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.

Hepatic Storage of Glycosaminoglycans in Feline and Canine Models of Mucopolysaccharidoses I, VI, and VII

1992 ◽  
Vol 29 (2) ◽  
pp. 112-119 ◽  
Author(s):  
M. E. Haskins ◽  
E. J. Otis ◽  
J. E. Hayden ◽  
P. F. Jezyk ◽  
L. Stramm
Keyword(s):  
Genetic Diseases ◽  
National Standards ◽  
University Of Pennsylvania ◽  
Laboratory Animals ◽  
Lysosomal Storage ◽  
Human Genetic Disease ◽  
Enzyme Replacement ◽  
Mps Vi ◽  
Mps Vii ◽  
Mps I

Livers from normal cats and dogs, cats with mucopolysaccharidoses (MPS) I and VI, and dogs with MPS VII were analyzed biochemically and morphometrically to determine the lysosomal storage of glycosaminoglycans (GAG) in these animal models of human genetic disease. Analyses were performed on liver samples from seven normal cats ranging in age from 13 weeks to 15 months; six MPS I-affected cats ranging in age from 10 weeks to 26 months; four MPS VI-affected cats ranging in age from 9 months to 32 months; four normal dogs ranging in age from 1 month to 47 months; and three MPS VII-affected dogs, 5 days, 11 days, and 14 months of age. All of the animals were from the breeding colony at the University of Pennsylvania School of Veterinary Medicine and were maintained in accordance with national standards for the care and use of laboratory animals. Each GAG subclass was quantitated, and total GAG concentration was determined. Liver from cats with MPS I had the highest total GAG concentration (5.7 times that of the control), followed by liver from dogs with MPS VII (1.8 times) and cats with MPS VI (1.5 times). These data were very closely correlated ( R2 = 0.982) with the results of the morphometric analyses of hepatocyte and Kupffer cell vacuolation associated with lysosomal storage and support the validity of both methods. This is particularly important for the quantification of total and individual GAG concentrations in tissue preparations. The values obtained should prove useful in future assessments of therapeutic regimes, such as enzyme replacement, bone marrow transplantation, and gene therapy, for these genetic diseases.

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 Toward Engineering the Mannose 6-Phosphate Elaboration Pathway in Plants for Enzyme Replacement Therapy of Lysosomal Storage Disorders

2019 ◽  
Vol 8 (12) ◽  
pp. 2190
Author(s):  
Ying Zeng ◽  
Xu He ◽  
Tatyana Danyukova ◽  
Sandra Pohl ◽  
Allison R. Kermode
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Substantial Reduction ◽  
Cost Effective ◽  
Biologically Active ◽  
Lysosomal Storage ◽  
In Planta ◽  
Enzyme Replacement ◽  
Mannose 6 Phosphate ◽  
Mps I

Mucopolysaccharidosis (MPS) I is a severe lysosomal storage disease caused by α-L-iduronidase (IDUA) deficiency, which results in accumulation of non-degraded glycosaminoglycans in lysosomes. Costly enzyme replacement therapy (ERT) is the conventional treatment for MPS I. Toward producing a more cost-effective and safe alternative to the commercial mammalian cell-based production systems, we have produced recombinant human IDUA in seeds of an Arabidopsis mutant to generate the enzyme in a biologically active and non-immunogenic form containing predominantly high mannose N-linked glycans. Recombinant enzyme in ERT is generally thought to require a mannose 6-phosphate (M6P) targeting signal for endocytosis into patient cells and for intracellular delivery to the lysosome. Toward effecting in planta phosphorylation, the human M6P elaboration machinery was successfully co-expressed along with the recombinant human IDUA using a single multi-gene construct. Uptake studies using purified putative M6P-IDUA generated in planta on cultured MPS I primary fibroblasts indicated that the endocytosed recombinant lysosomal enzyme led to substantial reduction of glycosaminoglycans. However, the efficiency of the putative M6P-IDUA in reducing glycosaminoglycan storage was comparable with the efficiency of the purified plant mannose-terminated IDUA, suggesting a poor in planta M6P-elaboration by the expressed machinery. Although the in planta M6P-tagging process efficiency would need to be improved, an exciting outcome of our work was that the plant-derived mannose-terminated IDUA yielded results comparable to those obtained with the commercial IDUA (Aldurazyme® (Sanofi, Paris, France)), and a significant amount of the plant-IDUA is trafficked by a M6P receptor-independent pathway. Thus, a plant-based platform for generating lysosomal hydrolases may represent an alternative and cost-effective strategy to the conventional ERT, without the requirement for additional processing to create the M6P motif.

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 Hubungan kebisingan terhadap fungsi pendengaran pekerja mesin pembangkit listrik tenaga diesel di PLTD Suluttenggo kota Manado

2016 ◽  
Vol 4 (1) ◽  
Author(s):  
Ramdan P. I. Timang ◽  
Vennetia R. Danes ◽  
Fransiska Lintong
Keyword(s):  
Hearing Loss ◽  
Power Plant ◽  
Hearing Impairment ◽  
Bivariate Analysis ◽  
P Value ◽  
Frequency Noise ◽  
Cross Sectional ◽  
Mixed Hearing Loss ◽  
Hearing Function ◽  
Cross Sectional Design

Abstract: Noise is unwanted sound heard by ears. Damages of ears usually take place on the tympanic membrane or on the ossicles. Initially, there will be loss of hearing to high frequency noises, and it will gradually decrease to the lowest frequency noise. This study aimed to obtain the relationship of noise and hearing function among diesel power plant workers at PLTD Suluttenggo Manado. This was an analitycal study using a cross sectional design. Samples were 20 workers at PLTD Suluttenggo in Manado. Data were obtained by using questionnaires and examintaion of hearing function with an audiometry. The data were analyzed by using SPSS and the Spearmen test. The results showed that there were hearing impairment in 30% of the workers. According to the bivariate analysis, there was a significant relationship between the level of noise and the hearing impairment among the workers with a p value = 0.015 (p < 0.05). The most frequent hearing impairment among the workers was mixed hearing loss. Conclusion: Workers who worked in a place with high intensity noise had higher risk to develop hearing impairment.Keywords: diesel power plant machine, noise, hearingAbstrak: Kebisingan adalah suara yang tidak dikehendaki oleh telinga. Kerusakan telinga biasanya terjadi pada gendang telinga atau ossicles. Awalnya akan terjadi kehilangan pendengaran terhadap frekuensi tinggi, namun perlahan pada frekuensi yang semakin menurun sampai kepada frekuensi rendah. Penelitian ini bertujuan untuk mengetahui hubungan kebisingan terhadap fungsi pendengaran pada pekerja mesin pembangkit listrik tenaga diesel di PLTD Suluttenggo Kota Manado. Metode penelitian yang digunakan yaitu metode analitik dengan menggunakan rancangan potong lintang. Sampel berjumlah 20 orang yang diambil dari pekerja mesin pembangkit listrik tenaga diesel di PLTD Suluttenggo Kota Manado. Data diperoleh melalui kuisioner dan pemeriksaan fungsi pendengaran dengan menggunakan audiometri. Data dianalisis dengan menggunakan Statistical Program Product and Service Solution (SPSS) dan menggunakan uji Spearman. Hasil penelitian menunjukkan bahwa terdapat gangguan pendengaran sebesar 30% pada seluruh pekerja. Hasil analisis bivariat didapatkan bahwa terdapat hubungan bermakna antara tingkat kebisingan dan gangguan pendengaran dengan nilai p = 0,015 ( p < 0,05). Gangguan pendengaran yang paling banyak diderita oleh pekerja ialah tuli campuran (Mixed Hearing Loss). Simpulan: Pekerja yang bekerja pada intensitas bising yang tinggi memiliki resiko lebih besar menderita gangguan pendengaran.Kata kunci: mesin PLTD, bising, pendengaran

scholarly journals Differences in MPS I and MPS II Disease Manifestations

2021 ◽  
Vol 22 (15) ◽  
pp. 7888
Author(s):  
Christiane S. Hampe ◽  
Brianna D. Yund ◽  
Paul J. Orchard ◽  
Troy C. Lund ◽  
Jacob Wesley ◽  
...  
Keyword(s):  
Dermatan Sulfate ◽  
Treatment Options ◽  
Neurological Involvement ◽  
Type I ◽  
Ionic Balance ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Mps Ii ◽  
Corneal Clouding ◽  
Mps I

Mucopolysaccharidosis (MPS) type I and II are two closely related lysosomal storage diseases associated with disrupted glycosaminoglycan catabolism. In MPS II, the first step of degradation of heparan sulfate (HS) and dermatan sulfate (DS) is blocked by a deficiency in the lysosomal enzyme iduronate 2-sulfatase (IDS), while, in MPS I, blockage of the second step is caused by a deficiency in iduronidase (IDUA). The subsequent accumulation of HS and DS causes lysosomal hypertrophy and an increase in the number of lysosomes in cells, and impacts cellular functions, like cell adhesion, endocytosis, intracellular trafficking of different molecules, intracellular ionic balance, and inflammation. Characteristic phenotypical manifestations of both MPS I and II include skeletal disease, reflected in short stature, inguinal and umbilical hernias, hydrocephalus, hearing loss, coarse facial features, protruded abdomen with hepatosplenomegaly, and neurological involvement with varying functional concerns. However, a few manifestations are disease-specific, including corneal clouding in MPS I, epidermal manifestations in MPS II, and differences in the severity and nature of behavioral concerns. These phenotypic differences appear to be related to different ratios between DS and HS, and their sulfation levels. MPS I is characterized by higher DS/HS levels and lower sulfation levels, while HS levels dominate over DS levels in MPS II and sulfation levels are higher. The high presence of DS in the cornea and its involvement in the arrangement of collagen fibrils potentially causes corneal clouding to be prevalent in MPS I, but not in MPS II. The differences in neurological involvement may be due to the increased HS levels in MPS II, because of the involvement of HS in neuronal development. Current treatment options for patients with MPS II are often restricted to enzyme replacement therapy (ERT). While ERT has beneficial effects on respiratory and cardiopulmonary function and extends the lifespan of the patients, it does not significantly affect CNS manifestations, probably because the enzyme cannot pass the blood–brain barrier at sufficient levels. Many experimental therapies, therefore, aim at delivery of IDS to the CNS in an attempt to prevent neurocognitive decline in the patients.

Dispersal of Therapeutic Donor Cells throughout the Brain of Mice with Lysosomal Storage Disease Occurs Following in Utero Transplantation of Fetal-Derived Neuronal Stem Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 247-247 ◽  
Author(s):  
Brian W. Soper ◽  
C. Bruce Anthony ◽  
Anna-Michelle Dendi-Young ◽  
Mark D. Lessard ◽  
Travis L. Alley ◽  
...  
Keyword(s):  
Stem Cells ◽  
Ventricular Zone ◽  
In Utero ◽  
Lysosomal Storage ◽  
Neuronal Stem Cells ◽  
Functional Changes ◽  
Enzyme Replacement ◽  
Donor Cells ◽  
Mps Vii ◽  
Histological Staining

Abstract Mucopolysaccharidosis Type VII (MPS VII) is one of many lysosomal storage diseases and is caused by a deficiency of beta-glucuronidase (GUS). Progressive accumulation of undegraded glycosaminoglycan (GAG) intermediates occurs in the lysosome diminishing intellect, mobility, organ function, and life span. Previously, the efficacy of enzyme replacement therapy (ERT), bone marrow transplantation, and gene therapy have been tested in MPS VII mice. GUS supplied to serum by ERT or released into extracellular spaces from transplanted (Tx) normal or gene transduced cells is taken up by receptor mediated endocytosis and transported to the lysosome. All these treatments reduce lysosomal storage in visceral organs, but poorly deliver sufficient enzyme to the central nervous system (CNS). We hypothesized that in utero intrathecal transplantation of primary neuronal stem cells (NSC) would remedy the GUS deficiency of MPS VII CNS. We isolated NSC from the cortical ventricular zone (CVZ) of E14 GUS+ eGFP+ fetuses. CVZ NSC incubated with EGF and bFGF formed neurospheres in 3–5 days. E14 MPS VII GUS- recipients were Tx intrathecally with NSC and examined for engraftment by histological staining for GUS and eGFP expressing cells. Successful engraftment occurred in 13 of 23 (56.5%) MPS VII recipients. Three animals Tx with 5–25,000 (K) had GUS+ cells in the rostral migratory stream (RMS). Two of seven animals Tx with 50-80K had donor cells in the RMS and five had donor cells in olfactory bulb, cerebrum (cortical layers, corpus callosum and striatum), midbrain, hippocampus (including dentate gyrus), and the cerebellum (Purkinje layers, peduncle, and lobular regions). This demonstrates “complete” dispersal. One mouse Tx with 90K had donor cells lining the lateral ventricle. Another Tx with 160K had donor cells lining ventricular spaces and throughout the cerebrum away from the RMS. An animal Tx with 180K NSC had “complete” donor engraftment like those above. Histological staining for GUS+ donor cells in mice with “complete” engraftment showed levels of staining greater than untreated heterozygous controls, both in numbers of cells positive and in intensity of staining. Biochemistry of tissue sections from these animals averaged 59.5 ±9.2% (mean ±SE) of normal (+/+) activity. The oldest animal detected with “complete” engraftment thus far was 7 months old at sacrifice, demonstrating long-term durability of engraftment. Using anti-eGFP, beta-tubulin III (neurons), and GFAP (astrocytes) antibodies, we confirmed the “complete” engraftment was due to widespread dispersal and integration of donor derived cells and not to diffusion of GUS enzyme from a few engrafted cells. The lineage markers confirmed normal differentiation of donor CVZ NSC. Further evaluations are underway to measure cognitive function in treated animals by the Repeated Acquisition and Performance Chamber (RAPC). Comparison of untreated MPS VII adult mice to normal controls by the RAPC indicates significant deficiencies in learning and memory in untreated MPS VII mice and confirms our ability to measure functional changes in treated animals. In summary, GUS+ eGFP+ fetal NSC primary isolates engraft brain of MPS VII fetal recipients and restore GUS activity ≥ phenotypically normal MPS VII heterozygotes.

Mucopolysaccharidoses

2019 ◽  
pp. 79-82
Author(s):  
Kevin B. Hoover
Keyword(s):  
Stem Cell ◽  
Soft Tissues ◽  
Lysosomal Storage Diseases ◽  
Appendicular Skeleton ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Enzyme Replacement ◽  
Mps Ii ◽  
Spine Mri ◽  
Mps I

Chapter 84 discusses mucopolysaccharidoses, which are genetic, lysosomal storage diseases resulting in the accumulation of glycosaminoglycans (GAG) in the soft tissues. Musculoskeletal complications of mucopolysaccharidosis (MPS) are common beginning in childhood. These result from abnormal ossification and periarticular GAG accumulation. Radiographs of the axial and appendicular skeleton (skeletal survey) are used for the baseline assessment of MPS disease. Progression of skeletal abnormalities is monitored with annual cervical spine MRI. Stem cell transplantation is the treatment of choice in MPS I, and enzyme replacement therapy (ERT) is the treatment of choice in MPS I Hurler-Scheie and Scheie, MPS II, and MPS VI.

scholarly journals Syngeneic bone marrow transplantation reduces the hearing loss associated with murine mucopolysaccharidosis type VII

Blood ◽  
1995 ◽  
Vol 86 (5) ◽  
pp. 2033-2040 ◽  
Author(s):  
MS Sands ◽  
LC Erway ◽  
C Vogler ◽  
WS Sly ◽  
EH Birkenmeier
Keyword(s):  
Bone Marrow ◽  
Hearing Loss ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Mucopolysaccharidosis Type ◽  
Lysosomal Storage ◽  
Middle Ear Mucosa ◽  
Mps Vii ◽  
The Impact

MPS VII mice are deficient in beta-glucuronidase and share many clinical, biochemical, and pathologic characteristics with human mucopolysaccharidosis type VII (MPS VII). We have shown that syngeneic bone marrow transplantation (BMT) prolongs survival and reduces lysosomal storage in many organs of the MPS VII mouse. In this report, we quantify the hearing loss and determine the impact of syngeneic BMT on the development of deafness and the associated pathology in the MPS VII mouse. Eleven weeks after syngeneic BMT performed at birth, treated MPS VII mice had normal auditory-evoked brainstem responses (ABR), whereas untreated MPS VII mice had ABR thresholds 43 dB higher than normal. Treated MPS VII mice had beta-glucuronidase-positive cells in the temporal bone and in the subepithelial connective tissue of the external auditory canal. There was less thickening of the tympanic membrane and middle ear mucosa and decreased distortion of the ossicles and the cochlear bone. Although transplanted MPS VII mice had increased ABR thresholds by 33 weeks of age, four of the six had thresholds 12 to 32 dB lower than untreated mutants. These data indicate that syngeneic BMT in newborn MPS VII mice prevents early hearing loss and, in some animals, results in long-term improved auditory function.

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