Mitochondrial dysfunction is associated with a wide range of chronic human disorders, including atherosclerosis and diabetes mellitus. Mitochondria are dynamic organelles that undergo constant turnover in living cells. Through the processes of mitochondrial fission and fusion, a functional population of mitochondria is maintained, that responds to the energy needs of the cell. Damaged or excessive mitochondria are degraded by mitophagy, a specialized type of autophagy. These processes are orchestrated by a number of proteins and genes, and are tightly regulated. When one or several of these processes are affected, it can lead to the accumulation of dysfunctional mitochondria, deficient energy production, increased oxidative stress and cell death—features that are described in many human disorders. While severe mitochondrial dysfunction is known to cause specific and mitochondrial disorders in humans, progressing damage of the mitochondria is also observed in a wide range of other chronic diseases, including cancer and atherosclerosis, and appears to play an important role in disease development. Therefore, correction of mitochondrial dynamics can help in developing new therapies for the treatment of these conditions. In this review, we summarize the recent knowledge on the processes of mitochondrial turnover and the proteins and genes involved in it. We provide a list of known mutations that affect mitochondrial function, and discuss the emerging therapeutic approaches.

Aim. To study the peculiarities of carrying clinically significant allelic variants of TPMT and DPYD genes associated with the response to drug therapy in cancer practice among 9 ethnic groups of the Russian Federation. Materials and methods. The study included 1446 conditionally healthy volunteers from 9 ethnic groups. Carriage of polymorphic TPMT and DPYD gene markers was detected by the Real-Time PCR (polymerase chain reaction) method. Results. In all ethnic groups, the distribution of genotypes and alleles matched the equilibrium of Hardy-Weinberg. TPMT*3A (rs1800460) and TPMT*3C (rs1142345) were observed in heterozygous state in all investigated ethnic groups. In the Kabardinian group (n=204) the frequency of the TPMT*3A minor allele (MAF, %) was 2.94%; Balkars (n=200) 1.25%; Ossetians (n=239) 1.67%; Chuvashes (n=238) 1.89%: Mari (n=206) 1.21%; Tatars (n=141) 1.77%; Russians (n=134) 4.85%. The frequency of the TPMT*3C minor allele (MAF, %) in the Kabardinian group (n=204) MAF was 4.90%; Balkars (n=200) 1. 75%; Buryats (n=114) 0.44%; Ossetians (n=239) 1.88%; Chuvashes (n=238) 1.68%: Mari (n=206) 1.21%; Tatars (n=141) 1.42%; Russians (n=134) 4.48%. The results of the analysis of DPYD*2A polymorphism (rs3918290) demonstrated ethnic peculiarities of distribution. In the heterozygous state it was found only in the groups of Kabardins (n=204, MAF 1.22%), Balkars (n=200, MAF 2.00%), and Ossetians (n=239, MAF 0.63%). Conclusion. The results obtained in the study will be useful for developing personalized algorithms of antitumor therapy in cancer practice, including those aimed at increasing the safety of chemotherapy.

Background: The PITX1 gene encodes a transcription factor that plays a crucial role in the development of the lower limbs, pelvis, and structures derived from the first branchial arch. Pathogenic variants in PITX1 are associated with a limited spectrum of rare disorders, including congenital talipes equinovarus with or without long bone anomalies and/or mirror-image polydactyly, and Liebenberg syndrome. In 2020, a novel clinical phenotype, Mandibular–Pelvic–Patellar (MPP) syndrome, resulting PITX1 missense variants, was proposed. Case presentation: We report the fourth documented case of MPP syndrome worldwide, identified in a 17-year-old female patient presenting with congenital lower limb deformities, patellar aplasia, and micrognathia. Whole-genome sequencing revealed a heterozygous PITX1 missense variant NM_002653.5: c.412A>C, p.(Lys138Gln). The clinical phenotype included knee flexion contractures and severe equinovarus and planovalgus foot deformities requiring multiple staged reconstructive surgical procedures. Conclusions: This case supports recognition of MPP syndrome as a clinically and genetically distinct PITX1-related disorder. Our findings expand the phenotypic spectrum of MPP syndrome and suggest that severe congenital foot deformities represent a consistent and clinically relevant feature of this condition.

BACKGROUND: Culler-Jones syndrome is a rare autosomal dominant disease caused by nucleotide sequence changes in the GLI2 gene. The prevalence of this pathology is unknown, as the number of observations is small, some carriers of variants in the GLI2 gene have no manifestations of the disease. The clinical phenotype of the disease is heterogeneous and includes hypopituitarism, malformations of internal organs, facial dysmorphisms, and polydactyly. Since the discovery of the GLI2 gene by Roessler E. et al. in 2003, the spectrum of clinical manifestations, as well as the understanding of the pathogenesis of the disease components, has expanded considerably. Incomplete penetrance has been described for the GLI2 gene, and the clinical phenotype of the disease differs even among members of the same family with the same nucleotide variant. AIM: Study clinical and molecular genetic polymorphism in patients with Culler-Jones syndrome. MATERIALS AND METHODS: A single-center, non-interventional, single-stage, non-comparative study was conducted. Children with Culler-Jones syndrome with a confirmed genetic cause of the disease were examined. All patients underwent a comprehensive examination, including laboratory and instrumental diagnostic methods and sequencing (by NGS (next-generation sequencing). RESULTS: 18 children (7 girls; 11 boys) with variants in the GLI2 gene were included in the study. The age at the time of examination was 8.95 years [4,6; 12.4]. Growth hormone deficiency was noted in all children at age of 2 years [1; 6,5]. Central hypothyroidism was diagnosed in 13 children at the age of 1.5 years [1; 3.5]. Free thyroxine level at the time of diagnosis was 8.9 pmol/L [7.5; 11.3]. Secondary hypoadrenocorticism was diagnosed in 10 children at the age of 2 years [1.5; 2.8], with a cortisol level of 84 nmol/L at the time of diagnosis [47; 152]. Extrahypophyseal manifestations characteristic of the syndrome were detected in half of the patients and included maxillofacial anomalies, malformations of the cardiovascular and urinary systems and eye malformations. Polydactyly was detected in two children. CONCLUSION: The present study demonstrates the clinical polymorphism of Culler-Jones syndrome and the lack of genotype-phenotype correlation for this disease.

The anatomy of the first vertebra, namely atlas, has significant clinical implications. Atlas is situated between the occipital bone and the second cervical vertebra (axis) and is one of the main points of head movement. Most congenital anomalies of the vertebra are diagnosed incidentally during imaging investigations and can be associated with cervical spine anomalies. The neurological symptoms may include weakness in the four limbs, acute neurologic deficits such as transient quadriparesis, paraparesis, Lhermitte's sign, chronic neck pain, and headache. This anomaly is also commonly seen in gonadal dysgenesis, Klippel-Feil syndrome, Arnold-Chiari malformations, and Turner and Down syndrome. Unlike other variations, which arise due to disturbances of ossification posterior midline clefts of the atlas, are different since they are a developmental failure of chondrogenesis. We therefore present an anatomical case and analysis of the literature about posterior arch clefts of atlas.

Background: Hemoglobin Rothschild (Hb Rothschild), NM_000518.5(HBB):c.112T>C, is an ultra-rare low-oxygen-affinity hemoglobin variant that persistently causes reduced peripheral oxygen saturation on pulse oximetry despite normal arterial oxygenation. Fewer than ten cases have been reported worldwide, and only one involved a child—an asymptomatic carrier identified incidentally. Methods: The patient underwent clinical examination, growth assessment, blood tests, hemoglobin electrophoresis, chest CT, abdominal ultrasound, echocardiography, and pulmonary perfusion scintigraphy. Whole genome sequencing (WGS) of the proband and parents was performed, followed by bioinformatic analysis and ACMG-based variant interpretation. A PRISMA-guided PubMed literature review was conducted. Results: We report on the first pediatric case exhibiting a symptomatic clinical course. A 4-year-old boy was referred for chronically low peripheral oxygen saturation (SpO₂), 78–86%, on pulse oximetry and recurrent lower respiratory tract infections. Early developmental history revealed episodes of apnea in infancy, perioral cyanosis, poor exercise tolerance, and low weight gain. Repeated cardiopulmonary assessments, chest computed tomography (CT), echocardiography, and pulmonary perfusion scintigraphy yielded unremarkable findings. Arterial blood gas analysis consistently showed normal arterial partial pressure of oxygen (PaO₂), excluding true hypoxemia. Hemoglobin electrophoresis revealed an abnormal HbD fraction; WGS identified a heterozygous variant NM_000518.5(HBB):c.112T>C inherited from the patient’s asymptomatic father. This variant increases the partial pressure of oxygen at which hemoglobin is 50% saturated (p50), thereby decreasing hemoglobin’s oxygen affinity and shifting the oxyhemoglobin dissociation curve to the right. These alterations explain the discordance between low peripheral oxygen saturation (SpO₂) and preserved oxygen delivery to tissues. Conclusions: This case expands the clinical spectrum of Hb Rothschild and demonstrates that symptomatic presentation may occur in early childhood. Awareness of low-affinity hemoglobin variants is essential to avoid misdiagnosis and unnecessary cardiopulmonary interventions. Early genetic testing facilitates accurate diagnosis and appropriate counseling.