The m.13513G>A (p.Asp393Asn) substitution in the MT-ND5 (Mitochondrially Encoded NADH/Ubiquinone Oxidoreductase Core Subunit 5) gene is a common pathogenic variant associated with primary mitochondrial disorders. It frequently causes Leigh syndrome and mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS). In this study, we present clinical data, heteroplasmy levels in various tissues (blood, urine, and skin fibroblasts), and bioenergetic characteristics from a cohort of 20 unrelated patients carrying the m.13513G>A mutation, classified according to the following phenotypes: Leigh syndrome (n = 12), MELAS (n = 2), and Leber’s hereditary optic neuropathy (LHON, n = 6). We observed a significant correlation between high respiratory ratios and heteroplasmy levels in fibroblast cell lines of the patients. Furthermore, fibroblast cell lines with heteroplasmy levels exceeding 55% exhibited markedly reduced mitochondrial membrane potential. These findings contribute to a better understanding of the clinical and bioenergetic profiles of patients with m.13513G>A-variant-related phenotypes across different heteroplasmy levels, based on data from a single genetic center. Our data suggest that even a slight shift in heteroplasmy can improve cellular function and, consequently, the patients’ phenotype, providing a solid foundation for the development of future gene therapies for mtDNA diseases.

Pyruvate dehydrogenase complex deficiency (PDC) is a mitochondrial disease associated with a violation of pyruvate metabolism and leading to a decrease in ATP production. PDC is responsible for the decarboxylation of pyruvate into acetyl-CoA. PDC deficiency can be caused by changes in any of the genes encoding its subunits. The clinical phenotype is very variable, mainly the central nervous system is affected. Diagnosis of the disease can cause significant difficulties due to the rarity of the pathology, the lack of specificity of clinical symptoms and pronounced clinical polymorphism. The purpose of this research was to describe and discuss the clinical, biochemical and genetic data of six recently observed patients with PDC deficiency who were identified in Russia. Authors have analyzed the clinical manifestations of a rare progressive pathology from the group of mitochondrial diseases caused by pathogenic variants of the nuclear X-linked PDHA1 gene (encodes the alpha subunit of pyruvate dehydrogenase) in six patients aged 8 to 120 months old. By the time of examination in the hospital the main clinical symptoms included as follows: delayed psychomotor development, epileptic seizures, severe delay in psychomotor development and - in a single patient - depression of consciousness to coma, the status of epileptic seizures and an unfavorable outcome. In all patients, magnetic resonance imaging (MRI) of the brain revealed changes as follows: cortical atrophy in all 6 patients, basal ganglia lesion in three cases, congenital brain defects in 3 patients and multicystic lesion in a single patient. All children had high lactate levels. Pathogenic variants of the PDHA1 gene were detected in all 6 children and on this basis the diagnosis was confirmed. As a result of treatment, 5 of the 6 children showed moderate positive dynamics as follows: a decrease in the frequency of epileptic seizures and lactate in the blood, improvement in psychomotor development and - in a single patient - a fatal outcome as a result of late diagnosis and rapidly progressing clinical symptoms. Conclusion: Authors have described the clinical characteristics of PDC in recent cases such as: age of manifestation, the disease course nature, results of molecular genetic studies. Clinical polymorphism in patients with this rare pathology was shown as well. The Article may be of great help to pediatricians, neurologists and geneticists in improving the diagnosis of PDC deficiency.

Митохондриальная миопатия, вызванная недостаточностью тимидинкиназы 2 (TK2), представляет собой наследственное моногенное заболевание, входящее в группу синдромов нарушения целостности и репликации митохондриальной ДНК (мтДНК). Эти заболевания, в основном, проявляются тяжелыми мультисистемными детскими формами и характеризуются существенным снижением числа копий мтДНК в пораженных клетках и тканях. В России первые случаи TK2-обусловленной миопатии были выявлены в 2019 г. Важность ранней диагностики заболевания обусловлена появлением новых методов лечения. Цель: проведение селективнного скрининга на TK2-недостаточность среди 150 пациентов с ранее исключенным диагнозом спинальной мышечной атрофии, а также 50 пациентов с предполагаемым диагнозом врожденной миопатии с отрицательным результатом анализа методом панельного секвенирования. Метод исследования: высокопроизводительное секвенирование с использованием панели генов митохондриальных заболеваний. Результаты: выявлен один гетерозиготный носитель патогенного варианта в гене TK2. Дополнительный анализ российских баз данных экзомного секвенирования Ruexac, Ru-seq browser показал расчетную частоту TK2-недостаточности равную 1:563900, доверительные интервалы CI (95%) – 218 894:1 454 451. Mitochondrial myopathy caused by thymidine kinase 2 (TK2) deficiency is an inherited monogenic disease that is part of a group of mitochondrial DNA (mtDNA) maintenance and replication syndromes. These diseases mainly manifest as severe multisystem childhood forms and are characterized by a significant reduction in mtDNA copies in the affected cells and tissues. In Russia, the first cases of TK2- associated myopathy were identified in 2019. The importance of early diagnosis of the disease is due to the emergence of new treatment methods. Aim of the study: to conduct selective screening for TK2 deficiency among 150 patients with a previously excluded diagnosis of spinal muscular atrophy, as well as 50 patients with a presumptive diagnosis of congenital myopathy with a negative test result using panel sequencing. Method: high-throughput sequencing using a panel of mitochondrial disease genes. Results: One heterozygous carrier of a pathogenic variant in the TK2 gene was identified. Additional analysis of Russian exome sequencing databases Ruexac, Ru-seq browser showed an estimated frequency of TK2 deficiency equal to 1:563900, confidence intervals CI (95%) – 218,894:1,454,451.

Актуальность.Наследственная оптическая нейропатия Лебера (НОНЛ) и аутосомнорецессивная оптическая нейропатия (АРОН) характеризуется выраженным снижением остроты зрения (ОЗ) в результате развития частичной атрофии зрительных нервов. Однако в отдаленном периоде возможно улучшение ОЗ, степень которого зависит от сохранности перипапиллярного слоя нервных волокон сетчатки и генетического варианта НОНЛ и АРОН. Цель.Оценить конечную ОЗ при НОНЛ и АРОН при различных мутациях мтД-НК и яДНК. Материал и методы.В исследование включено 100 пациентов (198 глаз) с генетически подтвержденным диагнозом НОНЛ или АРОН. Проведена оценка ОЗ по таблице Головина – Сивцева на пятый год заболевания. Результаты. Средний показатель ОЗ при различных генетических вариантах НОНЛ и АРОН на пятый год заболевания составил 0,3 ± 0,37 (0,001–1,0): ОЗ 0,1 и ниже была зарегистрирована в 47 % случаев; 0,5 и выше — в 38 %. Средний показатель ОЗ при мутациях мтДНК: m.11778G>А (64 глаза) — 0,1 ± 0,2 (0,002–0,8); m.3460 G>A (28 глаз) — 0,2 ± 0,28 (0,001–0,8); m.14484T>C (14 глаз) — 0,67 ± 0,35 (0,07–1,0); редких и кандидатных мутациях мтДНК (m.4171C>A, m.3635G>A, m.13513 G>A, m.3472Т>С, m.13379A>G, m.14597 A>G, m.14477A>G, m.12847GG p.(Y51C) (56 глаз) 0,6 ± 0,36 (0,01–1,0). Повышение ОЗ 0,5 и выше выявлено при АРОН в 62,5 %, при мутациях мтДНК m.14484T>C — 78,6 %, редких и кандидатных мутациях — 52,8 %, m.3460 G>A — 21,4 %, m.11778G>А — 7,8 % случаев. Прогноз восстановления зрения при m.3460 G>A выше, чем при m.11778G>А, несмотря на отсутствие разницы конечной ОЗ при этих мутациях (p = 0,6). Заключение. Показатели конечной остроты зрения различны в зависимости от генетического варианта заболевания. Наследственные оптические нейропатии, ассоциированные с мутациями c.152A>G и m.14484T>C, имеют прогностически более благоприятное течение.

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.

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 «plus», 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.

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.

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.

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.

Лизосомные болезни накопления (ЛБН) представляют собой группу, включающую около 70 заболеваний, характеризующихся дисфункцией лизосом, большинство из которых наследуются аутосомно-рецессивно. Несмотря на то, что каждая нозология сама по себе является довольно редким заболеванием, общая распространенность ЛБН, по разным оценкам, составляет от 1:5 000 до 1:7 500 живых новорожденных, с более высокой частотой в определенных этнических группах (финны, евреи-ашкенази). Накопление макромолекул внутри органелл эндосомно-аутофагической лизосомальной системы рассматривают в качестве основного механизма патогенеза всех ЛБН. В последние десятилетия особый интерес вызывают общие механизмы патогенеза, лежащие в основе развития ЛБН и распространенных нейродегенеративных заболеваний, таких как болезни Альцгеймера, Паркинсона, боковой амиотрофический склероз. В данном обзоре рассмотрены основные общие молекулярно-генетические механизмы, лежащие в основе патогенеза этих двух групп заболеваний. Понимание общности развития этих сходных групп заболеваний позволит по-новому взглянуть на их природу и перспективы медикаментозной терапии. Lysosomal storage diseases (LSDs) comprise the group of about 70 disorders characterized by lysosomal dysfunction, most of which have autosomal recessive trait of inheritance. Despite the fact that each nosology itself is a rather rare disease, the overall prevalence of LSD ranges from 1:5,000 to 1:7,500 among newborns, with a higher incidence among the population (Finns, Ashkenazi Jews). The accumulation of macromolecules in the organelles of endosomal-autophagic-lysosomal system is considered to be a common link of the pathogenesis for all LSD. Last decade, there has been a particular interest in the common ground of pathogenesis underlying the development of lysosomal diseases and frequent neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis. This review we provide the main molecular mechanisms underlying these two human disease groups. Understanding the resemblance of the pathogenesis of theses groups can help for look at their etiology from the other side and open new perspectives on the drug therapy.

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.

Митохондриальные заболевания - клинически и генетически гетерогенная группа заболеваний, возникающих в результате нарушения окислительного фосфорилирования в митохондриях. Одним из наиболее распространенных представителей этой группы среди пациентов детского возраста является синдром Ли или подострая некротизирующая энцефаломиелопатия - тяжелое нейродегенеративное заболевание, манифестирующее в раннем детском возрасте. Характерными нейрорадиологическими признаками являются двусторонняя симметричная гипоинтенсивность в базальных ганглиях на компьютерной томограмме или двусторонние симметричные гиперинтенсивные очаги в стволе головного мозга и/или базальных ганглиях на Т2-взвешенной магнитно-резонансной томограмме. В настоящее время известно более 80 генов, ответственных за развитие заболевания, что значительно затрудняет диагностику. В данном обзоре рассмотрены основные клинические и молекулярно-генетические особенности синдрома Ли, а также современные подходы возможной медикаментозной и этиотропной терапии. Представлен алгоритм комплексной диагностики синдрома Ли с учетом данных об особенностях спектра и частот мутаций у пациентов из России. Mitochondrial diseases are clinically and genetically heterogeneous group of inherited diseases resulting from impaired oxidative phosphorylation in mitochondria. One of the most common representatives of this group among children is Leigh syndrome, or subacute necrotizing encephalomyelopathy, a severe neurodegenerative disease with manifestation in childhood. The characteristic neuroradiological features are bilateral symmetrical hypointensities in the basal ganglia on CT or bilateral symmetrical hyperintense lesions in the brainstem and/or basal ganglia on T2-weighted MRI. Currently, 80 genes are known that are responsible for the development of LS, which significantly complicates the diagnosis. In the review we provide clinical and molecular genetic features, current approaches in diagnostic and treatment for LS. Finally, an algorithm for the complex diagnosis of LS including regional aspects of mutational spectrum is described.

Mitochondrial neurogastrointestinal encephalomyopathy is an extremely rare (1–9:1 000 000, Orphanet, 2021) multisystem genetic disease caused by mutations in the TYMP gene encoding the enzyme thymidine phosphorylase.The article presents the data of a thirteen‑year survey on 40‑year‑old patient D. with clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy syndrome associated with the previously undescribed missense mutation c.1301G>T (p.Gly434Val) of the TYMP gene. Detailed clinical picture (gastrointestinal dysfunction, cachexia, blepharoptosis, ophthalmoparesis, peripheral polyneuropathy and leukoaraiosis), electroneuromyography data (demyelination with secondary axonopathy), high blood serum level of dihydrothymine together with normal levels of thymidine and deoxyuridine made it possible to verify the diagnosis. Histopathological examination revealed atrophy of the longitudinal (outer) muscle layer of the small and large intestines and a significant decrease in the number of CD117+ cells (telocytes), signs of damage to the striated skeletal muscles of a mixed nature with a predominance of the myogenic pattern, as well the destruction of the myelin sheaths of peripheral nerves. Histochemical examination did not reveal “ragged red fibers” characteristic of mitochondrial pathology. Transmission electron microscopy demonstrated the presence of megalomitochondria in the myocardium.

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.

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.

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.

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.

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.

Introduction. Epilepsy is a common feature of mitochondrial disorders, including those associated with mutations in the POLG gene. Nevertheless, brain electrical activity features of POLG-related disorders in adult patients have not been adequately studied. Objective. To study the features and characteristics of the electroencephalography (EEG) pattern in adult patients with POLG-related disorders. Material and methods. Eight patients were examined: 7 with SANDO (Sensory Ataxic Neuropathy, Dysarthria, Ophthalmoparesis) syndrome, and 1 with MEMSA (Myoclonic Epilepsy Myopathy Sensory Ataxia) syndrome; median age was 32.5 years. All patients underwent routine EEG monitoring using a 19-channel electroencephalograph according to the generally accepted method. Results. Epileptic seizures were found in 3 patients, for 2 of them – as the first manifestation of the disease. In 6 patients, theta waves predominated in the occipital regions. Of those 6 patients, in 5 bilateral synchronous bursts of theta and delta wave groups were identified being more prominent in the frontocentral regions; 4 patients had transient non-lateralized delta activity in the occipital and parieto-occipital brain regions. In all patients, opening eyes led to the depression of rhythms and burst suppression. After photostimulation, in 2 cases bilateral synchronous bursts of delta and theta wave groups were recorded predominantly in frontal lobes. In 3 patients during hyperventilation an increase in delta activity in the occipital lobes and bilateral synchronous bursts of delta wave groups were observed. Epileptiform activity was recorded in 2 cases. Conclusion. In adult patients with POLG-related disorders, regardless of the clinical manifestation, typical EEG features include generalized background slowing, theta and delta bursts in occipital lobes with their suppression by opening eyes.

Purpose. To assess the retinal ganglion cells function in patients with Leber's hereditary optic neuropathy (LHON) by registering the photopic negative response (PhNR) while the photopic electroretinography is performed. Material and methods. 14 patients with different LHON mutations and 9 healthy individuals were examined. A standard ophtalmological examination was performed, including visual fields, spectral optical coherence tomography, photopic electroretinography and PhNR tests. Results. Significant differences in the PhNR latency (68.4±4.01/64.28±5.37, p<0,01) and the PhNR amplitude (21.5±9.34/32.72±12.73, p<0,003) were revealed in patients with LHON and the control group. The study revealed significant differences between the PhNR latency (р<0.01) and the PhNR amplitude (р<0.008) in patients with visual acuity (VA) ≤ 0.1 and the control group, and between the PhNR amplitude in patients with VA≥0.13 and the control group (р<0.05). There were found significant correlations between the PhNR parameters and visual acuity, mean sensitivity, RNFL and GCC thickness. A strong positive correlation was found between the PhNR amplitude and the GCC thickness in patients with VA≥0.3. Conclusion. The PhNR parameters reflect the retinal ganglion cells function in patients with LHON and correlate with RNFL and GCC structural changes. Key words: Leber hereditary optic neuropathy, mitochondrial optical neuropathies, retinal ganglion cell, photopic negative response, PhNR.