Enzyme Replacement Therapy with Idursulfase in Patients with Mucopolysaccharidosis Type II: Literature Review

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is X-linked hereditary disease from the group of lysosomal storage disease. Its prevalence is 3–7 cases per 1 million live-born boys. MPS II occurs due to the deficiency of iduronate-2-sulfatase enzyme because of pathological changes in the structure of the IDS gene. Enzyme deficiency leads to the accumulation of glycosaminoglycans (GAGs), dermatan sulfate and heparan sulfate, in lysosomes. This leads to the damage of various organs and systems in the body with further development of clinical picture of the disease: coarse face, recurrent infections of upper respiratory tract, hearing loss up to deafness, cardiovascular and respiratory systems pathologies, hepatosplenomegaly, musculoskeletal system abnormalities, low growth, central nervous system damage. Enzyme replacement therapy with idursulfase, that was introduced in clinical practice 15 years ago, has significantly changed the quality of life of these patients. Idursulfase is purified form of natural lysosomal enzyme iduronate-2-sulfatase obtained via human cell line. Exogenous enzyme entry promotes GAGs catabolism in cells. This article provides outcomes analysis of foreign and Russian studies on the efficacy and safety of this medication, and its effect on MPS II patients survivability.

Complex Communication Needs of a Child with Dandy-Walker Syndrome and Mucopolysaccharidosis Type II Case Study

There exist few publications describing the cases of children diagnosed with two rare diseases. Most of them are medical case studies. The purpose of the research was to describe the complex communication needs of a child and the resulting needs in the area of me as a person and in the home, social, educational, therapeutic and medical environment. The research involved a boy in early school age diagnosed with the Dandy-Walker syndrome and mucopolysaccharidosis type II (Hunter syndrome). The research was embedded in qualitative orientation using an individual case study. The research was conducted over a period of four years (2016 to 2020). The complex communication needs diagnosed in the boy triggered the following needs in the area of “me as a person”: to notice the effects of one’s actions, to have a sense of being a member of a group, to engage in activities that will help develop one’s own competencies and gain experience, and to be included in group activities. The research suggests that all of the above mentioned needs exist in the home and social environment area. In terms of education, it was determined that there is no need for a teaching assistant/aide who would know alternative methods of communication and could adapt the classroom to multimodal communication and train other persons. In terms of therapy, there was no need to create a controlled space in an institution, as therapy, the same as education, takes place in the boy’s home. In terms of medical care, Adam has all the above mentioned needs.

Allergic Reactions at Enzyme Replacement Therapy in Children with Mucopolysaccharidosis Type II

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is rare hereditary disease caused by changes in the IDS gene and associated deficiency of lysosomal enzyme iduronate-2-sulfatase (I2S). The main treatment scheme for children with MPS II is enzyme replacement therapy (ERT) with recombinant human I2S. The major issue of ERT is development of allergic (sometimes up to severe anaphylaxis) reactions to recombinant enzymes. The article covers features of infusion-related reactions to ERT, it describes pathogenesis, diagnostic criteria management algorithm of anaphylaxis. Whereas, there is the need of further studies on allergic infusion-related reactions to ERT in children.

Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II

Mucopolysaccharidosis type II (MPS II) results from the dysfunction of a lysosomal enzyme, iduronate-2-sulfatase (IDS). Dysfunction of IDS triggers the lysosomal accumulation of its substrates, glycosaminoglycans, leading to mental retardation and systemic symptoms including skeletal deformities and valvular heart disease. Most patients with severe types of MPS II die before the age of 20. The administration of recombinant IDS and transplantation of hematopoietic stem cells are performed as therapies for MPS II. However, these therapies either cannot improve functions of the central nervous system or cause severe side effects, respectively. To date, 729 pathogenetic variants in the IDS gene have been reported. Most of these potentially cause misfolding of the encoded IDS protein. The misfolded IDS mutants accumulate in the endoplasmic reticulum (ER), followed by degradation via ER-associated degradation (ERAD). Inhibition of the ERAD pathway or refolding of IDS mutants by a molecular chaperone enables recovery of the lysosomal localization and enzyme activity of IDS mutants. In this review, we explain the IDS structure and mechanism of activation, and current findings about the mechanism of degradation-dependent loss of function caused by pathogenetic IDS mutation. We also provide a potential therapeutic approach for MPS II based on this loss-of-function mechanism.

Preimplantation genetic testing for mucopolysaccharidosis type II: a case report

Цель: представление клинического случая успешного преимплантационного генетического тестирования моногенного заболевания (ПГТ-М) - мукополисахаридоза второго типа (МПС II, синдром Хантера). Методы. Супружеская пара (32 и 31 год), имеющая ребенка с МПС II, обратилась за проведением ПГТ-М (патогенный вариант гена IDS - c.613delG). У женщины также имелась инверсия хромосомы 10. Для семьи была разработана система таргетного преимплантационного тестирования МПС II, валидирована на единичных лимфоцитах и продуктах полногеномной амплификации. Использовали метод двухраундной ПЦР с детекцией фрагментным анализом. В двух программах экстракорпорального оплодотворения (ЭКО) применяли стандартные протоколы стимуляции суперовуляции, оплодотворение проводили методом ИКСИ (инъекция сперматозоида в цитоплазму ооцита). Биопсию эмбрионов выполняли на пятые сутки развития (один эмбрион на шестые), эмбрионы витрифицировали. ПГТ-М проводили в транспортном варианте по схеме, разработанной на подготовительном этапе. Пренатальную диагностику выполняли методом хорионбиопсии, анализировали кариотип, ген IDS и пол плода. Результаты. При разработке системы были подобраны и протестированы 14 STR-маркеров (коротких тандемных повторов), сцепленных с геном IDS, из которых половина была информативна и давала амплификацию для единичных клеток. Разработанная для семьи система ПГТ-М МПС II включала анализ патогенного варианта гена IDS, семи информативных STR-маркеров, генов AMEL и SRY. Преимплантационное тестирование анеуплоидии не проводилось (пациентка отказалась). В первой программе ЭКО протестировано и рекомендовано к переносу три эмбриона, однако перенос был отложен по желанию супружеской пары. Во второй программе ЭКО пять эмбрионов были протестированы, три рекомендованы к переносу. Проведен криоперенос одного эмбриона мужского пола с нормальной хромосомой X в отношении патогенного варианта гена IDS. Наступила одноплодная беременность. Пренатальная диагностика полностью подтвердила результаты ПГТ-М. Беременность успешно завершилась срочными родами здорового мальчика в июле 2021 года. Заключение Разработанная нами система, успешное проведение всех этапов ЭКО и ПГТ-М и хороший репродуктивный потенциал супружеской пары позволили достичь беременности и рождения здорового ребенка в семье с высоким генетическим риском в отношении МПС II. Aim: we report of our data of successful preimplantation genetic testing (PGT-M) for mucopolysaccharidosis type II (MPS II, Hunter syndrome). Methods. A couple (32 and 31 years old) with Hunter syndrome affected child asked for PGT-M for MPS II (pathogenic variant c.613delG of the IDS gene). In addition, the woman has an inversion of chromosome 10. A system of targeted preimplantation testing was developed for the family, validated on single lymphocytes and whole genome amplification products.. Nested PCR method and fragmentary analysis were used for molecular genetic studies. Two IVF (in vitro fertilization) programs was carried out. Standard protocols for controlled ovarian hyperstimulation with fertilization by ICSI (intracytoplasmic sperm injection) were used. Embryo biopsy was performed on the 5th day of embryo development (day 6th for one embryo), embryos were vitrified. Transport PGT-M (PGT for monogenic/single gene defects) was carried using system created at pre-examination setup. Prenatal diagnosis was performed using the chorion villus biopsy method; karyotype, IDS gene and fetal sex were analyzed. Results. During setup, 14 STR (short tandem repeat) markers linked to the IDS gene were selected and tested, half of them were informative and acceptable for single cells. Developed for the family the PGT-M MPS II system included analysis of a pathogenic variant of the IDS gene, seven informative STR markers, AMEL and SRY genes. No PGT-A (PGT for aneuploidy) was carried out. In the first IVF program, three embryos were tested and recommended for transfer, but the transfer was postponed at the patient request. In the second IVF program, five embryos were tested, three recommended for transfer. Frozen single embryo transfer of normal male embryo at the second of IVF-PGT-M program was carried out. A singleton pregnancy was achieved. Prenatal diagnosis fully confirmed PGT-M results. A healthy boy was delivered in July 2021. Conclusions. The successful implementation IVF-PGT-M with developed system and good reproductive potential of the couple made it possible to achieve pregnancy and the birth of a healthy child in a family with a high genetic risk for MPS II.