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Molecular Genetics and Metabolism Dec 2018Mucopolysaccharidosis (MPS) disorders are caused by deficiencies in lysosomal enzymes, leading to impaired glycosaminoglycan (GAG) degradation. The resulting GAG... (Review)
Review
Mucopolysaccharidosis (MPS) disorders are caused by deficiencies in lysosomal enzymes, leading to impaired glycosaminoglycan (GAG) degradation. The resulting GAG accumulation in cells and connective tissues ultimately results in widespread tissue and organ dysfunction. The seven MPS types currently described are heterogeneous and progressive disorders, with somatic and neurological manifestations depending on the type of accumulating GAG. Heparan sulfate (HS) is one of the GAGs stored in patients with MPS I, II, and VII and the main GAG stored in patients with MPS III. These disorders are associated with significant central nervous system (CNS) abnormalities that can manifest as impaired cognition, hyperactive and/or aggressive behavior, epilepsy, hydrocephalus, and sleeping problems. This review discusses the anatomical and pathophysiological CNS changes accompanying HS accumulation as well as the mechanisms believed to cause CNS abnormalities in MPS patients. The content of this review is based on presentations and discussions on these topics during a meeting on the brain in MPS attended by an international group of MPS experts.
Topics: Brain; Cognitive Dysfunction; Epilepsy; Heparitin Sulfate; Humans; Mucopolysaccharidoses
PubMed: 30145178
DOI: 10.1016/j.ymgme.2018.08.003 -
Molecular Genetics and Metabolism Dec 2017The mucopolysaccharidosis (MPS) disorders are caused by deficiencies of specific lysosomal enzymes involved in the catabolism of glycosaminoglycans (GAGs). The resulting... (Review)
Review
The mucopolysaccharidosis (MPS) disorders are caused by deficiencies of specific lysosomal enzymes involved in the catabolism of glycosaminoglycans (GAGs). The resulting GAG accumulation in cells and tissues throughout the body leads to progressive multi-organ dysfunction. MPS patients present with several somatic manifestations, including short stature, musculoskeletal abnormalities, and cardiorespiratory dysfunction, and several primary and secondary neurological signs and symptoms. Epileptic seizures are neurological signs of MPS thought to develop due to accumulation of GAGs in the brain, triggering alterations in neuronal connectivity and signaling, and release of inflammatory mediators. The amount of literature on the prevalence, pathophysiology, clinical features, and management of epileptic seizures in patients with MPS is limited. This review discusses current knowledge on this topic, as well as two case examples, presented and discussed during a closed meeting on MPS and the brain among an international group of experts with extensive experience in managing and treating MPS.
Topics: Adolescent; Anticonvulsants; Brain; Child; Electroencephalography; Epilepsy; Female; Glycosaminoglycans; Humans; Magnetic Resonance Imaging; Male; Mucopolysaccharidoses; Prevalence; Treatment Outcome
PubMed: 29170080
DOI: 10.1016/j.ymgme.2017.10.006 -
Italian Journal of Pediatrics Nov 2018Enzyme replacement therapy (ERT) is available for mucopolysaccharidosis (MPS) I, MPS II, MPS VI, and MPS IVA. The efficacy of ERT has been evaluated in clinical trials... (Review)
Review
Enzyme replacement therapy (ERT) is available for mucopolysaccharidosis (MPS) I, MPS II, MPS VI, and MPS IVA. The efficacy of ERT has been evaluated in clinical trials and in many post-marketing studies with a long-term follow-up for MPS I, MPS II, and MPS VI. While ERT is effective in reducing urinary glycosaminoglycans (GAGs) and liver and spleen volume, cartilaginous organs such as the trachea and bronchi, bones and eyes are poorly impacted by ERT probably due to limited penetration in the specific tissue. ERT in the present formulations also does not cross the blood-brain barrier, with the consequence that the central nervous system is not cured by ERT. This is particularly important for severe forms of MPS I and MPS II characterized by cognitive decline. For severe MPS I patients (Hurler), early haematopoietic stem cell transplantation is the gold standard, while still controversial is the role of stem cell transplantation in MPS II. The use of ERT in patients with severe cognitive decline is the subject of debate; the current position of the scientific community is that ERT must be started in all patients who do not have a more effective treatment. Neonatal screening is widely suggested for treatable MPS, and many pilot studies are ongoing. The rationale is that early, possibly pre-symptomatic treatment can improve prognosis. All patients develop anti-ERT antibodies but only a few have drug-related adverse reactions. It has not yet been definitely clarified if high-titre antibodies may, at least in some cases, reduce the efficacy of ERT.
Topics: Enzyme Replacement Therapy; Humans; Mucopolysaccharidoses; Patient Selection; Treatment Outcome
PubMed: 30442189
DOI: 10.1186/s13052-018-0562-1 -
Molecular Genetics and Metabolism Feb 2018Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders (LSDs) caused by a deficiency of lysosomal enzymes, leading to a wide range of various clinical... (Review)
Review
Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders (LSDs) caused by a deficiency of lysosomal enzymes, leading to a wide range of various clinical symptoms depending upon the type of MPS or its severity. Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), substrate reduction therapy (SRT), and various surgical procedures are currently available for patients with MPS. However, there is no curative treatment for this group of disorders. Gene therapy should be a one-time permanent therapy, repairing the cause of enzyme deficiency. Preclinical studies of gene therapy for MPS have been developed over the past three decades. Currently, clinical trials of gene therapy for some types of MPS are ongoing in the United States, some European countries, and Australia. Here, in this review, we summarize the development of gene therapy for MPS in preclinical and clinical trials.
Topics: Genetic Therapy; Humans; Mucopolysaccharidoses
PubMed: 29295764
DOI: 10.1016/j.ymgme.2017.12.434 -
Journal of Inherited Metabolic Disease Mar 2013MPS encompasses a group of rare lysosomal storage disorders that are associated with the accumulation of glycosaminoglycans (GAG) in organs and tissues. This... (Review)
Review
MPS encompasses a group of rare lysosomal storage disorders that are associated with the accumulation of glycosaminoglycans (GAG) in organs and tissues. This accumulation can lead to the progressive development of a variety of clinical manifestations. Ear, nose, throat (ENT) and respiratory problems are very common in patients with MPS and are often among the first symptoms to appear. Typical features of MPS include upper and lower airway obstruction and restrictive pulmonary disease, which can lead to chronic rhinosinusitis or chronic ear infections, recurrent upper and lower respiratory tract infections, obstructive sleep apnoea, impaired exercise tolerance, and respiratory failure. This review provides a detailed overview of the ENT and respiratory manifestations that can occur in patients with MPS and discusses the issues related to their evaluation and management.
Topics: Airway Obstruction; Humans; Mucopolysaccharidoses; Respiratory System; Sleep Wake Disorders
PubMed: 23151682
DOI: 10.1007/s10545-012-9555-1 -
Molecular Genetics and Metabolism Dec 2017The mucopolysaccharidosis (MPS) disorders are a group of lysosomal storage diseases caused by lysosomal enzyme deficits that lead to glycosaminoglycan accumulation,... (Review)
Review
The mucopolysaccharidosis (MPS) disorders are a group of lysosomal storage diseases caused by lysosomal enzyme deficits that lead to glycosaminoglycan accumulation, affecting various tissues throughout the body based on the specific enzyme deficiency. These disorders are characterized by their progressive nature and a variety of somatic manifestations and neurological symptoms. There are established treatments for some MPS disorders, but these mostly alleviate somatic and non-neurological symptoms and do not cure the disease. Patients with MPS I, II, III, and VII can present with neurological manifestations such as neurocognitive decline and behavioral problems. Treatment of these neurological manifestations remains challenging due to the blood-brain barrier (BBB) that limits delivery of therapeutic agents to the central nervous system (CNS). New therapies that circumvent this barrier and target brain disease in MPS are currently under development. They primarily focus on facilitating penetration of drugs through the BBB, delivery of recombinant enzyme to the brain by gene therapy, or direct CNS administration. This review summarizes existing and potential future treatment approaches that target brain disease in MPS. The information in this review is based on current literature and presentations and discussions during a closed meeting by an international group of experts with extensive experience in managing and treating MPS.
Topics: Animals; Blood-Brain Barrier; Brain; Child; Child Behavior; Child Development; Child, Preschool; Clinical Trials as Topic; Cognitive Dysfunction; Congresses as Topic; Drug Carriers; Enzyme Replacement Therapy; Genetic Therapy; Glycosaminoglycans; Hematopoietic Stem Cell Transplantation; Humans; Injections, Intraventricular; Injections, Spinal; Molecular Chaperones; Mucopolysaccharidoses; Nanoparticles; Recombinant Proteins
PubMed: 29153844
DOI: 10.1016/j.ymgme.2017.10.007 -
Molecular Genetics and Metabolism Feb 2014The mucopolysaccharidoses (MPS) result from attenuation or loss of enzyme activities required for lysosomal degradation of the glycosaminoglycans, hyaluronan, heparan... (Review)
Review
The mucopolysaccharidoses (MPS) result from attenuation or loss of enzyme activities required for lysosomal degradation of the glycosaminoglycans, hyaluronan, heparan sulfate, chondroitin/dermatan sulfate, and keratan sulfate. This review provides a summary of glycan biomarkers that have been used to characterize animal models of MPS, for diagnosis of patients, and for monitoring therapy based on hematopoietic stem cell transplantation and enzyme replacement therapy. Recent advances have focused on the non-reducing terminus of the glycosaminoglycans that accumulate as biomarkers, using a combination of enzymatic digestion with bacterial enzymes followed by quantitative liquid chromatography/mass spectrometry. These new methods provide a simple, rapid diagnostic strategy that can be applied to samples of urine, blood, cerebrospinal fluid, cultured cells and dried blood spots from newborn infants. Analysis of the non-reducing end glycans provides a method for monitoring enzyme replacement and substrate reduction therapies and serves as a discovery tool for uncovering novel biomarkers and new forms of mucopolysaccharidoses.
Topics: Animals; Biomarkers; Chromatography, Liquid; Disease Models, Animal; Dried Blood Spot Testing; Enzyme Assays; Enzyme Replacement Therapy; Glycosaminoglycans; Hematopoietic Stem Cell Transplantation; Humans; Immunoassay; Infant, Newborn; Mass Spectrometry; Mucopolysaccharidoses; Oxidation-Reduction
PubMed: 23958290
DOI: 10.1016/j.ymgme.2013.07.016 -
Orphanet Journal of Rare Diseases Jun 2017Mucopolysaccharidosis I-Hurler (MPS I-H) is the most severe form of a metabolic genetic disease caused by mutations of IDUA gene encoding the lysosomal α-L-iduronidase... (Review)
Review
Mucopolysaccharidosis I-Hurler (MPS I-H) is the most severe form of a metabolic genetic disease caused by mutations of IDUA gene encoding the lysosomal α-L-iduronidase enzyme. MPS I-H is a rare, life-threatening disease, evolving in multisystem morbidity including progressive neurological disease, upper airway obstruction, skeletal deformity and cardiomyopathy. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the gold standard for the treatment of MPS I-H in patients diagnosed and treated before 2-2.5 years of age, having a high rate of success. Beyond the child's age, other factors influence the probability of treatment success, including the selection of patients, of graft source and the donor type employed. Enzyme replacement therapy (ERT) with human recombinant laronidase has also been demonstrated to be effective in ameliorating the clinical conditions of pre-transplant MPS I-H patients and in improving HSCT outcome, by peri-transplant co-administration. Nevertheless the long-term clinical outcome even after successful HSCT varies considerably, with a persisting residual disease burden. Other strategies must then be considered to improve the outcome of these patients: one is to pursue early pre-symptomatic diagnosis through newborn screening and another one is the identification of novel treatments. In this perspective, even though newborn screening can be envisaged as a future attractive perspective, presently the best path to be pursued embraces an improved awareness of signs and symptoms of the disorder by primary care providers and pediatricians, in order for the patients' timely referral to a qualified reference center. Furthermore, sensitive new biochemical markers must be identified to better define the clinical severity of the disease at birth, to support clinical judgement during the follow-up and to compare the effects of the different therapies. A prolonged neuropsychological follow-up of post-transplant cognitive development of children and residual disease burden is needed. In this perspective, the reference center must guarantee a multidisciplinary follow-up with an expert team. Diagnostic and interventional protocols of reference centers should be standardized whenever possible to allow comparison of clinical data and evaluation of results. This review will focus on all these critical issues related to the management of MPS I-H.
Topics: Child, Preschool; Hematopoietic Stem Cell Transplantation; Humans; Iduronidase; Infant, Newborn; Mucopolysaccharidosis I; Neonatal Screening; Rare Diseases
PubMed: 28619065
DOI: 10.1186/s13023-017-0662-9 -
Molecules (Basel, Switzerland) Sep 2021Although mucopolysaccharidoses (MPS) are caused by mutations in genes coding for enzymes responsible for degradation of glycosaminoglycans, storage of these compounds is... (Review)
Review
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.
Topics: Animals; Antioxidants; Enzyme Replacement Therapy; Genetic Therapy; Glycosaminoglycans; Humans; Mucopolysaccharidoses; Oxidative Stress
PubMed: 34577086
DOI: 10.3390/molecules26185616 -
Molecular Genetics and Metabolism Dec 2017The mucopolysaccharidosis (MPS) disorders are caused by deficiencies of specific lysosomal enzymes, resulting in progressive glycosaminoglycan (GAG) accumulation in... (Review)
Review
The mucopolysaccharidosis (MPS) disorders are caused by deficiencies of specific lysosomal enzymes, resulting in progressive glycosaminoglycan (GAG) accumulation in cells and tissues throughout the body. Excessive GAG storage can lead to a variety of somatic manifestations as well as primary and secondary neurological symptoms. Behavioral problems (like hyperactivity, attention difficulties, and severe frustration) and sleeping problems are typical primary neurological symptoms of MPS caused by GAG accumulation in neurons, and are frequently observed in patients with MPS I, II, III, and VII. As these problems often place a significant burden on the family, proper management is important. This review summarizes current insights into behavioral and sleeping problems in MPS disorders and the most optimal management approaches, as presented and discussed during a meeting of an international group of experts with extensive experience in managing and treating MPS.
Topics: Behavior Therapy; Brain; Central Nervous System Depressants; Child; Child Behavior; Child, Preschool; Congresses as Topic; Dyssomnias; Glycosaminoglycans; Humans; Mucopolysaccharidoses; Treatment Outcome
PubMed: 29170079
DOI: 10.1016/j.ymgme.2017.09.010