Study of the hereditary non-syndromic ophthalmological pathology of child population of the Karachay-Cherkess Republic: estimations of genetic load and molecular genetic analysis

V.V. Kadyshev1, A.V. Marakhonov1, S.I. Kutsev1,2, R.A. Zinchenko1,3 1 Research Centre of Medical Genetics of the Russian Academy of Medical Sciences, Moscow,&nbsp;Russian Federation 2 Pirogov Russian National Research Medical University, Moscow, Russian Federation 3 M. F. Vladimirsky Moscow Regional Research and Clinical Institute (MONIKI), Moscow,&nbsp;Russian Federation Abstract The publication continues the previously presented data on the study of the epidemiology of ophthalmic diseases in the children of the Karachay-Cherkess Republic. Genetic epidemiological study of the population includes the study of a wide range of aspects. The structure of the nosological spectrum was published previously. The study of the genetic load is an integral part of this work. Aim: the purpose of this study was to investigate the specific features of the genetic load of hereditary non-syndromic ophthalmologic pathology in the population of the Karachay-Cherkess Republic. Patients and Methods: 90 793 children from 10 districts of the Karachay-Cherkess Republic aged 0–18 were examined, of which 121 were included in the sample. The biomaterial (peripheral venous blood) is taken from a part of patients taking into account the legislative and legal standards of the Russian Federation. In the study, genetic-epidemiological, statistical, molecular-genetic methods of examination were used. Results: the values of genetic load of non-syndromic hereditary eye pathology in the child population of 10 districts of the Karachay-Cherkess Republic and the city of Cherkessk is established. The total load of the non-syndromic hereditary pathology of the eye was 1.33±0.12. Statistical analysis of the obtained genetic load data demonstrated significant differences between autosomal dominant pathology in rural and urban populations (for rural population — t=2.3, for urban — t=2.8). The group of patients underwent confirmatory molecular genetic diagnosis. Conclusions: 1. The genetic load of the hereditary pathology of the organ of vision in the Karachay-Cherkess Republic among children was 1.33±0.12. 2. The prevalence of AD pathology over diseases with AR inheritance in both rural and urban subpopulations was revealed. 3. Region-specific molecular genetic markers for the hereditary pathology of the organ of vision are not established at this stage. Key words: epidemiology, genetics, genetic load, DNA diagnosis, children, Karachay-Cherkess Republic. For citation: Kadyshev V.V., Marakhonov A.V., Kutsev S.I., Zinchenko R.A. Study of the hereditary non-syndromic ophthalmological pathology of child population of the Karachay-Cherkess Republic: estimations of genetic load and molecular genetic analysis.&nbsp;RMJ “Clinical ophthalmology”. 2018;3:134–139. <br

Efficacy and tolerability of a specialized dietary therapeutic product in long-chain and very long-chain fatty acid metabolism disorders in children

Aim: to assess the efficacy and tolerability of a specialized dietary therapeutic product in long-chain and very long-chain fatty acid metabolism disorders in children. Patients and Methods: this open-label prospective uncontrolled study enrolled 5 children aged 35 ± 14 months who were diagnosed with long-chain and very long-chain fatty acid metab-olism disorders. Diet therapy using the tested product (“Monogen”) was prescribed and corrected after the analysis of actual diet. Physical development and neurological status were evaluated, blood levels of specific acyl-carnitines (С16-ОН, С18-ОН, С18:1-ОН, С14:1, С14) were measured. Tolerability was assessed by the rate and severity of adverse events (including allergic reactions) and the changes in vital functions compared to baseline. Patient and doctor satisfaction was evaluated using a questionnaire. Results: children received the tested product throughout the study (30±2 days). The lev-els of acyl-carnitines were within normal ranges in all children. No dyspepsia, allergic reactions, somatic dysfunction, or neurological deviations were reported. Physical exam consistently fell in the range of normal for age. Parents and doctors were fully satisfied with the tested product (“Monogen”). Conclusions: “Monogen” is highly effective for therapeutic feeding of children with long-chain and very long-chain fatty acid metabolism disorders. Keywords: long-chain fatty acid oxidation disorders, β-oxidation of fatty acids, long-chain acyl-coA dehydrogenase deficiency, biallelic mutation, therapeutic feeding. </p

Study of hereditary non-syndromic ophthalmic pathology of child population of the Karachay-Cherkess Republic: features and structure of nosological spectrum

V.V. Kadyshev1, A.V. Marakhonov1, S.I. Kutsev1,2, R.A. Zinchenko1,3 1 Research Centre of Medical Genetics of the Russian Academy of Medical Sciences, Moscow, &nbsp;Russian Federation 2 Pirogov Russian National Research Medical University, Moscow, Russian Federation 3 M.F. Vladimirsky Moscow Regional Research and Clinical Institute (MONIKI), Moscow,&nbsp; &nbsp;Russian Federation The publication is a continuation of the previously submitted data on the study of the epidemiology of ophthalmic diseases in children of the Karachay-Cherkess Republic. Genetic and epidemiological study of the population includes a research of a wide range of indicators. A burden assessment of the hereditary ocular pathology of the child population of the surveyed region and the data of molecular genetic diagnostics were published earlier. This article presents structure and features of a nosological spectrum of the visual organ hereditary pathology. Aim: to study the nosological spectrum and its features of hereditary non-syndromic ophthalmic pathology among the child population of the Karachay-Cherkess Republic. Patients and Methods: 90793 children from 10 regions of the Karachay-Cherkess Republic between the ages of 0 and 18 were examined, of which 121 people were enrolled in set. To solve the problem, genetic and epidemiological, clinical, paraclinical examination methods were used. Results: the structure and features of the nosological spectrum of non-syndromic hereditary ophthalmic pathology were determined in the child population of 10 regions of the Karachay-Cherkess Republic and the city of Cherkessk. Congenital malformations of the visual organ and hereditary pathology of the posterior segment of an eye (58%) make the main contribution to the prevalence. An overall prevalence of hereditary ocular pathology was at ratio 1:671. It was revealed that a large proportion of hereditary diseases of the visual organ with an autosomal dominant inheritance pattern (1:1163). The prevalence of autosomal recessive pathology was at ratio 1:2268 of people. Conclusion: autosomal dominant diseases make a greater contribution to the structure of the nosological spectrum — 1:1163. Congenital malformations of the visual organ and pathology of the posterior segment of the eye are prevalent in the structure of the pediatric nosological spectrum. Key words: epidemiology, genetics, hereditary pathology, nosological spectrum, children, Karachay-Cherkess Republic. For citation: Kadyshev V.V., Marakhonov A.V., Kutsev S.I., Zinchenko R.A. Study of hereditary non-syndromic ophthalmic pathology of child population of the Karachay-Cherkess Republic: features and structure of nosological spectrum. Russian Journal of Clinical Ophthalmology. 2019;19(1):7–12. About the authors:&nbsp; 1Vitalii V. Kadyshev — MD, PhD, Senior Researcher of the Laboratory of Genetic Epidemiology;&nbsp; 1Andrei V. Marakhonov — PhD, Biology, Senior Researcher of the Laboratory of Genetic Epidemiology;&nbsp; 1,2&nbsp;Sergei I. Kutsev — MD, PhD, Professor, Сorresponding Member of RAS, Head of the Research Centre of Medical Genetics, Head of the Department of Molecular and Cell Genetics;&nbsp; 1,3Rena A. Zinchenko — MD, PhD, Professor, Deputy Director of the Scientific and Clinical Study, Head of the Laboratory of Genetic Epidemiology.&nbsp; 1Research Center of Medical Genetics. 1, Moskvorechie str., Moscow, 115522, Russian Federation.&nbsp; 2Pirogov Russian National Research Medical University. 1, Ostrovityanova str., Moscow, 117997, Russian Federation.&nbsp; 3Moscow Regional Research and Clinical Institute. 61/2, Shchepkina str., Moscow, 129110, Russian Federation.&nbsp; Contact information:&nbsp;Vitalii V. Kadyshev, e-mail:&nbsp;[email protected].&nbsp;Financial Disclosure:&nbsp;no author has a financial or property interest in any material or method mentioned. There is no&nbsp;conflict of interests. Received&nbsp;06.12.2018.<br

Epidemiology of hereditary eye disease in the populations of Russian Federation

V.V. Kadyshev1, E.K. Ginter1, S.I. Kutsev1, Zh.G. Oganezova1,2, R.A. Zinchenko1,3 1Research Center for Medical Genetics, Moscow, Russian Federation 2Pirogov Russian National Research Medical University, Moscow, Russian Federation 3N.A. Semashko National Research Institute of Public Health, Moscow, Russian Federation Aim: genetic epidemiological study of hereditary eye diseases in various populations of the Russian Federation and comparative analysis of these findings. Patients and Methods: the sample included 12 ethnic groups from 14 regions of European Russia. The entire population irrespective of gender or age was examined. To confirm a certain type of inheritance of diseases from heterogeneous groups, the material was subjected to the multicomponent analysis used in multiple family registration. The rate of segregation was evaluated using the Weinberg proband method. Molecular genetic tests (Sanger sequencing, MLPA, AFLP, RFLP, whole exome sequencing) were applied. To identify the cases of hereditary disease accumulation in individual populations and/or ethnic groups, the prevalence of certain diseases in this population was calculated using F-distribution to compare the samples of rare diseases. Results: more than 46,000 patients and their relatives with presumably hereditary conditions were examined and data were collected. 554 clinically diverse hereditary diseases in 9,979 individuals were identified. Isolated hereditary eye disease (60 clinical variants) was identified in 1,407 patients (14.56%). The mean prevalence of isolated hereditary eye disease was 1:2,272 (or 44.01 per 100,000). When assessing patterns of nosological spectrum and prevalence of isolated hereditary eye disease in each population/ethnic group using principal component analysis, 2 clusters were isolated. The first cluster includes 6 Russian populations and the second cluster includes 5 ethnic Volga Region groups, which are more similar to Russian populations than the North Caucasus people. In general, 57 hereditary syndromes (affecting anterior and posterior eye segments) in 1,051 patients were discovered. The mean prevalence of syndromic hereditary eye disease was 1:3,040 (or 32.89 per 100,000). Keywords: ophthalmogenetics, genetic epidemiological study, spectrum, ethnic grou p, type of inheritance, segregation, accumulation, isolated and syndromic hereditary eye diseases, prevalence, retinal degeneration. For citation: Kadyshev V.V., Ginter E.K., Kutsev S.I. et al. Epidemiology of hereditary eye disease in the populations of Russian Federation. Russian Journal of Clinical Ophthalmology. 2022;22(2):69–79 (in Russ.). DOI: 10.32364/2311-7729-2022-22-2-69-79. <br

Clinical and genetic characteristics of a total or partial congenital aniridia

N.V. Sukhanova1, V.V. Kadyshev1, T.A. Vasilieva1, A.V. Marakhonov1, L.A. Katargina 2, S.I. Kutsev1, R.A. Zinchenko1,3 1Research Center for Medical Genetics, Moscow, Russian Federation 2Helmholtz National Medical Research Center for Eye Diseases, Moscow, Russian Federation 3N.A. Semashko National Research Institute of Public Health, Moscow, Russian Federation Aim: to assess clinical and genetic correlations between the specific clinical manifestations of congenital aniridia (CA) and the spectrum of mutations in the PAX6 gene (including chromosomal deletions involving the entire PAX6 gene or its regions). Patients and Methods: the study included 83 patients fr om 76 unrelated families with clinical patterns of congenital aniridia. The mean age of patients was 11.5±10.3 years. All patients underwent a comprehensive eye exam, molecular and genetic testing, as well as specialist consultation. To find a genetic cause of CA, the analysis of minor mutations in the PAX6 gene was performed by Sanger sequencing in order to determine the nucleotide sequence of 13 exons and adjacent intronic regions. Also, the number of gene copies of a chromosomal region 11p13 was evaluated by using multiplex reaction of Ligation-dependent Probe Amplification (MLPA) assay. In those cases wh ere a chromosomal deletion involving the WT1 gene was detected, a target fluorescent in situ hybridization (FISH) with a locus-specific DNA-probe for the WT1 gene was carried out to prove the MLPA results. The functional in vitro analysis of the impact of intronic nucleotide sequence variants was performed in the laboratory of functional genomics of the Research Center for Medical Genetics (RCMG) using the original technique. Results: the most common features associated with CA included foveal hypoplasia, nystagmus, disorders of the eye lens, and limbal stem cells deficiency (LSCD). These findings were reported in more than 60% of cases. Partial CA was significantly more prevalent in patients with splice-site mutations (p=0.004996) as compared to other mutation types. Optic nerve hypoplasia (p=0.04779), internal strabismus (p=0.010882), aniridia-associated keratopathy co-occurring with LSCD (p=0.013236) were diagnosed more frequently in patients with nonsense mutations. Secondary glaucoma was a more common finding in patients with the deletion of 3'-cis-regulatory region (p=0.020381). Conclusion: the analysis of genotypic and phenotypic correlations has revealed statistical regularities which may underpin the relationship between the clinical pattern of CA and the types of mutations. Keywords: congenital aniridia, foveal hypoplasia, PAX6, mutations, features of the clinical picture, geno-phenotypic correlations. For citation: Sukhanova N.V., Kadyshev V.V., Vasilieva T.A. et al. Clinical and genetic characteristics of a total or partial congenital aniridia. Russian Journal of Clinical Ophthalmology. 2023;23(1):2–8 (in Russ.). DOI: 10.32364/2311-7729-2023-23-1-2-8. </p

The prevalence and diagnosis of rare (orphan) diseases in pediatric population of the Russian Federation

Objective of the research: to determine the prevalence of various nosological forms of rare (orphan) diseases in pediatric population of the Russian Federation (RF) to expand and improve diagnostic resources. Materials and methods: the prevalence of individual nosological forms of life-threatening and chronic progressive rare diseases in pediatric populationwas calculated according to the regional segments of the Federal Register. The results of fetus ultrasound screening, samples for biochemical screening and coverage of children with neonatal screening in the Russian Federation are evaluated. Results: the study revealed an increase in the prevalence of rare diseases due to the majority of nosological forms without changing their structure. For many nosological forms, an increase in their prevalence was accompanied by a decrease in the proportion of children among all patients. A high coverage of pregnant women with ultrasound screening was revealed. The number of fetuses with identified congenital malformations did not exceed 2%. Disorders during biochemical screening tests were recorded in 3-5% of cases. Neonatal screening coverage was not more than 95%. In 2013-2018, 49, 9 million screening tests were performed and 7, 7 thousand newborns with congenital and hereditary diseases were identified. The necessity of including in the neonatal screening of orphan diseases in which the use of pathogenetic therapy is possible is substantiated. Conclusion: determining the prevalence of various nosological forms of orphan diseases is extremely important and necessary to expand and improve their diagnosis, which will increase the detection of this pathology. © 2020, Pediatria Ltd.. All rights reserved

Clinical efficacy of dry nutritional treatment products for phenylketonuria in children, adults, and pregnant women: study results

N.A. Semenova1, G.V. Baydakova1, N.V. Nikitina2, V.K. Podolina2, E.Yu. Belyashova3,&nbsp;V.N. Kuznetsova3, E.M. Kochegurova4, L.P. Andreeva5, O.N. Khaylova5, S.I. Kutsev1 1Research Centre for Medical Genetics, Moscow, Russian Federation 2Clinical and Diagnostic Center “Protection of Health of Mother and Child”, Yekaterinburg, Russian Federation 3Orenburg Regional Clinical Hospital No. 2, Orenburg, Russian Federation 4E.M. Bakunina Regional Clinical Perinatal Center, Tver, Russian Federation 5Saratov Regional Children’s Clinical Hospital, Saratov, Russian Federation Abstract Aim: to assess the efficacy of domestic nutritional treatment products for phenylketonuria (PKU) in children, adults, and pregnant women. Patients and Methods: 46 patients with verified PKU were enrolled in this open-label multicenter prospective non-controlled study. Patients were allocated to the groups depending on nutritional treatment products which were prescribed according to the Clinical Guidelines of the Ministry of Health of Russian Federation. Clinical efficacy of the products was assessed according to the Good Clinical Practice guidelines based on clinical and laboratory tests. Results: all patients taken nutritional treatment products throughout the study. No dyspepsia, abnormal poop, or allergic reactions were reported. Most patients reported on more pleasant smell and odor of the products as compared with the products taken previously. At baseline, mean phenylalanine levels were within normal limits. After the treatment, phenylalanine levels were stable&nbsp; in all patients. Clinical and biochemical tests were within normal limits. Conclusion: dry nutritional treatment products are highly effective in children, adults, and pregnant women with PKU. Keywords: phenylketonuria, specialized food, phenylalanine, mixture, products. For citation: Semenova N.A., Baydakova G.V., Nikitina N.V. et al. Clinical efficacy of dry nutritional treatment products for phenylketonuria in children, adults, and pregnant women: study results. Russian Journal of Woman and Child Health. 2019;2(4):355–360. <br