scholarly journals Growth Plate Pathology in the Mucopolysaccharidosis Type VI Rat Model—An Experimental and Computational Approach

Diagnostics ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 360
Author(s):  
Johana M. Guevara-Morales ◽  
Michael Frohbergh ◽  
Hector Castro-Abril ◽  
Juan J. Vaca-González ◽  
Luis A. Barrera ◽  
...  
Keyword(s):  
Growth Plate ◽  
Metabolic Diseases ◽  
Histological Evaluation ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type Vi ◽  
Mps Vi ◽  
In Silico Simulation ◽  
Advanced Stages ◽  
Experimental Approaches ◽  
Experimental Findings

Background: Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases caused by impaired function or absence of lysosomal enzymes involved in degradation of glycosaminoglycans. Clinically, MPS are skeletal dysplasias, characterized by cartilage abnormalities and disturbances in the process of endochondral ossification. Histologic abnormalities of growth cartilage have been reported at advanced stages of the disease, but information regarding growth plate pathology progression either in humans or in animal models, as well as its pathophysiology, is limited. Methods: Histological analyses of distal femur growth plates of wild type (WT) and mucopolysaccharidosis type VI (MPS VI) rats at different stages of development were performed, including quantitative data. Experimental findings were then analyzed in a theoretical scenario. Results: Histological evaluation showed a progressive loss of histological architecture within the growth plate. Furthermore, in silico simulation suggest the abnormal cell distribution in the tissue may lead to alterations in biochemical gradients, which may be one of the factors contributing to the growth plate abnormalities observed, highlighting aspects that must be the focus of future experimental works. Conclusion: The results presented shed some light on the progression of growth plate alterations observed in MPS VI and evidence the potentiality of combined theoretical and experimental approaches to better understand pathological scenarios, which is a necessary step to improve the search for novel therapeutic approaches.

scholarly journals Overexpression of N-acetylgalactosamine-4-sulphatase induces a multiple sulphatase deficiency in mucopolysaccharidosis-type-VI fibroblasts

1993 ◽  
Vol 294 (3) ◽  
pp. 657-662 ◽  
Author(s):  
D S Anson ◽  
V Muller ◽  
J Bielicki ◽  
G S Harper ◽  
J J Hopwood
Keyword(s):  
Practical Importance ◽  
High Titre ◽  
Skin Fibroblasts ◽  
Mucopolysaccharidosis Type ◽  
Subcellular Compartment ◽  
Mucopolysaccharidosis Type Vi ◽  
Steroid Sulphatase ◽  
Mps Vi ◽  
Genetically Determined ◽  
Processing Mechanism

High-titre stocks of an amphotropic retrovirus, constructed so as to express a full-length cDNA encoding the human lysosomal enzyme N-acetylgalactosamine-4-sulphatase (4-sulphatase) from the cytomegalovirus immediate early promoter, were used to infect skin fibroblasts from a clinically severe mucopolysaccharidosis type VI (MPS VI) patient. The infected MPS VI cells showed correction of the enzymic defect with the enzyme being expressed at high levels and in the correct subcellular compartment. Surprisingly this did not result in correction of glycosaminoglycan turnover as measured by accumulation of 35S in metabolically labelled cells. We demonstrate that this is apparently caused by an induced reduction of the activities of other lysosomal sulphatases, presumably due to competition for a sulphatase-specific processing mechanism by the over-expressed 4-sulphatase. The level of steroid sulphatase, which is a microsomal sulphatase, was also reduced. Infection of skin fibroblasts from a second, clinically mildly affected, MPS VI patient with the same virus also resulted in no significant change in the level of glycosaminoglycan storage. However, in this case the cause of the observed phenomenon was less clear. These results are of obvious practical importance when considering gene therapy for a sulphatase deficiency such as MPS VI and also provide possible new avenues for exploration of the processes involved in sulphatase synthesis and genetically determined multiple sulphatase deficiency.

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.

Hydrocephalus in mucopolysaccharidosis Type VI successfully treated with endoscopic third ventriculostomy

2013 ◽  
Vol 11 (3) ◽  
pp. 327-330 ◽  
Author(s):  
Ângelo Raimundo da Silva Neto ◽  
Gervina Brady Moreira Holanda ◽  
Maria Cláudia Saldanha Farias ◽  
Gladstone Santos da Costa ◽  
Hougelle Simplício Gomes Pereira
Keyword(s):  
Carpal Tunnel Syndrome ◽  
Fourth Ventricle ◽  
Endoscopic Third Ventriculostomy ◽  
Third Ventriculostomy ◽  
Communicating Hydrocephalus ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type Vi ◽  
Mps Vi ◽  
Arylsulfatase B ◽  
Tunnel Syndrome

Mucopolysaccharidosis (MPS) Type VI, or Maroteaux-Lamy syndrome, is characterized by a deficiency of the enzyme arylsulfatase B (ASB). In patients with this disorder, craniocervical compression, carpal tunnel syndrome, and communicating hydrocephalus are common. Traditionally, hydrocephalus occurring in patients with MPS VI has been treated with shunt placements. Considering obstruction of the outlets from the fourth ventricle at the craniocervical transition, the authors decided to treat a female patient with MPS VI via endoscopic third ventriculostomy. She was 12 years old and had refractory headaches. This seems to be the first reported instance of the neuroendoscopic treatment of hydrocephalus in a patient with MPS VI. The pathophysiology is briefly discussed.

scholarly journals Human N-acetylgalactosamine-4-sulphatase biosynthesis and maturation in normal, Maroteaux-Lamy and multiple-sulphatase-deficient fibroblasts

1990 ◽  
Vol 268 (2) ◽  
pp. 379-386 ◽  
Author(s):  
J A Taylor ◽  
G J Gibson ◽  
D A Brooks ◽  
J J Hopwood
Keyword(s):  
Monoclonal Antibodies ◽  
Clinical Characteristics ◽  
Intracellular Transport ◽  
Culture Medium ◽  
Clinical Phenotype ◽  
Immunoaffinity Chromatography ◽  
Enzyme Synthesis ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type Vi ◽  
Mps Vi

The biosynthesis and maturation of N-acetylgalactosamine-4-sulphatase (4-sulphatase) was studied in normal fibroblasts and in fibroblasts from patients with either mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome) or multiple sulphatase deficiency (MSD). Fibroblasts were incubated in culture medium containing [3H]leucine or [35S]methionine, and radiolabelled 4-sulphatase was isolated by immunoaffinity chromatography using 4-sulphatase-specific monoclonal antibodies. In normal fibroblasts a precursor of 66 kDa, detected intracellularly after 3 h and in NH4Cl-induced secretions, was processed intracellularly, within an additional 3 h, to a polypeptide of 57 kDa composed of disulphide-linked polypeptides of 43 kDa and 8 kDa. All fibroblast lines obtained from MPS VI patients, exhibiting clinical characteristics ranging from no clearly recognized symptoms to the severe classical phenotype, incorporated radioactivity into immune-purified 4-sulphatase at a rate less than 10% of that seen in normal fibroblasts. Maturation of the residual 4-sulphatase showed, variously, features which may be indicative of delayed intracellular transport, decreased intracellular stability, failure of lysosomal targetting or resistance to enzyme processing. Although some features of the residual enzyme synthesis and maturation were consistent with the patient's clinical phenotype, this was infrequent. The maturation of 4-sulphatase in fibroblasts from MSD patients was indistinguishable from that in normal fibroblasts, and the half-life of 4-sulphatase in these fibroblasts, determined after a 24 h pulse and prolonged chase, was only slightly less than that in normal fibroblasts.

scholarly journals Restoration of arylsulphatase B activity in human mucopolysaccharidosis-type-VI fibroblasts by retroviral-vector-mediated gene transfer

1991 ◽  
Vol 276 (2) ◽  
pp. 499-504 ◽  
Author(s):  
C Peters ◽  
W Rommerskirch ◽  
S Modaressi ◽  
K von Figura
Keyword(s):  
Gene Transfer ◽  
Retroviral Vector ◽  
Mucopolysaccharidosis Type ◽  
Lysosomal Storage ◽  
Packaging Cell Line ◽  
Retroviral Gene Transfer ◽  
Gene Replication ◽  
Packaging Cell ◽  
Mucopolysaccharidosis Type Vi ◽  
Mps Vi

The Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI; MPS VI) is a lysosomal storage disease caused by deficiency of the enzyme arylsulphatase B (ASB). A human ASB cDNA has been subcloned into the retroviral vector pXT1 containing the bacterial neomycin-resistance gene and an internal thymidine kinase promoter for transcription of the inserted gene. Replication defective retrovirus was generated by transfecting the construct into the amphotropic packaging cell line PA317. Human MPS VI fibroblasts infected with recombinant retrovirus integrated the provirus into their genome and expressed retrovirus-encoded ASB mRNAs. In infected fibroblasts the level of ASB was up to 36-fold higher than in normal fibroblasts. Biosynthesis and processing of ASB in infected MPS VI fibroblasts was accomplished as in normal fibroblasts, and mature, enzymically active, ASB accumulated in dense lysosomes, indicating that the ASB deficiency in MPS VI fibroblasts was corrected by the retroviral gene transfer.

scholarly journals Knee and ankle disorders during functional gait in mucopolysaccharidosis type VI

2021 ◽  
Vol 28 (1) ◽  
pp. 117-123
Author(s):  
Bárbara Bernardo Figueirêdo ◽  
Paulo Magalhães ◽  
Breno Azevedo ◽  
Maria Lucila Cavalcanti ◽  
Maria Emília Melo ◽  
...  
Keyword(s):  
Cross Sectional Study ◽  
Initial Contact ◽  
Mucopolysaccharidosis Type ◽  
Adult Group ◽  
Cross Sectional ◽  
Adolescent Group ◽  
Child Group ◽  
Mucopolysaccharidosis Type Vi ◽  
Mps Vi ◽  
Functional Gait

ABSTRACT To evaluate knee and ankle disorders during functional gait assessment in individuals with Mucopolysaccharidosis type VI (MPS VI). 19 subjects were included in this cross-sectional study and allocated in three groups according to age: Children Group (n=11); Adolescent Group (n=4); and Adult Group (n=4). Subphases of one gait cycle were analyzed: Initial contact; Medium support, and Pre-Balance. All volunteers with MPS VI presented greater knee and ankle flexion angles, in all gait subphases, when compared to the normal values defined by literature (p<0.05). Initial contact subphase: knee flexion angle ranging from 8.5º to 15º; Ankle = Child Group −23.73º ± 8.53º; Adolescent Group = −25º ± 11.22º; Adult Group = −27.75º ± 3.3º. Medium support subphase: Knee = Child Group 19.64º ± 10.47º; Adolescent Group 16.75º ± 10.34º; Adult Group = 21.25º ± 12.84º. Ankle = Child Group −18.82º ± 8.91º ± 8.53º; Adolescent Group = −16.5º ± 9.33º; Adult Group = −22.25º ± 4.19º. Pre-Balance subphase: Knee = Child Group 22.72º ± 13.49º; Adolescent Group 21.25º ± 7.97º; Adult Group = 27º ± 16.27º. Ankle = Child Group -15º ± 9.76º; Adolescent Group = −15.75º ± 5.31º; Adult Group = −14.75º ± 3.86º. In this study, MPS VI individuals presented hyperflexion of knee and ankle as the main joint disorders during functional gait, regardless of age.

scholarly journals Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome): defining and measuring functional impacts in pediatric patients

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Beth Leiro ◽  
Dawn Phillips ◽  
Melanie Duiker ◽  
Paul Harmatz ◽  
Sharon Charles
Keyword(s):  
Focus Group ◽  
Upper Extremity ◽  
Pediatric Patients ◽  
Fine Motor ◽  
Motor Deficits ◽  
Mucopolysaccharidosis Type ◽  
Impaired Mobility ◽  
Mucopolysaccharidosis Type Vi ◽  
Mps Vi ◽  
Disease Concepts

Abstract Background Research about pediatric patients’ perspective on mucopolysaccharidosis type VI (MPS VI) and its impact on daily life is limited. We aimed to identify the disease concepts of interest that most impact function and day-to-day life of pediatric patients with MPS VI, and to consider clinical outcome assessments (COAs) that may potentially measure meaningful improvements in these concepts. Methods Potential focus group participants were identified by the National MPS Society (USA) and invited to participate if they self-reported a clinician-provided diagnosis of MPS VI and were 4 to 18 years, receiving enzyme replacement therapy (ERT), and available to attend a 1-day focus group with their caregiver in Dallas, TX, USA. The focus group consisted of a series of polling and open-ended concept elicitation questions and a cognitive debriefing session. The discussion was audio recorded, transcribed verbatim, and analyzed to identify disease concepts of interest and functional impacts most relevant to participants. Results Overall, caregivers (n = 9) and patients with MPS VI (n = 9) endorsed that although their children/they receive ERT, residual symptoms exist and impact health-related quality of life. The key disease concepts of interest identified were impaired mobility, upper extremity and fine motor deficits, pain, and fatigue. Pain was unanimously reported by all patients across many areas of the body and impacted daily activity. Key disease concepts were mapped to a selection of pediatric COAs including generic measures such as PROMIS®, PODCI, CHAQ, and PedsQL™. Caregivers endorsed the relevance of PODCI and PROMIS Upper Extremity, Mobility, and Pain items and all patients completed the NIH Toolbox Pegboard Dexterity Test. Additional COAs that aligned with the disease concepts included range of motion, the 2- and 6-min walk tests, timed stair climbs, Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition, grip strength, pain visual analog scale, and the Faces Pain Scale-Revised. Conclusion An MPS VI focus group of pediatric patients and their caregivers identified impaired mobility, upper extremity and fine motor deficits, pain, and fatigue as key disease concepts of interest. These disease concepts were mapped to existing pediatric COAs, which were provided to the group for endorsement of their relevance.

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