MPS Disorders Research Articles

Longitudinal studies of brain structure and function in MPS disorders: a study of the lysosomal disease network

Longitudinal studies of brain structure and function in MPS disorders: a study of the lysosomal disease network

Transplantation of human umbilical mesenchymal stem cells cures the corneal defects of mucopolysaccharidosis VII mice

Mucopolysaccharidosis (MPS) are a family of related disorders caused by a mutation in one of the lysosomal exoglycosidases which leads to the accumulation of glycosaminoglycans (GAGs). MPS VII, caused by a mutation in β-glucuronidase, manifests hepatomegaly, skeletal dysplasia, short stature, corneal clouding, and developmental delay. Current treatment regimens for MPS are not effective for treating corneal clouding and impaired mental development. We hypothesized that human umbilical mesenchymal stem cells (UMSCs) transplanted into the corneal stroma could participate in the catabolism of GAGs providing a means of cell therapy for MPS. For such treatment, human UMSCs were intrastromally transplanted into corneas of MPS VII mice. UMSC transplantation restored the dendritic and hexagonal morphology of host keratocytes and endothelial cells, respectively, and in vivo confocal microscopy (HRT-II) revealed reduced corneal haze. Immunohistochemistry using antibodies against heparan sulfate and chondroitin sulfate chains as well as lysosomal-associated membrane protein 2 revealed a decrease in GAG content and both lysosomal number and size in the treated corneas. Labeling UMSC intracellular compartments prior to transplantation revealed the distribution of UMSC vesicles throughout the corneal stroma and endothelium. An in vitro coculture assay between skin fibroblasts isolated from MPS VII mice and UMSC demonstrated that neutral vesicles released by the UMSC are taken up by the fibroblasts and proceed to fuse with the acidic lysosomes. Therefore, transplanted UMSCs participate both in extracellular GAG turnover and enable host keratocytes to catabolize accumulated GAG products, suggesting that UMSC could be a novel alternative for treating corneal defects associated with MPS and other congenital metabolic disorders.

Longitudinal studies of brain structure and function in MPS disorders: A study of the Lysosomal Disease Network

Increased susceptibility for developing alcohol dependence (AD) might be related to structural differences in brain circuits that influence the salience of rewards and/or modify the efficiency of information processing. The role of the orbitofrontal cortex (OFC) in regulating emotional processing is increasingly being recognized along with its association with impulsive behavior.Magnetic resonance imaging was used to measure the OFC in 107 high- and low-risk offspring (mean age 17.6 ± 4.69 years) from either multiplex AD families or control families. Region of interest measures including segmented values were obtained by reliable raters using BRAINS2 software. Statistical analyses were adjusted for intracranial volume, age, socioeconomic status (SES), IQ, and handedness. The Multidimensional Personality Questionnaire (MPQ) was administered to determine scale scores for Control. Genotyping was performed for the serotonin transporter (5-HTT) gene and the brain-derived neurotrophic factor (BDNF) gene.High-risk offspring from multiplex for AD families showed decreased right/left OFC volumes in comparison with control subjects. Smaller volume in the right hemisphere was significantly associated with variation in the 5-HTT and BDNF genes. White matter (WM) ratios showed a positive correlation with MPQ Control scale scores, indicating that reduced OFC WM is related to greater impulsivity.Offspring from multiplex families for AD manifest genetic susceptibility by exhibiting disruption in the laterality of the OFC volume that is related to greater impulsivity (lower Control scale scores). This disruption in OFC laterality is related to variation in genes associated with neuronal growth.

Rhodamine B and 2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-d-glucopyranose (F-GlcNAc) inhibit chondroitin/dermatan and keratan sulphate synthesis by different mechanisms in bovine chondrocytes

MPS disorders result from a deficiency or absence of glycosaminoglycan (GAG) degrading enzymes leading to an imbalance between the synthesis and degradation of GAGs and their subsequent accumulation in a range of cells. The inhibition of GAG synthesis using small chemical inhibitors has been proposed as a novel therapeutic approach to treatment. Several inhibitors have been shown to decrease heparan sulphate GAG synthesis and in this study we evaluated a novel fluorinated analog of N-acetylglucosamine (2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-d-glucopyranose (F-GlcNAc)) and rhodamine B for their ability to also inhibit the synthesis of chondroitin/dermatan and keratan sulphate GAGs present in bovine cartilage. Both inhibitors decreased GAG synthesis in chondrocyte monolayer culture and in cartilage chip explant culture in a dose dependent manner. Both inhibitors decreased the size of newly synthesised proteoglycans and in the case of F-GlcNAc this was due to a decrease in newly synthesised GAG chain size. Rhodamine B, however, did not affect GAG chain size, while both inhibitors decreased the amount of chondroitin/dermatan and keratan sulphate GAG equally. The expression of genes responsible for the initiation and elongation of chondroitin/dermatan sulphate and keratan sulphate GAGs were downregulated in the presence of rhodamine B but not in the presence of F-GlcNAc. Thus the 2 inhibitors appear to have differing effects on GAG synthesis, with F-GlcNAc inhibiting the epimerisation of UDP-GlcNAc to UDP-GalNAc thus decreasing the availability of monosaccharides for addition to the growing GAG chain, whereas rhodamine B is more likely to reduce the number of GAG chains. Together with previous data these 2 inhibitors are capable of non-specific inhibition of GAG synthesis, reducing the production of chondroitin/dermatan sulphate, keratan sulphate and heparan sulphate GAGs. As such they would be applicable to therapy in a range of MPS disorders.

Longitudinal Studies of Brain Structure and Function in MPS disorders: A Study of the Lysosomal Disease Network

Longitudinal Studies of Brain Structure and Function in MPS disorders: A Study of the Lysosomal Disease Network

The Mild Side of MPS Disorders: Are These Cases Being Missed by Urine Screening and Other Common Diagnostic Methods?

The Mild Side of MPS Disorders: Are These Cases Being Missed by Urine Screening and Other Common Diagnostic Methods?

Intellectual and neurological functioning in Morquio syndrome (MPS IVa)

Mucopolysaccharidosis type IVa (MPS IVa, Morquio syndrome OMIM #253000) is a lysosomal storage disease caused by deficiency in N-acetylgalactosamine-6-sulfatase (GALNS, EC 3.1.6.4; encoded by GALNS gene at 16q24.3). Unlike other MPS disorders involving excessive heparan and dermatan sulfate, Morquio syndrome has not been associated with neurological involvement nor with intellectual impairment as this disorder of keratan sulfate has been described as a purely visceral and skeletal disorder. Neurocognitive assessment was undertaken of MPS IVa patients with age appropriate intellectual tests as well as a Child Behaviour Checklist as part of clinical follow up. Available neuroimaging studies (MRI and MR spectroscopy) were reviewed. Whilst more than half of the overall IQ scores fell in the average range, scores for 3/8 children fell below average. A number of behavioural problems were highlighted, including anxiety/depression, attention and somatic complaints. Subtle neuroimaging abnormalities were demonstrated in over half of the children. These findings present a challenge to existing assumptions about the nature of Morquio A syndrome. A hypothesis regarding the potential role of calcium signalling is explored.

Recent Advances in Treatment Approaches of Mucopolysaccharidosis VI

Mucopolysaccharidosis VI is caused by accumulation of the glycosaminoglycan dermatan sulfate in all tissues due to decreased activity of the enzyme arylsulfatase B. Patients exhibit multisystemic signs and symptoms in a chronic and progressive manner, especially with changes in the skeleton, cardiopulmonary system, cornea, skin, liver, spleen and meninges. Patients usually have normal intelligence. In the past, treatment of mucopolysaccharidoses was limited to palliative medical care. The outcome for affected patients improved with the introduction of new technologies as hematopoietic stem cell transplantation, relegated to specific situations after enzyme replacement therapy (ERT) became available. The specific ERT for MPS VI, galsulfase (Naglazyme®, Biomarin Pharmaceutical) was approved in 2005 by FDA and in 2006 by EMEA, and three clinical studies including 56 patients have evaluated the efficacy and safety. Long-term follow up data with patients treated up to 5 years showed that ERT is well tolerated and associated with sustained improvements in the patients' clinical condition. Intrathecal ERT may be considered in situations of high neurosurgical risk but still it is experimental in humans, as is intra-articular ERT. It is possible that the full impact of this therapy will only be demonstrated when patients are identified and treated soon after birth, as it was shown that early introduction of ERT produced immune tolerance and improved enzyme effectiveness in the cat model. New insights on the pathophysiology of MPS disorders are leading to alternative therapeutic approaches, as gene therapy, inflammatory response modulators and substrate reduction therapy.

Intrathecal Enzyme Replacement Therapy for Mucopolysaccharidosis I: Translating Success in Animal Models to Patients

Intrathecal enzyme replacement therapy has been proposed to treat central nervous system (CNS) disease due to mucopolysaccharidosis type I. Our research has shown that repeated injections of recombinant enzyme into the spinal fluid corrects enzyme deficiency and normalizes lysosomal storage in the canine model. The challenge is to translate the success in the animal where there are fewer study limitations to human patients where studies are more restricted. This review will explore what is known about the measurement of clinically-relevant outcomes of intrathecal enzyme replacement therapy for MPS I (including ongoing clinical trials), the challenges in translating therapies for the CNS in rare diseases, and new outcome measures that could aid translation of CNS therapies for MPS disorders.

Longitudinal studies of brain structure and function in MPS disorders: A study of the Lysosomal Disease network

Longitudinal studies of brain structure and function in MPS disorders: A study of the Lysosomal Disease network

Comparison of ventricular and intravenous lentiviral-mediated gene therapy for murine MPS VII

Mucopolysaccharidosis type VII (MPS VII) is caused by the deficiency of the lysosomal hydrolase β-glucuronidase. Symptoms include intellectual impairment, growth retardation, visual and hearing deficits and organ malfunction. The MPS VII mouse displays most of the symptoms variously associated with the MPS disorders, and has been widely used as a developmental paradigm for gene therapy. In this study, a lentiviral vector expressing murine β-glucuronidase was delivered to 6-week-old MPS VII affected mice, either by intravenous injection, or by ventricular infusion. Therapeutic outcomes were assessed 7 months after gene transfer. Intravenous vector delivery restored liver β-glucuronidase to normal levels. Consequently, most somatic pathology was corrected, and brain pathology was reduced. In mice that received ventricular vector most brain regions appeared biochemically and histologically normal. These animals showed significantly improved behavioural performance within the open-field test. An additional positive outcome of ventricular vector delivery was the significant reduction of lysosomal storage within the eye. The blood–brain barrier is not completely impervious to lysosomal enzymes, therefore, therapeutic enzyme can be distributed widely throughout the brain via the extensive cerebral vasculature. However, improvements in somatic gene delivery and expression are required for this to be completely successful. Ventricular vector delivery cleared lysosomal storage within the CNS making this a reasonable, albeit more challenging, therapeutic option for the MPS. The best therapeutic outcomes, with possible synergistic effects within the CNS, might be expected to occur when vector delivery to the brain is used in combination with somatic gene transfer.

126. Longitudinal studies of brain structure and function in MPS disorders: A study of the Lysosomal Disease Network

126. Longitudinal studies of brain structure and function in MPS disorders: A study of the Lysosomal Disease Network

2. Visual aid skills and socioeconomic status in children with Batten disease

2. Visual aid skills and socioeconomic status in children with Batten disease

Guidelines for the Management of Mucopolysaccharidosis Type I

Mucopolysaccharidosis type I (MPS I) is the prototype of the MPS disorders, a subgroup of lysosomal storage diseases. The incidence of MPS I in Brazil is unknown, but a retrospective population study in Australia conducted between 1980 and 1996 yielded an overall prevalence of 1 in 22 500 for all MPS types. 1 In British Columbia, cases ascertained between 1952 and 1986 determined that the frequency of MPS type I Hurler, the most severe form of the disease, was approximately 1 in 144 000 newborns, 2 a result similar to that found in The Netherlands. 3 A recent analysis of data collected by the Society for Mucopolysaccharides in the United Kingdom in patients with MPS I found a prevalence of 1.07 per 100 000 births. 4 MPS I is characterized by a deficiency in a-L-iduronidase enzyme activity, leading to buildup and urinary excretion of high levels of glycosaminoglycans (GAGs), specifically dermatan and heparan sulfates. The disease is genetically determined and shows autosomal recessive inheritance. 5,6 MPS

Progression of skeletal disease in MPS disorders

Progression of skeletal disease in MPS disorders

Mucopolysaccharidoses in the Scandinavian countries: incidence and prevalence. Acta Paediatr 2008, Malm et al.

Acta PaediatricaVolume 97, Issue 12 p. 1773-1773 Free Access Mucopolysaccharidoses in the Scandinavian countries: incidence and prevalence. Acta Paediatr 2008, Malm et al. This article corrects the following: Mucopolysaccharidoses in the Scandinavian countries: incidence and prevalence Gunilla Malm, Allan M. Lund, Jan-Eric Månsson, Arvid Heiberg, Volume 97Issue 11Acta Pædiatrica pages: 1577-1581 First Published online: August 4, 2008 First published: 06 November 2008 https://doi.org/10.1111/j.1651-2227.2008.01138_1.xCitations: 1AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat DOI: 10.1111/j.1651-2227.2008.00965.x The authors of the above mentioned article1 would like to correct the text on pp1578 under the heading Materials and Methods. The correct sentence should read: In Norway the diagnosis of MPS disorders has partly been carried out at the Department of Clinical Chemistry and Neurochemistry in Mölndal and more recently at the Section for biochemical genetics, Department of medical biochemistry, Rikshospitalet. Reference 1 Malm G, Lund AM, Månsson J-E & Heiberg A. Mucopolysaccharidoses in the Scandinavian countries: incidence and prevalence. Acta Paediatr 2008; 97: 1577– 81. Citing Literature Volume97, Issue12December 2008Pages 1773-1773 ReferencesRelatedInformation

Mucopolysaccharidoses in the Scandinavian countries: incidence and prevalence

The aim of this study was to estimate the incidence and prevalence of mucopolysaccharidoses (MPS disorders) in Scandinavia. The retrospective period used for the incidence study covered the period from 1975 to 2004 in Sweden and Denmark and from 1979 to 2004 in Norway. Prevalence was derived from the number of MPS patients alive as of December 31, 2007. The incidence of all MPS disorders was 1.75 cases in Sweden, 3.08 cases in Norway and 1.77 cases in Denmark per 100 000 newborns. The incidence of MPS I was the most common in all three countries, with 0.67, 1.85 and 0.54 cases per 100 000 newborns, respectively; for MPS II, numbers were 0.27, 0.13 and 0.27, respectively. For patients with other MPS disorders the incidence varied widely. The prevalence for all MPS disorders was 4.24, 7.06 and 6.03 per 1 000 000 inhabitants in Sweden, Norway and Denmark, respectively. From three Scandinavian countries the incidence of MPS disorders is retrospectively evaluated for 25 years in Norway and 30 years in Sweden and Denmark. Incidence and prevalence studies of lysosomal disorders are prerequisites for cost benefit calculations in the face of newly developed and expensive therapies in the future.

76 Quality-of-life and psychosocial outcomes in patients with MPS disorders who have undergone hematopoietic stem cell transplant

76 Quality-of-life and psychosocial outcomes in patients with MPS disorders who have undergone hematopoietic stem cell transplant

Improvement in behaviour after substrate deprivation therapy with rhodamine B in a mouse model of MPS IIIA

Mucopolysaccharidosis type IIIA (MPS IIIA) is a specific lysosomal storage disorder caused by an enzyme deficiency in sulphamidase, which is required for the degradation of heparan sulphate glycosaminoglycan (gag). This deficiency results in widespread gag storage and leads to severe CNS degeneration and mild somatic pathology. We have developed substrate deprivation as a therapy (SDT) for MPS disorders to reduce the initial production of gag substrate for the deficient enzyme, using the compound rhodamine B as an inhibitor of gag biosynthesis. This should restore the balance between gag level and residual enzyme activity towards normal and improve patient outcome. To determine if SDT improved CNS function, MPS IIIA mice were treated for 6 months with weekly, intravenous 1 mg/kg rhodamine B and then tested in a 4-arm water cross maze, which measures spatial learning and memory. MPS IIIA untreated mice were unable to perform to the same level as normal littermates, having increased escape latency, increased incorrect entries and decreased correct entries. Rhodamine B treatment improved MPS IIIA performance towards normal with treated mice having decreased escape latency, decreased incorrect entries and increased correct entries when compared to MPS IIIA untreated littermates. This provides the first report of SDT resulting in a beneficial effect on CNS function in an MPS disorder and SDT targeting gag synthesis may be a viable treatment option for children with MPS.

Correction of Clinical Manifestations of Canine Mucopolysaccharidosis I with Neonatal Retroviral Vector Gene Therapy

Mucopolysaccharidosis I (MPS I) (Hurler syndrome) is due to deficient alpha-L-iduronidase (IDUA) activity and is the most common of the MPS disorders. Neonatal MPS I dogs were injected intravenously (IV) with a gamma retroviral vector containing a complete long-terminal repeat (LTR) and an internal human alpha(1)-antitrypsin (hAAT) promoter upstream of the canine IDUA complementary DNA (cDNA). This resulted in stable serum IDUA activity of 366 +/- 344 units (U)/ml (28-fold normal) for up to 1.8 years, which likely derived primarily from secretion of IDUA by transduced liver cells. Retroviral vector (RV)-treated dogs had >18% of normal IDUA activity in organs and had decreased severity and/or incidence of hernias, chest deformities, joint disease, facial dysmorphia, corneal clouding, valvular heart disease, and aortic dilatation as compared with untreated MPS I dogs. The marked reduction that was observed in lysosomal storage in the brain of RV-treated dogs may have been due in part to expression from the LTR of the vector in cells in the brain. This possibility will be explored in future studies, because the potential for insertional mutagenesis has raised concerns about using vectors with an intact LTR. If proven safe, this gene therapy technique may be utilized in treating children with Hurler syndrome.