Articular Syndrome Characteristics in Children with Mucopolysaccharidosis Type 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.

Impaired ion homeostasis as a possible associate factor in mucopolysaccharidosis pathogenesis: transcriptomic, cellular and animal studies

Mucopolysaccharidoses (MPS) are a group of diseases caused by mutations resulting in deficiencies of lysosomal enzymes which lead to the accumulation of partially undegraded glycosaminoglycans (GAG). This phenomenon causes severe and chronic disturbances in the functioning of the organism, and leads to premature death. The metabolic defects affect also functions of the brain in most MPS types (except types IV, VI, and IX). The variety of symptoms, as well as the ineffectiveness of GAG-lowering therapies, question the early theory that GAG storage is the only cause of these diseases. As disorders of ion homeostasis increasingly turn out to be co-causes of the pathogenesis of various human diseases, the aim of this work was to determine the perturbations related to the maintenance of the ion balance at both the transcriptome and cellular levels in MPS. Transcriptomic studies, performed with fibroblasts derived from patients with all types/subtypes of MPS, showed extensive changes in the expression of genes involved in processes related to ion binding, transport and homeostasis. Detailed analysis of these data indicated specific changes in the expression of genes coding for proteins participating in the metabolism of Ca2+, Fe2+ and Zn2+. The results of tests carried out with the mouse MPS I model (Idua−/−) showed reductions in concentrations of these 3 ions in the liver and spleen. The results of these studies indicate for the first time ionic concentration disorders as possible factors influencing the course of MPS and show them as hypothetical, additional therapeutic targets for this rare disease.

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

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.

Molecular Analysis of Vietnamese Patients with Mucopolysaccharidosis Type I

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder caused by deleterious mutations in the α‑L‑iduronidase (IDUA) gene. Until now, MPS I in Vietnamese has been poorly addressed. Five MPS I patients were studied with direct DNA sequencing using Illumina technology confirming pathogenic variants in the IDUA gene. Clinical characteristics, additional laboratory results, and family history were collected. All patients have presented with the classical characteristic of MPS I, and α‑L‑iduronidase activity was low with the accumulation of glycosaminoglycans. Three variants in the IDUA gene (c.1190‑10C>A (Intronic), c.1046A>G (p.Asp349Gly), c.1862G>C (p.Arg621Pro) were identified. The c.1190‑10C>A variant represents six of the ten disease alleles, indicating a founder effect for MPS I in the Vietnamese population. Using biochemical and genetic analyses, the precise incidence of MPS I in this population should accelerate early diagnosis, newborn screening, prognosis, and optimal treatment

Hyo-Mental Angle and Distance: An Important Adjunct in Airway Assessment of Adult Mucopolysaccharidosis

Background: Mucopolysaccharidosis (MPS) is a rare congenital lysosomal storage disorder with complex airways. High anterior larynx is assessed by thyromental distance (TMD) nasendoscopy. A simpler method to assess this hyoid bone is described. The distance between the central-hyoid and symphysis of the mandible (hyo-mental distance; HMD) and inclination of this line to the horizontal axis (hyo-mental angle; HMA) in neutrally positioned patients is investigated. Methods: HMA, HMD in MPS, and non-MPS were compared, and their correlation with height and weight were assessed. Results: 50 adult MPS patients (M = 32, F = 18, age range = 19–66 years; mean BMI = 26.8 kg/m2) of MPS I, II, III, IV, and VI were compared with 50 non-MPS (M = 25, F = 25; age range = 22–84 years; mean BMI = 26.5 kg/m2). Mean HMA in MPS was 25.72° (−10 to +50) versus 2.42° (−35 to +28) in non-MPS. Mean HMD was 46.5 (25.7–66) millimeters in MPS versus 41.8 (27–60.3) in non-MPS. HMA versus height and weight showed a moderate correlation (r = −0.4, p < 0.05) in MPS and no significant correlation (r < 0.4, p > 0.05) in non-MPS. HMD versus height and weight showed no correlation (r < 0.4, p > 0.05) in both groups. Conclusions: HMA seems more acute in MPS despite nearly the same HMD as non-MPS, signifying a high larynx, which may be missed by TMD.

Which Is the Best In Silico Program for the Missense Variations in IDUA Gene? A Comparison of 33 Programs Plus a Conservation Score and Evaluation of 586 Missense Variants

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease characterized by the deficiency of alpha-L-iduronidase (IDUA), an enzyme involved in glycosaminoglycan degradation. More than 200 disease-causing variants have been reported and characterized in the IDUA gene. It also has several variants of unknown significance (VUS) and literature conflicting interpretations of pathogenicity. This study evaluated 586 variants obtained from the literature review, five population databases, in addition to dbSNP, Human Genome Mutation Database (HGMD), and ClinVar. For the variants described in the literature, two datasets were created based on the strength of the criteria. The stricter criteria subset had 108 variants with expression study, analysis of healthy controls, and/or complete gene sequence. The less stringent criteria subset had additional 52 variants found in the literature review, HGMD or ClinVar, and dbSNP with an allele frequency higher than 0.001. The other 426 variants were considered VUS. The two strength criteria datasets were used to evaluate 33 programs plus a conservation score. BayesDel (addAF and noAF), PON-P2 (genome and protein), and ClinPred algorithms showed the best sensitivity, specificity, accuracy, and kappa value for both criteria subsets. The VUS were evaluated with these five algorithms. Based on the results, 122 variants had total consensus among the five predictors, with 57 classified as predicted deleterious and 65 as predicted neutral. For variants not included in PON-P2, 88 variants were considered deleterious and 92 neutral by all other predictors. The remaining 124 did not obtain a consensus among predictors.

In vivo adenine base editing corrects newborn murine model of Hurler syndrome

Mucopolysaccharidosis type I (MPS I) is a severe disease caused by loss-of-function mutations variants in the α-L-iduronidase (IDUA) gene. In vivo genome editing represents a promising strategy to correct IDUA mutations, and has the potential to permanently restore IDUA function over the lifespan of the patients. Here, we used adenine base editing to directly convert A>G (TAG>TGG) in newborn murine model harboring Idua-W392X mutation, which recapitulates the human condition and is analogous to the highly prevalent human W402X mutation. We engineered a split-intein dual-adeno-associated virus (AAV) 9 in vivo adenine base editor to circumvent the package size limit of AAV vectors. Intravenous injection of AAV9-base editor system into MPS I newborn mice led to sustained enzyme expression sufficient for correction of metabolic disease (GAGs substrate accumulation) and prevention of neurobehavioral deficits. We observed a reversion of the W392X mutation in 22.46 plus-or-minus sign 6.74% of hepatocytes, 11.18 plus-or-minus sign 5.25% of heart and 0.34 plus-or-minus sign 0.12% of brain, along with decreased GAGs storage in peripheral organs (liver, spleen, lung and kidney). Collectively, these data showed the promise of a base editing approach to precisely correct a common genetic cause of MPS I in vivo and could be broadly applicable to the treatment of a wide array of monogenic diseases.

Lysosomal storage diseases: mucopolysaccharidosis type I and II

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

Assumption of heparin-induced thrombocytopenia in mucopolysaccharidoses

Background: Mucopolysaccharidoses (MPSs) are a group of lysosomal storage diseases, resulted from glycosaminoglycans’ breakdown failure (GAGs). The study aims to determine the presence of thrombocytopenia, its prevalence, clinical implication, and correlation with the types of MPSs and with the types of glycosaminoglycans storage. Methods: A retrospective cross-sectional study of complete blood count data was conducted among 108 children with a confirmed diagnosis of MPS in the National Medical Research Center for Children's Health, Moscow, Russian Federation. STATISTICA 10 (Stat Soft, Inc. 1984-2011) was used for statistical analysis. A p-value of ≤0.05 was considered significant. Results: The median age of children was 65 [IQR: 41; 102] months, range: 3 – 102 months. The male to female ratio was 3:1. The prevalence of fluctuating or persistent thrombocytopenia in all children with MPS was 19.0%. Thrombocytopenia occurred in patients with MPS I (14.0%), II (19.0%), and III (31.0%). Neither of the patients with MPS IV nor VI demonstrated low platelet count. There was a non-significant predominance (P=0.068) of thrombocytopenia frequency in patients with heparan sulfate storage (22.0%) compared with patients without heparan sulfate burden (0%). Conclusion: Routine checkups of patients with MPSs must include complete blood count with platelet measurement. Cases of thrombocytopenia that requiring treatment, immunomodulatory/ immunosuppressive therapy should be considered. Further research is needed to look for the laboratory confirmation of autoimmune variants of HIT in patients with MPS I, II, III.