Search

Objective: To explore the long-term efficacy of allogeneic hematopoietic stem cell transplantation (alloHSCT) in patients with Mucopolysaccharidosis (MPS), which has rarely been reported in China., Methods: A 18-month-old boy and a 23-month-old girl undergoing alloHSCT for MPS VI and MPS IH Shanghai Children's Medical Center on March 30, 2006 and September 6, 2006 were selected as the study subjects. A busulfan-based myeloablative regimen was used as the conditioning regimen. Peripheral stem cells were respectively collected from a human leucocyte antigen (HLA) matched sibling carrier donor and a HLA 9/10 matched unrelated donor. Both patients were followed up for more than 15 years. The functions of internal organs before and after the transplantation were compared, and child 1 was also compared with his untreated brother and healthy brother., Results: Both children have achieved full donor chimerism after the transplantation, and their enzymatic activities have remained stable. The enzymatic activity of the child 1 was slightly lower than normal but similar to that of his carrier donor, whilst that of the child 2 was normal. Both children have attended schools with good academic performance. Compared with his untreated brother, the respiratory function and hearing of child 1 have significantly improved. However, his orthopedic and cardiac disorders have still remained and required medical intervention. For child 2, her obstructive pulmonary disease was resolved and cognitive development was well preserved after the HSCT. Her heart disease has become stabilized and even improved with time, though her corneal clouding and skeletal malformation still required surgery., Conclusion: MPS patients can sustain long-term and stable enzymatic activities after successful alloHSCT. Compared with untreated patients, their health can be significantly improved, along with considerably prolonged survival, though the long-term efficacy of HSCT for different organs may vary to a certain extent.

Although mucopolysaccharidoses (MPS) are caused by mutations in genes coding for enzymes responsible for degradation of glycosaminoglycans, storage of these compounds is crucial but is not the only pathomechanism of these severe, inherited metabolic diseases. Among various factors and processes influencing the course of MPS, oxidative stress appears to be a major one. Oxidative imbalance, occurring in MPS and resulting in increased levels of reactive oxidative species, causes damage of various biomolecules, leading to worsening of symptoms, especially in the central nervous system (but not restricted to this system). A few therapeutic options are available for some types of MPS, including enzyme replacement therapy and hematopoietic stem cell transplantation, however, none of them are fully effective in reducing all symptoms. A possibility that molecules with antioxidative activities might be useful accompanying drugs, administered together with other therapies, is discussed in light of the potential efficacy of MPS treatment.

The aim of this review is to summarize the evidence on efficacy, effectiveness and safety of intravenous enzyme replacement therapy (ERT) available for mucopolysaccharidoses (MPSs) I, II, IVA, VI and VII, gained in phase III clinical trials and in observational post-approval studies. Post-marketing data are sometimes conflicting or controversial, possibly depending on disease severity, differently involved organs, age at starting treatment, and development of anti-drug antibodies (ADAs). There is general agreement that ERT is effective in reducing urinary glycosaminoglycans and liver and spleen volume, while heart and joints outcomes are variable in different studies. Effectiveness on cardiac valves, trachea and bronchi, hearing and eyes is definitely poor, probably due to limited penetration in the specific tissues. ERT does not cross the blood-brain barrier, with the consequence that the central nervous system is not cured by intravenously injected ERT. All patients develop ADAs but their role in ERT tolerance and effectiveness has not been well defined yet. Lack of reliable biomarkers contributes to the uncertainties about effectiveness. The data obtained from affected siblings strongly indicates the need of neonatal screening for treatable MPSs. Currently, other treatments are under evaluation and will surely help improve the prognosis of MPS patients.

Mucopolysaccharidosis (MPS) consists of a group of 11 enzymatic defects which result in accumulation of undegraded glycosaminoglycans (GAG) in lysosomes. MPS is a severe metabolic disease for which only bone marrow/hematopoietic stem cell transplantation and enzyme replacement therapy are current therapeutic options. However, they are available for only a few of MPS types, and are ineffective in treatment of central nervous system. Recent studies indicated that the autophagy process can be impaired in MPS, but various contradictory conclusions have been published in this matter. Nevertheless, stimulation of autophagy has been proposed as a potential therapeutic option for MPS, and very recent results suggest that such approach might be effective in improving MPS symptoms. Still the mechanisms of autophagy changes in MPS are not clear, and efficiency of autophagy activation in clearing the storage material requires further investigation. These problems are summarized and discussed in this review.

Previously, we reported a novel disease of impaired glycosaminoglycans (GAGs) metabolism without deficiency of known lysosomal enzymes-mucopolysaccharidosis-plus syndrome (MPSPS). MPSPS, whose pathophysiology is not elucidated, is an autosomal recessive multisystem disorder caused by a specific mutation p.R498W in the VPS33A gene. VPS33A functions in endocytic and autophagic pathways, but p.R498W mutation did not affect both of these pathways in the patient's skin fibroblast. Nineteen patients with MPSPS have been identified: seventeen patients were found among the Yakut population (Russia) and two patients from Turkey. Clinical features of MPSPS patients are similar to conventional mucopolysaccharidoses (MPS). In addition to typical symptoms for conventional MPS, MPSPS patients developed other features such as congenital heart defects, renal and hematopoietic disorders. Diagnosis generally requires evidence of clinical picture similar to MPS and molecular genetic testing. Disease is very severe, prognosis is unfavorable and most of patients died at age of 10-20 months. Currently there is no specific therapy for this disease and clinical management is limited to supportive and symptomatic treatment.

Mucopolysaccharidosis (MPS) is a group of inherited conditions involving metabolic dysfunction. Lysosomal enzyme deficiency leads to the accumulation of glycosaminoglycan (GAG) resulting in systemic symptoms, and is categorized into seven types caused by deficiency in one of eleven different enzymes. The pathophysiological mechanism of these diseases has been investigated, indicating impaired autophagy in neuronal damage initiation, association of activated microglia and astrocytes with the neuroinflammatory processes, and involvement of tauopathy. A new inherited error of metabolism resulting in a multisystem disorder with features of the MPS was also identified. Additionally, new therapeutic methods are being developed that could improve conventional therapies, such as new recombinant enzymes that can penetrate the blood brain barrier, hematopoietic stem cell transplantation with reduced intensity conditioning, gene therapy using a viral vector system or gene editing, and substrate reduction therapy. In this review, we discuss the recent developments in MPS research and provide a framework for developing strategies.

Enzyme replacement therapy is currently considered the standard of care for the treatment of mucopolysaccharidoses (MPS) type I, II, VI, and IV. This approach has shown substantial efficacy mainly on somatic symptoms of the patients, but no benefit was found for other clinical manifestations, such as neurological involvement. New strategies are currently being tested to address these limitations, in particular to obtain sufficient therapeutic levels in the brain. Intrathecal delivery of recombinant enzymes or chimeric enzymes represent promising approaches in this respect. Further innovation will likely be introduced by the recent advancements in the knowledge of lysosomal biology and function. It is now clear that the clinical manifestations of MPS are not only the direct effects of storage, but also derive from a cascade of secondary events that lead to dysfunction of several cellular processes and pathways. Some of these pathways may represent novel therapeutic targets and allow for development of novel or adjunctive therapies for these disorders.

Introduction: The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders with high phenotypic and genotypic heterogeneity, making precise diagnosis challenging. Although enzyme activity assay is considered the gold standard for the diagnosis of these disorders, molecular testing can greatly refine this task. New methods for rapid detection of variants are useful to reduce the 'diagnostic odyssey' faced by patients and their family, to lead to appropriate genetic counseling and to select the most appropriate therapy for each case. Areas covered: We review and discuss the advantages, disadvantages and limitations of the modern technologies in the field of molecular diagnosis of MPS, presenting our own experience. Expert commentary: While current molecular genetics testing for MPS mostly relies on PCR and Sanger sequencing, promising alternative techniques have emerged over the last few years, and its application into routine clinical practice is gaining momentum.

The mucopolysaccharidosis (MPS) disorders are ultra-rare lysosomal storage disorders associated with progressive accumulation of glycosaminoglycans (GAGs) in cells and tissues throughout the body. Clinical manifestations and progression rates vary widely across and within the different types of MPS. Neurological symptoms occur frequently, and may result directly from brain damage caused by infiltration of GAGs, or develop secondary to somatic manifestations such as spinal cord compression, hydrocephalus, and peripheral nerve entrapment. Management of secondary neurological manifestations often requires surgical correction of the underlying somatic cause. The present review discusses the surgical management of neurological disease in patients with MPS, including diagnostic imaging. Background information is derived from presentations and discussions during a meeting on the brain in MPS, attended by an international group of experts (April 28-30, 2016, Stockholm, Sweden), and additional literature searches., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We report a patient with stage 3 ganglioneuroblastoma who initially presented with clinical and laboratory features consistent with mucopolysaccharidosis including coarse facial features, developmental delay, and an elevated quantitative urine glycosaminoglycan (GAG) level. All mucopolysaccharidosis features resolved following successful treatment of neuroblastoma. High GAG levels have been documented in the pediatric oncology literature, yet not as a potential marker of malignancy or other target for clinical utility. This patient prompts further investigation into the relationship between neuroblastoma and elevated GAG levels.

Deficiency of glycosaminoglycan (GAG) degradation causes a subclass of lysosomal storage disorders called mucopolysaccharidoses (MPSs), many of which present with severe neuropathology. Critical steps in the degradation of the GAG heparan sulfate remain enigmatic. Here we show that the lysosomal arylsulfatase G (ARSG) is the long-sought glucosamine-3-O-sulfatase required to complete the degradation of heparan sulfate. Arsg-deficient mice accumulate heparan sulfate in visceral organs and the central nervous system and develop neuronal cell death and behavioral deficits. This accumulated heparan sulfate exhibits unique nonreducing end structures with terminal N-sulfoglucosamine-3-O-sulfate residues, allowing diagnosis of the disorder. Recombinant human ARSG is able to cleave 3-O-sulfate groups from these residues as well as from an authentic 3-O-sulfated N-sulfoglucosamine standard. Our results demonstrate the key role of ARSG in heparan sulfate degradation and strongly suggest that ARSG deficiency represents a unique, as yet unknown form of MPS, which we term MPS IIIE.

The mucopolysaccharidoses (MPSs) are a series of rare genetic disorders in which progressive bone and joint disease represents a key source of morbidity for patients. The recent introduction of enzyme replacement therapy for many of the MPSs has led to a need for increased physician awareness of these rare conditions in order to ensure that treatment is initiated at a time that leads to optimal benefit for patients. In addition, the current experiences of the clinical responsiveness of patient's symptoms to enzyme replacement approaches have also fuelled an interest in the development of alternative and adjunctive therapeutic approaches directed particularly to the rheumatological aspects of disease. Understanding the underlying pathogenesis of the MPSs is a key element for advancements in both of these areas. This review highlights the current knowledge underlying the pathophysiology of disease symptoms in the MPSs and underscores the importance and role of pathogenic cascades.

The mucopolysaccharidoses (MPSs) are a group of rare, inherited lysosomal storage disorders that are clinically characterized by abnormalities in multiple organ systems and reduced life expectancy. The MPSs are heterogeneous, progressive disorders. Patients typically appear normal at birth, but during early childhood they experience the onset of clinical disease, including skeletal, joint, airway and cardiac involvement, hearing and vision impairment, and mental retardation in the severe forms of MPS I, MPS II and MPS VII and all subtypes of MPS III. There are two treatment options for patients with MPS that are directed at the underlying pathophysiology: haematopoietic stem cell transplantation, which is useful for selected patients, and recombinant i.v. enzyme replacement therapy, which is available for MPS I, II and VI. Early diagnosis and treatment can improve patient outcomes and may reduce the disease burden on patients and caregivers. As skeletal and joint abnormalities are characteristic of many patients with MPS, rheumatologists are positioned to recognize the features of the disease and to facilitate early diagnosis and referral. In this overview, the clinical features of the MPS disorders and a brief review of treatment options will be presented in order to aid the rheumatologist in recognizing the features of these rare genetic disorders.

Hyaluronan is a major carbohydrate component of the extracellular matrix. Besides its structural role, it also appears to regulate cell transformation and migration during embryogenesis in vertebrates. Hyaluronan is synthesized by hyaluronan synthetases, transmembrane proteins expressed at several embryonic stages, as early as gastrulation. Inactivation or upregulation of hyaluronan synthetases elicits cardiac or skeletal development anomalies (atrioventricular septal defects caused by abnormal endocardial cushion formation, impaired chondrogenesis). Hyaluronidases degrade hyaluronan and interact with cell surface receptors involved in cell activation. Hyluronan binds not only extracellular matrix glycoproteins, but also cell surface receptors (CD44, RHAMM) also involved in cell signalling, differentiation and proliferation pathways. It facilitates migration and transformation and decreases contact inhibition. Hence, hyaluronan has a central regulating role during embryogenesis., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Hyaluronic acid, or hyaluronan, is a polymer made of the repetition of a unique disaccharidic unit, D-glucuronic acid and D-N-acetylglucosamine, that can reach a molecular mass of 10(7) daltons. This primitive polymer has emerged as a remarkable extracellular matrix component by its viscoelastic properties, its hygroscopic capacities and the diversity of cell processes it controls. Identified in all vertebrate tissues, more than 50% of acid hyaluronic of the organism is present in skin. Having no protein core, its synthesis is performed through a unique process, depending on enzymatic activity of hyaluronan synthases acting at the internal face of the plasmatic membrane and extruding the nascent polymer to the extracellular medium. This polymer constitutes a scaffold on which a large number of sulfated proteoglycans, up to one hundred, can be linked. These supramolecular structures of considerable size are able to entrap large amounts of water and ions to provide tissues with hydration and turgescence. Hyaluronic acid is recognized by cell membrane receptors, notably CD44 which is the best known. Interaction of hyaluronic acid with its receptors triggers several intracellular signaling pathways regulating proliferation, migration and differentiation. Cell response is largely influenced by the size of the polymer and by that of the fragments generated upon degradation by hyaluronidases or free radicals. Hyaluronic acid is metabolically very active, as, for example, its half-life in skin is less than one day. Detected in epidermis where it could play a role in the control of proliferation and differentiation of basal cells, it is however prominent in dermis in association with versican. The remarkable physicochemical properties of hyaluronic acid as well as the diversity of biological processes it controls largely surpass the primitive character of this polymer., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Unlabelled: Progress in understanding how a particular genotype produces the phenotype of an inborn error of metabolism, such as a mucopolysaccharidosis, in human patients has been facilitated by the study of animals with mutations in the orthologous genes. These are not just animal models, but true orthologues of the human genetic disease, with defects involving the same evolutionarily conserved genes and the same molecular, biochemical, and anatomic lesions as in human patients. These animals are often domestic species because of the individual medical attention paid to them, particularly dogs and cats. In addition, naturally occurring mouse models have also been found in breeding colonies. Within the last several decades, advances in molecular biology have allowed the production of knockout mouse models of human genetic disease, including the lysosomal storage diseases. The ability to use both inbred strains of a small, prolific species together with larger out-bred animals found because of their disease phenotype provides a powerful combination with which to investigate pathogenesis, develop approaches to therapy, and define biomarkers to evaluate therapeutic success. This has been true for the inborn errors of metabolism and, in particular, the mucopolysaccharidoses., Conclusion: Animal models of human genetic disease continue to play an important role in understanding the molecular and physiological consequences of lysosomal storage diseases and to provide an opportunity to evaluate the efficacy and safety of therapeutic interventions.

Studies were carried out to determine the changes in glycosaminnoglycan (GAG) metabolism in rats fed cassava with varying cyanoglucoside levels and two levels of protein. Results indicated that there was an enhancement in the level of total and individual GAG with a corresponding reduction in the activity of enzymes involved in the degradation of glycosaminoglycan. These changes were significant for rats given a cassava diet (raw and boiled cassava) and low protein. The changes in total and individual GAG and the decrease in the activity of degrading enzymes was more for high cyanide (raw cassava) groups compared with other groups showing that consumption of untreated cassava is an additive factor for the promotion of mucopolysaccharidosis.

Mucopolysaccharidosis Type I (MPS I) is the lysosomal storage disease caused by the deficient activity of alpha-L-iduronidase (IDUA). In man, MPS I can occur in severe, mild, or intermediate forms known as the Hurler, Scheie, or Hurler/Scheie syndromes, respectively. MPS I also has been described in cats, dogs, and mice. This manuscript reports the identification and characterization of the mutation causing MPS I in cats. To obtain wild-type feline IDUA cDNAs, two PCR-based strategies were used. PCR primers were constructed from a conserved region of the published human and dog sequences and used to amplify a 224-bp IDUA fragment from normal cat genomic DNA. This fragment was then used to screen a feline uterus cDNA library. PCR also was used to directly amplify IDUA fragments from the same cDNA library. Two overlapping feline IDUA cDNAs encoding 466 amino acid residues of the feline IDUA polypeptide ( approximately 85% of the mature protein based on comparison to the human, dog, and mouse sequences) were obtained by these strategies. To identify the mutation causing MPS I in cats, DNA sequencing was carried out on the corresponding IDUA region from several affected animals. A 3-bp deletion was found on both IDUA alleles in each of the MPS I animals, predicting the deletion of a single aspartate residue from the feline IDUA polypeptide. To confirm the authenticity of this mutation, heteroduplex, SSCP, and transient expression studies were carried out. Over 100 animals from the MPS I colony were screened for the presence of the mutation by heteroduplex and SSCP analyses-in all cases the presence of the 3-bp deletion was 100% concordant with the disease phenotype. For transient expression studies, the two partial, overlapping feline cDNAs were combined and joined in-frame to the 5' end of the canine IDUA cDNA. This wild-type, hybrid cDNA expressed IDUA activity up to sixfold over endogenous levels after transfection into COS-1 cells. A modified full-length IDUA cDNA containing the 3-bp deletion did not express IDUA activity in a transient expression system, providing proof that this lesion was the cause of feline MPS I., (Copyright 1999 Academic Press.)

A patient had papular and nodular cutaneous deposits of mucin and cutaneous and systemic manifestations of lupus erythematosus (LE). Since many of the mucinous deposits occurred at sites that were clinically free of skin lesions of LE, we considered initially that the patient had both LE and papular mucinosis. However, after a review of the English literature and further study of the patient, it seemed more likely that the papular and nodular deposits of mucin were secondary to LE and not a previously unreported simultaneous occurrence of the two diseases in the same patient. To our knowledge, this is the third case report of a patient with papular and nodular cutaneous mucinosis secondary to LE. In addition to the case report, this article is concerned with a discussion of cutaneous mucinosis in LE and other "collagen vascular" diseases.

Lysosomal hydrolases participate substantially in the degradation of all classes of biological macromolecules. They act physiologically within the lysosome. The enzymes are either primarily included within primary lysosomes or are transported to these cell organelles after secretion and subsequent adsorptive pinocytosis. The involvement of these enzymes in a variety of pathological conditions can be understood on the basis of the known functions of lysosomal hydrolases. Inactivity of one or several of the enzymes causes lysosomal storage disorders. Similar metabolic consequences are found when the enzymes are unable to be concentrated within the lysosome. Lysosomal hydrolases participate, furthermore, in the pathogenesis of numerous diseases. A distinction can be made between lysosomal overload, pathologically-increased enzyme secretion into the extracellular space, and a release of lysosomal enzymes into the cytosol.