - in 22.4% of cases. Cytological studies using high-resolution respirometry confirmed the presence of mitochondrial dysfunction not only in the cells of patients harboring pathogenic mutations, but also of those harboring candidate mutations. An algorithm for clinical and genetic verification of HON together with a set of cytological studies allows identification of the mitochondrial genesis of the disease and is indispensable in confirming the pathogenicity of new or candidate mutations.

[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.

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.

[Modern opportunities and prospects for studying pathogenesis, diagnosing and treating hereditary optic neuropathies].

OBJECTIVE: To evaluate modern opportunities and prospects for studying pathogenesis and improving diagnostics and treatment of hereditary optic neuropathies (HON). MATERIAL AND METHODS: The article presents summarized data on the pathogenesis, diagnostics, and treatment of HON based on modern methods of assessment. RESULTS: The results of long-term worldwide studies and those performed in the Research Institute of Eye Diseases in collaboration with several other institutions are presented. Genetic testing for mitochondrial and nucleus DNA mutations that have a known association with Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic neuropathy (ADON) allow verification only in half of the cases. Particular features of hereditary diseases, such as incomplete penentrance, variable expression, clinical polymorphism, difficulties in detection of hereditary sings, and genetic heterogeneity, are shown to complicate the diagnosis of HON. Spectral retinal tomography revealed characteristic morphometric changes in the macular region and peripapillary nerve fiber layer in the acute stage of LHON. Hereditary optic neuropathies result from a genetically determined decrease in mitochondrial respiratory chain complexes activity, which is associated with a decrease in ATP production. From that standpoint, studying of mitochondrial oxidative phosphorylation biochemical defects in LHON and ADON is an option for detection of mitochondrial dysfunction. Results of a newly proposed method of mitochondrial membrane potential assessment in skin fibroblasts, which can be used for differential diagnosis of mitochondrial optic nerve diseases, are presented. Possible therapeutic measures for HON are discussed. CONCLUSION: In the prevailing number of cases the described clinical, molecular genetic, and cytological methods ensure proper diagnosis of hereditary optic neuropathies. Prospects of HON treatment, rather ambiguous, are associated with further studying of pathogenesis, development of drugs and gene therapy.

[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.

[Molecular genetics and clinical aspects of monogenic diabetes mellitus].

The paper is dedicated to clinical and laboratory aspects of Diabetes Mellitus non-immune forms, such as neonatal Diabetes Mellitus, Maturity Onset Diabetes of young (MODY), DIDMOAD-syndrome, Wolframe syndrome, Alstrom syndrome and its determinating genes. The analysis of proper clinical results are present in this paper.

Mitochondrial DNA maintenance disorders in 102 patients from different parts of Russia: Mutational spectrum and phenotypes.

Currently, pathogenic variants in more than 25 nuclear genes, involved in mtDNA maintenance, are associated with human disorders. mtDNA maintenance disorders manifest with a wide range of phenotypes, from severe infantile-onset forms of myocerebrohepatopathy to late-onset forms of myopathies, chronic progressive external ophthalmoplegia, and parkinsonism. This study represents the results of molecular genetic analysis and phenotypes of 102 probands with mtDNA maintenance disorders. So far, this is the largest Russian cohort for this group of diseases. Mutations were identified in 10 mtDNA maintenance genes: POLG (n = 59), DGUOK (n = 14), TWNK (n = 14), TK2 (n = 8), MPV17 (n = 2), OPA3 (n = 1), FBXL4 (n = 1), RRM2B (n = 1), SUCLG1 (n = 1) and TYMP (n = 1). We review a mutation spectrum for the DGUOK and TWNK genes, that can be specific for the Russian population. In 34 patients we measured the blood mtDNA copy number and showed its significant reduction. Novel variants were found in 41 cases, which significantly expands the mutational landscape of mtDNA maintenance disorders.

[High resolution respirometry in diagnostic of mitochondrial disorders caused by mitochondrial complex I deficiency]. / Respirometriia vysokogo razresheniia v diagnostike mitokhondrial'nykh zabolevanii s narusheniem raboty I kompleksa dykhatel'noi tsepi mitokhondrii.

Complex I (CI) deficiency is one of the most common defects in the OXPHOS system; it represents more than 30% cases of mitochondrial diseases. The group is characterized by clinical and genetic heterogeneity and comprise several nosological forms. The most prevalent phenotypes for CI are LHON and Leigh syndrome. In this study we have analyzed skin fibroblasts from 11 patients with mutations in mtDNA, which cause LHON or Leigh-like phenotypes: m.11778 G>A (n=3), m.3460 A>G (n=2), m.3635 G>A (n=1), m.3308 T>G (n=2), m.3472 T>C (n=1) and 2 patients with earlier unknown substitutions m.3945 C>A and m.14441T>C. High-resolution respirometry (HRR) on the Oxygraph-2k instrument ("Oroboros corp.", Austria) was performed for complex analysis of the mitochondrial respiratory function in intact and permeabilized fibroblasts of patients and healthy controls. Flux control rations in intact cells R/E, (R-L)/E (p<0.05) were raised compared to the control. Rates of R, E, L normalized on the CS were statistically varied between patients and controls. In permeabilized fibroblasts we observed differences in CII/E, Rot/E, R/CII, CI/CII (p<0.05) between groups. These data highlight the dysfunction of the OXPHOS system and particularly CI. Increased citrate synthase level and decreased CI/CII ratio indicate compensatory metabolic response to respiratory chain dysfunction. Our results show applicability of HRR in revealing the biochemical abnormalities of complex I in fibroblasts of patients with LHON and Leigh-like syndrome. We also suggest HRR to be a useful method for inspection of other mutations causing complex I deficiency.

[Syndrome Leigh caused by mutations in the SURF1 gene: clinical and molecular-genetic characteristics].

Syndrome Leigh (SL) or subacute necrotizing encephalomyelopathy - is a rare hereditary genetically heterogeneous disease from the group of mitochondrial encephalomyopathies. Twenty-seven children with SL were examined using clinical, laboratory (measuring lactate levels), MRI and molecular-genetic (polymerase chain reaction genotyping of 9 exons of the SURF1 gene) studies. The mean age of manifestation was 11,6 months. The main manifestations of SL were: delay of psychomotor development, diffuse muscle hypertonic, cerebellar syndrome, ophthalmoparesis, hypertrichosis. The disease had a progressive course with the loss of acquired skills. The blood lactate concentration was increased on average up to 3,1 mM/ml (from 1,9 to 5,1 mM/ml) compared to normal values (1,8 mM/ml). Brain MRI revealed the subcortical and cortical atrophy (80% of cases), symmetrical distinctly delineated hyperintense lesions on T2-weighted images (demyelization) in the basal ganglia and the brain stem (50%), as well as in the cerebellum (25%). Genotyping identified 7 different mutations. The most frequent (64,8%) was the deletion of 2 nucleotides (845delCT) in exon 8 that was in line with early data of Polish researchers thus indicating the Slavic origin of this mutation. Other mutations (574-575insCTGT, 311-321del10insAT and IVS8-1G>) were also frequent in the Russian population.