Characterization of disease-specific chondroitin sulfate nonreducing end accumulation in mucopolysaccharidosis IVA

Glycobiology ◽  
2020 ◽  
Vol 30 (7) ◽  
pp. 433-445
Author(s):  
Roger Lawrence ◽  
Heather Prill ◽  
Preejith P Vachali ◽  
Evan G Adintori ◽  
Greg de Hart ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Keratan Sulfate ◽  
Autosomal Recessive Disorder ◽  
Pilot Studies ◽  
Mucopolysaccharidosis Iva ◽  
Enzyme Replacement ◽  
Mps Iva ◽  
Morquio Syndrome ◽  
Disease Specific

Abstract Morquio syndrome type A, also known as MPS IVA, is a rare autosomal recessive disorder caused by deficiency of N-acetylgalactosamine-6-sulfatase, a lysosomal hydrolase critical in the degradation of keratan sulfate (KS) and chondroitin sulfate (CS). The CS that accumulates in MPS IVA patients has a disease-specific nonreducing end (NRE) terminating with N-acetyl-D-galactosamine 6-sulfate, which can be specifically quantified after enzymatic depolymerization of CS polysaccharide chains. The abundance of N-acetyl-D-galactosamine 6-sulfate over other possible NRE structures is diagnostic for MPS IVA. Here, we describe an assay for the liberation and measurement of N-acetyl-D-galactosamine 6-sulfate and explore its application to MPS IVA patient samples in pilot studies examining disease detection, effects of age and treatment with enzyme-replacement therapy. This assay complements the existing urinary KS assay by quantifying CS-derived substrates, which represent a distinct biochemical aspect of MPS IVA. A more complete understanding of the disease could help to more definitively detect disease across age ranges and more completely measure the pharmacodynamic efficacy of therapies. Larger studies will be needed to clarify the potential value of this CS-derived substrate to manage disease in MPS IVA patients.

scholarly journals Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management

2020 ◽  
Vol 21 (4) ◽  
pp. 1517 ◽  
Author(s):  
Kazuki Sawamoto ◽  
José Álvarez González ◽  
Matthew Piechnik ◽  
Francisco Otero ◽  
Maria Couce ◽  
...  
Keyword(s):  
Skeletal Dysplasia ◽  
Keratan Sulfate ◽  
Life Time ◽  
Preclinical Study ◽  
Biochemical Tests ◽  
Lysosomal Disease ◽  
Hematopoietic Stem ◽  
Mucopolysaccharidosis Iva ◽  
Enzyme Replacement ◽  
Mps Iva

Mucopolysaccharidosis type IVA (MPS IVA, or Morquio syndrome type A) is an inherited metabolic lysosomal disease caused by the deficiency of the N-acetylglucosamine-6-sulfate sulfatase enzyme. The deficiency of this enzyme accumulates the specific glycosaminoglycans (GAG), keratan sulfate, and chondroitin-6-sulfate mainly in bone, cartilage, and its extracellular matrix. GAG accumulation in these lesions leads to unique skeletal dysplasia in MPS IVA patients. Clinical, radiographic, and biochemical tests are needed to complete the diagnosis of MPS IVA since some clinical characteristics in MPS IVA are overlapped with other disorders. Early and accurate diagnosis is vital to optimizing patient management, which provides a better quality of life and prolonged life-time in MPS IVA patients. Currently, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are available for patients with MPS IVA. However, ERT and HSCT do not have enough impact on bone and cartilage lesions in patients with MPS IVA. Penetrating the deficient enzyme into an avascular lesion remains an unmet challenge, and several innovative therapies are under development in a preclinical study. In this review article, we comprehensively describe the current diagnosis, treatment, and management for MPS IVA. We also illustrate developing future therapies focused on the improvement of skeletal dysplasia in MPS IVA.

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 Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model

2019 ◽  
Vol 20 (17) ◽  
pp. 4139 ◽  
Author(s):  
Kazuki Sawamoto ◽  
Shunji Tomatsu
Keyword(s):  
Positive Impact ◽  
Bone Lesion ◽  
Enzyme Therapy ◽  
Bone Pathology ◽  
Mucopolysaccharidosis Iva ◽  
Enzyme Replacement ◽  
Substrate Degradation ◽  
Mps Iva ◽  
Ph Range ◽  
Optimal Ph

Mucopolysaccharidosis IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Conventional enzyme replacement therapy (ERT) is approved for MPS IVA. However, the fact that the infused enzyme cannot penetrate avascular lesions in cartilage leads to minimal impact on the bone lesion. Moreover, short half-life, high cost, instability, and narrow optimal pH range remain unmet challenges in ERT. Thermostable keratanase, endo-β-N-acetylglucosaminidase, has a unique character of a wide optimal pH range of pH 5.0–7.0. We hypothesized that this endoglycosidase degrades keratan sulfate (KS) polymer in circulating blood and, therefore, ameliorates the accumulation of KS in multiple tissues. We propose a novel approach, Substrate Degradation Enzyme Therapy (SDET), to treat bone lesion of MPS IVA. We assessed the effect of thermostable keratanase on blood KS level and bone pathology using Galns knock-out MPS IVA mice. After a single administration of 2 U/kg (= 0.2 mg/kg) of the enzyme at 8 weeks of age via intravenous injection, the level of serum KS was significantly decreased to normal range level, and this suppression was maintained for at least 4 weeks. We administered 2 U/kg of the enzyme to MPS IVA mice every fourth week for 12 weeks (total of 3 times) at newborns or 8 weeks of age. After a third injection, serum mono-sulfated KS levels were kept low for 4 weeks, similar to that in control mice, and at 12 weeks, bone pathology was markedly improved when SDET started at newborns, compared with untreated MPS IVA mice. Overall, thermostable keratanase reduces the level of KS in blood and provides a positive impact on cartilage lesions, demonstrating that SDET is a novel therapeutic approach to MPS IVA.

scholarly journals Characterization of keratan sulfate isolated from liver affected by Morquio syndrome.

1983 ◽  
Vol 139 (3) ◽  
pp. 321-326 ◽  
Author(s):  
RYOJI MINAMI ◽  
TOMOYASU IKENO ◽  
CHIHARU IGARASHI ◽  
SATOSHI TSUGAWA ◽  
TOORU NAKAO
Keyword(s):  
Keratan Sulfate ◽  
Morquio Syndrome

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 A 9-Month-Old with Skeletal Abnormalities and a Consanguineous Sibling with Mucopolysaccharidosis IVA: The Role of Urinary Glycosaminoglycan Testing in Disease Diagnosis and Treatment Monitoring

2021 ◽  
Vol 14 ◽  
pp. 117954762199940
Author(s):  
Eric Goldman ◽  
Angela Vu ◽  
Kelly Dietz ◽  
Stefani N Thomas
Keyword(s):  
Autosomal Recessive ◽  
Disease Diagnosis ◽  
Lysosomal Storage ◽  
Mucopolysaccharidosis Iva ◽  
Enzyme Replacement ◽  
Mps Iva ◽  
Normal Urine

Mucopolysaccharidosis IVA (MPS IVA) is a rare autosomal recessive lysosomal storage disorder resulting from N-acetylgalactosamine-6-sulfatase (GALNS) deficiency that occurs in approximately 1 in 76 000 to 1 in 640 000 live births. Given that the diagnosis of MPS IVA relies heavily on the results of initial urine glycosaminoglycan (GAG) screening, cases that present with falsely normal urine GAG concentrations can delay the diagnosis and follow-up care for patients. This case study follows a patient diagnosed with MPS IVA at 9 months of age based on relation to a consanguineous 3-year-old sibling with MPS IVA and the use of direct enzyme activity analysis. Details regarding skeletal presentation and identification of genetic variants are presented along with data on follow-up urinary GAG monitoring during treatment with enzyme replacement therapy and treatment for a growth hormone disorder.

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.

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