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International Journal of Molecular... Jan 2020Previously, we reported a novel disease of impaired glycosaminoglycans (GAGs) metabolism without deficiency of known lysosomal enzymes-mucopolysaccharidosis-plus...
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 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.
Topics: Diagnosis, Differential; Female; Geography; Humans; Male; Mucopolysaccharidoses; Pedigree; Russia; Syndrome
PubMed: 31936524
DOI: 10.3390/ijms21020421 -
Fluids and Barriers of the CNS Sep 2022Mucopolysaccharidoses comprise a set of genetic diseases marked by an enzymatic dysfunction in the degradation of glycosaminoglycans in lysosomes. There are eight... (Review)
Review
Mucopolysaccharidoses comprise a set of genetic diseases marked by an enzymatic dysfunction in the degradation of glycosaminoglycans in lysosomes. There are eight clinically distinct types of mucopolysaccharidosis, some with various subtypes, based on which lysosomal enzyme is deficient and symptom severity. Patients with mucopolysaccharidosis can present with a variety of symptoms, including cognitive dysfunction, hepatosplenomegaly, skeletal abnormalities, and cardiopulmonary issues. Additionally, the onset and severity of symptoms can vary depending on the specific disorder, with symptoms typically arising during early childhood. While there is currently no cure for mucopolysaccharidosis, there are clinically approved therapies for the management of clinical symptoms, such as enzyme replacement therapy. Enzyme replacement therapy is typically administered intravenously, which allows for the systemic delivery of the deficient enzymes to peripheral organ sites. However, crossing the blood-brain barrier (BBB) to ameliorate the neurological symptoms of mucopolysaccharidosis continues to remain a challenge for these large macromolecules. In this review, we discuss the transport mechanisms for the delivery of lysosomal enzymes across the BBB. Additionally, we discuss the several therapeutic approaches, both preclinical and clinical, for the treatment of mucopolysaccharidoses.
Topics: Blood-Brain Barrier; Child, Preschool; Glycosaminoglycans; Humans; Lysosomes; Mucopolysaccharidoses
PubMed: 36117162
DOI: 10.1186/s12987-022-00373-5 -
Pediatrics and Neonatology Feb 2023The mucopolysaccharidoses (MPSs) are a subset of lysosomal storage diseases caused by deficiencies in the enzymes required to metabolize glycosaminoglycans (GAGs), a... (Review)
Review
The mucopolysaccharidoses (MPSs) are a subset of lysosomal storage diseases caused by deficiencies in the enzymes required to metabolize glycosaminoglycans (GAGs), a group of extracellular heteropolysaccharides that play diverse roles in human physiology. As a result, GAGs accumulate in multiple tissues, and affected patients typically develop progressive, multi-systemic symptoms in early childhood. Over the last 30 years, the treatments available for the MPSs have evolved tremendously. There are now multiple therapies that delay the progression of these debilitating disorders, although their effectiveness varies according to MPS sub-type. In this review, we discuss the basic principle underlying MPS treatment (enzymatic "cross correction"), and we review the three general modalities currently available: hematopoietic stem cell transplantation, enzymatic replacement, and gene therapy. For each treatment type, we discuss its effectiveness across the MPS subtypes, its inherent risks, and future directions. Long term, we suspect that treatment for the MPSs will continue to evolve, and through a combination of early diagnosis and effective management, these patients will continue to live longer lives with improved outcomes for quality of life.
Topics: Humans; Child, Preschool; Quality of Life; Enzyme Replacement Therapy; Glycosaminoglycans; Mucopolysaccharidoses; Hematopoietic Stem Cell Transplantation
PubMed: 36464587
DOI: 10.1016/j.pedneo.2022.10.001 -
International Journal of Molecular... Nov 2021The accumulation of glycosaminoglycans (GAGs) in bone and cartilage leads to progressive damage in cartilage that, in turn, reduces bone growth by the destruction of the... (Review)
Review
The accumulation of glycosaminoglycans (GAGs) in bone and cartilage leads to progressive damage in cartilage that, in turn, reduces bone growth by the destruction of the growth plate, incomplete ossification, and growth imbalance. The mechanisms of pathophysiology related to bone metabolism in mucopolysaccharidoses (MPS) include impaired chondrocyte function and the failure of endochondral ossification, which leads to the release of inflammatory cytokines via the activation of Toll-like receptors by GAGs. Although improvements in the daily living of patients with MPS have been achieved with enzyme replacement, treatment for the bone disorder is limited. There is an increasing need to identify biomarkers related to bone and cartilage to evaluate the progressive status and to monitor the treatment of MPS. Recently, new analysis methods, such as proteomic analysis, have identified new biomarkers in MPS. This review summarizes advances in clinical bone metabolism and bone biomarkers.
Topics: Biomarkers; Bone Remodeling; Bone and Bones; Cytokines; Humans; Mucopolysaccharidoses; Proteomics
PubMed: 34884458
DOI: 10.3390/ijms222312651 -
Molecular Genetics and Metabolism Jun 2020Glycosaminoglycans (GAGs) are negatively charged long linear (highly sulfated) polysaccharides consisting of repeating disaccharide units that are expressed on the... (Review)
Review
BACKGROUND
Glycosaminoglycans (GAGs) are negatively charged long linear (highly sulfated) polysaccharides consisting of repeating disaccharide units that are expressed on the surfaces of all nucleated cells. The expression of GAGs is required for embryogenesis, regulation of cell growth and proliferation, maintenance of tissue hydration, and interactions of the cells via receptors. Mucopolysaccharidoses (MPS) are caused by deficiency of specific lysosomal enzymes that result in the accumulation of GAGs in multiple tissues leading to organ dysfunction. Therefore, GAGs are important biomarkers for MPS. Without any treatment, patients with severe forms of MPS die within the first two decades of life.
SCOPE OF REVIEW
Accurate measurement of GAGs is important to understand the diagnosis and pathogenesis of MPS and to monitor therapeutic efficacy before, during, and after treatment of the disease. This review covers various qualitative and quantitative methods for measurement of GAGs, including dye specific, thin layer chromatography (TLC), capillary electrophoresis, high-performance liquid chromatography (HPLC), liquid chromatography-tandem mass spectrometry (LC-MS/MS), gas chromatography, ELISA, and automated high-throughput mass spectrometry. Major conclusion: There are several methods for GAG detection however, specific GAG detection in the various biological systems requires rapid, sensitive, specific, and cost-effective methods such as LC-MS/MS.
GENERAL SIGNIFICANCE
This review will describe different methods for GAG detection and analysis, including their advantages and limitation.
Topics: Biomarkers; Glycosaminoglycans; Humans; Mucopolysaccharidoses
PubMed: 32247585
DOI: 10.1016/j.ymgme.2020.03.004 -
International Journal of Molecular... Apr 2020The recent advancements in the knowledge of lysosomal biology and function have translated into an improved understanding of the pathophysiology of mucopolysaccharidoses... (Review)
Review
The recent advancements in the knowledge of lysosomal biology and function have translated into an improved understanding of the pathophysiology of mucopolysaccharidoses (MPSs). The concept that MPS manifestations are direct consequences of lysosomal engorgement with undegraded glycosaminoglycans (GAGs) has been challenged by new information on the multiple biological roles of GAGs and by a new vision of the lysosome as a signaling hub involved in many critical cellular functions. MPS pathophysiology is now seen as the result of a complex cascade of secondary events that lead to dysfunction of several cellular processes and pathways, such as abnormal composition of membranes and its impact on vesicle fusion and trafficking; secondary storage of substrates; impairment of autophagy; impaired mitochondrial function and oxidative stress; dysregulation of signaling pathways. The characterization of this cascade of secondary cellular events is critical to better understand the pathophysiology of MPS clinical manifestations. In addition, some of these pathways may represent novel therapeutic targets and allow for the development of new therapies for these disorders.
Topics: Autophagy; Glycosaminoglycans; Humans; Lysosomes; Mucopolysaccharidoses; Oxidative Stress; Protein Transport
PubMed: 32260444
DOI: 10.3390/ijms21072515 -
Journal of Inherited Metabolic Disease Jan 2021Mucopolysaccharidosis type III (MPS III) or Sanfilippo disease is an orphan inherited lysosomal storage disease and one of the most common MPS subtypes. The classical... (Review)
Review
Mucopolysaccharidosis type III (MPS III) or Sanfilippo disease is an orphan inherited lysosomal storage disease and one of the most common MPS subtypes. The classical presentation is an infantile-onset neurodegenerative disease characterised by intellectual regression, behavioural and sleep disturbances, loss of ambulation, and early death. Unlike other MPS, no disease-modifying therapy has yet been approved. Here, we review the numerous approaches of curative therapy developed for MPS III from historical ineffective haematopoietic stem cell transplantation and substrate reduction therapy to the promising ongoing clinical trials based on enzyme replacement therapy or adeno-associated or lentiviral vectors mediated gene therapy. Preclinical studies are presented alongside the most recent translational first-in-man trials. In addition, we present experimental research with preclinical mRNA and gene editing strategies. Lessons from animal studies and clinical trials have highlighted the importance of an early therapy before extensive neuronal loss. A disease-modifying therapy for MPS III will undoubtedly mandate development of new strategies for early diagnosis.
Topics: Animals; Clinical Trials as Topic; Disease Models, Animal; Enzyme Replacement Therapy; Gene Editing; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Molecular Chaperones; Mucopolysaccharidosis III; RNA, Messenger
PubMed: 32944950
DOI: 10.1002/jimd.12316 -
International Journal of Molecular... Jan 2020Genome editing holds the promise of one-off and potentially curative therapies for many patients with genetic diseases. This is especially true for patients affected by... (Review)
Review
Genome editing holds the promise of one-off and potentially curative therapies for many patients with genetic diseases. This is especially true for patients affected by mucopolysaccharidoses as the disease pathophysiology is amenable to correction using multiple approaches. Ex vivo and in vivo genome editing platforms have been tested primarily on MSPI and MPSII, with in vivo approaches having reached clinical testing in both diseases. Though we still await proof of efficacy in humans, the therapeutic tools established for these two diseases should pave the way for other mucopolysaccharidoses. Herein, we review the current preclinical and clinical development studies, using genome editing as a therapeutic approach for these diseases. The development of new genome editing platforms and the variety of genetic modifications possible with each tool provide potential applications of genome editing for mucopolysaccharidoses, which vastly exceed the potential of current approaches. We expect that in a not-so-distant future, more genome editing-based strategies will be established, and individual diseases will be treated through multiple approaches.
Topics: Gene Editing; Humans; Mucopolysaccharidosis I; Mucopolysaccharidosis II
PubMed: 31941077
DOI: 10.3390/ijms21020500 -
International Journal of Molecular... Feb 2022Mucopolysaccharidoses are rare paediatric lysosomal storage disorders, characterised by accumulation of glycosaminoglycans within lysosomes. This is caused by... (Review)
Review
Mucopolysaccharidoses are rare paediatric lysosomal storage disorders, characterised by accumulation of glycosaminoglycans within lysosomes. This is caused by deficiencies in lysosomal enzymes involved in degradation of these molecules. Dependent on disease, progressive build-up of sugars may lead to musculoskeletal abnormalities and multi-organ failure, and in others, to cognitive decline, which is still a challenge for current therapies. The worsening of neuropathology, observed in patients following recovery from flu-like infections, suggests that inflammation is highly implicated in disease progression. This review provides an overview of the pathological features associated with the mucopolysaccharidoses and summarises current knowledge regarding the inflammatory responses observed in the central nervous system and periphery. We propose a model whereby progressive accumulation of glycosaminoglycans elicits an innate immune response, initiated by the Toll-like receptor 4 pathway, but also precipitated by secondary storage components. Its activation induces cells of the immune system to release pro-inflammatory cytokines, such as TNF-α and IL-1, which induce progression through chronic neuroinflammation. While TNF-α is mostly associated with bone and joint disease in mucopolysaccharidoses, increasing evidence implicates IL-1 as a main effector of innate immunity in the central nervous system. The (NOD)-like receptor protein 3 inflammasome is therefore implicated in chronic neuroinflammation and should be investigated further to identify novel anti-inflammatory treatments.
Topics: Animals; Cytokines; Humans; Immunity, Innate; Inflammation; Joint Diseases; Lysosomal Storage Diseases; Lysosomes; Mucopolysaccharidoses
PubMed: 35216110
DOI: 10.3390/ijms23041999 -
Italian Journal of Pediatrics Nov 2018Mucopolysaccharidoses (MPS) are a group of rare lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs) in different parts of the eye.... (Review)
Review
Mucopolysaccharidoses (MPS) are a group of rare lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs) in different parts of the eye. Ocular problems are very common in MPS children, and the cornea, sclera, trabecular meshwork, retina, and optic nerve may all be involved. Early diagnosis is very important to preserve the visual function, and the diagnosis requires experience and different evaluations. Follow-up is mandatory to allow a correct pathway to consequent therapy. This article aims to provide a review of ocular alterations and treatment options in MPS. The ophthalmologist is sometimes the first physician who can suspect a metabolic disease and can help to make the correct diagnosis. It is important to stimulate awareness of MPS among ophthalmologists.
Topics: Eye Diseases; Humans; Mucopolysaccharidoses
PubMed: 30442167
DOI: 10.1186/s13052-018-0559-9