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Background: In mucopolysaccharidosis type III (MPS III, also known as Sanfilippo syndrome), a pediatric neurodegenerative disorder, accumulation of abnormal glycosaminoglycans (GAGs) induces severe neuroinflammation by triggering the microglial pro-inflammatory cytokines production via a TLR4-dependent pathway. But the extent of the microglia contribution to the MPS III neuropathology remains unclear. Extracellular vesicles (EVs) mediate intercellular communication and are known to participate in the pathogenesis of adult neurodegenerative diseases. However, characterization of the molecular profiles of EVs released by MPS III microglia and their effects on neuronal functions have not been described. Methods: Here, we isolated EVs secreted by the microglial cells after treatment with GAGs purified from urines of Sanfilippo patients (sfGAGs-EVs) or from age-matched healthy subjects (nGAGs-EVs) to explore the EVs' proteins and small RNA profiles using LC–MS/MS and RNA sequencing. We next performed a functional assay by immunofluorescence following nGAGs- or sfGAGs-EVs uptake by WT primary cortical neurons and analyzed their extensions metrics after staining of βIII-tubulin and MAP2 by confocal microscopy. Results: Functional enrichment analysis for both proteomics and RNA sequencing data from sfGAGs-EVs revealed a specific content involved in neuroinflammation and neurodevelopment pathways. Treatment of cortical neurons with sfGAGs-EVs induced a disease-associated phenotype demonstrated by a lower total neurite surface area, an impaired somatodendritic compartment, and a higher number of immature dendritic spines. Conclusions: This study shows, for the first time, that GAGs from patients with Sanfilippo syndrome can induce microglial secretion of EVs that deliver a specific molecular message to recipient naive neurons, while promoting the neuroinflammation, and depriving neurons of neurodevelopmental factors. This work provides a framework for further studies of biomarkers to evaluate efficiency of emerging therapies. [ABSTRACT FROM AUTHOR]

Background: To inform the development of a core outcome set (COS) for children and youth with mucopolysaccharidoses (MPS), we aimed to identify all outcomes and associated outcome measurement instruments that are reported in recent clinical trials and recommended as measurements in clinical management guidelines. Methods: To identify English-language clinical trials and guidelines pertaining to MPS published between 2011 and mid-2021, we applied a comprehensive peer-reviewed search strategy to relevant databases and registers on May 16, 2021. Two reviewers independently screened retrieved citations and then full-text articles to determine eligibility for inclusion. From articles meeting inclusion criteria, we extracted details of the study design, population, intervention, and comparator, along with verbatim outcomes and associated outcome measurement instruments. Outcomes were organized into domains within five a priori core areas: life impact, pathophysiological manifestations, growth and development, resource use, and death. We conducted descriptive analyses at the study level, grouping articles arising from the same study. Results: From 2593 unique citations, 73 articles from 61 unique studies were included in the review, pertaining to all MPS subtypes except for exceptionally rare subtypes. Eighty-four unique outcomes were reported across the studies, 33 (39%) of which were reported by three or fewer studies. Most outcomes (55; 65%) were in the pathophysiological manifestations core area, followed by life impact (17; 20%) and growth and development (10; 12%); one outcome each pertained to resource use and death. The most frequently reported outcomes were general adverse events (45; 74%), immune-related adverse events (39; 64%), and urinary glycosaminoglycans (38; 62%). Substantial variability existed in the reporting of outcome measurement instruments. Some differences in outcome reporting were observed by MPS subtype and publication year. Discussion: Outcomes reported in clinical trials and guidelines for MPS in children and youth vary considerably and largely focus on pathophysiological manifestations. A COS is needed to standardize the selection and measurement of meaningful outcomes across future studies. We will present the outcomes identified in this review to knowledge users as part of a consensus process to select the most critical outcomes for inclusion in the COS. Trial Registration The protocol for this study was registered in PROSPERO (CRD42021267531) and in the COMET Database. [ABSTRACT FROM AUTHOR]

Background/Aims: Mucopolysaccharidoses (MPSs) are a group of progressive multisystemic diseases, and it is unknown whether there is a relationship between these system involvements. In this study, we aimed to investigate whether there is a relationship between cardiac involvement and carpal tunnel syndrome (CTS) in MPS patients. Methods: The study was conducted as a cross-sectional study between May 12, 2023, and June 30, 2024. Patients between the ages of 2 and 20 years who were diagnosed with MPS Types I, II, IV A, and VI enzymatically and genetically and who underwent electromyography for CTS screening and transthoracic echocardiography for cardiac involvement were included in the study. Results: Twenty-six MPS patients were included in the study. The mean age of the patients was 128±58 months. There was cardiac involvement in 21 (80.8%) of the patients. Heart valve involvement was present in 20 (76.9%) patients. Our study found that 14 (53.8%) of our MPS patients had CTS. CTS was present in all patients in the MPS type I, II, and VI groups but not in any MPS type IV A patients. As a result of the statistical analysis, the presence of MPS Type IV A was statistically significantly higher in the group without CTS than in the group with CTS (p<0.001). The presence of cardiac involvement, combined involvement of the aortic and mitral valves, and the severity of heart valve involvement were found to be statistically significantly higher in the patient group with CTS than in the patient group without CTS (p=0.007, p=0.005, p=0.009, respectively). Conclusions: Our study found that CTS was more common in patients with cardiac involvement, especially heart valve involvement. It seems considerable to screen these patients for CTS. [ABSTRACT FROM AUTHOR]

Infiltrative heart disease (InHD) is a group of diseases characterized by the deposition of abnormal substances in the heart tissue, causing diastolic, less often systolic, dysfunction of the ventricle(s). Their classification still does not exist. In 2013, the MOGE(S) classification of cardiomyopathies was published, taking into account, along with the morphological and functional characteristics of the heart, damage to other organs, the presence of genetic mutations, acquired causes (e.g., myocardial inflammation, autoimmune diseases, storage diseases, amyloidosis), etc. By analogy with it we offer the MORAL-STAGE classification for InHD. It includes ten features: morphofunctional characteristics (M), organ damage (O), risk of cardiac death (R), age of clinical presentation, age of disease-specific therapy initiation (A), localization of the infiltrative process (inside or outside the cell, L), information about the functional class heart failure and stage of infiltrative heart disease (S), treatment (T), abnormal rhythm or conduction (A), genetic or familial nature of inheritance (G), etiology of the process (E). This article summarizes the cornerstones of the MORAL-STAGE classification and its clinical relevance. In addition, new issues are discussed that can be considered in future versions of the MORAL-STAGE classification. [ABSTRACT FROM AUTHOR]

Background: Mucopolysaccharidosis (MPS) comprises a group of metabolic diseases with a disorder in the function of lysosomal enzymes that lead to the accumulation of glycosaminoglycans (mucopolysaccharides) (Kubaski et al. in Diagnostics 10:161, 2020; Hampe et al. in Cells 9:1838, 2020; Tomatsu et al. Mol Genet Metab 110(1–2):42–53, 2013). At least seven variants of this disorder have been identified to date (Muenzer et al. in Pediatrics 124(6):e1228–e1239, 2009; Muenzer et al. in Eur J Pediatr 171:181–8, 2012). this study aims to report a case of mucopolysaccharidosis in a 9-year-old child. Also, the treatments and dental observations made for the child have been described. Also, a review of past articles has been done to report the types of diseases, medical and dental considerations, etc. of this disease. Case description: the present case report describes the orofacial and systemic characteristics, diagnostic methods, and dental management of a 9-year-old boy with MPS with a one-year follow-up in association with a brief review of past articles. Conclusion: Since MPS patients have many changes in their oral and dental structures, they pose many challenges for dentists. Also, these patients need considerations in dentistry due to the involvement of different body organs. Knowing the oral-dental and systemic problems of these patients can help their dentists to provide effective and safe treatment for them. [ABSTRACT FROM AUTHOR]

Childhood dementias are a group of rare, fatal neurodegenerative disorders, characterised by global cognitive decline, loss of previously acquired developmental skills and behaviours and psychological symptoms of dementia (BPSD). Batten disease, or neuronal ceroid lipofuscinosis, and Sanfilippo syndrome, or mucopolysaccharidosis type III, are two of the more common forms of childhood dementia disorders worldwide. While psychosocial interventions are the best available therapeutic approach for BPSD management in adult-onset dementia, there is very limited literature or clinical experience in the context of childhood dementia. To address this gap, we conducted a descriptive case analysis of BPSD profiles, associated contributing factors and targeted psychosocial interventions in two cases with childhood dementia disorders (Sanfilippo syndrome and CLN3 (juvenile onset) Batten disease) who were referred to Dementia Support Australia, a national dementia behaviour support service in Australia. Primary BPSD identified in these disorders included physical and verbal aggression and irritability/lability. In these cases, contributing factors to the development of BPSD were not monolithic, encompassing pain, caregiver's approach and over or under-stimulation. Improvement in BPSD were observed using the Neuropsychiatric Inventory-Quesionnaire and globally noted as per the qualitative feedback reported by family and caregivers. Person-centred, multimodal psychosocial interventions were recognised as effective therapies in resolving BPSD in these cases. In conclusion, the case studies described the nature and presentation of BPSD in two common forms of childhood dementia and demonstrated the potential benefits of person-centred psychosocial interventions (delivered through national dementia-specific support programs) in alleviating BPSD such as irritability and aggression in these disorders. [ABSTRACT FROM AUTHOR]

Several years ago, dozens of cases were described in patients with symptoms very similar to mucopolysaccharidosis (MPS). This new disease entity was described as mucopolysaccharidosis-plus syndrome (MPSPS). The name of the disease indicates that in addition to the typical symptoms of conventional MPS, patients develop other features such as congenital heart defects and kidney and hematopoietic system disorders. The symptoms are highly advanced, and patients usually do not survive past the second year of life. MPSPS is inherited in an autosomal recessive manner and is caused by a homozygous-specific mutation in the gene encoding the VPS33A protein. To date, it has been described in 41 patients. Patients with MPSPS exhibited excessive excretion of glycosaminoglycans (GAGs) in the urine and exceptionally high levels of heparan sulfate in the plasma, but the accumulation of substrates is not caused by a decrease in the activity of any lysosomal enzymes. Here, we discuss the pathomechanisms and symptoms of MPSPS, comparing them to those of MPS. Moreover, we asked the question whether MPSPS should be classified as a type of MPS or a separate disease, as contrary to 'classical' MPS types, despite GAG accumulation, no defects in lysosomal enzymes responsible for degradation of these compounds could be detected in MPSPS. The molecular mechanism of the appearance of GAG accumulation in MPSPS is suggested on the basis of results available in the literature. [ABSTRACT FROM AUTHOR]

Introduction: Hematopoietic stem cell transplantation (HSCT) comprises one of the two main treatment regimens for patients with mucopolysaccharidoses (MPS). There is a scarcity of literature concerning the process of growth in children with Mucopolysaccharidosis type I (MPS I) and Mucopolysaccharidosis type I (MPS II) after HSCT. The aim of this manuscript was to evaluate the therapeutic effect of HSCT on the heights of patients with MPS I and MPS II. Material and methods: It was an observational, single-center study on patients with MPS I and II treated with HSCT. Results: 6 MPS patients, including 4 MPS I and 2 MPS II, underwent HSCT at a median age of 2 years. All patients are alive to date, with a median age of 7.7 years (range 5.5–12 years) at the last follow-up. In both (MPS I and MPS II) groups of patients treated with HSCT, the growth rate was higher than in untreated patients and was found to be in line with the population norm. In both MPS I and MPS II patients who were treated with HSCT, normalization of urinary GAG excretion was observed. Additionally, no bands of DS and HS in GAG electrophoresis were visible. Conclusions: Both MPS I and MPS II patients presented height gain after HSCT compared to the curves of untreated patients. The absence of dermatan sulphate after HSCT could lead to normal growth in bone length. [ABSTRACT FROM AUTHOR]

Abstract Background To inform the development of a core outcome set (COS) for children and youth with mucopolysaccharidoses (MPS), we aimed to identify all outcomes and associated outcome measurement instruments that are reported in recent clinical trials and recommended as measurements in clinical management guidelines. Methods To identify English-language clinical trials and guidelines pertaining to MPS published between 2011 and mid-2021, we applied a comprehensive peer-reviewed search strategy to relevant databases and registers on May 16, 2021. Two reviewers independently screened retrieved citations and then full-text articles to determine eligibility for inclusion. From articles meeting inclusion criteria, we extracted details of the study design, population, intervention, and comparator, along with verbatim outcomes and associated outcome measurement instruments. Outcomes were organized into domains within five a priori core areas: life impact, pathophysiological manifestations, growth and development, resource use, and death. We conducted descriptive analyses at the study level, grouping articles arising from the same study. Results From 2593 unique citations, 73 articles from 61 unique studies were included in the review, pertaining to all MPS subtypes except for exceptionally rare subtypes. Eighty-four unique outcomes were reported across the studies, 33 (39%) of which were reported by three or fewer studies. Most outcomes (55; 65%) were in the pathophysiological manifestations core area, followed by life impact (17; 20%) and growth and development (10; 12%); one outcome each pertained to resource use and death. The most frequently reported outcomes were general adverse events (45; 74%), immune-related adverse events (39; 64%), and urinary glycosaminoglycans (38; 62%). Substantial variability existed in the reporting of outcome measurement instruments. Some differences in outcome reporting were observed by MPS subtype and publication year. Discussion Outcomes reported in clinical trials and guidelines for MPS in children and youth vary considerably and largely focus on pathophysiological manifestations. A COS is needed to standardize the selection and measurement of meaningful outcomes across future studies. We will present the outcomes identified in this review to knowledge users as part of a consensus process to select the most critical outcomes for inclusion in the COS. Trial Registration The protocol for this study was registered in PROSPERO (CRD42021267531) and in the COMET Database.

Abstract Background Patients with mucopolysaccharidosis (MPS) often face delayed diagnoses, limited treatment options and high healthcare costs, that may significantly affect patients' quality of life. The objective of this study was to understand medical service utilization related to diagnosis and treatment, economic burden during diagnosis period, and health-related quality of life among MPS patients in China. Methods A series of patients diagnosed with MPS registered in the national patient organization were recruited for a cross-sectional survey from May to July 2019. Information were collected from patients or their parents via phone interview, including demographic data, utilization of services related to diagnosis and treatment, total cost during the period of MPS diagnosis and health-related quality of life (HRQoL). HRQoL was assessed by PedsQL 4.0 Generic Core Scale (PedsQL) and 36-item short-form health survey (SF-36) depending on the age of patients with MPS and compared with the general Chinese population. Results A total of 180 MPS patients (50, 67, 15, 46, 1 and 1 for type I, II, III, IV, VI and VII), with a mean age of 9.54 years and 137 (76.11%) males, were included in analysis. The mean age at first visit to a medical doctor for MPS related symptoms was 3.65 ± 2.58 years old, while only 12 patients (6.67%) were diagnosed on their first visit. The mean diagnostic delay, which is defined as the time between the first visit to a medical doctor for MPS related symptoms and the final diagnosis, was 9.42 months, with no significant difference between types. The average number of misdiagnosis was 4.56. Before the confirmed diagnosis, the patients made an average of 6.31 visits and visited 4.3 hospitals. During diagnosis period, the mean of ¥81,086.72 direct medical costs accounted for 63.75% of the total cost. Only 32.78% of the patients had ever received specific treatments. The mean scores of PedsQL and SF-36 of patients were significantly lower than the Chinese norms. Household annual income per person, specific treatment use and MPS subtype were significantly associated HRQoL of patients. Conclusion The results highlight challenges faced by MPS patients in terms of diagnosis, access to specific treatments, economic burden and low HRQoL. There is an urgent need to improve early detection and diagnosis, create fair and consistent mechanisms to increase access to specialized treatment and reduce the economic burden of MPS patients in China.

Introduction: Mucopolysaccharidosis type VI (MPS VI) is a rare inherited metabolic disorder, primarily attributed to the deficiency of the enzyme N-acetylgalactosamine-4-sulfatase, responsible for the degradation of dermatan sulfate and chondroitin-4-sulfate. Therefore, there is a widespread accumulation of partially degraded glycosaminoglycans. Corneal opacification is the hallmark ocular feature in the MPS. Retinal and scleral involvement in this MPS is extremely rare. The purpose of this work was to describe novel fundoscopic alterations present in patients with MPS VI. Case Presentation: This is a case series involving three non-related patients referred to our department from the Unit of Inherited Metabolic Diseases. Multimodal imaging was performed in every patient. Fundus photography and enhanced depth imaging optical coherence tomography (EDI-OCT) were performed. Multiple areas of yellow/orange patches were observed on fundus photography, corresponding to areas in which deposits of intermediate reflectivity in the EDI-OCT could be seen at the scleral level with associated choroidal thinning. This finding suggested the presence of scleral deposits of glycosaminoglycans. Conclusion: To our knowledge, this is the first case series in the literature encompassing patients with MPS VI with suspected deposits of glycosaminoglycans in the sclera. The better control of the systemic comorbidities, the increase in life expectancy, and the timely management of corneal disease have allowed the identification of new, late-onset ocular manifestations in MPS patients. In addition, new imaging techniques have introduced the possibility of better characterizing and understanding these manifestations.

Background and Objectives: Mucopolysaccharidosis (MPS) is a group of lysosomal storage disorders that cause the deposition of polysaccharides in cells. This causes systemic and oral manifestations, which can be observed clinically and radiographically. The present study aimed to assess dental caries, the effect of salivary pH, and the change of microflora on teeth in patients diagnosed with MPS. Materials and Methods: The study included children affected with mucopolysaccharidosis (n = 50) and healthy children (n = 50) in the control group between 3 and 15 years of age. The pH of saliva and decayed, missing, and filled teeth/decayed extracted and filled teeth index were noted and recorded. For the microbial analysis, saliva was inoculated into blood agar, MacConkey agar, Candida CHROMagar, and Mitis Salivarius agar, then inspected for colony-forming units, which were counted and recorded based on the colony characteristics and gram staining. Statistical Analysis: Intergroup comparison of the test parameters was done using the Mann–Whitney test. P < 0.05 was considered statistically significant. Results: The results showed significantly higher total microbial load (P = 0.00008), streptococcus viridans species (P = 0.00001), and Candida species (P = 0.0038) in the study group. The caries incidence was also higher in the study group for both primary (P = 0.0096) and permanent dentition (P = 0.0251), and salivary pH was more acidic (P = 0.00001) in the patients diagnosed with MPS. Interpretation and Conclusion: Patients diagnosed with MPS have a higher microbial load, more acidic saliva, and subsequently, a higher caries incidence than normal healthy children. Hence, regular dental evaluation, prevention, and treatment must be integrated into their health-care regimen.

Abstract Mucopolysaccharidosis type IIIA (MPS IIIA) is a rare paediatric lysosomal storage disorder, caused by the progressive accumulation of heparan sulphate, resulting in neurocognitive decline and behavioural abnormalities. Anecdotal reports from paediatricians indicate a more severe neurodegeneration in MPS IIIA patients, following infection, suggesting inflammation as a potential driver of neuropathology. To test this hypothesis, we performed acute studies in which WT and MPS IIIA mice were challenged with the TLR3-dependent viral mimetic poly(I:C). The challenge with an acute high poly(I:C) dose exacerbated systemic and brain cytokine expression, especially IL-1β in the hippocampus. This was accompanied by an increase in caspase-1 activity within the brain of MPS IIIA mice with concomitant loss of hippocampal GFAP and NeuN expression. Similar levels of cell damage, together with exacerbation of gliosis, were also observed in MPS IIIA mice following low chronic poly(I:C) dosing. While further investigation is warranted to fully understand the extent of IL-1β involvement in MPS IIIA exacerbated neurodegeneration, our data robustly reinforces our previous findings, indicating IL-1β as a pivotal catalyst for neuropathological processes in MPS IIIA.

Iduronate‐2‐sulfatase (IDS) is a Ca2+‐dependent enzyme belonging to the family of sulfatases that catalyzes the hydrolysis of sulphurylated glycosaminoglycans (GAGs), like dermatan and heparan sulphate. Its deficiency or modification leads to the accumulation of GAGs in the human body and to the occurrence of severe conditions, such as Hunter disease, or Mucopolysaccharidosis type II. Due to its involvement in this syndrome, it is of interest to understand the action mechanism of the enzyme to design new drugs for more efficient medical strategies. In the present work, we carried out a detailed multiscale modelling‐based investigation, adopting molecular dynamics simulation (MDs) and QM/MM calculations to study the enzyme‐dermatan sulfate interactions and to investigate the reaction mechanism of IDS. The analysis of molecular dynamics trajectories helped to shed light on the contribution of the individual residues of the active site in the recognition of dermatan sulfate. The role of FGly84 and His229, investigated in both neutral and protonated states in the case of the latter, is highlighted for the binding of the substrate. QM/MM calculations demonstrated that the reaction mechanism is a two‐steps process occurring via a sulphurylation‐desulphurylation mechanism where the FGly84 first attacks the sulphate group of the dermatan sulphate (DS), and later is desulphurylated. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidoses (MPS) comprise a group of 12 metabolic disorders where defects in specific enzyme activities lead to the accumulation of glycosaminoglycans (GAGs) within lysosomes. This classification expands to 13 when considering MPS IIIE. This type of MPS, associated with pathogenic variants in the ARSG gene, has thus far been described only in the context of animal models. However, pathogenic variants in this gene also occur in humans, but are linked to a different disorder, Usher syndrome (USH) type IV, which is sparking increasing debate. This paper gathers, discusses, and summarizes arguments both for and against classifying dysfunctions of arylsulfatase G (due to pathogenic variants in the ARSG gene) in humans as another subtype of MPS, called MPS IIIE. Specific difficulties in diagnostics and the classification of some inherited metabolic diseases are also highlighted and discussed. [ABSTRACT FROM AUTHOR]

Introduction: Mucopolysaccharidosis type VI (MPS VI) is a rare inherited metabolic disorder, primarily attributed to the deficiency of the enzyme N-acetylgalactosamine-4-sulfatase, responsible for the degradation of dermatan sulfate and chondroitin-4-sulfate. Therefore, there is a widespread accumulation of partially degraded glycosaminoglycans. Corneal opacification is the hallmark ocular feature in the MPS. Retinal and scleral involvement in this MPS is extremely rare. The purpose of this work was to describe novel fundoscopic alterations present in patients with MPS VI. Case Presentation: This is a case series involving three non-related patients referred to our department from the Unit of Inherited Metabolic Diseases. Multimodal imaging was performed in every patient. Fundus photography and enhanced depth imaging optical coherence tomography (EDI-OCT) were performed. Multiple areas of yellow/orange patches were observed on fundus photography, corresponding to areas in which deposits of intermediate reflectivity in the EDI-OCT could be seen at the scleral level with associated choroidal thinning. This finding suggested the presence of scleral deposits of glycosaminoglycans. Conclusion: To our knowledge, this is the first case series in the literature encompassing patients with MPS VI with suspected deposits of glycosaminoglycans in the sclera. The better control of the systemic comorbidities, the increase in life expectancy, and the timely management of corneal disease have allowed the identification of new, late-onset ocular manifestations in MPS patients. In addition, new imaging techniques have introduced the possibility of better characterizing and understanding these manifestations. [ABSTRACT FROM AUTHOR]

Key Clinical Message: It is important to consider all potential pain management modalities including alternative treatment on managing complex pain presentations. Acupuncture is a treatment modality that may result in reduction of pain in patients with significant medical comorbidities due to MPS IVA. [ABSTRACT FROM AUTHOR]

We aimed to cardiologically evaluate the consequences of glycosaminoglycan (GAG) accumulation in the large vessels of patients with mucopolysaccharidosis (MPS). The left ventricular wall thickness, left ventricular mass (LVmass) were evaluated and aortic annulus diameter (AA), aortic sinus valsalva diameter (SV), sinotubular junction diameter (STJ), systolic aortic diameter (ADs), diastolic aortic diameter (ADd) body indices were obtained by dividing by the surface area. Aortic distensibility and stiffness index were obtained using aortic strain. Ejection fraction, mitral E and A velocities, mitral early diastolic tissue velocity (e′), E/A ratio, and E/e′ ratio were evaluated. The LVED-i, LVmass-i, AA-i, SV-i, STJ-i, ADs-i, and ADd-i values were significantly higher in the MPS group. While the E and e′ velocities and E/A ratio were significantly low in the MPS group, the A velocity and E/e′ ratio were significantly high. While the stiffness index, SBP, and PP values were significantly higher in the MPS group, the aortic strain and distensibility were significantly lower. There was a correlation between the stiffness index and the aortic strain, distensibility, SBP, PP, and ventricular function. Cardiac function, aortic diameter, and aortic elasticity characteristics were similar between patients with MPS who received ERT and those who did not. In the MPS group, aortic elasticity properties were impaired, and aortic stiffness increased. ERT has positive effects on cardiac function, aortic diameter, and aortic stiffness in MPS patients. An increased LVmass-i and impaired ventricular geometric structure in patients with MPS may be associated with increased aortic stiffness. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type 10 is caused by biallelic variants in ARSK, which encodes for a lysosomal sulfatase. To date, seven patients with a mild phenotype resembling spondyloepiphyseal dysplasia or multiple epiphyseal dysplasia have been described. In this report, we present two novel ARSK variants and report clinical and radiological findings of three patients. The patients' initial complaints were hip or knee pain and a waddling gait. All patients showed normal intelligence, normal hearing and eye examinations, and none had organomegaly. While typical dysostosis multiplex findings were not observed, mild platyspondyly with anterior beaking of some vertebral bodies, irregular vertebral endplates, wide ribs, inferior tapering of the ilea with a poorly developed acetabulum, irregularity of the central part of the femoral head, delayed ossification of the carpals were noted. Remarkably, all patients showed metaphyseal striation of the long bones, a crucial diagnostic clue to identify ARSK‐related MPS type 10. Interestingly, vertebral involvement regressed during follow‐up. On the other hand, hip dysplasia progressed in all patients. In conclusion, this study provides valuable long‐term results on a recently discovered form of MPS. [ABSTRACT FROM AUTHOR]

Key Clinical Message: In Hurler syndrome, corneal opacification is a common finding but rarely manifests as hypertrophic scars. A 6‐year‐old boy with Hurler syndrome had a hypertrophic scar on his left eye, which was successfully treated with superficial keratectomy. [ABSTRACT FROM AUTHOR]

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Mucopolysaccharidosis type IIIA (MPS IIIA) is a rare paediatric lysosomal storage disorder, caused by the progressive accumulation of heparan sulphate, resulting in neurocognitive decline and behavioural abnormalities. Anecdotal reports from paediatricians indicate a more severe neurodegeneration in MPS IIIA patients, following infection, suggesting inflammation as a potential driver of neuropathology. To test this hypothesis, we performed acute studies in which WT and MPS IIIA mice were challenged with the TLR3-dependent viral mimetic poly(I:C). The challenge with an acute high poly(I:C) dose exacerbated systemic and brain cytokine expression, especially IL-1β in the hippocampus. This was accompanied by an increase in caspase-1 activity within the brain of MPS IIIA mice with concomitant loss of hippocampal GFAP and NeuN expression. Similar levels of cell damage, together with exacerbation of gliosis, were also observed in MPS IIIA mice following low chronic poly(I:C) dosing. While further investigation is warranted to fully understand the extent of IL-1β involvement in MPS IIIA exacerbated neurodegeneration, our data robustly reinforces our previous findings, indicating IL-1β as a pivotal catalyst for neuropathological processes in MPS IIIA. Synopsis: A more severe neurocognitive decline is documented in Mucopolysaccharidosis type IIIA (MPS IIIA) patients who contract viral infections. To explore the link between inflammation and neurodegeneration, MPS IIIA mice were challenged with the TLR3-dependent viral mimetic poly(I:C) and the impact on brain pathology was assessed. Exacerbated Il-1β levels and caspase-1 activity were observed in the serum and brain of MPS IIIA mice challenged with a high acute poly(I:C) dose. MPS IIIA spatial memory deficit worsened in a dose-dependent manner following chronic administration of poly(I:C). Existing microgliosis and astrogliosis were exacerbated in the cortex and amygdala of MPS IIIA mice following chronic poly(I:C) administration. Neuronal and astrocytic cell damage was observed in the hippocampus of MPS IIIA mice following chronic poly(I:C) administration. Il-1β and the inflammasome remain central to neuropathological progression in MPS IIIA, as confirmed by our previous findings. A more severe neurocognitive decline is documented in Mucopolysaccharidosis type IIIA (MPS IIIA) patients who contract viral infections. To explore the link between inflammation and neurodegeneration, MPS IIIA mice were challenged with the TLR3-dependent viral mimetic poly(I:C) and the impact on brain pathology was assessed. [ABSTRACT FROM AUTHOR]

Background: Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by biallelic variants in the N-acetylgalactosamine-6-sulfatase (GALNS) gene and is characterized by progressive and multi-system involvements, dominantly with skeletal deformities. A mild form of MPS IVA often presents with atypical symptoms and can go unrecognized for years. Methods: The diagnosis of MPS IVA was confirmed via GALNS enzyme activity testing in leukocytes. Clinical features were collected. Molecular analysis was performed by next generation sequence and Sanger sequencing of the GALNS gene. The pathogenicity of the deep intron variant was verified by mRNA analyses. Results: Thirteen patients with mild MPS IVA from six families were included. All probands first visit pediatric orthopedists and it took 5.6 years to be diagnosed after the disease onset. The most common symptoms in our series were waddling gait (85%), short neck (69%) and flat feet (62%). Radiologic findings indicated skeletal abnormalities in all patients, especially modification of the vertebral bodies (100%) and acetabular and femoral head dysplasia (100%). Five novel GALNS variants, including c.121-2_121-1insTTTGCTGGCATATGCA, E2 deletion, c.569 A > G, c.898 + 2 T > A, and c.1139 + 2 T > C, were identified. The most common variant, a deep intron variant NM_000512.5: c.121–210 C > T (NM_001323544.2: c.129 C > T, p.G43G), was revealed to result in an 11 bp deletion (c.128_138delGCGATGCTGAG, p.Gly43Aspfs*5) on GALNS mRNA in the GALNS transcript of NM_001323544.2. Conclusions: This study provides significant insights into the clinical features and molecular characteristics that contribute to the early diagnosis of mild MPS IVA. On the basis of our cohort, orthopedists need to be able to recognize signs and symptoms of mild MPS IVA as well as the molecular and biochemical diagnosis so that an early diagnosis and treatment can be instituted. [ABSTRACT FROM AUTHOR]

Glycosaminoglycans (GAGs) serve as a biomarker for mucopolysaccharidoses disease. In this study, a novel fluorometric method was developed to measure total GAGs in urine. Graphene oxide (GO) and rhodamine B (RhB), a cationic fluorescent dye, were employed in the development of the method. RhB attaches to the GO surface via electrostatic attraction, leading to the quenching of its fluorescence upon the establishment of the RhB–GO complex. However, the presence of GAGs prompts a resurgence of intense fluorescence. The linear range of the method is between 5.00 and 70.00 mg/L. The total GAG levels of urine samples analyzed using the method agree with the results of the biochemistry analysis laboratory (65.85 and 79.18 mg/L; 73.30 ± 1.76 and 72.21 ± 2.21). The method is simple, accurate, and sensitive and may be used for both first‐step diagnosis of the mucopolysaccharidoses and detection of individual GAGs for studies of GAG‐related research and other biological applications. [ABSTRACT FROM AUTHOR]

One of the most common causes of carpal tunnel syndrome (CTS) in childhood is mucopolysaccharidosis (MPS). While ultrasonography (US) can aid in the diagnosis of CTS in adult patients, there is limited experience of this in the pediatric group. We aimed to investigate the results of wrist ultrasonography, which may be a candidate alternative to electrophysiological examination. The participants were evaluated for symptoms, physical examination findings, electrophysiological tests and grayscale US. CTS was diagnosed in accordance with the American Academy of Orthopedic Surgeons Management of Carpal Tunnel Syndrome: Evidence-Based Clinical Practice Guideline. Included in the study were 27 MPS patients aged 4.5–32 years and 30 healthy control subjects aged 4.3–26 years. Of the 54 wrists in the MPS group, 30 were diagnosed with CTS. The median cross-sectional area (CSA) at the proximal carpal tunnel, the CSA at the forearm, and the wrist-forearm ratio (WFR) were higher in the wrists of the MPS with CTS group than in those without CTS and the healthy control subjects. The WFR cutoff of ≥1.35, 56.6% (95% CI: 437.4–74.5) sensitivity, and 89.8% (95% CI: 81.0–95.5) specificity were consistent with a diagnosis of CTS (receiver operating characteristics analysis, area under the curve = 0.775, 95% CI: 0.673–0.877). Although the US provides results with unsatisfactory specificity and sensitivity, it is a candidate for further investigation for the diagnosis of CTS because it is an innovative, noninvasive, and more accessible method. WFR value may produce more meaningful results than wrist or forearm nerve area measurements. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage diseases caused by a deficiency of glycosaminoglycan (GAG) catalytic enzymes, resulting in an accumulation of unprocessed or partly degraded GAGs in different tissues, including bones and joints. Notably, skeletal and joint abnormalities may be the first complaint that prompts patients to seek medical attention, especially in the milder forms of the disease. To our knowledge, there are no prior imaging reports that have documented capsuloligamentous thickening in patients with MPS on MRI. In this study, we present four cases of patients with clinically and genetically confirmed diagnosis of type II MPS, encompassing seven MRI examination of different joints, including cervical spine, hip, wrist, knee, and shoulder. All of the patients were male, aged between 14 and 35 years, and exhibited varying degrees of joint stiffness in the clinical examination and carpal tunnel syndrome in cases of the wrist joint was affected. None of the patients had a history of surgical procedures on the affected joint, other metabolic or deposit diseases, or sports activity practice. The MRI revealed significant capsuloligamentous and retinaculum thickening, up to eight times greater than the normal capsular thickness reported in the literature. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type IIIA (MPS IIIA) is characterized by neurological and skeletal pathologies caused by reduced activity of the lysosomal hydrolase, sulfamidase, and the subsequent primary accumulation of undegraded heparan sulfate (HS). Respiratory pathology is considered secondary in MPS IIIA and the mechanisms are not well understood. Changes in the amount, metabolism, and function of pulmonary surfactant, the substance that regulates alveolar interfacial surface tension and modulates lung compliance and elastance, have been reported in MPS IIIA mice. Here we investigated changes in lung function in 20-wk-old control and MPS IIIA mice with a closed and open thoracic cage, diaphragm contractile properties, and potential parenchymal remodeling. MPS IIIA mice had increased compliance and airway resistance and reduced tissue damping and elastance compared with control mice. The chest wall impacted lung function as observed by an increase in airway resistance and a decrease in peripheral energy dissipation in the open compared with the closed thoracic cage state in MPS IIIA mice. Diaphragm contractile forces showed a decrease in peak twitch force, maximum specific force, and the force-frequency relationship but no change in muscle fiber cross-sectional area in MPS IIIA mice compared with control mice. Design-based stereology did not reveal any parenchymal remodeling or destruction of alveolar septa in the MPS IIIA mouse lung. In conclusion, the increased storage of HS which leads to biochemical and biophysical changes in pulmonary surfactant also affects lung and diaphragm function, but has no impact on lung or diaphragm structure at this stage of the disease. NEW & NOTEWORTHY Heparan sulfate storage in the lungs of mucopolysaccharidosis type IIIA (MPS IIIA) mice leads to changes in lung function consistent with those of an obstructive lung disease and includes an increase in lung compliance and airway resistance and a decrease in tissue elastance. In addition, diaphragm muscle contractile strength is reduced, potentially further contributing to lung function impairment. However, no changes in parenchymal lung structure were observed in mice at 20 wk of age [ABSTRACT FROM AUTHOR]

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Pulmonologists may be involved in managing pulmonary diseases in children with complex clinical pictures without a diagnosis. Moreover, they are routinely involved in the multidisciplinary care of children with rare diseases, at baseline and during follow-up, for lung function monitoring. Lysosomal storage diseases (LSDs) are a group of genetic diseases characterised by a specific lysosomal enzyme deficiency. Despite varying pathogen and organ involvement, they are linked by the pathological accumulation of exceeding substrates, leading to cellular toxicity and subsequent organ damage. Less severe forms of LSDs can manifest during childhood or later in life, sometimes being underdiagnosed. Respiratory impairment may stem from different pathogenetic mechanisms, depending on substrate storage in bones, with skeletal deformity and restrictive pattern, in bronchi, with obstructive pattern, in lung interstitium, with altered alveolar gas exchange, and in muscles, with hypotonia. This narrative review aims to outline different pulmonary clinical findings and a diagnostic approach based on key elements for differential diagnosis in some treatable LSDs like Gaucher disease, Acid Sphingomyelinase deficiency, Pompe disease and Mucopolysaccharidosis. Alongside their respiratory clinical aspects, which might overlap, we will describe radiological findings, lung functional patterns and associated symptoms to guide pediatric pulmonologists in differential diagnosis. The second part of the paper will address follow-up and management specifics. Recent evidence suggests that new therapeutic strategies play a substantial role in preventing lung involvement in early-treated patients and enhancing lung function and radiological signs in others. Timely diagnosis, driven by clinical suspicion and diagnostic workup, can help in treating LSDs effectively. [ABSTRACT FROM AUTHOR]

Scheie syndrome is a mild variant of mucopolysaccharidosis type I (MPS I), a rare group of lysosomal storage diseases that affect multiple organ systems. It is rarely associated with neoplasia. To the best of our knowledge, only a single case of mucopolysaccharidosis associated with a brain tumor has been reported, and it was nearly three decades ago. We present the case of a 10-year-old female with Scheie syndrome associated with a brain tumor. Physical and laboratory findings were suggestive of Scheie syndrome. A skeletal survey also revealed a spectrum of dysostosis multiplex supporting MPS. Children with MPS can have rapidly enlarging head sizes due to hydrocephalus, but our patient had several red flags that demanded further evaluation. A brain MRI revealed a mass in the fourth ventricle and a biopsy of the mass revealed pilocytic astrocytoma grade 1. Intraventricular pilocytic astrocytoma itself is a rare occurrence, accounting for only 4%–15.6 % of all pilocytic astrocytomas. Altered mucopolysaccharide metabolism can be involved in tumor pathogenesis, but the exact mechanism is unknown. Mucopolysaccharidoses, being a group of complicated disorders, are difficult to manage, and many symptoms can be missed in children due to intellectual disability. This case highlights the importance of suspecting brain tumors in children with mucopolysaccharidoses who present with signs and symptoms of increased intracranial pressure. Prompt diagnosis and management can save the child from dire neurological consequences.

Mucopolysaccharidosis (MPS) syndromes are a group of heterogeneous genetic disorders in terms of genetic basis and clinical manifestations, ranging from mild to fatal forms. There are a number of applied or prospective treatment modalities for MPS, including bone marrow transplantation, enzyme replacement therapy, targeted gene therapy and substrate reduction therapy. Recently, CRISPR/Cas9 technology has emerged as a novel tool for several metabolic disorders, such as MPS. This review concentrates on the application of this technique in the treatment of MPS, particularly MPS I, and modeling of disease-causing mutations.

Fluoxetine has been identified as a potential treatment for mucopolysaccharidosis IIIA (MPS IIIA), a debilitating and progressive lysosomal storage disorder for which no treatments are approved. In the MPS IIIA mouse model, fluoxetine decreases the accumulation of glycosaminoglycans and aggregated autophagic substrates, reducing inflammation, and slowing cognitive deterioration. 1 We treated a single patient, 6 years old, under off-label prescription of fluoxetine, a selective serotonin reuptake inhibitor (SSRI). The primary endpoint was safety. Secondary exploratory assessments included urine quantitative heparan sulfate. Fluoxetine was well-tolerated in this patient and the patient continued treatment following the 12-month monitoring period. The patient experienced an increase in daytime somnolence which resolved with rescheduling fluoxetine administration to bedtime. Quantitative heparan sulfate levels remained elevated during treatment. Parents reported improved sleep latency time and less nighttime waking. These findings support general tolerability and further study of fluoxetine as a potential therapy for MPS IIIA.

Skeletal dysplasias or osteochondrodysplasias comprise a large heterogeneous group of genetic disorders and possess significant overlap on imaging, which adds to the dilemma of the reporting radiologist. These entities are routinely evaluated with a detailed skeletal survey and hand radiographs form a crucial part of a complete survey. Certain conditions have characteristic imaging findings that enable a diagnosis be made on hand radiograph alone. Additionally, hand radiographs may also demonstrate findings that may be suggestive of a particular diagnosis/differential diagnoses and would warrant further assessment for proving the same. We aim to demonstrate the use of hand radiographs in diagnosis of various such entities through this review. Although they cannot replace a complete skeletal survey in the diagnosis, hand radiographs performed for other indications might alert a radiologist to the diagnosis of an unsuspected skeletal dysplasia.

Mucopolysaccharidoses (MPS) are a group of diseases caused by mutations in genes encoding lysosomal enzymes that catalyze reactions of glycosaminoglycan (GAG) degradation. As a result, GAGs accumulate in lysosomes, impairing the proper functioning of entire cells and tissues. There are 14 types/subtypes of MPS, which are differentiated by the kind(s) of accumulated GAG(s) and the type of a non-functional lysosomal enzyme. Some of these types (severe forms of MPS types I and II, MPS III, and MPS VII) are characterized by extensive central nervous system disorders. The aim of this work was to identify, using transcriptomic methods, organelle-related genes whose expression levels are changed in neuronopathic types of MPS compared to healthy cells while remaining unchanged in non-neuronopathic types of MPS. The study was conducted with fibroblast lines derived from patients with neuronopathic and non-neuronopathic types of MPS and control (healthy) fibroblasts. Transcriptomic analysis has identified genes related to cellular organelles whose expression is altered. Then, using fluorescence and electron microscopy, we assessed the morphology of selected structures. Our analyses indicated that the genes whose expression is affected in neuronopathic MPS are often associated with the structures or functions of the cell nucleus, endoplasmic reticulum, or Golgi apparatus. Electron microscopic studies confirmed disruptions in the structures of these organelles. Special attention was paid to up-regulated genes, such as PDIA3 and MFGE8, and down-regulated genes, such as ARL6IP6, ABHD5, PDE4DIP, YIPF5, and CLDN11. Of particular interest is also the GM130 (GOLGA2) gene, which encodes golgin A2, which revealed an increased expression in neuronopathic MPS types. We propose to consider the levels of mRNAs of these genes as candidates for biomarkers of neurodegeneration in MPS. These genes may also become potential targets for therapies under development for neurological disorders associated with MPS and candidates for markers of the effectiveness of these therapies. Although fibroblasts rather than nerve cells were used in this study, it is worth noting that potential genetic markers characteristic solely of neurons would be impractical in testing patients, contrary to somatic cells that can be relatively easily obtained from assessed persons.

Zinc-finger nuclease (ZFN)-based in vivo genome editing is a novel treatment that can potentially provide lifelong protein replacement with single intravenous administration. Three first-in-human open-label ascending single-dose phase 1/2 studies were performed in parallel (starting November 2017) primarily to assess safety and tolerability of ZFN in vivo editing therapy in mucopolysaccharidosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1). Treatment was well tolerated with no serious treatment-related adverse events. At the 1e13 vg/kg dose, evidence of genome editing was detected through albumin-transgene fusion transcripts in liver for MPS II (n = 2) and MPS I (n = 1) subjects. The MPS I subject also had a transient increase in leukocyte iduronidase activity to the lower normal range. At the 5e13 vg/kg dose, one MPS II subject had a transient increase in plasma iduronate-2-sulfatase approaching normal levels and one MPS I subject approached mid-normal levels of leukocyte iduronidase activity with no evidence of genome editing. The hemophilia B subject was not able to decrease use of factor IX concentrate; genome editing could not be assessed. Overall, ZFN in vivo editing therapy had a favorable safety profile with evidence of targeted genome editing in liver, but no long-term enzyme expression in blood.

BackgroundLysosomal storage diseases (LSDs) are inherited metabolic disorders that may lead to severe multi-organ disease. Current ERTs are limited by anti-drug antibodies, the blood-brain barrier, and early disease onset and progression before ERT is started. We have opened a phase I clinical trial of enzyme replacement therapy (ERT) for fetuses with LSDs (NCT04532047). We evaluated the attitudes of parents and patients with LSDs towards fetal clinical trials and therapies.MethodsA multidisciplinary team designed a survey which was distributed by five international patient advocacy groups. We collected patients' demographic, diagnostic, and treatment information. Associations between respondent characteristics and attitudes towards fetal therapies/trials were analyzed using multivariate ordinal logistic regression.ResultsThe survey was completed by 181 adults from 19 countries. The majority of respondents were mothers from the United States. The most common diseases were MPS1 (26%), MPS3 (19%), and infantile-onset Pompe (14%). Most patients (88%) were diagnosed after birth, at a median of 21 months. Altogether, 65% of participating patients and children of participants had received ERT, 27% a stem cell transplant, and 4% gene therapy. We found that half (49%) of respondents were unlikely to terminate a future affected pregnancy, 55% would enroll in a phase I clinical trial for fetal ERT, and 46% would enroll in a fetal gene therapy trial. Respondents who received postnatal ERT were significantly more likely enroll in a trial for fetal ERT or gene therapy (ERT OR 4.48, 95% CI 2.13-9.44, p

BackgroundImaging features obtained with Fourier-domain optical coherence tomography (FD-OCT) and in vivo confocal microscopy (IVCM) for corneal stromal disorders have been sparsely reported in dogs. This case report is a compilation of imaging features for three cases of different stromal disorders of the canine cornea which have not yet been reported elsewhere.Case presentationLipid deposition in case 1 appeared as needle-shaped hyperreflective lines along the collagen lamellae, which correlated histologically with lipid clefts. In case 2, glycosaminoglycan accumulation by mucopolysaccharidosis type 1 caused diffuse stromal hyperreflectivity and depletion of keratocytes on IVCM and was associated with secondary corneal degeneration presumed to be calcium deposition. In case 3, posterior corneal stromal opacities in the absence of ocular inflammation were identified. Hyperreflective particles were scattered in the middle and posterior corneal stroma on FD-OCT. With IVCM, hyperreflective deposits were identified within keratocytes and the number of enlarged keratocytes containing hyperreflective deposits increased towards the posterior stroma. The bilateral, non-inflammatory nature and unique appearance with IVCM is most consistent with a posterior stromal dystrophy reminiscent of pre-Descemet corneal dystrophy described in humans.ConclusionsIn vivo multimodal corneal imaging facilitated instantaneous microstructural analysis and may be valuable in the differential diagnosis of corneal stromal disorders in veterinary clinical practice. The non-specific nature of imaging findings occurs in some conditions such as mucopolysaccharidosis, thus in vivo corneal imaging should be complemented with other gold standard methods of definitive diagnosis.

Mucopolysaccharidosis III type C (MPS IIIC) is an untreatable neuropathic lysosomal storage disease caused by a genetic deficiency of the lysosomal N-acetyltransferase, HGSNAT, catalyzing a transmembrane acetylation of heparan sulfate. HGSNAT is a transmembrane enzyme incapable of free diffusion between the cells or their cross-correction, which limits development of therapies based on enzyme replacement and gene correction. Since our previous work identified neuroinflammation as a hallmark of the CNS pathology in MPS IIIC, we tested whether it can be corrected by replacement of activated brain microglia with neuroprotective macrophages/microglia derived from a heterologous HSPC transplant. Eight-week-old MPS IIIC (HgsnatP304L) mice were transplanted with HSPC from congenic wild type mice after myeloablation with Busulfan and studied using behavior test battery, starting from the age of 6 months. At the age of ~8 months, mice were sacrificed to study pathological changes in the brain, heparan sulfate storage, and other biomarkers of the disease. We found that the treatment corrected several behavior deficits including hyperactivity and reduction in socialization, but not memory decline. It also improved several features of CNS pathology such as microastroglyosis, expression of pro-inflammatory cytokine IL-1β, and accumulation of misfolded amyloid aggregates in cortical neurons. At the periphery, the treatment delayed development of terminal urinary retention, potentially increasing longevity, and reduced blood levels of heparan sulfate. However, we did not observe correction of lysosomal storage phenotype in neurons and heparan sulfate brain levels. Together, our results demonstrate that neuroinflammation in a neurological lysosomal storage disease, caused by defects in a transmembrane enzyme, can be effectively ameliorated by replacement of microglia bearing the genetic defect with cells from a normal healthy donor. They also suggest that heterologous HSPC transplant, if used together with other methods, such as chaperone therapy or substrate reduction therapy, may constitute an effective combination therapy for MPS IIIC and other disorders with a similar etiology. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the spectrum of skeletal dysplasia in short stature children at National Institute of Child Health (NICH), Pakistan. Study Design: Case Series study. Setting: Department of Endocrinology, NICH, Karachi, Pakistan. Period: January 2022 to November 2023. Methods: Short statured (height < -2.0 SD) children of either gender aged between 1 month up to 16 years and diagnosed with skeletal dysplasia were analyzed. At the time enrollment, gender, age, anthropometric measures, antenatal history, and family history were noted. Complete skeletal survey was performed. Results: In a total of 131 short statured children with skeletal dysplasia, 77 (58.8%) were male. The mean and median age were 5.54±4.33 and 5.0 (1.5-8) years. Consanguinity was reported in 85 (64.9%) cases whereas siblings were affected among 9 (6.9%) cases. The most frequent presenting complaints and clinical features were joint pain, facial dysmorphism, movement limitations, and infections, reported by 67 (51.1%), 67 (51.1%), 65 (49.6%), and 63 (48.1%) children respectively. Mucopolysaccharidosis (29.0%), achondrodysplasia (13.7%), and osteogenesis imperfecta (10.7%) were the most common types of skeletal dysplasia. Conclusion: Mucopolysaccharidosis, achondrodysplasia, and osteogenesis imperfecta were the most frequent types of skeletal dysplasia. The most frequent presenting complaints and clinical features were joint pain, facial dysmorphism, movement limitations, and infections. The high prevalence of consanguinity and familial history emphasizes a probable genetic basis for skeletal dysplasia. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type II (MPS II) results from the genetic deficiency of a lysosomal enzyme and is associated with central nervous system (CNS) dysfunction. In Japan, in addition to intravenous enzyme administration, intracerebroventricular enzyme delivery through the Ommaya reservoir has recently gained approval. Nevertheless, the ideal approach for safely implanting the reservoir into the narrow ventricles of infantile MPS II patients remains uncertain. In this report, we present two cases of successful reservoir placement in infantile MPS II patients using ultrasound guidance via the anterior fontanelle, coupled with flameless electromagnetic neuronavigation. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis increases morbidity and mortality by causing physical and mental limitations in children. Parents experience various difficulties, mostly due to delayed diagnosis and difficult treatment processes. This study aims to examine the experiences of parents regarding their child's illness process. In this qualitative study, semi-structured in-depth interviews were conducted with parents (n = 10) who had a child who had suffered from MPS for at least six months. Interviews were conducted and recorded after the parents were contacted through the MPS-LH association and informed consent was obtained. The conducting and reporting of the research were carried out according to the "Consolidated criteria for reporting qualitative research (COREQ)" checklist. The mean age of the parents was 41.3 ± 7.83. The diagnosis for most of the children was MPS type 4 A (n = 4) and the mean age of the children was 11.3 ± 6.0. Three main themes were identified: 1) psychosocial effects; 2) difficulties and needs; and 3) coping resources. It was determined that the parents were affected socially and emotionally due to the child's diagnosis and the subsequent process. It will be possible to provide the necessary support to parents with comprehensive nursing care that is planned according to the differing needs of children with MPS. • Children with Mucopolysaccharidosis (MPS) have special needs and are increasingly dependent on their parents. • Parents of children with MPS experiences some limitations in their social life. • Parents also experiences some difficulties related to hereditary features of the disease, barriers in the health care system, and lack of emphatic approaches. • Faith-spiritual beliefs and social support groups are the coping resources of the parents. [ABSTRACT FROM AUTHOR]

Background: Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying promising avenues of treatment. Enzyme replacement therapy, gene therapy, and bone marrow transplant have all shown efficacy in the MPS IIIB model systems. A ubiquitous finding across rodent models of lysosomal storage diseases is that the best treatment outcomes resulted from intervention prior to symptom onset. Therefore, the aim of the current study was to identify early markers of disease in the MPS IIIB mouse model as well as examine clinically-relevant behavioral domains not yet explored in this model. Methods: Using the MPS IIIB mouse model, we explored early developmental trajectories of communication and gait, and later social behavior, fear-related startle and conditioning, and visual capabilities. In addition, we examined brain structure and function via magnetic resonance imaging and diffusion tensor imaging. Results: We observed reduced maternal isolation-induced ultrasonic vocalizations in MPS IIIB mice relative to controls, as well as disruption in a number of the spectrotemporal features. MPS IIIB also exhibited disrupted thermoregulation during the first two postnatal weeks without any differences in body weight. The developmental trajectories of gait were largely normal. In early adulthood, we observed intact visual acuity and sociability yet a more submissive phenotype, increased aggressive behavior, and decreased social sniffing relative to controls. MPS IIIB mice showed greater inhibition of startle in response to a pretone with a decrease in overall startle response and reduced cued fear memory. MPS IIIB also weighed significantly more than controls throughout adulthood and showed larger whole brain volumes and normalized regional volumes with intact tissue integrity as measured with magnetic resonance and diffusion tensor imaging, respectively. Conclusions: Together, these results indicate disease markers are present as early as the first two weeks postnatal in this model. Further, this model recapitulates social, sensory and fear-related clinical features. Our study using a mouse model of MPS IIIB provides essential baseline information that will be useful in future evaluations of potential treatments. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type IIIC (MPS IIIC) is one of inherited lysosomal storage disorders, caused by deficiencies in lysosomal hydrolases degrading acidic mucopolysaccharides. The gene responsible for MPS IIIC is HGSNAT, which encodes an enzyme that catalyses the acetylation of the terminal glucosamine residues of heparan sulfate. So far, few studies have focused on the genetic landscape of MPS IIIC in China, where IIIA and IIIB were the major subtypes. In this study, we utilized whole‐exome sequencing (WES) to identify novel compound heterozygous variants in the HGSNAT gene from a Chinese patient with typical MPS IIIC symptoms: c.743G>A; p.Gly248Glu and c.1030C>T; p.Arg344Cys. We performed in silico analysis and experimental validation, which confirmed the deleterious pathogenic nature of both variants, as evidenced by the loss of HGSNAT activity and failure of lysosomal localization. To the best of our knowledge, the MPS IIIC is first confirmed by clinical, biochemical and molecular genetic findings in China. Our study thus expands the spectrum of MPS IIIC pathogenic variants, which is of importance to dissect the pathogenesis and to carry out clinical diagnosis of MPS IIIC. Moreover, this study helps to depict the natural history of Chinese MPS IIIC populations. [ABSTRACT FROM AUTHOR]

Background: Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by iduronate-2-sulfatase gene (IDS) deficiency and downstream glycosaminoglycan accumulation. Two-thirds of patients present with neuronopathic disease and evaluating cognitive function in these patients is challenging owing to limitations of currently available tests. During the clinical development of intrathecal idursulfase (idursulfase-IT), regulatory authorities requested qualitative data to further understand the neurocognitive changes observed by the investigators through the clinical trials. Results: This qualitative study consisted of semi-structured interviews with all nine of the principal investigators who participated in the idursulfase-IT phase 2/3 (NCT02055118) and extension (NCT02412787) trials. These investigators enrolled the 56 patients with neuronopathic MPS II who qualified for the extension phase of the trial. The investigators were asked to rate the disease status of their patients. Of the 56 patients, 49 (88%) were rated as having disease that was improved/improving, stabilized or slowing progression compared with the expected outcomes with no treatment. Three patients were rated as worsening, while the remaining four patients were considered to have slowing progression or worsening disease. Similar results were demonstrated for patients aged from 3 to under 6 years at baseline, with 33 of 39 patients (85%) rated as having disease that was improved/improving, stabilized or slowing progression. Of the seven patients rated with slowing progression/worsening or worsening disease, five of them had an IDS variant other than missense, while two had a missense class variant. All the assigned improved/improving ratings were in patients receiving idursulfase-IT from the start of the phase 2/3 trial. Moreover, patients under 3 years of age at baseline were all rated as either improved/improving or stabilized disease. In a blinded review of patient profiles, investigators were requested to assign a disease status rating to 18 patients with large IDS deletions; 67% of these patients were rated as improved/improving or stabilized disease. Conclusions: This qualitative analysis provides a snapshot of clinicians' considerations when evaluating treatment in patients with neuronopathic MPS II, compared with the expected decline in cognitive function in the absence of treatment. The results highlight the importance of robust assessment tools in treatment evaluation. [ABSTRACT FROM AUTHOR]

To study the role of adenotonsillectomy (ADT) for obstructive sleep apnea (OSA) in children with mucopolysaccharidosis (MPS). A systematic review were performed following the PRISMA guideline. PubMed and Embase were searched for studies regarding adenotonsillectomy for OSA in children with MPS. The MINOR Score were applied for quality assessment of the included studies. Nineteen studies were eligible for inclusion: fifteen were retrospective and four prospective. A total of 1406 subjects were included. The samples size varied from 2 to 336, the male to female ratio is 1.2 and mean age varied from 2.4 to 11 years. Overall, 56.2 % (IC 95%: 53.6–58.8) of the included subjects underwent ADT. MPS I and II are the two most operated types. Three studies, including 50 children, reported improvement in polysomnographic parameters after surgery. Two authors described the duration of follow-up: 8.4 and 9.8 years, respectively. More than half of children with MPS underwent ADT for the treatment of OSA, although few evidence demonstrated improvement in term of polysomnographic parameters. The two types of MPS most involved are type I and II. Considering the disease progression and anesthetic risks, multidisciplinary management may help identify the subgroup of children with MPS who benefit from ADT for the treatment of OSA. • Sleep disordered breathing is diagnosed in up to 80% of MPS patients. • Adenotonsillar hypertrophy is almost universal in MPS children. • Adenotonsillectomy is the first line surgical treatment for OSA in MPS children. • Few data have demonstrated improvement of polysomnographic parameters after surgery. • Surgical outcome is related to progressive multilevel airway obstructions. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type II (MPSII) is a rare pediatric X-linked lysosomal storage disease, caused by heterogeneous mutations in the iduronate-2-sulfatase (IDS) gene, which result in accumulation of heparan sulfate (HS) and dermatan sulfate within cells. This leads to severe skeletal abnormalities, hepatosplenomegaly, and cognitive deterioration. The progressive nature of the disease is a huge obstacle to achieve full neurological correction. Although current therapies can only treat somatic symptoms, a lentivirus-based hematopoietic stem cell gene therapy (HSCGT) approach has recently achieved improved central nervous system (CNS) neuropathology in the MPSII mouse model following transplant at 2 months of age. In this study, we evaluate neuropathology progression in 2-, 4- and 9-month-old MPSII mice, and using the same HSCGT strategy, we investigated somatic and neurological disease attenuation following treatment at 4 months of age. Our results showed gradual accumulation of HS between 2 and 4 months of age, but full manifestation of microgliosis/astrogliosis as early as 2 months. Late HSCGT fully reversed the somatic symptoms, thus achieving the same degree of peripheral correction as early therapy. However, late treatment resulted in slightly decreased efficacy in the CNS, with poorer brain enzymatic activity, together with reduced normalization of HS oversulfation. Overall, our findings confirm significant lysosomal burden and neuropathology in 2-month-old MPSII mice. Peripheral disease is readily reversible by LV.IDS-HSCGT regardless of age of transplant, suggesting a viable treatment for somatic disease. However, in the brain, higher IDS enzyme levels are achievable with early HSCGT treatment, and later transplant seems to be less effective, supporting the view that the earlier patients are diagnosed and treated, the better the therapy outcome. [ABSTRACT FROM AUTHOR]