Background: Currently more than 50 mutations of the INS gene are known to affect the various stages of insulin biosynthesis in the beta cells of the pancreas. However only individual cases of diabetes mellitus (DM) associated with heterozygous mutations in the coding region of the INS gene were reported in Russian Federation. We report a group of patients with a clinical manifestation of DM caused by mutations in both coding and non-coding regions of the INS gene. The patients with a mutation in the intron of the INS gene are reported for the first time in Russian FederationMaterials and methods: 60 patients with an isolated course of neonatal DM (NDM), 52 patients with a manifestation of DM at the age of 7–12 months and the absence of the main autoimmune markers of type 1 DM, 650 patients with the MODY phenotype were included in the study. NGS technology was used for molecular genetic research. Author’s panel of primers (Custom DNA Panel) was used for multiplex PCR and sequencing using Ion Ampliseq™ technology. The author’s panel “Diabetes Mellitus” included 28 genes (13 candidate genes of MODY and other genes associated with DM).Results: 13 heterozygous mutations were identified in 16 probands and 9 relatives. The majority of mutations were detected in patients with PNDM (18.75%) and in patients with an onset of DM at the age of 7–12 months (9.6%). Mutations in the INS gene were detected in 2 patients (0.3%) in the group with the MODY phenotype. Mutations in the INS gene were not detected in patients with transient NDM (TNDM). Analysis of clinical data in patients with PND and onset of diabetes at the age of 7–12 months did not show significant differences in the course of the disease. The clinical characteristics of the cases of MODY10 and diabetes caused by a mutation in the intron of the INS gene are reported in details.Conclusion: The role of INS gene mutations in NDM, MODY, and DM with an onset at the age of 7–12 months was analyzed in a large group of patients. The clinical characteristics of DM due to a mutation in the intron of the INS gene are reported for the first time in the Russian Federation.
The review, based on modern literature data and the results of many years of research conducted by the authors, highlights the problem of comorbidity (multimorbidity) in children with bronchial asthma (BA). There is a grouping of concomitant diseases in children with asthma depending on the type of comorbidity (causal, complicated, unspecified, reverse). Based on epidemiological data, observational and cohort studies, systematic reviews and meta-analyses, information on the frequency of BA in children with various comorbid diseases and comorbid diseases in children with BA was summarized. Scientific, theoretical and practical significance of comorbidity in BA, diagnostic and treatment programs in pediatric patients suffering from BA and comorbid diseases are substantiated.
CASE REPORT 384 | Сахарный диабет / Diabetes Mellitus ВВЕДЕНИЕИзучение молекулярных основ эндокринных заболева-ний является приоритетным направлением в эндокриноло-гии. Подтверждение моногенного характера заболевания позволяет четко регламентировать характер наблюдения пациента, назначить патогенетическую терапию и плани-ровать рождение здорового потомства. С 1974 г., когда впервые были описаны семьи с доминантно-наследуемым сахарным диабетом (СД), открыто около 30 генов, ответ-ственных за развитие моногенных форм диабета. Распро-страненность наследственных форм диабета активно изу-чается среди различных групп пациентов, прежде всего потому, что именно у этих больных возможна компенсация углеводного обмена без назначения инсулинотерапии. В конечном итоге это позволяет снизить расходы на обес-печение и лечение пациентов.Моногенные формы СД обусловлены, прежде всего, дефектами генов, регулирующих функцию β-клеток подже-лудочной железы (ПЖ), к которым относятся подтипы диа-бета MODY («maturity-onset diabetes of the young», «диабет зрелого типа у молодых»). Истинная распространенность 13 подтипов MODY, открытых к настоящему времени, не-известна. Большинство публикаций посвящено описанию мутаций в генах HNF1А, GCK и HNF4A, которые превали-руют среди MODY. Мутации в других генах-кандидатах Сахарный диабет типа MODY -генетически и клинически гетерогенная группа заболеваний, характеризующаяся аутосом но-доминантным типом наследования и обусловленная мутациями генов, приводящими к дисфункции β-клеток поджелудочной желе-зы. К настоящему времени верифицировано 13 подтипов MODY, наиболее распространенными из которых являются подтипы 1-3. MODY2 и MODY3 ранее неоднократно описаны в нашей стране. Описания более редких подтипов MODY в отечественной литературе единичны. В данной работе мы приводим клиническое и молекулярно-генетическое описание двух впервые выявленных в России случаев редкого подтипа MODY, обусловленного дефектом гена PAX4 (MODY9). Ген PAX4 кодирует фактор транскрипции PAX4, кото-рый участвует в дифференцировке β-клеток поджелудочной железы. Мутации в гене PAX4 приводят не только к нарушению развития β-клеток поджелудочной железы, но и снижению процессов их регенерации в последующей взрослой жизни. Молекулярно-генети-ческое подтверждение диагноза проведено с использованием технологии секвенирования нового поколения, позволяющей прово-дить одновременный анализ нескольких генов-кандидатов. Данная технология активно внедрена в последнее время в отечественную практику для генетической верификации моногенных заболеваний и, в частности, MODY. Найденные мутации ранее не описаны. Maturity-onset diabetes of the young (MODY) is a heterogeneous group of disorders characterised by autosomal dominant type of inheritance and caused by genetic defects leading to dysfunction of pancreatic beta-cells. To date, at least 13 subtypes of MODY have been described in the literature, the most frequent of which are MODY types 1-3. MODY2 and MODY3 are the most prevalent subtypes, and were previously described in our country, Russia. Seve...
Background. Beta-cell antibody tests are used for the differential diagnosis of diabetes mellitus. They permit to discriminate between the type 1 diabetes (T1D) and non-autoimmune diabetes types. To choose an appropriate test for ruling in or ruling out the T1D a physician needs to know how conclusive test results are. The most powerful estimate of test conclusiveness is its likelihood ratio (LHR). The higher LHR of a positive result (LHR+), the more posttest probability of T1D; the lower LHR of a negative result (LHR), the less posttest probability of T1D. Aims. To compare conclusiveness of single and combined tests for antibodies to islet cells (ICA), glutamate decarboxylase (GADA), and tyrosine phosphatase IA-2 (IA-2A), and to evaluate posttest probabilities of T1D at various pretest probabilities. Methods. All antibodies were tested in parallel in 169 children and adolescents with a new-onset T1D, and in 169 persons without this disease. ICA, GADA, and IA-2A were determined by indirect immunofluorescence, radioimmune assay, and ELISA, respectively. LHR+ and LHR were calculated with the MedCalc Statistical Software. Posttest T1D probabilities were calculated from Bayes theorem-based equation. Results. Among single tests, an ICA test had the greatest LHR+ and the smallest LHR, and consequently was the most reliable either for ruling in or ruling out the T1D. Among test combinations, an ICAGADA combination had the greatest LHR+ and was the most suitable for T1D confirmation. The triple combination ICAGADAIA-2A had the smallest LHR and was the most suitable for T1D exclusion. Conclusions. In the differential diagnosis of diabetes, the most appropriate test for ruling in the T1D is the double combination ICAGADA. With both antibodies positive, this combination provides the highest posttest T1D probabilities at any pretest probability. The most appropriate test for ruling out the T1D is the triple combination ICAGADAIA-2A. With all three antibodies negative, this combination provides the lowest posttest T1D probabilities.
Type 1 diabetes mellitus (DM1) is a world- and widespread disease in children and adolescents caused by the destruction of insulin-producing β-cells in the pancreas. As of today there is only one generally accepted approach to treating DM1, which is the insulin therapy, which in fact is a symptomatic therapy since it is aimed at correcting the outcome of the DM1 pathogenesis through compensation of insulin deficiency and elimination of hyperglycemia. The insulin therapy makes it possible to maintain the acceptable blood glucose levels for decades, but does not prevent the development of severe chronic complications of DM1, which in its turn are the main causes for disability cases and early deaths in such patients. Practitioners and scientists in diabetology are therefore actively searching for the ways to treating DM1 etiologically and pathogenetically. Among such methods there are various promising variants of immunotherapy aimed at prevention or suppression of an autoimmune reaction against β-cells. This review provides the basic information on DM1 and considers the modern approaches to its immunotherapy. The particular attention is paid to immunotherapy using cytotoxic monoclonal antibodies against B-lymphocytes autoreactive towards β-cells.
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