Background and Aims: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%–16%) and inherited metabolic diseases (14%–28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. Approach and Results: With this international, multicenter observational study, patients (0–18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. Results: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation. Conclusions: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics.

Leigh syndrome (LS), also known as infantile subacute necrotizing encephalopathy, is the most frequent mitochondrial disorder in children. Recently, more than 80 genes have been associated with LS, which greatly complicates the diagnosis. In this article, we present clinical and molecular findings of 219 patients with LS and give the detailed description of three cases with rare findings in nuclear genes MORC2, NARS2 and VPS13D, demonstrating wide genetic heterogeneity of this mitochondrial disease. The most common cause of LS in Russian patients are pathogenic variants in the SURF1 gene (44.3% of patients). The most frequent pathogenic variant is c.845_846delCT (66.0% of mutant alleles; 128/192), which is also widespread in Eastern Europe. Five main LS genes, SURF1, SCO2, MT-ATP6, MT-ND5 and PDHA1, account for 70% of all LS cases in the Russian Federation. Using next generation sequencing (NGS) technique, we were able to detect pathogenic variants in other nuclear genes: NDUFV1, NDUFS2, NDUFS8, NDUFAF5, NDUFAF6, NDUFA10, SUCLG1, GFM2, COX10, PMPCB, NARS2, PDHB and SLC19A3, including two genes previously associated with Leigh-like phenotypes—MORC2 and VPS13D. We found 49 previously undescribed nucleotide variants, including two deep intronic variants which affect splicing.

Причиной наследственной оптической нейропатии Лебера (НОНЛ) являются первичные мутации мтДНК, а также новые мутации мтДНК, которые при выявлении в нескольких независимых семьях с проявлениями НОНЛ получают статус кандидатных. Актуальным является описание новых генетических вариантов мтДНК, ассоциированных с НОНЛ. ЦЕЛЬ ИССЛЕДОВАНИЯ Определить особенности клинического течения НОНЛ, ассоциированной с мутацией мтДНК m.13513G>A и оценить долю пациентов с данным патогенным вариантом в выборке пациентов с генетически подтвержденной НОНЛ. МАТЕРИАЛ И МЕТОДЫ Обследовано 5 пациентов с НОНЛ с мутацией мтДНК m.13513G>A в гене ND5 в гетероплазмическом состоянии. Всем пациентам проводили традиционное офтальмологическое обследование, оценку цветового зрения, компьютерную периметрию, оптическую когерентную томографию. РЕЗУЛЬТАТЫ Клиническое течение НОНЛ, ассоциированной с m.13513G>A в гетероплазмическом состоянии в диапазоне 25—60%, характеризуется нарушением зрения без дополнительной неврологической или иной экстраокулярной симптоматики. У всех пациентов отмечено восстановление зрения до 0,3—1,0, начало которого было зафиксировано в диапазоне от 12 до 20 мес от начала заболевания. Восстановление остроты зрения (ОЗ) сопровождалось снижением плотности и размеров центральной скотомы, улучшением цветового зрения на фоне выраженного снижения средней толщины перипапиллярного слоя нервных волокон сетчатки и комплекса ганглиозных клеток сетчатки. Частота встречаемости мутации m.13513G>A составила 5% в выборке из 100 пациентов с генетически подтвержденной НОНЛ и 22,5% в выборке из 22 пациентов с НОНЛ, ассоциированной с кандидатными и редкими мутациями мтДНК. ЗАКЛЮЧЕНИЕ Мутацию m.13513G>A можно считать первичной при НОНЛ и включить ее в список рекомендованных для тестирования патогенных вариантов при подозрении на НОНЛ. Наличие мутации m.13513G>A определяет легкое течение НОНЛ и благоприятный прогноз зрительных функций у пациентов.

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.

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.