Санкт-Петербургский государственный педиатрический медицинский университет, Российская ФедерацияВВЕДЕНИЕ Мукополисахаридозы (МПС) -группа наследствен-ных нарушений обмена веществ, характеризующаяся накоплением избытка гликозаминогликанов (ГАГ) вслед-ствие дефицита специфических лизосомных фермен-тов. Для каждого типа МПС характерен определенный ферментный дефект, позволяющий классифицировать пациентов с МПС на различные типы (табл. 1).Для МПС характерно вовлечение в патологический процесс всех органов и систем, включая центральную нервную, опорно-двигательную и сердечно-сосудистую систему. Часто заболевание сопровождается задерж-кой психомоторного развития. Ключевым моментом, определяющим судьбу пациента с МПС, является ран-няя диагностика, позволяющая вовремя начать фер-ментзаместительную терапию (ФЗТ) и решить вопрос
Mucopolysaccharidosis type I (MPS I) is a hereditary metabolic disease that manifests itself in childhood by systemic damage to tissues and organs, a constantly progressive course leading to disability. Diagnosis of mild forms of the disease is particularly difficult due to the absence of specific symptoms. A specific symptom of the mild forms of MPS I (as for other types of MPS) is joint stiffness in children combined with hernia, frequent infections, or valvular defects. Stiffness in MPS I is often interpreted as a manifestation of rheumatological diseases (arthrogriposis, juvenile idiopathic arthritis). The article offers a simple algorithm for diagnosing MPS I, which helps to eliminate the disease using a simple test for determining the activity of an enzyme called alpha-L-iduronidase in a dried blood spot.
The epidemiology, clinical biochemical and molecular genetic characteristics of glycosphingolipidoses with impaired metabolism and excessive accumulation in parenchymal organs, bone and brain not only of sphingolipids, but also free cholesterol are presented. First of all, it is sphingomyelin lipidosis, or NiemannPick disease, a clinically polymorphic and genetically heterogeneous group of rare monogenic diseases. Types A and B, which differ in onset and severity, are allelic diseases and are caused by the presence of recessive mutations in the lysosomal acid sphingomyelinase (SMPD1) gene. Type A is a classic acute neuronopathy, which starts in 85% of cases before 6 months, death occurs before the age of 3 years. The cause of the disease is mutations with premature termination of translation or severe impairment of the catalytic activity of the enzyme. In type B, missense mutations are more common. This is a chronic visceral form, in which neurological symptoms are usually absent, and patients survive into adolescence. Juvenile and adult forms of chronic neuronopathy type C are genetically heterogeneous. In 95% of cases they are caused by mutations in the NPC1 gene (type C1) and in 5% in the NPC2 gene (type C2). The products of these genes are transmembrane proteins responsible for the transport of cholesterol and other lipids. Cholesterol ester storage disease, or Wolman disease, is caused by hereditary deficiency of lysosomal acid lipase A. The possibility of early diagnosis of these diseases based on neonatal screening is discussed in order to increase the effectiveness of their prevention and treatment. The importance of experimental models for studying the molecular basis of the pathogenesis of these severe hereditary diseases and developing various therapeutic approaches, such as bone marrow transplantation, enzyme replacement therapy, and substrate-reducing therapy, is emphasized. A clinical example of NiemannPick disease type C is presented.
The review is devoted to the clinical, biochemical, and molecular genetic characteristics of autosomal recessive mucopolysaccharidoses (MPS) types IV, VI, and VII. MPS IV type, or Morquios syndrome, is represented by 2 types A and B. The cause of the most frequent MPS IVA is hereditary deficiency of galactose-6-sulfatase, due to the presence of inactivating mutations in the GALNS gene. The pathogenetic basis of the disease is associated with excessive accumulation in lysosomes, mainly of cartilage tissue of keratan sulfate and chondroitin-6-sulfate. Main clinical manifestations of MPS IVA are dwarfism and progressive deformity of the spine, sternum, and knees. The milder MPS IVB is due to hereditary -galactosidase deficiency and is an allelic variant of GM1 gangliosidosis. The cause of MPS VI, or MarotoLamy syndrome, and MPS VII, or Sly syndrome, is hereditary deficiency of arylsulfatase B and -glucuronidase, respectively. The pathogenesis of these diseases is due to the excessive accumulation of dermatan sulfate and, in the second case, additionally, heparan sulfate. Patients with type VI and VII MPS have a Hurler-like phenotype, but in the first case, intellectual deficiency are usually absent, while in Sly syndrome, moderate mental retardation is observed. The possibility of neonatal screening and early diagnosis of these MPS in order to increase the effectiveness of their prevention and treatment is discussed. The importance of experimental models for studying the molecular basis of the pathogenesis of these severe hereditary diseases and the development of various therapeutic approaches, such as bone marrow transplantation, enzyme replacement therapy and substrate-reducing therapy, is emphasized. Descriptions of clinical cases of MPS IVA and VI types are presented.
Mucopolysaccharidosis (MPS) are a genetically heterogeneous group of rare monogenic metabolic diseases associated with hereditary insufficiency of lysosomal enzymes involved in the catabolism of glycosaminoglycans, or mucopolysaccharides. The pathogenesis of MPS is due to the accumulation of non-cleaved glycosaminoglycans in lysosomes, which can destroy cells. All MPS are characterized by a polysystemic manifestation, the simultaneous involvement of many organs and tissues in the pathological process, first of all, connective tissues, bones and cartilaginous. This review presents the epidemiology, clinical, biochemical, and molecular genetic characteristics of MPS types I and II, caused by the recessive mutations in the alpha-L-iduronidase and iduronate-2-sulfatase genes, respectively, and by the accumulation of dermatan and heparan sulfate. Each of these diseases is characterized by clinical polymorphism, especially observed in MPS I, which often manifests in a severe form of Hurler syndrome, but can also occur in a milder form of Scheie syndrome. Currently, there is an increased interest in MPS in the world due to the identification of the spectrum and frequencies of mutations in theIDUAandIDSgenes in various populations, including in Russia, and the practical availability of methods for individual molecular diagnostics. The description of the existing experimental models, their role in the study of the biochemical basis of the pathogenesis of these severe hereditary diseases and the development of various therapeutic approaches are given. Discusses the possibility of early diagnosis of MPS I and II types based on neonatal screening in order to increase the effectiveness of their prevention and treatment, as well as the advantages and disadvantages of the main approaches to the treatment of these serious diseases, such as hematopoietic stem cell transplantation, enzyme replacement and substrate-reducing therapy. A clinical example of a combination therapy for a severe form of mucopolysaccharidosis type I Hurler syndrome is presented
Е. Н. Архипова, к.м.н., отдел нервно-мышечной патологии человека ФГБУ «Федеральный научноклинический центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздрава России М.О. Ковальчук, невролог, член правления Региональной общественной организации «Общество специалистов по нервно-мышечным болезням» Н. В. Бучинская, к.м.н., ГБОУ ВПО «Санкт-Петербургский государственный педиатрический медицинский университет» Минздрава России Данные клинические рекомендации рассмотрены и утверждены на заседании 2-го Российcкого совета экспертов по болезни Помпе 24 сентября 2014 г., прошедшего в рамках 5-й Российской школы миологии в г. Санкт-Петербурге (22-25 сентября 2014 г.). Согласованы в октябре 2014 г., утверждены главным внештатным специалистом по медицинской генетике Минздрава России д.м.н. С. И. Куцевым. Клинические рекомендации пересмотрены и утверждены на заседании 3-го Российcкого совета экспертов по болезни Помпе 14 ноября 2015 г., прошедшего в рамках Международной междисциплинарной конференции «Управляй болью» в г. Москве (13-14 ноября 2015 г.). Согласованы в ноябре 2015 г., утверждены главным внештатным специалистом по медицинской генетике Минздрава России д.м.н. С. И. Куцевым.
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