Dauren Yerezhepov

Monogenic epilepsies and developmental and epileptic encephalopathies are biologically heterogeneous, and evidence for plant-derived interventions ranges from ethnopharmacology to randomized clinical trials. This review critically maps that evidence using a four-level genotype-relevance framework while separating antiseizure, neuroprotective, mechanistic, and clinical endpoints. Highly purified cannabidiol (CBD) has the strongest evidence chain: antiseizure activity in Scn1a-based Dravet models is complemented by randomized clinical efficacy at the syndrome level. However, current trial evidence does not establish an SCN1A-genotype-specific treatment response. β-Caryophyllene has direct preclinical evidence in a genetically relevant Dravet model. Luteolin has direct CDKL5-model evidence for reducing microglial overactivation and improving neuronal and neurodevelopmental outcomes, but seizure-frequency or video-EEG efficacy in CDKL5 deficiency disorder has not been demonstrated. Curcumin, resveratrol, epigallocatechin-3-gallate (EGCG), quercetin, and sulforaphane are supported mainly by non-genetic seizure models and therefore remain mechanistically plausible candidates rather than validated treatments for monogenic epilepsy. Medicinal plants, crude extracts, standardized preparations, and isolated compounds are considered separately. Translational prioritization should require a reproducible genotype-associated secondary phenotype, clinically meaningful functional outcomes, achievable systemic and brain exposure, acceptable safety and drug-interaction profiles, and reproducible formulation. Plant-derived compounds should therefore be viewed as potential adjuncts to established antiseizure, syndrome-specific, and gene-directed therapies rather than substitutes.

Background/Objectives: Alzheimer’s disease (AD) has a substantial genetic component, yet Central Asian populations remain markedly underrepresented in genomic studies of the disease. Methods: to address this gap, we generated array-based genotype data using an immune-focused genotyping platform from a Kazakh AD case–control cohort and performed an exploratory association analysis. Following quality control, 180 individuals of Kazakh ancestry, including 92 individuals with AD and 88 cognitively normal controls, were analyzed. Population structure was assessed using principal component analysis, and association testing was performed using covariate-adjusted logistic regression under an additive model (primary analysis), with case–control tests under several genetic models as secondary analyses. Results: no variant reached study-wide significance; however, several exploratory association signals (p < 1 × 10⁻⁴) were identified, including variants on chromosome 9p24 and in ADARB2, MAST4, and ADAM23, which remained nominally associated after adjustment for sex, age, and principal components. In addition, APOE ε4 carrier status was evaluated in cases and controls. The proportion of APOE ε4 carriers was numerically higher among individuals with AD than among controls (40.7% vs. 26.6%), although the difference did not reach statistical significance (p = 0.074). These findings should be considered hypothesis-generating and require replication in larger independent cohorts. Conclusions: this study provides one of the first immune-focused array-based genotype datasets for AD in a Central Asian population. The publicly available genotype data and association results provide a foundation for future replication, meta-analysis, and comparative population-genetic studies of AD across diverse ancestry groups.

Background/Objectives: Genetic factors are known to influence overall immune vulnerability to diseases, such as tuberculosis (TB); however, isolating the genetic component can be challenging as social and environmental causes, such as smoking, alcohol consumption, and unemployment, also drive disease risk. To reduce heterogeneity related to these factors, we performed a targeted immunogenetic association study of TB susceptibility in a Kazakh case–control cohort selected among individuals without the typical socioeconomic and nutritional risk factors linked to TB. Methods: We performed genotyping using an immune-focused targeted array; after quality control at sample and variant level, removal of ancestry-based outliers, and adjustment for population stratification, the final dataset included 164 participants (84 cases, 80 controls) and 181,595 variants. We performed four complementary analyses: single-variant association testing using logistic regression with Firth correction where required adjusted for sex and genetic ancestry, gene-based aggregation testing, functional annotation, and polygenic risk scoring using existing multi-ancestry TB genetic resources. Results: While no variant reached formal significance, the top nominal signal, rs1560036 (OR = 2.98, p = 2.4 × 10⁻⁵), lies within CPLX2, which ranked among the top genes in gene-based analysis, a result driven largely by the same variant. A nominally associated variant in the classical MHC region, rs9263600, is separately reported in GTEx as a cis-eQTL for HLA-B and HLA-C. Similarly, polygenic risk scores showed directionally consistent but statistically non-significant associations with case status (Asia-base AUC = 0.560; Europe-base AUC = 0.537). Conclusions: Although our study was not adequately powered to detect small-to-moderate genetic effects, it offers an important perspective on TB genetics in a population underrepresented in existing research. These findings provide an openly available dataset and candidate signals for replication in larger, independent cohorts.

Epilepsy and autism spectrum disorder (ASD) frequently co-occur and share complex genetic determinants. However, molecular diagnosis remains challenging because of incomplete penetrance, variable expressivity, and the limited representation of Central Asian populations in genomic reference databases. This case report describes a Kazakhstani family with 9-year-old monozygotic twin girls who developed focal seizures with secondary generalization at approximately one year of age and were subsequently diagnosed with ASD. Family-based whole-exome sequencing was performed for both affected twins and their clinically unaffected, non-consanguineous parents. No pathogenic or likely pathogenic variant explaining the shared epilepsy–ASD phenotype was identified. A paternally inherited NPRL3 missense variant, c.121A>G (p.Lys41Glu), was considered biologically plausible because of the established association of NPRL3 with focal epilepsy. However, it remained a variant of uncertain significance (VUS), was not reported in the queried gnomAD dataset, and had an AlphaMissense score of 0.14. Additional heterozygous VUS were identified in SPTBN4, ANK2, VPS33A, SLC25A46, and GFM1. Two ZC2HC1C variants inherited from different parents supported a possible biallelic hypothesis, but their clinical significance was uncertain. We interpreted a heterozygous pathogenic ALDOB variant as an incidental carrier finding unrelated to the presenting phenotype. This case illustrates the distinction between candidate variants and a molecular diagnosis. Further evaluation may include periodic exome reanalysis, copy-number analysis, genome sequencing, and targeted validation where justified. Broader population reference resources could improve variant interpretation in Kazakhstan.

The Beijing genotype is the main component of the M. tuberculosis population in Kazakhstan. In this study, we investigated the association of drug resistance (including MDR) and clinical forms of tuberculosis with the Beijing genotype and its dominant clusters, and compared obtained results among new, recurrent and all TB cases. In total, 759 M. tuberculosis isolates were collected from new (n = 540) and recurrent TB cases (n = 219). Drug susceptibility testing was performed on the BACTEC-MGIT 960 system; 24 MIRU-VNTR analysis was carried out to identify M. tuberculosis genotypes. The Beijing genotype was detected in 65.2% (495/759) of all TB cases and was associated with recurrent TB compared with new cases (78% vs. 60%, p < 0.0001). Among both new and recurrent TB cases, the Beijing genotype was associated with drug resistance (p < 0.0001 and p < 0.0001), including MDR (p < 0.0001 and p = 0.0118). Central Asian/Russian cluster 94-32 was the most widespread Beijing cluster in Kazakhstan (52.5%; 260/495). Association of cluster 94-32 with drug-resistant TB in general was confirmed across all cases (p = 0.010) and recurrent TB cases (p = 0.0191; OR = 4.8958; 95%CI: 1.2965–18.4883), while individuals with new TB cases were more likely to be diagnosed with MDR-TB specifically (p = 0.021). Among clinical forms of TB, a significant association was detected between fibrous–cavernous tuberculosis and drug resistance (p = 0.0019; OR = 3.3801; 95%CI: 1.5692–7.2807), including MDR (p = 0.0054; OR = 3.2453; 95%CI: 1.4167–7.4345), among all TB cases. TB patients with Beijing cluster 94-15 mostly had drug-susceptible TB among all TB cases and recurrent cases (p < 0.05). Drug-susceptible tuberculosis was observed among patients with focal TB among new cases (p = 0.0254; OR = 0.1723; 95%CI: 0.0369–0.8050). Tuberculous pleurisy was more commonly diagnosed in individuals with non-Beijing genotypes among all TB cases (p = 0.0430; OR = 0.3643; 95%CI: 0.1371–0.9686). The M. tuberculosis Beijing genotype, particularly the Central Asian cluster 94-32, plays a significant role in the distribution of drug-resistant TB among all TB cases and recurrent cases, including MDR-TB among new TB cases in Kazakhstan. On the contrary, the Beijing cluster 94-15 may contribute to the spread of drug-susceptible TB among all TB cases and recurrent TB cases.

Introduction. Elite athletes undergo regular high-intensity training to maintain fitness and improve performance. Training overload is necessary to achieve significant results. However, failure to balance training and recovery can lead to overtraining syndrome. To prevent this, regular monitoring of biochemical markers is required to assess the body's adaptive processes. Aim of the study. Comparative analysis of blood biochemical parameters in Olympic athletes of Kazakhstan to assess training load effects and prevent overtraining syndrome Methods. A biochemical analysis was conducted to measure levels of creatinine, creatine kinase (CK), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in Olympic athletes. Results. Significant differences in biochemical markers were observed among sports disciplines. Creatinine (p<0.001), alkaline phosphatase (p<0.001), AST (p<0.001), CK (p=0.008), and LDH (p<0.001) levels differed significantly between groups, whereas ALT showed no significant variation (p=0.191). Post hoc analyses revealed higher creatinine levels in weightlifters and freestyle wrestlers, elevated alkaline phosphatase levels in combat sport athletes, and significant sport-specific differences in AST, CK, and LDH, reflecting variations in muscle metabolism and training-related physiological adaptation. Conclusion. These findings underscore the importance of monitoring biochemical markers in elite athletes to prevent overtraining and optimize the training process. Keywords: biochemical markers, sports medicine, creatine kinase, lactate dehydrogenase, athletes of Kazakhstan.

Background: Pediatric epilepsy is a clinically and genetically heterogeneous group of disorders, particularly in early-onset and syndromic presentations. Data integrating molecular findings with detailed clinical phenotyping remain limited in Kazakhstan and Central Asia. Methods: We conducted a retrospective, single-center, clinically selected, referral-based case series study of 31 pediatric patients evaluated at a tertiary center in Kazakhstan for epilepsy or epilepsy-associated neurodevelopmental disorders and found to have clinically relevant or potentially relevant genetic findings. Clinical records were reviewed for demographics, age at seizure onset, seizure semiology, developmental profile, EEG, MRI, extra-neurological features, treatment response, and family history. Variants were interpreted using ACMG-based criteria, and inheritance/segregation data were incorporated where available. Results: The cohort included 15 males and 16 females. Median seizure onset was 5.0 months (IQR 2.0–13.0), and 22/31 patients (71.0%) presented within the first year of life. Developmental delay/intellectual impairment was observed in 20/31 cases (64.5%), speech delay in 17/31 (54.8%), motor delay in 15/31 (48.4%), and hypotonia in 12/31 (38.7%). Variants were identified in 23 genes, including several variants with limited or no prior support in ClinVar or peer-reviewed reports. Ion channelopathies were the largest mechanistic group (12/31, 38.7%), followed by mitochondrial/metabolic disorders (6/31, 19.4%), mTOR pathway disorders (5/31, 16.1%), and neurodevelopmental/chromatin/transcriptional disorders (4/31, 12.9%). SCN1A was the most recurrent gene (8/31, 25.8%) and showed a broad phenotypic continuum from Dravet-compatible to non-Dravet presentations. EEG and MRI abnormalities were common and often syndromic in pattern. Treatment response was frequently partial or poor, although selected genotype-linked treatment observations were noted in PRRT2 (carbamazepine), PNPO (pyridoxine), and one SCN1A case (stiripentol). Conclusions: This study expands the clinicogenetic characterization of pediatric epilepsy cases with clinically relevant or potentially relevant genetic findings in Kazakhstan and highlights the value of integrated molecular, phenotypic, and segregation analysis in underrepresented populations.

Introduction. One of the global causes of mortality and disability is neurological disorders, which have a mostly genetic aetiology. Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder caused by pathogenic mutations in the SMN1gene, leading to progressive degeneration of motor neurons. Advances in molecular genetics and the emergence of disease-modifying therapies have increased the importance of early diagnosis, including prenatal testing and carrier screening. Aim. To investigate the role of prenatal genetic testing in families at risk of SMA and to evaluate its importance for early diagnosis, assessment of disease severity, and informed reproductive decision-making. Materials and methods. Pregnant women at risk of SMA were recruited. Biomaterial (maternal blood and fetal samples via chorionic villus sampling or placentocentesis) was collected. DNA was extracted and analyzed by MLPA to assess copy number variation in the SMN1, SMN2, and NAIP genes. Variants identified by next-generation sequencing were confirmed by Sanger sequencing. Clinical and family histories were recorded for all participants. Discussion. Two clinical cases demonstrated the value of prenatal genetic testing. In one case, parents were carriers. Nevertheless, the fetus was unaffected. The pregnancy was recommended to continue. In the second case, a homozygous deletion of SMN1 was detected, leading to pregnancy termination after counseling. These findings highlight the critical role of prenatal diagnosis in identifying affected fetuses, guiding clinical decisions, and preventing recurrence. The variability of SMA severity, influenced by SMN2 copy number, further emphasizes the need for comprehensive molecular analysis. Conclusion. Prenatal diagnosis of SMA is an essential tool in high-risk families, enabling early detection, accurate risk assessment, and informed decision-making. Implementation of genetic screening programs and counseling significantly improves clinical management and helps reduce the burden of this severe hereditary disease. Актуальность. Одной из глобальных причин смертности и инвалидности являются неврологические заболевания, большинство из которых имеют генетическую этиологию. Спинальная мышечная атрофия (СМА) — одно из наиболее распространённых аутосомно-рецессивных нервно-мышечных заболеваний, обусловленное патогенными вариантами гена SMN1 и характеризующееся прогрессирующей дегенерацией мотонейронов. Развитие молекулярной генетики и появление модифицирующих течение заболевания терапий повысили значимость ранней диагностики, включая пренатальное тестирование и скрининг носительства. Цель. Изучить роль пренатального генетического тестирования в семьях с риском СМА и оценить его значение для ранней диагностики, определения тяжести заболевания и принятия информированных репродуктивных решений. Материалы и методы. В исследование были включены беременные женщины с риском СМА. Проводился забор биоматериала (материнская кровь и фетальные образцы, полученные с помощью биопсии хориона или плацентоцентеза). ДНК выделяли и анализировали методом MLPA для оценки вариаций числа копий генов SMN1, SMN2и NAIP. Варианты, выявленные с помощью секвенирования нового поколения, подтверждались методом секвенирования по Сэнгеру. Для всех участников собирались клинические и семейные анамнезы. Обсуждение. Два клинических случая продемонстрировали значимость пренатального генетического тестирования. В первом случае оба родителя являлись носителями, однако мутации и делеции у плода выялены не были, в связи с чем было рекомендовано продолжение беременности. Во втором случае была выявлена гомозиготная делеция гена SMN1, что после консультирования привело к прерыванию беременности. Эти результаты подчеркивают ключевую роль пренатальной диагностики в выявлении поражённых плодов, принятии клинических решений и предотвращении повторных случаев заболевания. Вариабельность тяжести СМА, зависящая от числа копий SMN2, дополнительно подчёркивает необходимость комплексного молекулярного анализа. Вывод. Пренатальная диагностика СМА является важным инструментом в семьях высокого риска, обеспечивая раннее выявление, точную оценку...

Introduction. Mitochondrial diseases (MDs) are clinically heterogeneous disorders caused by mutations across a wide spectrum of genes encoded by the nuclear or mitochondrial genome, and have complex inheritance patterns, including X-linked or autosomal inheritance for mutations in nDNA genes, and maternal inheritance for mtDNA mutations. Mitochondrial complex I (MCI) is the largest and most complicated component of the respiratory chain. The NDUFV1 gene encodes an essential core subunit of the electron-input (N) module of mitochondrial complex I within the oxidative phosphorylation (OXPHOS) system. Methods. Recruitment of the family took place at the Corporate Fund «University Medical Center» (UMC). Blood from the pregnant woman and her partner was collected into a blood collection tube. Chorionic villus sampling (CVS) was performed according to the standard operating procedure (SOP). DNA was isolated using commercially available kits. Variant verification was performed by Sanger sequencing. Sequencing data analyzed using Data Collection Software. Results. A Kazakhstani family with a history of mitochondrial complex I deficiency (MCID), nuclear type 4, autosomal recessive inheritance pattern (OMIM: 618225) was recruited on the basis of the UMC. The parents were verified by Sanger sequencing and are obligate heterozygous carriers of genetic variants in the NDUFV1 gene at the following points: mother – NM_007103.4: c.289C>T (p.Leu97Phe), father – NM_007103.4: c.357G>C (p.Glu119Asp). Prenatal testing detected both heterozygous mutations in points NM_007103.4: c.262C>T (p.Arg88Cys) and NM_007103.4 c.357G>C (p.Glu119Asp) in the fetus. It was recommended to observe by a pediatrician with no specific treatment. Also, medical and genetic counseling of the couple when planning the next pregnancy was recommended. Conclusion. NDUFV1-related MCID can lead to a broad spectrum of clinical outcomes and complications and may progress rapidly. Therefore, early recognition is essential to ensure timely diagnosis and appropriate management. Our findings highlight the importance of early prenatal genetic testing for NDUFV1-associated MCID, which can facilitate early detection and support informed decision-making during pregnancy. Key words: mitochondrial diseases, prenatal genetic testing, NDUFV1, mitochondrial complex I deficiency.

Mitochondria, commonly known as the cell’s power generator, carry out their primary function through oxidative phosphorylation (OXPHOS), a process that produces ATP, the main energy source of the cell and the only cell organelles with their own mitochondrial DNA. Any genetic alterations in DNA sequences that encode mitochondrial structural or functional proteins may cause mitochondrial disorders. Multiple mitochondrial dysfunction syndrome type 3 (MMDS3) is a rare autosomal recessive mitochondrial disorder caused by homozygous or biallelic pathogenic variants in the IBA57 gene. In the current study, we present a case report on prenatal genetic testing for multiple mitochondrial dysfunction syndrome (MMDS) type 3 caused by the IBA57 gene to highlight the importance of prenatal diagnostics for disease prognosis and treatment, appropriate genetic counselling, and informed reproductive decision-making. We recruited a 27-year-old G2P1001 at 22 weeks’ gestation with MMDS3 in family history, confirmed by whole exome sequencing (WES) and also verified by Sanger sequencing in the IBA57 gene c.286T>C (NM_001010867.4, p.Tyr96His) and c.667C>G (NM_001010867.4, p.Arg223Gly) in the proband and parents. The ccfDNA genetic test revealed the absence of the heterozygous IBA57 gene variant at position c.286T>C (NM_001010867.4, p.Tyr96His), but the heterozygous IBA57 gene variant at position c.667C>G (NM_001010867.4, p.Arg223Gly) was detected. The child is a heterozygous carrier of the genetic variant of the IBA57 gene at position c.667C>G (NM_001010867.4, p.Arg223Gly). No specific treatment is required; observation by a pediatrician and medical and genetic counseling of the couple when planning the next pregnancy are recommended. The IBA57 gene-related MMDS3 can have a wide range of outcomes and consequences and may progress rapidly. Early awareness is crucial to prompt and proper administration. Our study reveals the importance of early prenatal genetic testing for IBA57-related MMDS3 for early diagnostics and consent decision-making.