scholarly journals Characterization of New Proteomic Biomarker Candidates in Mucopolysaccharidosis Type IVA

2020 ◽  
Vol 22 (1) ◽  
pp. 226
Author(s):  
Víctor J. Álvarez ◽  
Susana B. Bravo ◽  
Maria Pilar Chantada-Vazquez ◽  
Cristóbal Colón ◽  
María J. De Castro ◽  
...  
Keyword(s):  
Keratan Sulfate ◽  
Bone Lesions ◽  
Mucopolysaccharidosis Type ◽  
Lysosomal Storage ◽  
Protein Biomarkers ◽  
Enzyme Replacement ◽  
Endurance Tests ◽  
Mps Iva ◽  
Mucopolysaccharidosis Type Iva ◽  
Potential Biomarkers

Mucopolysaccharidosis type IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. Skeletal dysplasia and the related clinical features of MPS IVA are caused by disruption of the cartilage and its extracellular matrix, leading to a growth imbalance. Enzyme replacement therapy (ERT) with recombinant human GALNS has yielded positive results in activity of daily living and endurance tests. However, no data have demonstrated improvements in bone lesions and bone grow thin MPS IVA after ERT, and there is no correlation between therapeutic efficacy and urine levels of keratan sulfate, which accumulates in MPS IVA patients. Using qualitative and quantitative proteomics approaches, we analyzed leukocyte samples from healthy controls (n = 6) and from untreated (n = 5) and ERT-treated (n = 8, sampled before and after treatment) MPS IVA patients to identify potential biomarkers of disease. Out of 690 proteins identified in leukocytes, we selected a group of proteins that were dysregulated in MPS IVA patients with ERT. From these, we identified four potential protein biomarkers, all of which may influence bone and cartilage metabolism: lactotransferrin, coronin 1A, neutral alpha-glucosidase AB, and vitronectin. Further studies of cartilage and bone alterations in MPS IVA will be required to verify the validity of these proteins as potential biomarkers of MPS IVA.

scholarly journals Plasma Proteomic Analysis in Morquio A Disease

2021 ◽  
Vol 22 (11) ◽  
pp. 6165
Author(s):  
José V. Álvarez ◽  
Susana B. Bravo ◽  
María Pilar Chantada-Vázquez ◽  
Sofía Barbosa-Gouveia ◽  
Cristóbal Colón ◽  
...  
Keyword(s):  
Bone Growth ◽  
Keratan Sulfate ◽  
Study Groups ◽  
Bone Lesions ◽  
Protein Biomarkers ◽  
Lysosomal Disease ◽  
Enzyme Replacement ◽  
Morquio A ◽  
Mps Iva ◽  
Potential Biomarkers

Mucopolysaccharidosis type IVA (MPS IVA) is a lysosomal disease caused by mutations in the gene encoding the enzymeN-acetylgalactosamine-6-sulfate sulfatase (GALNS), and is characterized by systemic skeletal dysplasia due to excessive storage of keratan sulfate (KS) and chondroitin-6-sulfate in chondrocytes. Although improvements in the activity of daily living and endurance tests have been achieved with enzyme replacement therapy (ERT) with recombinant human GALNS, recovery of bone lesions and bone growth in MPS IVA has not been demonstrated to date. Moreover, no correlation has been described between therapeutic efficacy and urine levels of KS, which accumulates in MPS IVA patients. The objective of this study was to assess the validity of potential biomarkers proposed by other authors and to identify new biomarkers. To identify candidate biomarkers of this disease, we analyzed plasma samples from healthy controls (n=6) and from untreated (n=8) and ERT-treated (n=5, sampled before and after treatment) MPS IVA patients using both qualitative and quantitative proteomics analyses. The qualitative proteomics approach analyzed the proteomic profile of the different study groups. In the quantitative analysis, we identified/quantified 215 proteins after comparing healthy control untreated, ERT-treated MPSIVA patients. We selected a group of proteins that were dysregulated in MPS IVA patients. We identified four potential protein biomarkers, all of which may influence bone and cartilage metabolism: fetuin-A, vitronectin, alpha-1antitrypsin, and clusterin. Further studies of cartilage and bone samples from MPS IVA patients will be required to verify the validity of these proteins as potential biomarkers of MPS IVA.

scholarly journals Treatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joan Bertolin ◽  
Víctor Sánchez ◽  
Albert Ribera ◽  
Maria Luisa Jaén ◽  
Miquel Garcia ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Viral Vector ◽  
Keratan Sulfate ◽  
Whole Body ◽  
Mucopolysaccharidosis Type ◽  
Lysosomal Storage ◽  
Peripheral Tissues ◽  
Enzyme Replacement ◽  
Morquio A ◽  
Mucopolysaccharidosis Type Iva

AbstractMucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. There is no cure and enzyme replacement therapy cannot correct skeletal abnormalities. Here, using CRISPR/Cas9 technology, we generate the first MPSIVA rat model recapitulating all skeletal and non-skeletal alterations experienced by patients. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encoding Galns (AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to long-term (1 year) increase of GALNS activity and whole-body correction of KS levels, thus preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. This study demonstrates the potential of AAV9-Galns gene therapy to correct the disabling MPSIVA pathology, providing strong rationale for future clinical translation to MPSIVA patients.

scholarly journals Proteomic Analysis in Morquio A Cells Treated with Immobilized Enzymatic Replacement Therapy on Nanostructured Lipid Systems

2019 ◽  
Vol 20 (18) ◽  
pp. 4610 ◽  
Author(s):  
J. Víctor Álvarez ◽  
Susana B. Bravo ◽  
María García-Vence ◽  
María J. De Castro ◽  
Asteria Luzardo ◽  
...  
Keyword(s):  
Replacement Therapy ◽  
Delivery System ◽  
Skeletal Dysplasia ◽  
Cellular Protein ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Morquio A ◽  
Mps Iva ◽  
Mucopolysaccharidosis Type Iva

Morquio A syndrome, or mucopolysaccharidosis type IVA (MPS IVA), is a lysosomal storage disease due to mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. Systemic skeletal dysplasia and the related clinical features of MPS IVA are due to disruption of cartilage and its extracellular matrix, leading to an imbalance of growth. Enzyme replacement therapy (ERT) with recombinant human GALNS, alpha elosulfase, provides a systemic treatment. However, this therapy has a limited impact on skeletal dysplasia because the infused enzyme cannot penetrate cartilage and bone. Therefore, an alternative therapeutic approach to reach the cartilage is an unmet challenge. We have developed a new drug delivery system based on a nanostructure lipid carrier with the capacity to immobilize enzymes used for ERT and to target the lysosomes. This study aimed to assess the effect of the encapsulated enzyme in this new delivery system, using in vitro proteomic technology. We found a greater internalization of the enzyme carried by nanoparticles inside the cells and an improvement of cellular protein routes previously impaired by the disease, compared with conventional ERT. This is the first qualitative and quantitative proteomic assay that demonstrates the advantages of a new delivery system to improve the MPS IVA ERT.

scholarly journals Bisphosphonate Treatment in a Patient Affected by MPS IVA with Osteoporotic Phenotype

2013 ◽  
Vol 2013 ◽  
pp. 1-4 ◽  
Author(s):  
Albina Tummolo ◽  
Orazio Gabrielli ◽  
Alberto Gaeta ◽  
Maristella Masciopinto ◽  
Lucia Zampini ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Keratan Sulfate ◽  
Inherited Metabolic Disorder ◽  
Allogenic Bone ◽  
Enzyme Replacement ◽  
Morquio A ◽  
Mps Iva ◽  
Or Gene ◽  
Mucopolysaccharidosis Type Iva ◽  
Morquio A Syndrome

Morquio A syndrome (Mucopolysaccharidosis type IVA) (MPS IVA) is a rare inherited metabolic disorder characterized by the defective degradation of keratan sulfate and chondroitin-6-sulfate. Classically, MPS IVA patients present with severe multisystemic involvement and have a short life expectancy. Attenuated forms with clinical features limited to minor skeletal abnormalities and short stature have also been described, sometimes associated to an early-onset osteoporotic phenotype. No treatment with allogenic bone marrow transplantation or gene therapy is currently available for Morquio A syndrome, and enzyme replacement therapy is under evaluation. We report a case of MPS IVA, who manifested tardily attenuated phenotype and significant bone mass reduction, which was treated with a bisphosphonate (BPN), resulting in an improvement of X-ray skeletal aspects and functional bone performance. We suggest that the use of bisphosphonates may be an interesting supportive therapeutic option for Morquio A patients with osteoporotic phenotype, but further studies involving more patients are necessary to confirm our findings.

scholarly journals Morquio’s Syndrome: A Case Report of Two Siblings

2017 ◽  
Vol 2017 ◽  
pp. 1-4
Author(s):  
Sathish Muthukumar Ramalingam ◽  
Daya Srinivasan ◽  
Sandhya ArunKumar ◽  
Joe Louis ChiriyanKandath ◽  
Sriram Kaliamoorthy
Keyword(s):  
Storage Disease ◽  
Mucopolysaccharidosis Type ◽  
Lysosomal Storage ◽  
Enamel Hypoplasia ◽  
Rare Type ◽  
Diagnostic Aid ◽  
Mps Iva ◽  
Morquio Syndrome ◽  
Mucopolysaccharidosis Type Iva ◽  
Morquio's Syndrome

Morquio syndrome or MPS IVA is a rare type of lysosomal storage disease associated with highly specific dental abnormalities. We present two siblings with enamel hypoplasia and skeletal abnormalities. A diagnosis of mucopolysaccharidosis type IVA was reached based on the clinical, radiographic, and dental findings of the patients. The dental findings are useful diagnostic aid for the early diagnosis of this debilitating disorder.

scholarly journals Hearing Loss in Mucopolysaccharidoses: Current Knowledge and Future Directions

Diagnostics ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 554
Author(s):  
Jeremy Wolfberg ◽  
Keerthana Chintalapati ◽  
Shunji Tomatsu ◽  
Kyoko Nagao
Keyword(s):  
Hearing Loss ◽  
Current Knowledge ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Mixed Hearing Loss ◽  
Hearing Function ◽  
Common Clinical Presentation ◽  
Mps Iva ◽  
Mps Vii ◽  
Mps I

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by a deficiency of one of the enzymes involved in the degradation of glycosaminoglycans. Hearing loss is a common clinical presentation in MPS. This paper reviews the literature on hearing loss for each of the seven recognized subtypes of MPS. Hearing loss was found to be common in MPS I, II, III, IVA, VI, and VII, and absent from MPS IVB and MPS IX. MPS VI presents primarily with conductive hearing loss, while the other subtypes (MPS I, MPS II, MPS III, MPS IVA, and MPS VII) can present with any type of hearing loss (conductive, sensorineural, or mixed hearing loss). The sensorineural component develops as the disease progresses, but there is no consensus on the etiology of the sensorineural component. Enzyme replacement therapy (ERT) is the most common therapy utilized for MPS, but the effects of ERT on hearing function have been inconclusive. This review highlights a need for more comprehensive and multidisciplinary research on hearing function that includes behavioral testing, objective testing, and temporal bone imaging. This information would allow for better understanding of the progression and etiology of hearing loss. Owing to the prevalence of hearing loss in MPS, early diagnosis of hearing loss and annual comprehensive audiological evaluations are recommended.

scholarly journals Gaucher’s Disease in Lithuania: Its Diagnosis and Treatment

Medicina ◽  
2011 ◽  
Vol 47 (7) ◽  
pp. 405
Author(s):  
Gražina Kleinotienė ◽  
Anna Tylki-Szymanska ◽  
Barbara Czartoryska
Keyword(s):  
Clinical Picture ◽  
Hematological Parameters ◽  
Bone Lesions ◽  
Lysosomal Storage ◽  
Gaucher's Disease ◽  
Gaucher’S Disease ◽  
Lysosomal Disease ◽  
Therapeutic Goals ◽  
Enzyme Replacement

Gaucher’s disease is a lysosomal storage disease caused by the lack of beta-glucocerebrosidase enzyme, leading to the accumulation of glucocerebroside. Gaucher’s disease is the most frequent type of sphingolipidosis as well as the most frequent lysosomal disease. Clinically, two forms of Gaucher’s disease are defined: nonneuronopathic form, so-called type 1, characterized by hepatosplenomegaly, thrombocytopenia, anemia, and osteopenia, and neuronopathic form, known as types 2 and 3, which are also characterized by hepatosplenomegaly, hematological and bone changes; however, involvement of the central nervous system dominates in the clinical picture. Severe deficiency of beta-glucocerebrosidase activity allows confirming the diagnosis based on the clinical picture or the findings of bone marrow examination. Treatment with human glucocerebrosidase was introduced in 1991. Clinically good results are achieved: not only accumulation of glucocerebroside is stopped, but also positive changes in the reticuloendothelial system and an improvement in development and hematological parameters of children are observed as well as the development of bone lesions is reduced. To date, Gaucher’s disease has been diagnosed in 8 patients in Lithuania: 3 persons have type 3 and 5 have type 1 disease. Enzyme replacement therapy was started in 2001, and currently 6 persons are being treated. In majority of patients, Gaucher’s disease was suspected after exclusion of other possible proliferative diseases. All patients within the first or second year of treatment achieved the therapeutic goals, namely: normalization of hematological parameters, reduction in liver and spleen volumes, and bone pain relief.

scholarly journals Treating a teenager with Morquio A syndrome (mucopolysaccharidosis IV A) with Vimizim

2021 ◽  
Vol 66 (4) ◽  
pp. 109-117
Author(s):  
E. E. Gurinova ◽  
A. L. Sukhomyasova ◽  
A. N. Semyachkina ◽  
P. V. Ochirova
Keyword(s):  
Muscle Tone ◽  
Interdisciplinary Approach ◽  
Fine Motor ◽  
Enzyme Replacement ◽  
Lack Of Information ◽  
Morquio A ◽  
Mps Iva ◽  
Mucopolysaccharidosis Type Iva ◽  
Morquio A Syndrome ◽  
Elosulfase Alfa

The article describes a clinical case of enzyme replacement therapy (ERT) with elosulfase alfa for a teenager with mucopolysaccharidosis type IVA (MPS IVA, Morquio A syndrome). Treatment was started quite late, at the age of 12, against the background of a severe course of Morquio A syndrome. Nevertheless, the child showedan improvement in enduranceand fine motor skills, and an increase in muscle tone. The article discusses lack of information on modern methods of enzymereplacement therapy, as well as the limitations of this type of therapy. The paper emphasizes the need for an interdisciplinary approach to treat such diseases and alleviate the condition of patients.

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

2021 ◽  
Author(s):  
Dmitry V. Ivanov ◽  
Anna I. Ostrun ◽  
Vladimir M. Kenis ◽  
Tatiana V. Markova ◽  
Ekaterina Yu. Zakharova
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Clinical Case ◽  
Mucopolysaccharidosis Type ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Mucopolysaccharidosis Type Vi ◽  
Mps Vi ◽  
Arylsulfatase B ◽  
Arsb Gene

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.

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