scholarly journals Articular Syndrome Characteristics in Children with Mucopolysaccharidosis Type I

2021 ◽  
Author(s):  
Nato D. Vashakmadze ◽  
Mikhail M. Kostik ◽  
Nataliya V. Zhurkova ◽  
Nataliya V. Buchinskaia ◽  
Ekaterina Yu. Zakharova ◽  
...  
Keyword(s):  
The State ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Hurler Syndrome ◽  
Mucopolysaccharidosis Type I ◽  
Cervical Stenosis ◽  
Hematopoietic Stem ◽  
Hand Joints ◽  
Small Hand ◽  
Mps I

Background. Mucopolysaccharidosis type I is disease from the group of lysosomal storage disease developing due to mutations in the IDUA gene. It leads to the accumulation of glycosaminoglycans (GAGs) in organs and tissues. Joints damage in this disease is systemic and progressive.Objective. The aim of the study. Nowadays, relevant issue is to investigate the effects of various types of pathogenetic therapy on the state of the osteoarticular system in patients with severe and mild phenotypes of MPS I to prevent further progression of joint pathology.Methods. The study included 46 patients diagnosed with “mucopolysaccharidosis type I”. 35 children had severe phenotype (Hurler syndrome) and 11 — with mild phenotypes (Hurler-Scheie and Scheie syndromes). The onset age of clinical manifestations in osteoarticular system, the state of large and small joints, and the presence of cervical stenosis according to the therapy were evaluated in these patients.Results. The osteoarticular system pathology can be usually revealed in all patients with MPS I, in both mild and severe phenotypes. The contractures of shoulder, ulnar, wrist, and small hand joints have been revealed in most patients with Hurler syndrome, regardless of the administered therapy. Hip joints pathology was observed in children who was administered with: enzyme replacement therapy (ERT) — in 46.7% of cases, hematopoietic stem cell transplantation (HSCT) in combination with ERT — in 34.4% of cases. Patients with Hurler syndrome administered with HSCT in combination with ERT had cervical stenosis statistically significantly more rarely (p = 0.018) compared to patients treated with ERT only. Patients with Hurler syndrome who were on ERT had statistically significantly lower growth rates than patients after HSCT in combination with ERT. Lesions in ulnar, wrist, knee and small hand joints were the most common in children with mild phenotypes (in 90% of cases).Conclusion. Combined therapy (HSCT and ERT) in patients with Hurler syndrome reduces severe manifestations in osteoarticular system.

scholarly journals Lysosomal storage diseases: mucopolysaccharidosis type I and II

2021 ◽  
Vol 12 (3) ◽  
pp. 69-83
Author(s):  
Victoria N. Gorbunova ◽  
Natalia V. Buchinskaia
Keyword(s):  
Severe Form ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Hurler Syndrome ◽  
Mucopolysaccharidosis Type I ◽  
Biochemical Basis ◽  
Hematopoietic Stem ◽  
Genetic Characteristics ◽  
Advantages And Disadvantages ◽  
Mps I

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

scholarly journals Mucopolysaccharidosis Type I: Current Treatments, Limitations, and Prospects for Improvement

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 189
Author(s):  
Christiane S. Hampe ◽  
Jacob Wesley ◽  
Troy C. Lund ◽  
Paul J. Orchard ◽  
Lynda E. Polgreen ◽  
...  
Keyword(s):  
Clinical Manifestations ◽  
Common Disease ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Hurler Syndrome ◽  
Mucopolysaccharidosis Type I ◽  
Lysosomal Disease ◽  
Hematopoietic Stem ◽  
Enzyme Replacement ◽  
Mps I

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease, caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). IDUA catalyzes the degradation of the glycosaminoglycans dermatan and heparan sulfate (DS and HS, respectively). Lack of the enzyme leads to pathologic accumulation of undegraded HS and DS with subsequent disease manifestations in multiple organs. The disease can be divided into severe (Hurler syndrome) and attenuated (Hurler-Scheie, Scheie) forms. Currently approved treatments consist of enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). Patients with attenuated disease are often treated with ERT alone, while the recommended therapy for patients with Hurler syndrome consists of HSCT. While these treatments significantly improve disease manifestations and prolong life, a considerable burden of disease remains. Notably, treatment can partially prevent, but not significantly improve, clinical manifestations, necessitating early diagnosis of disease and commencement of treatment. This review discusses these standard therapies and their impact on common disease manifestations in patients with MPS I. Where relevant, results of animal models of MPS I will be included. Finally, we highlight alternative and emerging treatments for the most common disease manifestations.

scholarly journals Mucopolysaccharidosis type I - Clinical and genetic characteristics of Romanian patients

2020 ◽  
Vol 28 (3) ◽  
pp. 279-286
Author(s):  
Camelia Alkhzouz ◽  
Cecilia Lazea ◽  
Diana Miclea ◽  
Carmen Asavoaie ◽  
Ioana Nascu ◽  
...  
Keyword(s):  
Severe Form ◽  
The Other ◽  
Compound Heterozygous ◽  
Type I ◽  
Ophthalmological Examination ◽  
Mucopolysaccharidosis Type ◽  
Hurler Syndrome ◽  
Mucopolysaccharidosis Type I ◽  
Genetic Characteristics ◽  
Mps I

AbstractBackground: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a deficiency of α-L-iduronidase (IDUA), which leads to the accumulation of partially digested glycosaminoglycans (dermatan sulfate and heparan sulfate) in the lysosomes and induces multisystemic alteration. Hurler (severe), Scheie (mild), and Hurler/Scheie (intermediate) syndromes are clinical subtypes of MPS-I. To date, more than 290 IDUA mutations have been reported. The purpose of this study was to present the clinical and genetic characteristics of Romanian MPS I syndrome patients and their genotype-phenotype correlation.Patients and methods: Seven patients (5 girls and 2 boys) with MPS type I, belonging to 4 unrelated families, aged 0,75-17.9 years, were enrolled. The study methods consisted in: clinical and standard auxological assessment, bone radiographs, joint ultrasonography, goniometry, neurological and psychological evaluation, hepatic and splenic ultrasonography, cardiological evaluation, otorhinolaryngology examination, ophthalmological examination, spirometry, α-L-iduronidase enzyme activity assay and molecular analysis.Results: The seven patients originated from 4 unrelated families, three patients with severe, two patients with intermediate and two with attenuated clinical phenotype. Each patient presented the classical picture of MPS type I picture, represented by: variable coarse facial features, arthropathy, hepatosplenomegaly, cardiac involvement, respiratory dysfunction and neurological impairment. Five patological variants, three point mutations (p.Q70 *, p.I238Q and p.K324R), two deletion c.1045_1047delGAC, c.46_57delTCGCTCCTG) and an insertion (c.1389 insC) were identified in both alleles of the ADUA gene in homozygous or heterozygous form. Two novel mutations (p.K324R and c.1389 insC) were reported. The p.Q70*(c.208C>T) variant was identified in 2 families with severe form of disease (Hurler syndrome) in homozygous status in one family and in compound heterozygous status in the other family.Conclusion: The p.Q70* missense variant was the most frequent, correlated in all the cases who presented it with severe form, Hurler syndrome, the other mutations being usually isolated and particular for each patient, associated in our patients with less severe MPS I phenotype, as Hurler-Scheie or Scheie syndrome. The results of this study indicated the mutational heterogeneity of the IDUA gene and the difficulty to indicate some correlation between the genotype and phenotype in MPS I patients.

scholarly journals Macular Changes in a Mucopolysaccharidosis Type I Patient with Earlier Systemic Therapies

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Augusto Magalhães ◽  
Ana Maria Cunha ◽  
Rodrigo Vilares-Morgado ◽  
Elisa Leão-Teles ◽  
Esmeralda Rodrigues ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Genetic Diagnosis ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Hematopoietic Stem ◽  
Enzyme Replacement ◽  
Mps I ◽  
Sd Oct ◽  
Systemic Therapies

Purpose. To describe retinal findings in a patient with mucopolysaccharidosis type I (MPS I) that underwent an early treatment with hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). Case Report. We describe a case of a 12-year-old female with a biochemical and genetic diagnosis of MPS I. She underwent HSCT and ERT on the first year of life. The visual acuity was 5/10 in both eyes and she had bilateral grade 2 corneal haze. Spectral domain optical coherence tomography (SD-OCT) revealed thickening of the external limiting membrane (ELM) at the fovea. In the parafoveal and perifoveal regions, SD-OCT displayed a loss of the interdigitation, ellipsoid, and myoid zones and of the ELM accompanied by progressive thinning of the outer nuclear layer. Fundus infrared imaging revealed a hyperreflective ring centred on the fovea and hyporeflective areas in temporal parafoveal regions in both eyes. En face OCT imaging revealed two hyperreflective rings on the outer retinal level. Conclusion. This patient developed macular changes with foveal deposition of hyperreflective material and parafoveal thinning, despite early systemic treatment. Systemic therapies can provide an increase in life expectancy and stabilize visual acuity and corneal clouding, although their effect on retinal degeneration is unknown.

Clinical and economic justification of screening for mucopolysaccharidosis type I in children at groups of risks

2021 ◽  
pp. 4-15
Author(s):  
I. S. Krysanov ◽  
V. S. Krysanova ◽  
V. Yu. Ermakova
Keyword(s):  
Average Cost ◽  
Weighted Average ◽  
Economic Assessment ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Selective Screening ◽  
Mucopolysaccharidosis Type I ◽  
Hematopoietic Stem ◽  
Enzyme Replacement ◽  
Mps I

Background. Mucopolysaccharidosis Type I (MPS I) has clinical heterogeneity without specific symptoms leading to difficulties with diagnostic on time. In-depth screening for MPS I in children has aim of early detection and timely treatment with an enzyme replacement therapy. Aim. The purpose of this study was to conduct a clinical and economic assessment of the feasibility of screening for MPS I in children at group of risks. Materials and methods. Model for evaluation of the social-economic burden of MPS I with calculation of expenditures has been created. Costs of diagnosed and non-diagnosed patients in group of risks were identified, including direct medical costs (pharmacotherapy, out-patient cure, hospital admission, complications treatment, hematopoietic stem cell transplantation; direct non-medical (payments for disability); indirect (expenses related to the reduction or loss of the ability to work of one of the parents performing the duties of caring for a disabled child). Results. The weighted average cost per 1 diagnosed patient with mild forms of MPS I with selective screening, was 405,974.22 rubles, which is 184,421.85 rubles less vs average cost per 1 undiagnosed patient. The management and treatment of patients with mild forms of MPS I after selective screening will allow saving up to 17.7 million rubles/year, which would possible to additionally screen 705 patients. Taking into account the size of the population of patients with undiagnosed MPS I, currently the costs for this group amount to 56.7 million rubles, while the «overspend» of budget funds for untimely diagnosis of MPS I for this cohort of children is about 22.6 million rubles/year. Conclusion. Selective screening for MPS I in children at group of risks is economically proved and can lead to treatment on-time for disability and complications prevention.

scholarly journals An evaluation of the efficacy of allogeneic hematopoietic stem cell transplantation in patients with mucopolysaccharidosis type I (Hurler syndrome): the experience of the R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation

2020 ◽  
Vol 19 (2) ◽  
pp. 83-92
Author(s):  
T. A. Bykova ◽  
V. N. Ovechkina ◽  
A. A. Osipova ◽  
A. S. Borovkova ◽  
A. A. Dotsenko ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Hurler Syndrome ◽  
Mucopolysaccharidosis Type I ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Conditioning Regimens

Mucopolysaccharidosis type I (MPS IH; Hurler syndrome) is a hereditary storage disease caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase. Enzyme replacement therapy may extend the lifespan of affected patients by 6–12 years but the only currently available radical treatment option is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Objectives: We aim to evaluate the influence of conditioning regimens of various intensities and “graft versus host” disease (GvHD) prophylaxis with anti-thymocyte globulin and post-transplant Cyclophosphamide (PTCy) on overall (OS) and event-free (EFS) survival, the incidence of GvHD, the normalization of alpha-L-iduronidase and glycosaminoglycan (GAG) levels over time as well as cardiovascular and cognitive recovery following allo-HSCT. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. We included 28 patients with MPS IH who had received allo-HSCT at the clinic at the R.М. Gorbacheva Memorial Institute of Children Oncology, Haematology and Transplantation. The five-year OS was 89%, the EFS – 57%. The use of myeloablative conditioning regimens and allo-HSCT within 12 months of diagnosis improve EFS in affected patients. The cumulative incidence of grade II–IV acute GvHD and grade III–IV acute GvHD was 43% and 18% respectively. The use of PTCy results in a significantly lower incidence of this complication (69% vs 33%, p = 0.013). After allo-HSCT, normal alpha-L-iduronidase levels and urinary GAG excretion were achieved in cases where graft function was normal. Allo-HSCT is an effective treatment for patients with MPS IH. Myeloablative conditioning regimens are the preferred treatment modality for this group of patients but in cases of comorbidities or poor physical status at the time of allo-HSCT, conditioning regimens with reduced intensity may be opted for instead. PTCy may be used for GVHD prevention in patients with MPS IH without increasing the risk of cardiac toxicity.

scholarly journals Improvement in time to treatment, but not time to diagnosis, in patients with mucopolysaccharidosis type I

2020 ◽  
pp. archdischild-2020-319040 ◽  
Author(s):  
Roberto Giugliani ◽  
Nicole Muschol ◽  
Hillary A. Keenan ◽  
Mark Dant ◽  
Joseph Muenzer
Keyword(s):  
Early Diagnosis ◽  
Age At Diagnosis ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Hematopoietic Stem ◽  
Enzyme Replacement ◽  
Time To First Treatment ◽  
Mps I ◽  
Over Time

ObjectiveEarly diagnosis and treatment initiation are important factors for successful treatment of mucopolysaccharidosis type I (MPS I). The purpose of this observational study was to assess whether age at diagnosis and time to first treatment for individuals with MPS I have improved over the last 15 years.Study designData from the MPS I Registry (NCT00144794) for individuals with attenuated or severe disease who initiated therapy with laronidase enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT) between 1 January 2003 and 31 December 2017 were included.ResultsData were available for 740 individuals with attenuated (n=291) or severe (n=424) MPS I (unknown n=25). Median age at diagnosis for attenuated disease did not change over time and ranged between 4.5 and 6 years of age while the median duration from diagnosis to first ERT decreased from 5.6 years before/during 2004 to 2.4 months in 2014–2017. For severe MPS I treated with HSCT, median age at diagnosis was less than 1 year and median time to first treatment was less than 3 months throughout the 15-year observation period.ConclusionsTimes to diagnosis and HSCT initiation for individuals with severe MPS I were consistent over time. For individuals with attenuated MPS I, the time to ERT initiation after diagnosis has improved substantially in the last 15 years, but median age at diagnosis has not improved. Efforts to improve early diagnosis in attenuated MPS I are needed to ensure that patients receive appropriate treatment at the optimal time.

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