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F1000Research 2024Hunter syndrome (MPS II), an X-linked recessive lysosomal storage disorder, is a result of deficiency of the iduronate 2-sulfatase enzyme (IDS), leading to cognitive...
Hunter syndrome (MPS II), an X-linked recessive lysosomal storage disorder, is a result of deficiency of the iduronate 2-sulfatase enzyme (IDS), leading to cognitive impairment, systemic organ involvement, and increased dental problems. This case report describes the management of a child with Hunter syndrome who was referred to the Department of Paediatric and Preventive Dentistry for pain in the upper front teeth. Intraoral examination revealed severe early childhood caries, prompting planning for full-mouth rehabilitation under general anaesthesia due to the child's uncooperative behaviour. In response to recommendations from the Department of Otolaryngology and the Department of Paediatric Surgery, a comprehensive treatment plan consolidated full-mouth rehabilitation in addition to adenoidectomy and inguinal and umbilical herniotomy procedures during a single session of general anaesthesia. Successful interventions were reflected in the uneventful one-month follow-up of the patient, highlighting the efficacy of the interdisciplinary approach. The key takeaway underscores the importance of collaborative interventions, emphasising singular intubation for patients requiring recurrent hospitalisations, providing both monetary relief and reducing post operative healing time. Designed to address global developmental delay in the child, a personalised home care plan was also implemented. Evaluation of plaque and gingival indices before and after the home care regimen demonstrated a notable improvement, indicating an enhanced oral quality of life.
Topics: Humans; Mucopolysaccharidosis II; Quality of Life; Male; Child; Holistic Health; Dental Care
PubMed: 38812528
DOI: 10.12688/f1000research.146468.1 -
Scientific Reports May 2024MPS III is an autosomal recessive lysosomal storage disease caused mainly by missense variants in the NAGLU, GNS, HGSNAT, and SGSH genes. The pathogenicity...
MPS III is an autosomal recessive lysosomal storage disease caused mainly by missense variants in the NAGLU, GNS, HGSNAT, and SGSH genes. The pathogenicity interpretation of missense variants is still challenging. We aimed to develop unsupervised clustering-based pathogenicity predictor scores using extracted features from eight in silico predictors to predict the impact of novel missense variants of Sanfilippo syndrome. The model was trained on a dataset consisting of 415 uncertain significant (VUS) missense NAGLU variants. Performance The SanfilippoPred tool was evaluated by validation and test datasets consisting of 197-labelled NAGLU missense variants, and its performance was compared versus individual pathogenicity predictors using receiver operating characteristic (ROC) analysis. Moreover, we tested the SanfilippoPred tool using extra-labelled 427 missense variants to assess its specificity and sensitivity threshold. Application of the trained machine learning (ML) model on the test dataset of labelled NAGLU missense variants showed that SanfilippoPred has an accuracy of 0.93 (0.86-0.97 at CI 95%), sensitivity of 0.93, and specificity of 0.92. The comparative performance of the SanfilippoPred showed better performance (AUC = 0.908) than the individual predictors SIFT (AUC = 0.756), Polyphen-2 (AUC = 0.788), CADD (AUC = 0.568), REVEL (AUC = 0.548), MetaLR (AUC = 0.751), and AlphMissense (AUC = 0.885). Using high-confidence labelled NAGLU variants, showed that SanfilippoPred has an 85.7% sensitivity threshold. The poor correlation between the Sanfilippo syndrome phenotype and genotype represents a demand for a new tool to classify its missense variants. This study provides a significant tool for preventing the misinterpretation of missense variants of the Sanfilippo syndrome-relevant genes. Finally, it seems that ML-based pathogenicity predictors and Sanfilippo syndrome-specific prediction tools could be feasible and efficient pathogenicity predictors in the future.
Topics: Mucopolysaccharidosis III; Mutation, Missense; Humans; Bayes Theorem; Machine Learning; ROC Curve; Computational Biology; Normal Distribution
PubMed: 38802532
DOI: 10.1038/s41598-024-62352-0 -
Antioxidants (Basel, Switzerland) May 2024Dimethyl sulfoxide (DMSO), an organosulfur compound, is widely used as the gold standard solvent in biological research. It is used in cell culture experiments and as a...
Dimethyl sulfoxide (DMSO), an organosulfur compound, is widely used as the gold standard solvent in biological research. It is used in cell culture experiments and as a component of formulations in in vivo studies. Unfortunately, parameters related to sulfur metabolism are often not taken into account when using DMSO. Therefore, in this work we aim to show that the addition of DMSO to the culture medium (even in amounts commonly considered acceptable) alters some parameters of sulfur metabolism. For this study, we used three cell lines: a commercially available Caco-2 line (HTB-37, ATCC) and two lines created as part of our early studies (likewise previously described in the literature) to investigate the anomalies of sulfur metabolism in mucopolysaccharidosis. As the negative effects of DMSO on the cell membrane are well known, additional experiments with the partial loading of DMSO into polymerosomes (poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide), PEG-PLGA) were performed to eliminate these potentially disruptive effects. The results show that DMSO is a source of interference in studies related to sulfur metabolism and that there are not just simple effects that can be corrected in the final result by subtracting control values, since complex synergisms are also observed.
PubMed: 38790687
DOI: 10.3390/antiox13050582 -
Healthcare (Basel, Switzerland) May 2024The aim of this study is to compare the dental profiles of Brazilian patients with rare genetic skeletal disorders and normotypical patients. A cross-sectional study was...
The aim of this study is to compare the dental profiles of Brazilian patients with rare genetic skeletal disorders and normotypical patients. A cross-sectional study was carried out with 210 individuals aged between 2 and 54 years old [105 with rare diseases (Mucopolysaccharidosis/MPS n = 27 and Osteogenesis Imperfecta/OI n = 78) and 105 without rare diseases] and their parents/caregivers. The parents/caregivers answered a questionnaire about individual aspects of their child and the dental profile was identified from questions related to dental history and the presence/absence of dental problems. The patients' oral cavity was also examined by three examiners for dental caries, malocclusion, gingivitis, and dental anomalies. The average age of individuals with a rare disease was 14.1 years (±12.2) and the median was 9.5 years. Participants who had already used the public health system (SUS) dental care services had a 2.24 times higher chance of belonging to the group with a rare disease (OR = 2.24; 95% CI: 1.07-4.89). Patients with rare diseases are 14.86 times more likely to have difficulty receiving dental treatment (OR = 14.86; 95% CI: 5.96-27.03) and 10.38 times more likely to have one or more dental problems (OR = 10.38; 95% CI: 1.95-35.17). Individuals with rare disorders have a greater history of difficulty in accessing dental treatment, using the SUS, and were diagnosed with more dental problems compared to normotypical individuals.
PubMed: 38786456
DOI: 10.3390/healthcare12101046 -
Cells May 2024Mucopolysaccharidosis III type C (MPS IIIC) is an untreatable neuropathic lysosomal storage disease caused by a genetic deficiency of the lysosomal N-acetyltransferase,...
Heterologous HSPC Transplantation Rescues Neuroinflammation and Ameliorates Peripheral Manifestations in the Mouse Model of Lysosomal Transmembrane Enzyme Deficiency, MPS IIIC.
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 () 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.
Topics: Animals; Mucopolysaccharidosis III; Disease Models, Animal; Mice; Neuroinflammatory Diseases; Lysosomes; Microglia; Mice, Inbred C57BL; Brain; Heparitin Sulfate; Inflammation
PubMed: 38786099
DOI: 10.3390/cells13100877 -
PloS One 2024Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal disease caused by lowered activity of the enzyme alpha-L-iduronidase (IDUA). Current therapeutic options...
Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal disease caused by lowered activity of the enzyme alpha-L-iduronidase (IDUA). Current therapeutic options show limited efficacy and do not treat some important aspects of the disease. Therefore, it may be advantageous to identify strategies that could improve the efficacy of existing treatments. Pharmacological chaperones are small molecules that protect proteins from degradation, and their use in combination with enzyme replacement therapy (ERT) has been proposed as an alternative therapeutic strategy. Using the SEE-Tx® proprietary computational drug discovery platform, a new allosteric ligand binding cavity in IDUA was identified distal from the active site. Virtual high-throughput screening of approximately 5 million compounds using the SEE-Tx® docking platform identified a subset of small molecules that bound to the druggable cavity and functioned as novel allosteric chaperones of IDUA. Experimental validation by differential scanning fluorimetry showed an overall hit rate of 11.4%. Biophysical studies showed that one exemplary hit molecule GT-01803 bound to (Kd = 22 μM) and stabilized recombinant human IDUA (rhIDUA) in a dose-dependent manner. Co-administration of rhIDUA and GT-01803 increased IDUA activity in patient-derived fibroblasts. Preliminary in vivo studies have shown that GT-01803 improved the pharmacokinetic (PK) profile of rhIDUA, increasing plasma levels in a dose-dependent manner. Furthermore, GT-01803 also increased IDUA enzymatic activity in bone marrow tissue, which benefits least from standard ERT. Oral bioavailability of GT-01803 was found to be good (50%). Overall, the discovery and validation of a novel allosteric chaperone for rhIDUA presents a promising strategy to enhance the efficacy of existing treatments for MPS I. The compound's ability to increase rhIDUA activity in patient-derived fibroblasts and its good oral bioavailability underscore its potential as a potent adjunct to ERT, particularly for addressing aspects of the disease less responsive to standard treatment.
Topics: Iduronidase; Mucopolysaccharidosis I; Humans; Allosteric Regulation; Animals; Mice; Enzyme Replacement Therapy; Drug Discovery; Fibroblasts; Recombinant Proteins; Enzyme Stability; Molecular Docking Simulation
PubMed: 38768102
DOI: 10.1371/journal.pone.0303789 -
Cureus Apr 2024Mongolian spots are bluish-grey, irregular, hyperpigmented macules present at birth or that appear in the first few weeks of life. They are classified as atypical if...
Mongolian spots are bluish-grey, irregular, hyperpigmented macules present at birth or that appear in the first few weeks of life. They are classified as atypical if they occur in unusual locations without spontaneous disappearance after infancy; or if new lesions continue to appear beyond early infancy. Although they are generally considered benign, recent studies have shown that atypical Mongolian spots may be associated with inborn errors of metabolism, such as lysosomal storage disorders and neurocristopathies. An 11-month-old male presented with multiple aberrant Mongolian spots on the abdomen, back, buttocks, arms, and legs, with the largest patch measuring 10x10 cm. Additionally, the child exhibited coarse facial features, a high-arched palate, low-set ears, and a depressed nasal bridge. Systemic examination revealed hepatosplenomegaly, fundus examination showed a hazy cornea, and the urine glycosaminoglycan test was positive, prompting us to conduct further research prioritising lysosomal storage disorders. The mucopolysaccharidosis (MPS) spot test was positive, and electrophoresis for MPS revealed bands for chondroitin sulfate and dermatan sulfate, confirming the diagnosis of MPS. Enzyme assay revealed no alpha-iduronidase activity and normal beta-galactosidase activity, thus confirming Hurler's disease. This case report highlights the importance of considering atypical Mongolian spots as a potential indicator of underlying storage disorders, enabling early intervention.
PubMed: 38765368
DOI: 10.7759/cureus.58501 -
Glycobiology Apr 2024Genetic deficiency of alpha-L-iduronidase causes mucopolysaccharidosis type I (MPS-I) disease, due to accumulation of glycosaminoglycans (GAGs) including...
Genetic deficiency of alpha-L-iduronidase causes mucopolysaccharidosis type I (MPS-I) disease, due to accumulation of glycosaminoglycans (GAGs) including chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) in cells. Currently, patients are treated by infusion of recombinant iduronidase or by hematopoietic stem cell transplantation. An alternative approach is to reduce the L-iduronidase substrate, through limiting the biosynthesis of iduronic acid. Our earlier study demonstrated that ebselen attenuated GAGs accumulation in MPS-I cells, through inhibiting iduronic acid producing enzymes. However, ebselen has multiple pharmacological effects, which prevents its application for MPS-I. Thus, we continued the study by looking for novel inhibitors of dermatan sulfate epimerase 1 (DS-epi1), the main responsible enzyme for production of iduronic acid in CS/DS chains. Based on virtual screening of chemicals towards chondroitinase AC, we constructed a library with 1,064 compounds that were tested for DS-epi1 inhibition. Seventeen compounds were identified to be able to inhibit 27%-86% of DS-epi1 activity at 10 μM. Two compounds were selected for further investigation based on the structure properties. The results show that both inhibitors had a comparable level in inhibition of DS-epi1while they had negligible effect on HS epimerase. The two inhibitors were able to reduce iduronic acid biosynthesis in CS/DS and GAG accumulation in WT and MPS-I fibroblasts. Docking of the inhibitors into DS-epi1 structure shows high affinity binding of both compounds to the active site. The collected data indicate that these hit compounds may be further elaborated to a potential lead drug used for attenuation of GAGs accumulation in MPS-I patients.
Topics: Mucopolysaccharidosis I; Humans; Fibroblasts; Glycosaminoglycans; Enzyme Inhibitors; Carbohydrate Epimerases; Molecular Docking Simulation; Antigens, Neoplasm; DNA-Binding Proteins; Neoplasm Proteins
PubMed: 38760939
DOI: 10.1093/glycob/cwae025 -
JAMA Network Open May 2024Newborn screening (NBS) for lysosomal storage disorders (LSDs) is becoming an increasing concern in public health. However, the birth prevalence of these disorders is...
IMPORTANCE
Newborn screening (NBS) for lysosomal storage disorders (LSDs) is becoming an increasing concern in public health. However, the birth prevalence of these disorders is rarely reported in the Chinese population, and subclinical forms of diseases among patients identified by NBS have not been evaluated.
OBJECTIVE
To evaluate the birth prevalence of the 6 LSDs in the Shanghai population and determine subclinical forms based on clinical, biochemical, and genetic characteristics.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study included 50 108 newborns recruited from 41 hospitals in Shanghai between January and December 2021 who were screened for 6 LSDs using tandem mass spectrometry (MS/MS). Participants with screen-positive results underwent molecular and biochemical tests and clinical assessments. Data were analyzed from January 2021 through October 2022.
EXPOSURES
All participants were screened for Gaucher, acid sphingomyelinase deficiency (ASMD), Krabbe, mucopolysaccharidosis type I, Fabry, and Pompe diseases using dried blood spots.
MAIN OUTCOMES AND MEASURES
Primary outcomes were the birth prevalence and subclinical forms of the 6 LSDs in the Shanghai population. Disease biomarker measurements, genetic testing, and clinical analysis were used to assess clinical forms of LSDs screened.
RESULTS
Among 50 108 newborns (26 036 male [52.0%]; mean [SD] gestational age, 38.8 [1.6] weeks), the mean (SD) birth weight was 3257 (487) g. The MS/MS-based NBS identified 353 newborns who were positive. Of these, 27 newborns (7.7%) were diagnosed with 1 of 6 LSDs screened, including 2 newborns with Gaucher, 5 newborns with ASMD, 9 newborns with Krabbe, 8 newborns with Fabry, and 3 newborns with Pompe disease. The combined birth prevalence of LSDs in Shanghai was 1 diagnosis in 1856 live births, with Krabbe disease the most common (1 diagnosis/5568 live births), followed by Fabry disease (1 diagnosis/6264 live births), and ASMD (1 diagnosis/10 022 live births). Biochemical, molecular, and clinical analysis showed that early-onset clinical forms accounted for 3 newborns with positive results (11.1%), while later-onset forms represented nearly 90% of diagnoses (24 newborns [88.9%]).
CONCLUSIONS AND RELEVANCE
In this study, the combined birth prevalence of the 6 LSDs in Shanghai was remarkably high. MS/MS-based newborn screening, combined with biochemical and molecular genetic analysis, successfully identified and characterized newborns who were screen-positive, which may assist with parental counseling and management decisions.
Topics: Humans; Infant, Newborn; Neonatal Screening; China; Lysosomal Storage Diseases; Male; Female; Prevalence; Cohort Studies; Tandem Mass Spectrometry
PubMed: 38739391
DOI: 10.1001/jamanetworkopen.2024.10754 -
Cureus Apr 2024Sanfilippo syndrome is a childhood-onset (1-4 years) autosomal recessive lysosomal storage disease that presents as a neurodegenerative disease by targeting the brain... (Review)
Review
Sanfilippo syndrome is a childhood-onset (1-4 years) autosomal recessive lysosomal storage disease that presents as a neurodegenerative disease by targeting the brain and spinal cord. It is also known as mucopolysaccharidosis III. Mucopolysaccharidosis III is divided into four subtypes (A, B, C, or D). It can cause delayed speech, behavior problems, and features of autism spectrum disorder. Sanfilippo syndrome is of a higher prevalence within consanguineous families that carry its gene alteration. If both parents have a nonfunctional copy of a gene linked to this condition, their children will have a 25% (1 in 4) chance of developing the disease. In Saudi Arabia, the incidence rate is estimated at 2 per 100,000 live births. Recent research focused on promising treatment approaches, such as gene therapy, modified enzyme replacement therapy, and stem cells. These approaches work by exogenous administration of the proper version of the mutant enzyme (enzyme replacement therapy), cleaning the defective enzyme in individuals with glycolipid storage disorders (substrate reduction therapy), or using a pharmacological chaperone to target improperly folded proteins. However, there is currently no approved curative medication for Sanfilippo syndrome that can effectively halt or reverse the disorder.
PubMed: 38738088
DOI: 10.7759/cureus.58023