Excretion Of Glycosaminoglycans Research Articles

Comparison of urine glycosaminoglycan excretion between children with autism spectrum disorder and typically developed children

BackgroundAbnormalities pertaining to glycosaminoglycan metabolism have been demonstrated in children with autism spectrum disorder. The aim of the present study was to compare urine excretion of sulfated glycosaminoglycans in children with autism spectrum disorder, with neurotypical controls and explore its association with co-occurring symptoms. MethodRandom urine samples were collected from children with autism spectrum disorder (n = 61) between the ages of 2 and 6 years, and age- and sex-matched neurotypical controls. Urine glycosaminoglycan levels were quantified by the dimethylmethylene blue (DMMB) dye-binding assay. ResultsMean glycosaminoglycan/creatinine ratio of children with autism spectrum disorder was 22.279 ± 13.044 mg/mmol while that of neurotypical controls was 19.121 ± 7.319 mg/mmol. Eight patients with autism spectrum disorder (13.11%) exhibited abnormally high glycosaminoglycan excretion. Unstandardized urine glycosaminoglycan levels are significantly higher (p = 0.019) in the autism spectrum disorder group when covariates such as age, urinary creatinine, and height are taken into consideration by ANCOVA. However, the outcome showed a trend towards significance when glycosaminoglycan/creatinine ratio was used in ANCOVA (p = 0.058). In neurotypical subjects, the urine glycosaminoglycan levels appear to decline with age, height, and weight while this trend was not apparent in subjects with autism spectrum disorder. Glycosaminoglycan excretion did not correlate with the presence of co-occurring symptoms of autism spectrum disorder; frequent gastrointestinal symptoms, self-injurious behaviors, food aversions, or parent-reported sleep problems. ConclusionsA subset of children with autism spectrum disorder exhibits higher urine glycosaminoglycan excretion. Further research is needed to explore the molecular basis of this finding.

Efficacy of a Combination Therapy with Laronidase and Genistein in Treating Mucopolysaccharidosis Type I in a Mouse Model.

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by α-L-iduronidase deficiency. The standard treatment, enzyme replacement therapy with laronidase, has limited effectiveness in treating neurological symptoms due to poor blood-brain barrier penetration. An alternative is substrate reduction therapy using molecules, such as genistein, which crosses this barrier. This study evaluated the effectiveness of a combination of laronidase and genistein in a mouse model of MPS I. Over 12 weeks, MPS I and wild-type mice received laronidase, genistein, or both. Glycosaminoglycan (GAG) storage in visceral organs and the brain, its excretion in urine, and the serum level of the heparin cofactor II-thrombin (HCII-T) complex, along with behavior, were assessed. The combination therapy resulted in reduced GAG storage in the heart and liver, whereas genistein alone reduced the brain GAG storage. Laronidase and combination therapy decreased liver and spleen weights and significantly reduced GAG excretion in the urine. However, this therapy negated some laronidase benefits in the HCII-T levels. Importantly, the combination therapy improved the behavior of female mice with MPS I. These findings offer valuable insights for future research to optimize MPS I treatments.

Retinitis pigmentosa and nanophthalmos in a patient with attenuated Hunter's syndrome.

To describe a case of retinitis pigmentosa and nanophthalmos in a patient with attenuated Hunter's syndrome. Fundus photography, total field electroretinogram, ultrasound, computerized visual field examination, biochemical examination and genetic testing were obtained. The fundus exam showed diffuse arteriolar attenuation, optic disc with regular contours, and pigment agglomerates like "bone spicules" in the middle periphery. Ultrasound examination revealed scleral thickening and short axial diameter in both eyes. The total field electroretinogram exam showed a subnormal result with greater impairment of the scotopic phase of the exam. Computerized visual field examination demonstrated a diffuse reduction in retinal sensitivity in the periphery. Biochemical examination showed increased urine glycosaminoglycan excretion and iduronate-2-sulphatase activity (IDS) deficiency in leukocytes, confirming the type II mucopolysaccharidosis. Molecular analysis revealed a novel missense mutation (p.A77D) in the IDS gene. The case report is about a patient presented an attenuated form of the syndrome, with no cognitive impairment. Ophthalmologic follow-up is still an important part of multidisciplinary treatment for Hunter's syndrome.

Joint Stiffness Leads to the Diagnosis of a Rare Disease

Introduction: A 6-year-old boy was referred to our hospital because of the stiffness of both knees, which had commenced two years ago and gradually progressed to both hips, ankles, elbows, fingers, and toes. He occasionally had arthralgia with no complaint of joint swelling. He had a long face, a prominent forehead and chin, and a short neck. There was a limitation in the range of motion in all appendicular joints with stiffness and deformity. Case Presentation: Skeletal survey images revealed central beaking and a bullet shape appearance in the cervical and lumbar vertebra, tapering of iliac wings, deformity of the femoral head, and short sacral length. A +3 glycosaminoglycan (GAG) excretion was detected in the urine test, but genetic analysis revealed Mucolipidosis type III. Conclusions: The diagnosis of metabolic diseases should be considered whenever there is joint stiffness without any evidence of inflammation. Mucopolysaccharidoses and Mucolipidoses are progressive storage disorders with many clinical and radiological characteristics.

A rare lysosomal storage disorder: Feline mucopolysaccharidosis VII

AbstractA 9‐week‐old, male domestic shorthair presented with a 2‐week history of progressive hindlimb weakness and reduction in normal play behaviour. At 17 weeks of age, the patient exhibited progressive hindlimb paresis and ataxia and had developed facial dysmorphia and bilateral corneal clouding, prompting investigation into a mucopolysaccharidosis disorder. Peripheral blood cytology, increased urinary glycosaminoglycan excretion and radiographic findings (generalised epiphyseal dysplasia, coxofemoral luxation and vertebral fusion) suggested mucopolysaccharidosis. Definitive diagnosis was obtained through serum enzymatic testing, which yielded a complete deficiency in β‐glucuronidase and increased compensatory activity in α‐L‐iduronidase and B‐arylsulfatase. This pattern was consistent with a diagnosis of feline mucopolysaccharidosis VII, and palliative therapy was initially implemented. The patient ultimately died at 21 months of age.

Аssociation between incidence of caries of temporary teeth and pathology of the musculoskeletal system in preschool children, considering biochemical markers of connective tissue metabolism

The aim is study biochemical markers of connective tissue metabolism in children with musculoskeletal disorders and their association with dental caries of temporary teeth. There were examined 232 children at the age of 5 (202 children with musculoskeletal disorders and 30 conditionally healthy children without somatic pathology). Among children with musculoskeletal disorders 68 (33.66%) had flat feet, 59 (29.21%) – postural impairment and 75 (37.13%) – combined pathology of the musculoskeletal sestem. For further research, the children were divided into three groups, 30 people in each. Group І included children with pathology of the musculoskeletal system, dental caries, without oxyproline in urine; group ІІ – with pathology of the musculoskeletal system, dental caries and oxyproline in urine; group ІІІ – with dental caries and without oxyproline in urine. Urinary excretion of glycosaminoglycans using a nephelometric test with cetylpyridinium chloride was determined. The concentration of creatinine in urine was measured in units of weight in the formation of a chromogenic complex of a solution of picric acid with creatinine in an alkaline medium. Dental status was assessed in terms of caries prevalence, deft index and severity of dental caries. The prevalence of caries of temporary teeth in 5-years old children with musculoskeletal disorders was on average 90.6±2.05%, deft index ─ 6.62±0.20, being significantly higher than in children without somatic pathology (respectively 70.83±4.45% and 5.15±0.34, р<0.001). Oxyprolin was detected only in the urine of children with combined pathology of musculoskeletal system (on average 3.53±0.11 units). The excretion rates of glycosaminoglycans in children with pathology of the musculoskeletal system, dental caries and oxyproline in urine (gr.ІІ) were two times higher than the reference range (415.37±15,09 CPCh units / 1 g creatinine, р<0.001). In the absence of oxyproline in urine, both in somatically healthy children (gr. ІІІ) and in children with pathology of the musculoskeletal system (gr. І), the levels of excretion of glycosoaminoglycans were within the reference range (respectively 198.83±10.71 and 203.87±12.52 CPCh units / 1 g creatinine. The levels of daily excretion of creatinine were within the normal range in children of gr. ІІІ (1.17±0.13 g/day; in children of gr. І they were 2.85 times lower (0.41±0.05 g/day, p<0.001); in children of gr. ІІ – 6.5 times lower (0.18±0.02 g/day р<0.001). In children of gr. ІІ, a negative correlation was found between the levels of creatinine and oxyproline (τ= -0.68, p<0.05). The absence of oxyproline in the urine of children of gr. І and ІІІ indicates the absence of collagen decay in their bodies. In children with pathology of the musculoskeletal system against the background of undifferentiated connective tissue dysplasia (gr. ІІ), a strong, positive correlation was found between the deft index and levels of urinary excretion of oxyproline (τ= +0.77, p<0.05) and glycosaminoglycans (τ= +0.90, p<0.05), which indicates that the development of dental caries depends on the severity of the pathology of the musculoskeletal system.

Hepatomegaly syndrome in mucopolysaccharidosis and type in children of ukraine: features of clinical characteristics

Summary. The article is devoted to a topical issue in pediatrics - hepatomegaly syndrome in a rare metabolic pathology - mucopolysaccharidosis type I. Goal. To study the possibilities of early diagnosis of hepatomegaly syndrome as one of the most important clinical manifestations of type I MPS and to determine early diagnostic criteria for the course of the disease. Materials and methods. Retrospective clinical study of 24 children with type I mucopolysaccharidosis who were diagnosed in Ukraine for 17 years (from 2004 to 2021). Patients underwent a complete comprehensive examination of the manifestations of the disease and determined the activity of the enzyme a-L-iduronidase in the lysosomes of leukocytes using a biochemical method, the study of the level of excretion of glycosaminoglycans in the urine. Results. Clinical symptoms and examination results in 24 children diagnosed with type I mucopolysaccharidosis in Ukraine were analyzed. The conducted comprehensive examination revealed a significant frequency of hepatomegaly syndrome among patients of this study. Its combination with other clinical symptoms. Hepatomegaly syndrome in children was found in 79 %, which was combined with other clinical symptoms of mucopolysaccharidosis, but never was the cause of the initial examination of the patient and the key symptom. Hepatomegaly was most often observed in the symptom complex with contractures and stiffness of the joints, curvature of the spine, lesions of the valvular apparatus of the heart and umbilical hernias. In contrast to the previously described studies, only 20% of hepatomegaly syndrome was combined with splenomegaly. Biochemical studies did not reveal liver dysfunction. There was also a direct relationship between the degree of hepatomegaly and the severity of glycosaminoglycan secretion. Conclusions. Liver enlargement syndrome in many childhood diseases, including orphan metabolic diseases, remains an underestimated diagnostic criterion. Detection of hepatomegaly syndrome can direct the diagnostic search of the practitioner to exclude hereditary metabolic disorders, including mucopolysaccharidosis. Early detection of such a complex and severe disease in children as mucopolysaccharidosis type I will allow to start treatment in time and prevent disability and early death.

Early Diagnosis and Results of Enzyme Replacement Therapy in the Patient with Mucopolysaccharidosis Type VI: Clinical Case

Background. Mucopolysaccharidosis type VI (MPS VI, Maroteaux–Lamy syndrome) is rare autosomal-recessive multisystem disease, one of the group of lysosomal storage diseases. The MPS VI pathogenesis is determined by arylsulfatase B enzyme deficiency caused by mutations in the ARSB gene. There are only few published clinical examples of this disease that covers the results of early enzyme replacement therapy (ERT) onset.Clinical case description. The child was suspected to have lysosomal storage disease at the age of 1.5 months, it was based on microscopic analysis of blood smears: Alder abnormality was revealed (granulations and red-violet inclusions in neutrophils, monocytes, lymphocytes cytoplasm). The diagnosis was confirmed at the age of 3 months: increased glycosaminoglycans (GAGs) concentration in the urine, arylsulfatase B activity decrease in dried blood spots, and pathogenic variant c.943C>T (p. R315X) in the ARSB gene in homozygous state were revealed. ERT with galsulfase was started at the age of 7 months. There was decrease in excretion of GAGs in urine to normal level after 9 and 15 months of therapy. Normal growth and body proportions for the patient’s age were determined 3 years after continuous ERT. However, there was progression of multiple dysostosis and joint stiffness, as well as eyes lesion.Conclusion. Early ERT onset cannot completely stop MPS VI progression but it allows to reduce the severity of several symptoms and improves patient’s quality of life.

Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency

BackgroundMucopolysaccharidoses (MPS) are monogenic metabolic disorders that significantly affect the skeleton. Eleven enzyme defects in the lysosomal degradation of glycosaminoglycans (GAGs) have been assigned to the known MPS subtypes (I–IX)....

Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome

BackgroundAllogeneic hematopoietic stem-cell transplantation is the standard of care for Hurler syndrome (mucopolysaccharidosis type I, Hurler variant [MPSIH]). However, this treatment is only partially curative and is associated with complications.MethodsWe are conducting an ongoing study involving eight children with MPSIH. At enrollment, the children lacked a suitable allogeneic donor and had a Developmental Quotient or Intelligence Quotient score above 70 (i.e., none had moderate or severe cognitive impairment). The children received autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with an α-L-iduronidase (IDUA)–encoding lentiviral vector after myeloablative conditioning. Safety and correction of blood IDUA activity up to supraphysiologic levels were the primary end points. Clearance of lysosomal storage material as well as skeletal and neurophysiological development were assessed as secondary and exploratory end points. The planned duration of the study is 5 years.ResultsWe now report interim results. The children’s mean (±SD) age at the time of HSPC gene therapy was 1.9±0.5 years. At a median follow-up of 2.10 years, the procedure had a safety profile similar to that known for autologous hematopoietic stem-cell transplantation. All the patients showed prompt and sustained engraftment of gene-corrected cells and had supraphysiologic blood IDUA activity within a month, which was maintained up to the latest follow-up. Urinary glycosaminoglycan (GAG) excretion decreased steeply, reaching normal levels at 12 months in four of five patients who could be evaluated. Previously undetectable levels of IDUA activity in the cerebrospinal fluid became detectable after gene therapy and were associated with local clearance of GAGs. Patients showed stable cognitive performance, stable motor skills corresponding to continued motor development, improved or stable findings on magnetic resonance imaging of the brain and spine, reduced joint stiffness, and normal growth in line with World Health Organization growth charts.ConclusionsThe delivery of HSPC gene therapy in patients with MPSIH resulted in extensive metabolic correction in peripheral tissues and the central nervous system. (Funded by Fondazione Telethon and others; ClinicalTrials.gov number, NCT03488394; EudraCT number, 2017-002430-23.)

Open-label phase 1/2 study of vestronidase alfa for mucopolysaccharidosis VII

Vestronidase alfa is an enzyme replacement therapy for mucopolysaccharidosis VII (MPS VII). In this open-label, phase 1/2 study, three subjects with MPS VII received intravenous vestronidase alfa administered every other week (QOW) for 14 weeks (2 mg/kg), followed by 24-week forced-dose titration (1, 4, and 2 mg/kg QOW; 8 weeks each), 36-week continuation (2 mg/kg), and long-term extension (4 mg/kg). Vestronidase alfa was well tolerated and led to dose-responsive, sustained reductions in urinary glycosaminoglycan excretion.

Порушення метаболізму протеогліканів і колагену у нирках за цукрового діабету: клініко-патогенетичні механізми та лабораторні маркери

The article considers the issue of disorders of connective tissue metabolism in diabetes mellitus. Glycosylation of structural components of connective tissue and glucose toxicity have been found to determine the pathogenesis of late complications of diabetes mellitus. The most common concept of the pathogenesis of diabetes is metabolic, according to which all variants of diabetes mellitus, including blood vessels, their basement membrane, are associated with primary disorders of lipid, glycoprotein, protein and carbohydrate metabolism due to complete or partial insufficiency. It has been found that the formation of interstitial fibrosis in the kidneys of patients with diabetes begins in the preclinical stages of diabetic nephropathy. The leading cause of interstitial fibrogenesis is hyperglycemia; exacerbate proteinuria fibrosis, activation of the renin-angiotensin system, chronic inflammation and the formation of myofibroblasts in the interstitium. According to the results of the study of aspects of early diagnosis of kidney damage in type 1 diabetes mellitus, it was found that the development of diabetic nephrosclerosis is characterized by qualitative and quantitative changes in collagen composition in the glomeruli and interstitium, rebalance between collagen synthesis and breakdown, glycosaminoglycans, increased synthesis of fibrogenic growth factors and oxidative modification of proteins. The formation of diabetic nephropathy in patients with diabetes is also characterized by the accumulation of collagen types IV and VI, the appearance of interstitial collagen types III and I in the glomeruli, as well as the accumulation of collagen of all types in tubulointerstitium. Quantitative and qualitative characteristics of sulfated glycosaminoglycans of urine in human diabetes indicated different degrees of development of diabetic nephropathy. Glycosaminoglycans hyperexcretion was observed in patients with diabetes mellitus without proteinuria. In patients with microalbuminuria, glycosaminoglycans hyperexcretion was even more pronounced. It was also found that in diabetes, the total excretion of sulfated glycosaminoglycans in the urine doubles. Conclusion. Thus, in diabetes mellitus, an important pathogenetic link in the violation of the morpho-functional state of the kidneys is the degradation of collagen and proteoglycans of the basement membranes of the glomeruli, as well as interstitial fibrosis. This is reflected in changes in urinary glycosaminoglycans excretion, in particular heparansulfate and chondroitin sulfate, which may serve as a marker of proteoglycan metabolism disorders in the kidneys. Patients with diabetes also have an increase in the urine of hydroxyproline, which indicates an increase in the intensity of collagen metabolism in patients

Clinical significance of urinary glycosaminoglycan excretion in inflammatory bowel disease patients.

The research focused on the diagnostic usefulness of urinary glycosaminoglycans excretion as new markers related to the ECM remodeling in the intestine. Their possible suitability in the diagnosis, differential diagnosis and treatment monitoring in the course of the two most common forms of inflammatory bowel diseases (IBD), i.e. ulcerative colitis (UC) and Crohn's disease (CD) were assessed in this study. Urinary excretion of total sulfated glycosaminoglycans (TGAG) and fraction of chondroitin sulfates (CS) were analysed in 47 patiens with IBD, including 31 patients with UC and 16 patients with CD at baseline and after one year of therapy. Sulfated GAGs excreted in urine were quantitated using standardized dye-binding method. A several-fold increase in urinary excretion of total GAG and CS fraction in both UC and CD patients compared to healthy subjects indicates the potential usefulness of quantitative urinary GAG analysis in the diagnosis of IBD. No differences were found in the amount of GAG excreted in the urine in patients with UC and CD. Adalimumab resulted in a decrease in the activity of the inflammatory process and the activity of the disease expressed in the Mayo scale, which was accompanied by an increase in the amount of CS excreted in the urine of UC patients. Moreover, significant correlation was found between Mayo scale and urinary total GAG and CS excretion in UC patients. The quantitative assessment of total glycosaminoglycans and chondroitin sulfates fraction in urine may be a marker helpful in the early diagnosis of IBD.

MODERN CONCEPTS IN REGULATORY MECHANISMS OF INDUCTION OF LABOR

In modern conditions of the development of obstetric science, one of the leading factors ensuring the reduction of maternal and perinatal morbidity and mortality is the solution of the problem of labor disorders by improving knowledge of the biological mechanisms of the birth process. The urgency of the problem of violations of labor is due to the frequency of distribution in the population, reaching 30%. The outcome of childbirth for the mother and fetus depends on the biological readiness of the woman’s body for childbirth. There is no doubt that the study of the mechanisms of preparation for physiological childbirth at the cellular-molecular level can provide important progress in this direction.The aim of research is to determine new mechanisms for regulating the preparation of a pregnant woman’s body for childbirth by studying the influence of hormonal and immunological factors on the maturation of the cervix.Materials and research methods. To achieve the goal, 80 primary pregnant women were examined at 38- 40 weeks of gestation, which, depending on the degree of ripe of the cervix upon admission to the hospital, were divided into the main and control groups. All pregnant women underwent anamnesis collection, a complete clinical and laboratory examination, regulated by the Order of the Ministry of Health of Ukraine No. 417 of 15.07.2011. The woman’s body readiness for childbirth was determined taking into account the assessment of the degree of “ripe” of the cervix using the scale proposed by E.H. Bishop. Immunological studies: the concentration of serum relaxin, the content of matrix metalloproteinases (MMP-1, MMP-9) in the peripheral blood serum were determined. The daily urinary excretion of information biochemical parameters, in particular, hydroxyproline and glycosaminoglycans, markers of collagen catabolism, was studied. The results were statistically processed on a personal computer using the STATISTICA-6 program.Research results and their discussion. The results of the study make it possible to identify the most significant factors characterizing the processes of preparing the body for childbirth, which include the “labor hormone” relaxin, as well as the immune mechanisms of regulation of the “ripe” of the cervix before childbirth. The data obtained allow us to regard relaxin as a positive regulator of the production of the main types of MMPs that affect type I collagen. Such a positive regulation of MMP-1 and MMP-9 due to increased levels of relaxin may be of unique importance for the development of remodeling processes of the connective tissue of the cervix, as evidenced by the change in the content of markers of metabolic processes in the cervix.Conclusions: Relaxin is an important factor in preparing the body of a pregnant woman for childbirth, due to the regulation of the production of proteolytic enzymes, matrix metalloproteinases, at the end of the gestational process. The investigated factors can be regarded as new markers of the onset of timely physiological labor, as well as the effectiveness of complex therapeutic measures for the induction of labor.

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

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.

Retrospective chart review of urinary glycosaminoglycan excretion and long-term clinical outcomes of enzyme replacement therapy in patients with mucopolysaccharidoses

BackgroundMucopolysaccharidoses (MPS) are a group of rare, inherited metabolic diseases that result from a deficiency in one of several lysosomal enzymes essential for stepwise glycosaminoglycan (GAG) degradation, leading to GAG accumulation and widespread cellular pathology and clinical disease. Although disease presentation is heterogeneous, the clinical hallmarks are largely comparable across several MPS subtypes. Extensive data have shown that the level of urinary GAG (uGAG) excretion above normal is strongly correlated with disease severity and clinical outcomes in MPS diseases. Thus, change in uGAG excretion may have significant value as a potential primary endpoint in clinical trials of MPS diseases that are too rare to study using traditional clinical endpoints. MethodsA retrospective medical chart review was undertaken of patients with MPS I, II, and VI who had been treated long term with enzyme replacement therapy (ERT). The relationship between uGAG reduction and clinical outcomes relevant to the major clinical manifestations of these MPS diseases was evaluated. A multi-domain responder index (MDRI) score was calculated, measuring the following 4 domains: 6-min walk test, pulmonary function, growth rate, and Clinician Global Impression of Change. For each domain, a minimal important difference (MID) was defined based on published information of these outcome measures in MPS and other diseases. ResultsOf the 50 patients evaluated, 18 (36%) had MPS I, 23 (46%) had MPS II, and 9 (18%) had MPS VI. Forty-two were clinical practice patients and 8 had participated in clinical trials. Across all MPS subtypes, the mean (± SD) uGAG level at baseline was 66.0 ± 51.5 mg/mmol creatinine (n = 48) and there was a mean reduction of 54.6% following ERT. Analysis of the MDRI score based on the MID defined for each domain showed a greater magnitude of improvement in patients with increased uGAG reduction when compared with those patients with lower uGAG reduction for all assessed uGAG thresholds, and a trend toward a higher likelihood of positive mean MDRI score in patients with a uGAG reduction ≥40%. ConclusionsIn this retrospective study, uGAG reduction was associated with long-term clinical outcomes as assessed by a number of approaches, supporting the use of uGAG reduction as a biomarker primary endpoint.

Odiparcil, a potential glycosaminoglycans clearance therapy in mucopolysaccharidosis VI-Evidence from in vitro and in vivo models.

Mucopolysaccharidoses are a class of lysosomal storage diseases, characterized by enzymatic deficiency in the degradation of specific glycosaminoglycans (GAG). Pathological accumulation of excess GAG leads to multiple clinical symptoms with systemic character, most severely affecting bones, muscles and connective tissues. Current therapies include periodic intravenous infusion of supplementary recombinant enzyme (Enzyme Replacement Therapy–ERT) or bone marrow transplantation. However, ERT has limited efficacy due to poor penetration in some organs and tissues. Here, we investigated the potential of the β-D-xyloside derivative odiparcil as an oral GAG clearance therapy for Maroteaux–Lamy syndrome (Mucopolysaccharidosis type VI, MPS VI). In vitro, in bovine aortic endothelial cells, odiparcil stimulated the secretion of sulphated GAG into culture media, mainly of chondroitin sulphate (CS) /dermatan sulphate (DS) type. Efficacy of odiparcil in reducing intracellular GAG content was investigated in skin fibroblasts from MPS VI patients where odiparcil was shown to reduce efficiently the accumulation of intracellular CS with an EC50 in the range of 1 μM. In vivo, in wild type rats, after oral administrations, odiparcil was well distributed, achieving μM concentrations in MPS VI disease-relevant tissues and organs (bone, cartilage, heart and cornea). In MPS VI Arylsulphatase B deficient mice (Arsb-), after chronic oral administration, odiparcil consistently stimulated the urinary excretion of sulphated GAG throughout the treatment period and significantly reduced tissue GAG accumulation in liver and kidney. Furthermore, odiparcil diminished the pathological cartilage thickening observed in trachea and femoral growth plates of MPS VI mice. The therapeutic efficacy of odiparcil was similar in models of early (treatment starting in juvenile, 4 weeks old mice) or established disease (treatment starting in adult, 3 months old mice). Our data demonstrate that odiparcil effectively diverts the synthesis of cellular glycosaminoglycans into secreted soluble species and this effect can be used for reducing cellular and tissue GAG accumulation in MPS VI models. Therefore, our data reveal the potential of odiparcil as an oral GAG clearance therapy for MPS VI patients.

High Levels of Glycosaminoglycans in the Urines of Children with Attention-Deficit/Hyperactivity Disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral/neurodevelopmental disorder. Some early studies indicated that increased intake of added sugars might have a role in ADHD. In the present study, we tested this possibility by evaluating the urinary excretion of oligosaccharides and glycosaminoglycans (GAGs) in ADHD and control subjects. Forty ADHD subjects matched with 34 controls were enrolled in the study. The subjects underwent a standardized dietary regimen. The urine levels of oligosaccharides and GAGs were quantified biochemically, and their covariance and association were evaluated statistically. Fructose (21/40, 52.5%), maltose (26/40, 65%), galactose (30/40, 75%), and lactose (38/40, 95%) excretions were frequently found in the urine of ADHD subjects (p < 0.05), an excretion which does not occur normally. Furthermore, these subjects showed a pathologic tGAG (glycosaminoglycan) excretion (40/40, 100%). The present study supportsthe thesis that carbohydrate metabolism differs in ADHD subjects compared with control subjects.

Impact of extended post-HSCT enzyme replacement therapy (ERT) on linear growth in mucopolysaccharidosis type IH (MPS IH)

Maroteaux–Lamy syndrome (mucopolysaccharidosis type VI, MPS VI) is a rare progressive metabolic disorder characterized by coarse facial features, hepatosplenomegaly, restrictive pulmonary function, cardiac abnormalities and stiff joints. The disease is caused by a deficiency of the lysosomal enzyme N-acetyl galactosamine 4-sulfatase which leads to glycosaminoglycan (GAG) storage in various tissues. It presents as a clinical spectrum with varying disease progressions and severities. While the phases I/II/III studies proved the effectiveness of enzyme-replacement therapy (ERT) with recombinant human arylsulfatase B, long-term data are still scarce.Over treatment periods ranging from 1.3 to 5.4 years, this prospective open-label follow-up study in 11 Dutch mucopolysaccharidosis type VI patients (age 2–18 years) showed that ERT had significant positive effects on cardiac-wall diameters (IVSd and LVMI), left and right shoulder flexions (p < 0.001), liver size and spleen size (p < 0.001), urinary GAG excretion (p < 0.001), and the scales of quality of life (motor functioning and body functioning). ERT did not affect cardiac valve regurgitation or hearing function; HRQoL decreased slightly in two domains (‘anxiety’ and ‘negative emotions’), and patients with the rapid and slow progressive forms of the disease differed with regard to baseline GAG excretion and GAG decrease during treatment.In conclusion, ERT had an effect on several clinical parameters. This effect was established in an open cohort of young mucopolysaccharidosis type VI patients.

Urinary sulphated glycosaminoglycans excretion in obese patients with type 2 diabetes mellitus treated with metformin

Objective The pattern of urinary excretion of total sulphated glycosaminoglycans (GAGs) and their particular types: chondroitin sulphate/dermatan sulphate (CS/DS) and heparan sulphate (HS) was analysed in obese patients with type 2 diabetes mellitus (T2DM) treated with metformin in monotherapy for the period of six months. Methods The urinary sulphated glycosaminoglycans were quantitated using standardised dye (1.9-dimethylmethylene blue)-binding method and normalised to creatinine level. Results Urinary total GAGs, CS/DS and HS levels were significantly higher in untreated diabetic patients in comparison to healthy subjects. Moreover, it was observed that urinary total GAGs, CS/DS and HS levels in diabetic patients after six-month metformin therapy were significantly decreased versus pre-treatment situation. Conclusions The obtained results suggest that the six-month treatment with metformin in obese patients with T2DM has a regulating influence on the systemic changes in proteoglycans/glycosaminoglycans, resulting in a decrease in the urinary excretion of total GAGs, CS/DS and HS.