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.

scholarly journals Modeling Mucopolysaccharidosis Type II in the Fruit Fly by Using the RNA Interference Approach

Life ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 263
Author(s):  
Laura Rigon ◽  
Nicole Kucharowski ◽  
Franka Eckardt ◽  
Reinhard Bauer
Keyword(s):  
Rna Interference ◽  
Enzymatic Activity ◽  
Dermatan Sulfate ◽  
Fruit Fly ◽  
Neurological Involvement ◽  
Mucopolysaccharidosis Type ◽  
Type Ii ◽  
Lysosomal Storage ◽  
Mucopolysaccharidosis Type Ii ◽  
Mps Ii

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder that occurs due to the deficit of the lysosomal enzyme iduronate 2-sulfatase (IDS) that leads to the storage of the glycosaminoglycan heparan- and dermatan-sulfate in all organs and tissues. It is characterized by important clinical features and the severe form presents with a heavy neurological involvement. However, almost nothing is known about the neuropathogenesis of MPS II. To address this issue, we developed a ubiquitous, neuronal, and glial-specific knockdown model in Drosophila melanogaster by using the RNA interference (RNAi) approach. Knockdown of the Ids/CG12014 gene resulted in a significant reduction of the Ids gene expression and enzymatic activity. However, glycosaminoglycan storage, survival, molecular markers (Atg8a, Lamp1, Rab11), and locomotion behavior were not affected. Even strongly reduced, IDS-activity was enough to prevent a pathological phenotype in a MPS II RNAi fruit fly. Thus, a Drosophila MPS II model requires complete abolishment of the enzymatic activity.

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 Ophthalmological Findings in Mucopolysaccharidoses

2019 ◽  
Vol 8 (9) ◽  
pp. 1467 ◽  
Author(s):  
Shizuka Tomatsu ◽  
Susanne Pitz ◽  
Ulrike Hampel
Keyword(s):  
Focal Point ◽  
Childhood Mortality ◽  
Research Progress ◽  
Type I ◽  
Lysosomal Storage ◽  
Hematopoietic Stem ◽  
Enzyme Replacement ◽  
Ocular Manifestations ◽  
Corneal Clouding ◽  
Low Incidence

The mucopolysaccharidoses (MPS) are a heterogenous group of lysosomal storage disorders caused by the accumulation of glycosaminoglycans (GAGs). The accrual of these compounds results in phenotypically varied syndromes that produce multi-organ impairment with widespread systemic effects. The low incidence of MPS (approximately 1/25,000 live births) in conjunction with the high childhood mortality rate had limited the availability of research into certain clinical features, especially ocular manifestations. As the recent successes of hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) have greatly increased life expectancy in these patients, they have served as a focal point for the transition of research towards improvement of quality of life. Ophthalmological findings in MPS include corneal clouding, glaucoma, optic neuropathies, and retinopathies. While corneal clouding is the most common ocular feature of MPS (especially type I, IVA, and VI), its response to HSCT and ERT is minimal. This review discusses known eye issues in the MPS subtypes, diagnosis of these ocular diseases, current clinical and surgical management, noteworthy research progress, and ultimately presents a direction for future studies.

Evidence that glycosaminoglycan storage and collagen deposition in the cauda epididymidis does not impair sperm viability in the Mucopolysaccharidosis type I mouse model

2020 ◽  
Vol 32 (3) ◽  
pp. 304 ◽  
Author(s):  
Cinthia Castro do Nascimento ◽  
Odair Aguiar ◽  
Gustavo Monteiro Viana ◽  
Vânia D'Almeida
Keyword(s):  
Sperm Morphology ◽  
Reproductive Age ◽  
Morphologic Change ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Cauda Epididymidis ◽  
Mps I

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by a deficiency of the lysosomal hydrolase, α-L-iduronidase (IDUA). IDUA degrades heparan and dermatan sulfates, two types of glycosaminoglycan (GAG), important signalling and structural molecules of the extracellular matrix. Because many cell types store GAGs, MPS I has been investigated in human and animal models. Enzyme replacement therapy is available for MPS I patients and has improved their life expectancy, allowing them to achieve reproductive age. The aim of this study was to evaluate epididymal and sperm morphology and function in a murine model of MPS I. We used C57BL Idua+/+ and Idua−/− adult male mice (6 months old) to investigate epididymal morphology, sperm ultrastructure, GAG characterisation and mating competence. Epithelial GAG storage, especially in the cauda epididymidis, was seen in Idua−/− mice. Regardless of the morphologic change and GAG storage found in the cauda epididymis, sperm morphology and motility were normal, similar to wild types. In the interstitium, vacuolated cells were found in addition to deposits of GAGs. Mating was not impaired in Idua−/− males and litter sizes were similar between groups. At the time point of the disease evaluated, the deficiency in IDUA affected the morphology of the epididymis in male Idua−/− mice, whereas sperm appearance and motility and the male’s capacity to mate and impregnate females were preserved.

scholarly journals Cathepsin B-associated Activation of Amyloidogenic Pathway in Murine Mucopolysaccharidosis Type I Brain Cortex

2020 ◽  
Vol 21 (4) ◽  
pp. 1459 ◽  
Author(s):  
Gustavo Monteiro Viana ◽  
Esteban Alberto Gonzalez ◽  
Marcela Maciel Palacio Alvarez ◽  
Renan Pelluzzi Cavalheiro ◽  
Cinthia Castro do Nascimento ◽  
...  
Keyword(s):  
Cathepsin B ◽  
Dermatan Sulfate ◽  
Fluorescent Microscopy ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Lysosomal Storage ◽  
App Processing ◽  
Mps I

Mucopolysaccharidosis type I (MPS I) is caused by genetic deficiency of α-l-iduronidase and impairment of lysosomal catabolism of heparan sulfate and dermatan sulfate. In the brain, these substrates accumulate in the lysosomes of neurons and glial cells, leading to neuroinflammation and neurodegeneration. Their storage also affects lysosomal homeostasis-inducing activity of several lysosomal proteases including cathepsin B (CATB). In the central nervous system, increased CATB activity has been associated with the deposition of amyloid plaques due to an alternative pro-amyloidogenic processing of the amyloid precursor protein (APP), suggesting a potential role of this enzyme in the neuropathology of MPS I. In this study, we report elevated levels of protein expression and activity of CATB in cortex tissues of 6-month-old MPS I (Idua -/- mice. Besides, increased CATB leakage from lysosomes to the cytoplasm of Idua -/- cortical pyramidal neurons was indicative of damaged lysosomal membranes. The increased CATB activity coincided with an elevated level of the 16-kDa C-terminal APP fragment, which together with unchanged levels of β-secretase 1 was suggestive for the role of this enzyme in the amyloidogenic APP processing. Neuronal accumulation of Thioflavin-S-positive misfolded protein aggregates and drastically increased levels of neuroinflammatory glial fibrillary acidic protein (GFAP)-positive astrocytes and CD11b-positive activated microglia were observed in Idua -/- cortex by confocal fluorescent microscopy. Together, our results point to the existence of a novel CATB-associated alternative amyloidogenic pathway in MPS I brain induced by lysosomal storage and potentially leading to neurodegeneration.

scholarly journals A charitable access program for patients with lysosomal storage disorders in underserved communities worldwide

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Atul Mehta ◽  
Uma Ramaswami ◽  
Joseph Muenzer ◽  
Roberto Giugliani ◽  
Kurt Ullrich ◽  
...  
Keyword(s):  
Replacement Therapy ◽  
Clinical Manifestations ◽  
Lysosomal Storage Disorders ◽  
Expert Committee ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Mps Ii ◽  
Access Program ◽  
Storage Disorders

Abstract Background Lysosomal storage disorders (LSDs) are rare genetic disorders, with heterogeneous clinical manifestations and severity. Treatment options, such as enzyme replacement therapy (ERT), substrate replacement therapy, and pharmacological chaperone therapy, are available for several LSDs, including Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (mucopolysaccharidosis type II [MPS II]). However, patients in some countries face challenges accessing treatments owing to limited availability of locally licensed, approved drugs. Methods The Takeda LSD Charitable access program aims to meet the needs of individuals with GD, FD or MPS II with the greatest overall likelihood of benefit, in selected countries, through donation of ERT to nonprofit organizations, and support for medical capacity-building as well as family support via independent grants. Long-term aims of the program are to establish sustainable healthcare services delivered by local healthcare providers for patients with rare metabolic diseases. Patients receiving treatment through the program are monitored regularly, and their clinical data and progress are reviewed annually by an independent medical expert committee (MEC). The MEC also selects patients for enrollment completely independent from the sponsoring company. Results As of 31 August, 2019, 199 patients from 13 countries were enrolled in the program; 142 with GD, 41 with MPS II, and 16 with FD. Physicians reported improvements in clinical condition for 147 (95%) of 155 patients with follow-up data at 1 year. Conclusions The response rate for follow-up data at 1 year was high, with data collected for > 90% of patients who received ERT through the program showing clinical improvements in the majority of patients. These findings suggest that the program can benefit selected patients previously unable to access disease-specific treatments. Further innovative solutions and efforts are needed to address the challenges and unmet needs of patients with LSDs and other rare diseases around the world.

scholarly journals Neonatal Screening for MPS Disorders in Latin America: A Survey of Pilot Initiatives

2020 ◽  
Vol 6 (4) ◽  
pp. 90
Author(s):  
Francyne Kubaski ◽  
Inês Sousa ◽  
Tatiana Amorim ◽  
Danilo Pereira ◽  
Joe Trometer ◽  
...  
Keyword(s):  
Latin America ◽  
Newborn Screening ◽  
Treatment Options ◽  
Digital Microfluidics ◽  
Premature Death ◽  
Lysosomal Storage ◽  
Pilot Studies ◽  
The Usa ◽  
History Of ◽  
Mps I

Newborn screening enables the diagnosis of treatable disorders at the early stages, and because of its countless benefits, conditions have been continuously added to screening panels, allowing early intervention, aiming for the prevention of irreversible manifestations and even premature death. Mucopolysaccharidoses (MPS) are lysosomal storage disorders than can benefit from an early diagnosis, and thus are being recommended for newborn screening. They are multisystemic progressive disorders, with treatment options already available for several MPS types. MPS I was the first MPS disorder enrolled in the newborn screening (NBS) panel in the USA and a few other countries, and other MPS types are expected to be added. Very few studies about NBS for MPS in Latin America have been published so far. In this review, we report the results of pilot studies performed in Mexico and Brazil using different methodologies: tandem mass spectrometry, molecular analysis, digital microfluidics, and fluorimetry. These experiences are important to report and discuss, as we expect to have several MPS types added to NBS panels shortly. This addition will enable timely diagnosis of MPS, avoiding the long diagnostic odyssey that is part of the current natural history of this group of diseases, and leading to a better outcome for the affected patients.

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 Incorporation of Second-Tier Biomarker Testing Improves the Specificity of Newborn Screening for Mucopolysaccharidosis Type I

2020 ◽  
Vol 6 (1) ◽  
pp. 10 ◽  
Author(s):  
Dawn S. Peck ◽  
Jean M. Lacey ◽  
Amy L. White ◽  
Gisele Pino ◽  
April L. Studinski ◽  
...  
Keyword(s):  
Newborn Screening ◽  
False Positive ◽  
Dermatan Sulfate ◽  
False Positive Rate ◽  
False Negative ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Second Tier ◽  
Mps I

Enzyme-based newborn screening for Mucopolysaccharidosis type I (MPS I) has a high false-positive rate due to the prevalence of pseudodeficiency alleles, often resulting in unnecessary and costly follow up. The glycosaminoglycans (GAGs), dermatan sulfate (DS) and heparan sulfate (HS) are both substrates for α-l-iduronidase (IDUA). These GAGs are elevated in patients with MPS I and have been shown to be promising biomarkers for both primary and second-tier testing. Since February 2016, we have measured DS and HS in 1213 specimens submitted on infants at risk for MPS I based on newborn screening. Molecular correlation was available for 157 of the tested cases. Samples from infants with MPS I confirmed by IDUA molecular analysis all had significantly elevated levels of DS and HS compared to those with confirmed pseudodeficiency and/or heterozygosity. Analysis of our testing population and correlation with molecular results identified few discrepant outcomes and uncovered no evidence of false-negative cases. We have demonstrated that blood spot GAGs analysis accurately discriminates between patients with confirmed MPS I and false-positive cases due to pseudodeficiency or heterozygosity and increases the specificity of newborn screening for MPS I.

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.

Sign in / Sign up

Export Citation Format

Share Document