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.

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiencies are rare fatal disorders of fatty acid β-oxidation with no apparent genotype–phenotype correlation. The measurement of acylcarnitines by MS/MS is a current diagnostic workup in these disorders. Nevertheless, false-positive and false-negative results have been reported, highlighting a necessity for more sensitive and specific biomarkers. This study included 54 patients with LCHAD/MTP deficiency that has been confirmed by biochemical and molecular methods. The analysis of acylcarnitines in dried blood spots was performed using ESI-MS/MS. The established “HADHA ratio” = (C16OH + C18OH + C18:1OH)/C0 was significantly elevated in all 54 affected individuals in comparison to the control group. Apart from 54 LCHAD deficiency patients, the “HADHA ratio” was calculated in 19 patients with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. As VLCAD-deficient patients did not show increased “HADHA ratio”, the results emphasized the high specificity of this new ratio. Therefore, the “HADHA ratio” was shown to be instrumental in improving the overall performance of MS/MS-based analysis of acylcarnitine levels in the diagnostics of LCHAD/MTP deficiencies. The ratio was demonstrated to increase the sensitivity and specificity of this method and reduce the chances of false-negative results.

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.

Movement disorders such as bradykinesia, tremor, dystonia, chorea, and myoclonus most often arise in several neurodegenerative diseases with basal ganglia and white matter involvement. While the pathophysiology of these disorders remains incompletely understood, dysfunction of the basal ganglia and related brain regions is often implicated. The VPS13D gene, part of the VPS13 family, has emerged as a crucial player in neurological pathology, implicated in diverse phenotypes ranging from movement disorders to Leigh syndrome. We present a clinical case of VPS13D-associated disease with two variants in the VPS13D gene in an adult female. This case contributes to our evolving understanding of VPS13D-related diseases and underscores the importance of genetic screening in diagnosing and managing such conditions.

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.