8 research outputs found
Неврологические и нейрохирургические аспекты гипофосфатазии
Hypophosphatasia is a rare hereditary progressive disease caused by a mutation in ALPL gene and characterized by low activity of alkaline phosphatase. Due to the disruption of the bone mineralization process, ricket-like deformations of the skeleton occur in the clinic picture more frequently but other systemic manifestations can be also observed as respiratory insufficiency, urinary tract damage, and neurological disorders. Seizures, delayed physical and psychomotor development, attention deficit disorder, muscle weakness, fatigue, intracranial hypertension associated with the development of craniosynostosis are revealed in these patients. The severity of the disease depends on age: the highest mortality is reported in younger patients, in perinatal and infantile forms of hypophosphatasia. Diagnosis is based on the identification of specific clinical manifestations: retardation of growth and development, skeletal deformities, pain in muscles and joints, premature tooth loss. In laboratory tests, a steady decrease in alkaline phosphatase level is detected taking into account age and sex specification. If possible, alkaline phosphatase substrates are measured: levels of pyridoxal-5-phosphate in the blood and phosphoethanolamine in urine are higher at low enzyme activity. Radiographs of long bones typically reveal characteristic ‘tongues’ of lucency projecting from growth plates into metaphyses, hypomineralization, osteopenia, various kinds of deformation. All patients with suspected hypophosphatasia should be consulted by a clinical geneticist and evaluated to identify possible mutation in the ALPL gene.Гипофосфатазия — редкое наследственное прогрессирующее заболевание, вызванное мутацией в гене ALPL, вследствие которой угнетается активность щелочной фосфатазы. Из-за нарушения процесса минерализации костной ткани в клинической картине преобладают рахитоподобные деформации скелета, но зачастую возникают и другие системные проявления — нарушение дыхания, поражение мочевыделительной системы и неврологические расстройства. У пациентов выявляют судороги, задержку физического и психомоторного развития, дефицит внимания, мышечную слабость, быструю утомляемость, внутричерепную гипертензию, связанную с развитием краниосиностозов. Тяжесть гипофосфатазии зависит от времени ее манифестации: наибольшая смертность регистрируется при перинатальной и инфантильной формах заболевания. Диагностика основана на выявлении характерных клинических симптомов — задержки роста и развития, деформации скелета, болей в мышцах и суставах, преждевременного выпадения зубов. В лабораторных анализах отслеживается стойкое снижение уровня щелочной фосфатазы с учетом возраста и пола пациента; при низкой активности фермента уровни субстратов щелочной фосфатазы пиридоксаль-5-фосфат в крови и фосфоэтаноламина в моче всегда повышены. На рентгенограммах длинных трубчатых костей обнаруживаются «языки» просветления, проецирующиеся от зоны роста в метафизы, а также гипоминерализация, остеопения и другие деформации. Все пациенты с подозрением на гипофосфатазию должны быть проконсультированы клиническим генетиком и обследованы на выявление мутации в гене ALPL.КОНФЛИКТ ИНТЕРЕСОВАвторы декларируют отсутствие конфликтов интересов, связанных с публикацией настоящей статьи
Влияние ферментозаместительной терапии на обструкцию верхних дыхательных путей у детей с мукополисахаридозами: ретроспективное когортное исследование
Background. Data on the efficacy of enzyme replacement therapy (ERT) in relation to the pathology of ENT organs and respiratory performance in sleep in children with mucopolysaccharidosis (MPS) is poorly presented in the literature. Our aim was to assess the effect of ERT on the upper respiratory tract in children with MPS. Methods. According to the case histories, we studied treatment results of children with MPS type I and II who received ERT in the Research Center of Children’s Health from January 2007 to November 2016. The severity of upper airway obstruction and its change during ERT was assessed according to indices of apnea-hypopnea and desaturation (SpO2), average/minimal SpO2, duration of SpO2 episodes < 90%, and hypertrophy degree of palatine tonsils and adenoids. Results. The severity of the obstructive sleep apnea syndrome did not progress in children (n = 15) with MPS against the background of ERT with a median duration of 38 (23; 48) months: initially, the apnea-hypopnea index was 3 (1.3; 7.7), while the repeated study — 2.6 (0.9; 13.5) (p = 0.507). There was also no statistically significant change in cardiorespiratory monitoring values. Conclusion. Long-term ERT in children with MPS type I and II interferes with the progression of airway obstruction.Обоснование. Данные об эффективности ферментозаместительной терапии (ФЗТ) в отношении патологии ЛОР- органов и показателей дыхания во сне у детей с мукополисахаридозом (МПС) в литературе представлены скудно.Цель исследования — оценить влияние ФЗТ на состояние верхних дыхательных путей у детей с МПС.Методы. По историям болезни изучали результаты лечения детей с МПС I и II типов, получавших ФЗТ в Научном центре здоровья детей (ныне ФГАУ «НМИЦ здоровья детей» Минздрава России) с января 2007 по ноябрь 2016 г. Выраженность обструкции верхних дыхательных путей и ее изменение на фоне ФЗТ оценивали по индексам апноэ-гипопноэ и десатурации (SpO2), средней/минимальной SpO2, продолжительности эпизодов SpO2< 90% и степени гипертрофии небных миндалин и аденоидов.Результаты. У детей (n=15) с МПС на фоне ФЗТ продолжительностью (медиана) 38 (23; 48) мес тяжесть синдрома обструктивного апноэ сна не прогрессировала: исходно индекс апноэ-гипопноэ составил 3 (1,3; 7,7), при повторном исследовании — 2,6 (0,9; 13,5) (р=0,507). Также не установлено статистически значимого изменения показателей кардиореспираторного мониторинга.Заключение. Длительная ФЗТ у детей с МПС I и II типов препятствует прогрессированию обструкции дыхательных путей.КОНФЛИКТ ИНТЕРЕСОВ Л.С. Намазова-Баранова — получение исследовательских грантов от фармацевтических компаний Пьер Фабр, Genzyme Europe B. V., ООО «Астра зенека Фармасьютикалз», Gilead / PRA «Фармасьютикал Рисерч Ассошиэйтс СиАйЭс», Bionorica, Teva Branded Pharmaceutical products R&D, Inc / ООО «ППД Девелопмент (Смоленск)», «Сталлержен С. А.» / «Квинтайлс ГезмбХ» (Австрия). Л.М. Кузенкова, А.К. Геворкян, Т.В. Подклетнова, Н.Д. Вашакмадзе читают лекции для компаний «Санофи Джензайм», «Шайер», «Биомарин». Остальные авторы подтвердили отсутствие конфликта интересов, о котором необходимо сообщить
EFFICACY AND SAFETY OF ENZYME REPLACEMENT THERAPY IN CHILDREN WITH MUCOPOLYSACCHARIDOSIS TYPE I, II, AND VI: A SINGLE-CENTER COHORT STUDY
Background. There are limited data on the efficacy of long-term enzyme replacement therapy (ERT) in children with mucopolysaccharidosis (MPS).Objective. Our aim was to study the efficacy and safety of long-term ERT in children with MPS type I, II, and VI.Methods. We analyzed the results of ERT with laronidase, idursulfase, and galsulfase in children with MPS type I, II, and VI admitted to the federal research center from January 2007 to November 2016. The response rate was assessed by the level of normalized urinary excretion of glycosaminoglycans (GAGs) (the ratio of GAGs concentration to urine creatinine) recalculated in percent (%) exceedance of the upper limit of normal for the corresponding age. Data on the administered therapy and its results, including adverse events, is extracted from the medical records of in-patients.Results. The results of treatment (intravenous infusions, intervals between administrations from 4 to 10 days) were studied in 33 children (5 of them were girls) with MPS type I (n = 4; laronidase at a dose of 0.58 mg/kg), II (n = 26; idursulfase at a dose of 0.5 mg/kg), and VI (n = 3; galsulfase at a dose of 1 mg/kg). A decrease in the normalized urinary excretion of GAGs from 376% (172; 791) to 54% (0; 146) exceedance of the upper limit of normal for the age (p < 0.001) was noted in the course of ERT lasting (median) 27 (14; 41) months. A decrease in the normalized GAGs excretion below the upper limit of normal for the age was established in 12/33 (36%) patients. ERT-associated adverse events were identified in 12 patients; one case required a two-fold therapy interruption. The development of nephrotic syndrome in the course of ERT in patients with severe MPS II was first described.Conclusion. Long-term ERT in children with MPS type I, II, and VI is characterized by acceptable efficacy and safety. Key words: children, mucopolysaccharidosis, enzyme replacement therapy, laronidase, idursulfase, galsulfase, glycosaminoglycans
The Impact of Enzyme-Replacement Therapy on Upper Airway Obstruction in Children with Mucopolysaccharidoses: Retrospective Cohort Study
Background. Data on the efficacy of enzyme replacement therapy (ERT) in relation to the pathology of ENT organs and respiratory performance in sleep in children with mucopolysaccharidosis (MPS) is poorly presented in the literature. Our aim was to assess the effect of ERT on the upper respiratory tract in children with MPS. Methods. According to the case histories, we studied treatment results of children with MPS type I and II who received ERT in the Research Center of Children’s Health from January 2007 to November 2016. The severity of upper airway obstruction and its change during ERT was assessed according to indices of apnea-hypopnea and desaturation (SpO2), average/minimal SpO2, duration of SpO2 episodes < 90%, and hypertrophy degree of palatine tonsils and adenoids. Results. The severity of the obstructive sleep apnea syndrome did not progress in children (n = 15) with MPS against the background of ERT with a median duration of 38 (23; 48) months: initially, the apnea-hypopnea index was 3 (1.3; 7.7), while the repeated study — 2.6 (0.9; 13.5) (p = 0.507). There was also no statistically significant change in cardiorespiratory monitoring values. Conclusion. Long-term ERT in children with MPS type I and II interferes with the progression of airway obstruction
Current Approaches in Management of Patients with Hypophosphatasia
he authors present the latest data on the hypophosphatasia (HPP) management in children. Hypophosphatasia is a rare genetic disease caused by deficiency of tissue-specific alkaline phosphatase due to mutation in the ALPL gene. The article covers all the features of epidemiology, etiology and pathogenesis, detailed stages of differential diagnostics. Treatment guidelines for pediatric patients are provided, they are based on the principles of evidence-based medicine. Special attention was given to the only effective method of hypophosphatasia management —enzyme replacement therapy (ERT). This material is the clinical guideline draft for the management of patients with hypophosphatasia prepared by the Union of Pediatricians of Russia and the Association of Medical Geneticists
Clinical and Genetic Characteristics of Pediatric Patients with Hypophosphatasia in the Russian Population
(1) Hypophosphatasia (HPP) is a rare inherited disease caused by mutations (pathogenic variants) in the ALPL gene which encodes tissue-nonspecific alkaline phosphatase (TNSALP). HPP is characterized by impaired bone mineral metabolism due to the low enzymatic activity of TNSALP. Knowledge about the structure of the gene and the features and functions of various ALPL gene variants, taking into account population specificity, gives an understanding of the hereditary nature of the disease, and contributes to the diagnosis, prevention, and treatment of the disease. The purpose of the study was to describe the spectrum and analyze the functional features of the ALPL gene variants, considering various HPP subtypes and clinical symptoms in Russian children. (2) From 2014–2021, the study included the blood samples obtained from 1612 patients with reduced alkaline phosphatase activity. The patients underwent an examination with an assessment of their clinical symptoms and biochemical levels of TNSALP. DNA was isolated from dried blood spots (DBSs) or blood from the patients to search for mutations in the exons of the ALPL gene using Sanger sequencing. The PCR products were sequenced using a reagent BigDye Terminator 3.1 kit (Applied Biosystems). Statistical analysis was performed using the GraphPad Prism 8.01 software. (3) The most common clinical symptoms in Russian patients with HPP and two of its variants (n = 22) were bone disorders (75%), hypomyotonia (50%), and respiratory failure (50%). The heterozygous carriage of the causal variants of the ALPL gene was detected in 225 patients. A total of 2 variants were found in 27 patients. In this group (n = 27), we identified 28 unique variants of the ALPL gene, of which 75.0% were missense, 17.9% were frameshift, 3.6% were splicing variants, and 3.6% were duplications. A total of 39.3% (11/28) of the variants were pathogenic, with two variants being probably pathogenic, and 15 variants had unknown clinical significance (VUS). Among the VUS group, 28.6% of the variants (7/28) were discovered by us for the first time. The most common variants were c.571G > A (p.Glu191Lys) and c.1171del (Arg391Valfs*12), with frequencies of 48.2% (13/28) and 11% (3/28), respectively. It was found that the frequency of nonsense variants of the ALPL gene was higher (p < 0.0001) in patients with the perinatal form compared to the infantile and childhood forms of HPP. Additionally, the number of homozygotes in patients with the perinatal form exceeded (p < 0.01) the frequencies of these genotypes in children with infantile and childhood forms of HPP. On the contrary, the frequencies of the compound-heterozygous and heterozygous genotypes were higher (p < 0.01) in patients with infantile childhood HPP than in perinatal HPP. In the perinatal form, residual TNSALP activity was lower (p < 0.0005) in comparison to the infantile and childhood (p < 0.05) forms of HPP. At the same time, patients with the heterozygous and compound-heterozygous genotypes (mainly missense variants) of the ALPL gene had greater residual activity (of the TNSALP protein) regarding those homozygous patients who were carriers of the nonsense variants (deletions and duplications) of the ALPL gene. Residual TNSALP activity was lower (p < 0.0001) in patients with pathogenic variants encoding the amino acids from the active site and the calcium and crown domains in comparison with the nonspecific region of the protein
Современные подходы к ведению детей с мукополисахаридозом I типа
This article presents modern data on epidemiology, etiology, and clinical manifestations of mucopolysaccharidosis (MPS) type I in children. MPS develops due to deficiency of particular lysosomal enzyme which determines the disease type. The article considers in details disease's pathogenesis and classification. Evidence-based approaches to diagnosis (differential diagnosis included) are covered, moreover, special attention is paid to pathogenetic, symptomatic, and surgical treatment of MPS.В статье представлены современные сведения об эпидемиологии, этиологии и клинических проявлениях мукополисахаридоза (МПС) I типа у детей. МПС развивается в результате дефицита того или иного лизосомального фермента, что определяет тип болезни. В статье подробно рассмотрены вопросы патогенеза и классификации заболевания. Освещены основанные на доказательной медицине подходы к диагностике, в том числе дифференциальной, особое внимание уделено патогенетическому, симптоматическому, хирургическому лечению МПС
Современные подходы к ведению пациентов с гипофосфатазией
he authors present the latest data on the hypophosphatasia (HPP) management in children. Hypophosphatasia is a rare genetic disease caused by deficiency of tissue-specific alkaline phosphatase due to mutation in the ALPL gene. The article covers all the features of epidemiology, etiology and pathogenesis, detailed stages of differential diagnostics. Treatment guidelines for pediatric patients are provided, they are based on the principles of evidence-based medicine. Special attention was given to the only effective method of hypophosphatasia management —enzyme replacement therapy (ERT). This material is the clinical guideline draft for the management of patients with hypophosphatasia prepared by the Union of Pediatricians of Russia and the Association of Medical Geneticists.Авторами представлены новейшие данные по ведению гипофосфатазии у детей. Гипофосфатазия — редкое генетическое заболевание, обусловленное дефицитом тканенеспецифической щелочной фосфатазы в результате мутации в гене ALPL. В статье отражены особенности эпидемиологии, этиологии и патогенеза, подробно освещаются этапы дифференциально-диагностического поиска. Для пациентов детского возраста приведены рекомендации по лече- нию, основанные на принципах доказательной медицины. Особое внимание уделено единственному эффективному методу лечения гипофосфатазии — ферментозаместительной терапии. Представленный материал является проектом клинических рекомендаций по ведению пациентов с гипофосфатазией Союза педиатров России и Ассоциации медицинских генетиков