Considering the absence of drugs with proven efficacy, it is necessary to find ways to influence the main pathogenetic components of LBSL. It is known that the majority of patients with this disease are DARS2 compound heterozygous carriers of mutation, and one of the mutations almost always affects the splicing site in intron 2, above exon 3, so exon 3 is not included in the transport RNA, which may lead to a shift in the reading frame, premature stop of protein synthesis or lack of functional protein. However, mutations of the intron 2 splicing site in LBSL result in partial disruption of translation, and a full-size functional protein is synthesized from a part of the mutated tRNA, and this, in turn, leads to a slowdown of energy processes in the cell, but not to their complete stoppage. We used EMHS as a pathogenetic therapy agent with antioxidant and membranotropic effect. The 3-hydroxypyridine molecule reduces glutamate excitotoxicity, modulates the functioning of receptors and membrane-linked enzymes, and restores the neurotransmitter balance. EMHC influences free radical processes (inhibits lipid peroxidation, reacts with primary and hydroxyl radicals of peptides, reduces the increased level of NO in the brain in pathological conditions), at the same time increases the activity of antioxidant enzymes (including superoxide dismutase, glutathione peroxidase) and has no prooxidant effect. The presence of succinate in the structure of EMHC, which is able to oxidize the respiratory chain in conditions of hypoxia, leads to an increase in the compensatory activation of aerobic glycolysis, a decrease in the oppression of oxidative processes in the Krebs cycle, and thus to an increase in the content of ATP, creatine phosphate, activation of energy-synthetic functions of mitochondria.
In both cases, there was a positive effect in the reduction of cerebellar abnormalities, sensory and pyramidal disorders, which may be due to increased functional activity of enzymes, inclusion of succinate as a substrate in the respiratory chain and activation of energy metabolism, inhibition of free-radical processes in cells of the brain and spinal cord in a histotoxic hypoxia.
Our observations may indicate that the use of drugs with the mechanism of action described above may be promising in this group of patients, but it is necessary to conduct further controlled studies.