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Journal, Genetic Engineering &... Nov 2023One of the 11 recognized mucopolysaccharidosis (MPS) diseases is Sanfilippo. It is autosomal recessive in its mode of transmission. There are four subtypes of Sanfilippo...
BACKGROUND
One of the 11 recognized mucopolysaccharidosis (MPS) diseases is Sanfilippo. It is autosomal recessive in its mode of transmission. There are four subtypes of Sanfilippo (A, B, C, and D). The most worldwide prevalent subtypes of mucopolysaccharidosis type III (MPS III) are A and B followed by C and D subtypes. To estimate the frequency of MPS IIIA among MPS III patients, we diagnose and compare their clinical features with those of MPS IIIB and also compare the prevalence of MPS IIIB versus MPS IIIA among diagnosed cases at the Biochemical Genetic Department at NRC. For every case that was referred, the quantitative determination of urine Glycosaminoglycans (GAGs) was assessed. Two-dimensional electrophoresis (2DE) of GAGs extracted from urine was performed on all cases with high urinary GAG levels. Both N-sulphoglucosamine sulphohydrolase (MPS IIIA) and N-alpha-acetylglucosaminidase (MPS IIIB) enzyme activity were determined fluorometrically.
RESULTS
From November 2019 to May 2022, 535 cases were referred to the National Research Centre's Biochemical Genetics Department. 233 (43%) MPS cases were diagnosed with high urinary GAG levels for their ages. 73 (31.3%) MPS III cases were diagnosed by 2DE out of the 233 MPS cases. Plasma N-alpha-acetylglucosaminidase enzyme assay was insufficient in 36 (49.3%) patients (Sanfilippo type B), while N-sulphoglucosamine sulphohydrolase enzyme activity was deficient in 15 (20.6%) patients. The other 22 (30.1%) patients are either Sanfilippo type C or D.
CONCLUSION
N-sulphoglucosamine sulphohydrolase enzyme activity was measured for the first time in Egypt. Thirty-one percent of all diagnosed MPS cases during the last 3 years were MPS type III, making Sanfilippo the most common MPS type among the referred cases to our Biochemical Genetics Department. MPS IIIA accounts for 20.6% of MPSIII cases in this study. Still, MPS type IIIB is the commonest type among diagnosed patients.
PubMed: 37947910
DOI: 10.1186/s43141-023-00586-7 -
Frontiers in Genetics 2024Bibliometrics can trace general research trends in a particular field. Mucopolysaccharidoses (MPS), as a group of rare genetic diseases, seriously affect the quality of...
Bibliometrics can trace general research trends in a particular field. Mucopolysaccharidoses (MPS), as a group of rare genetic diseases, seriously affect the quality of life of patients and their families. Scholars have devoted themselves to studying MPS's pathogenesis and treatment modalities and have published many papers. Therefore, we conducted a bibliometric and visual study of the top 100 most highly cited articles to provide researchers with an indication of the current state of research and potential directions in the field. The Web of Science Core Collection was searched for articles on MPS from 1 January 1900, to 8 November 2023, and the top 100 most cited articles were screened. The title, year of publication, institution, country, and first author of the articles were extracted and statistically analyzed using Microsoft Excel 2007. Keyword co-occurrence and collaborative networks were analyzed using VOSviewer 1.6.16. A total of 9,273 articles were retrieved, and the top 100 most cited articles were filtered out. The articles were cited 18,790 times, with an annual average of 188 citations (122-507). Forty-two journals published these articles, with Molecular Genetics and Metabolism and Proceedings of the National Academy of Sciences of the United States being the most published journal (N = 8), followed by Pediatrics (N = 7), Blood (N = 6). The United States (N = 68), the UK (N = 25), and Germany (N = 20) were the top contributing countries. The Royal Manchester Children's Hospital (N = 20) and the University of North Carolina (N = 18) were the most contributing institutions. Muenzer J was the most prolific author (N = 14). We conducted a bibliometric and visual analysis of the top 100 cited articles in MPS. This study identifies the most influential articles currently available in the field of MPS, which provides a good basis for a better understanding of the disease and informs future research directions.
PubMed: 38680422
DOI: 10.3389/fgene.2024.1377743 -
Molecular Genetics and Metabolism... Dec 2023Approximately two-thirds of patients with mucopolysaccharidosis II (MPS II; Hunter syndrome) have neuronopathic disease, with central nervous system involvement;...
Clinical characteristics and somatic burden of patients with mucopolysaccharidosis II with or without neurological involvement: An analysis from the Hunter Outcome Survey.
Approximately two-thirds of patients with mucopolysaccharidosis II (MPS II; Hunter syndrome) have neuronopathic disease, with central nervous system involvement; one-third have non-neuronopathic disease. This analysis of data from the Hunter Outcome Survey (HOS) compared the clinical manifestations and surgical and nonsurgical procedure history in patients with neuronopathic or non-neuronopathic MPS II. Prospective patients were identified in July 2018 in HOS for inclusion in this analysis as those with stable cognitive impairment status as assessed at 10 years of age and at a minimum of one follow-up visit at 11 to <20 years of age. Patients were stratified according to cognitive impairment status at 10 years into neuronopathic and non-neuronopathic groups, and clinical manifestations and surgical and nonsurgical procedure history were compared between the two groups. In total, 193 patients had cognitive impairment status assessments available (at 10 years and 11 to <20 years of age), 151 of whom had stable cognitive impairment status and were included; 100/151 (66.2%) were in the neuronopathic group and 51/151 (33.8%) in the non-neuronopathic group. The proportion of patients demonstrating manifestations by system organ class and the number of surgical and nonsurgical procedures per patient were broadly comparable in the neuronopathic and non-neuronopathic groups both before and after patients' 10th birthdays. The most common manifestations before patients' 10th birthdays, including facial features, joint stiffness and limited function, and hepatomegaly were reported in >80% of patients in both groups. For the neuronopathic and non-neuronopathic groups, the median [10th percentile, 90th percentile] number of different types of surgical and nonsurgical procedures per patient (3 [1, 6] and 3 [1, 7], respectively) and of all procedures per patient (4 [1, 10] and 5 [2, 11], respectively) before patients' 10th birthdays were similar, although the type of procedure may have differed. Thus, in the first two decades of life, patients with non-neuronopathic disease were found to have similar somatic manifestations to those of the neuronopathic group and undergo procedures for complications as often as those with neuronopathic disease.
PubMed: 38053935
DOI: 10.1016/j.ymgmr.2023.101005 -
Orphanet Journal of Rare Diseases Apr 2024Mucopolysaccharidoses (MPSs) are caused by a deficiency in the enzymes needed to degrade glycosaminoglycans (GAGs) in the lysosome. The storage of GAGs leads to the... (Review)
Review
Mucopolysaccharidoses (MPSs) are caused by a deficiency in the enzymes needed to degrade glycosaminoglycans (GAGs) in the lysosome. The storage of GAGs leads to the involvement of several systems and even to the death of the patient. In recent years, an increasing number of therapies have increased the treatment options available to patients. Early treatment is beneficial in improving the prognosis, but children with MPSs are often delayed in their diagnosis. Therefore, there is an urgent need to develop a method for early screening and diagnosis of the disease. Tandem mass spectrometry (MS/MS) is an analytical method that can detect multiple substrates or enzymes simultaneously. GAGs are reliable markers of MPSs. MS/MS can be used to screen children at an early stage of the disease, to improve prognosis by treating them before symptoms appear, to evaluate the effectiveness of treatment, and for metabolomic analysis or to find suitable biomarkers. In the future, MS/MS could be used to further identify suitable biomarkers for MPSs for early diagnosis and to detect efficacy.
Topics: Humans; Mucopolysaccharidoses; Tandem Mass Spectrometry; Biomarkers; Glycosaminoglycans
PubMed: 38685110
DOI: 10.1186/s13023-024-03195-w -
Brazilian Journal of Anesthesiology... 2023Mucopolysaccharidosis (MPS) are a group of rare genetic inherited diseases with a progressive course due to the accumulation of glycosaminoglycans resulting in anatomic...
Mucopolysaccharidosis (MPS) are a group of rare genetic inherited diseases with a progressive course due to the accumulation of glycosaminoglycans resulting in anatomic abnormalities and organ dysfunction, including the respiratory, cardiovascular, skeletal, and neurological systems that can increase the risk of anesthesia complications. Clinical manifestations are variable, multisystemic, and include severe morphological changes. The anesthetic management of these patients is complex, particularly airway management, which can be planned to include a fiberoptic airway investigation prior to surgery. We present two cases of patients with MPS type VI and VII who underwent fiberoptic airway mapping under conscious sedation, with no complications. Since MPS is a rare but challenging disease concerning the airway management, we propose a safe and effective anesthetic technique that could be used for fiberoptic bronchoscopy and allow fiberoptic-assisted tracheal intubation at the time of surgery.
Topics: Humans; Wakefulness; Mucopolysaccharidoses; Airway Management; Intubation, Intratracheal; Bronchoscopy
PubMed: 34216700
DOI: 10.1016/j.bjane.2021.06.005 -
Cureus Dec 2023Mucopolysaccharidoses are rare lysosomal storage disorders in which glycosaminoglycans accumulate in tissues, causing multiorgan dysfunction. Mucopolysaccharidosis type...
Mucopolysaccharidoses are rare lysosomal storage disorders in which glycosaminoglycans accumulate in tissues, causing multiorgan dysfunction. Mucopolysaccharidosis type I is an autosomal recessive disease caused by a deficiency of the enzyme alpha-L-iduronidase, resulting in the accumulation of dermatan and heparan sulfate. Early diagnosis is crucial for early treatment and improved outcomes. We report the case of a female child with classic clinical features who was diagnosed early which allowed hematopoietic stem cell transplantation and slowed disease progression. She presented at birth with linea alba and umbilical and inguinal hernias. Since the first months of life, she had recurrent respiratory infections. At nine months, a motor delay was noticed, and at 20 months, craniosynostosis was corrected with surgery. Coarse facial features, thoracolumbar kyphosis, and hepatomegaly prompted a urinary glycosaminoglycan study at 22 months, which showed elevated levels. Alfa-L-iduronidase activity in dried blood spot testing was low, compatible with mucopolysaccharidosis type I. Molecular testing of gene performed for genetic counseling, revealed the pathogenic variants c.1205G>A (p.Trp402Ter) and c.1598C>G (p.Pro533Arg) in compound heterozygosity. At 26 months, her development quotient was average for her age. She started enzyme replacement therapy at 29 months and underwent hematopoietic stem cell transplantation at 33 months, which softened the coarse features, reduced respiratory infections, and improved hepatomegaly. However, at age five, her development quotient was 76 (mean = 100, standard deviation = 15). This intellectual impairment might have been prevented with an earlier diagnosis and treatment.
PubMed: 38222174
DOI: 10.7759/cureus.50595 -
Scientific Reports Feb 2024Lysosomal storage diseases (LSDs) are a group of monogenic diseases characterized by mutations in genes coding for proteins associated with the lysosomal function....
Lysosomal storage diseases (LSDs) are a group of monogenic diseases characterized by mutations in genes coding for proteins associated with the lysosomal function. Despite the monogenic nature, LSDs patients exhibit variable and heterogeneous clinical manifestations, prompting investigations into epigenetic factors underlying this phenotypic diversity. In this study, we focused on the potential role of epigenetic mechanisms in the pathogenesis of mucopolysaccharidosis IIIB (MPS IIIB) and mucopolysaccharidosis IVA (MPS IVA). We analyzed DNA methylation (5mC) and histone modifications (H3K14 acetylation and H3K9 trimethylation) in MPS IIIB and MPS IVA patients' fibroblasts and healthy controls. The findings revealed that global DNA hypomethylation is present in cell lines for both diseases. At the same time, histone acetylation was increased in MPS IIIB and MPS IVA cells in a donor-dependent way, further indicating a shift towards relaxed open chromatin in these MPS. Finally, the constitutive heterochromatin marker, histone H3K9 trimethylation, only showed reduced clustering in MPS IIIB cells, suggesting limited alterations in heterochromatin organization. These findings collectively emphasize the significance of epigenetic mechanisms in modulating the phenotypic variations observed in LSDs. While global DNA hypomethylation could contribute to the MPS pathogenesis, the study also highlights individual-specific epigenetic responses that might contribute to phenotypic heterogeneity. Further research into the specific genes and pathways affected by these epigenetic changes could provide insights into potential therapeutic interventions for these MPS and other LSDs.
Topics: Humans; Mucopolysaccharidosis IV; Mucopolysaccharidosis III; Heterochromatin; Histones; DNA
PubMed: 38368436
DOI: 10.1038/s41598-024-54626-4 -
Glycoconjugate Journal Oct 2023In recent years, several rational designed therapies have been developed for treatment of mucopolysaccharidoses (MPS), a group of inherited metabolic disorders in which...
In recent years, several rational designed therapies have been developed for treatment of mucopolysaccharidoses (MPS), a group of inherited metabolic disorders in which glycosaminoglycans (GAGs) are accumulated in various tissues and organs. Thus, improved disease-specific biomarkers for diagnosis and monitoring treatment efficacy are of paramount importance. Specific non-reducing end GAG structures (GAG-NREs) have become promising biomarkers for MPS, as the compositions of the GAG-NREs depend on the nature of the lysosomal enzyme deficiency, thereby creating a specific pattern for each subgroup. However, there is yet no straightforward clinical laboratory platform which can assay all MPS-related GAG-NREs in one single analysis. Here, we developed and applied a GAG domain mapping approach for analyses of urine samples of ten MPS patients with various MPS diagnoses and corresponding aged-matched controls. We describe a nano-LC-MS/MS method of GAG-NRE profiling, utilizing 2-aminobenzamide reductive amination labeling to improve the sensitivity and the chromatographic resolution. Diagnostic urinary GAG-NREs were identified for MPS types IH/IS, II, IIIc, IVa and VI, corroborating GAG-NRE as biomarkers for these known enzyme deficiencies. Furthermore, a significant reduction of diagnostic urinary GAG-NREs in MPS IH (n = 2) and MPS VI (n = 1) patients under treatment was demonstrated. We argue that this straightforward glycomic workflow, designed for the clinical analysis of MPS-related GAG-NREs in one single analysis, will be of value for expanding the use of GAG-NREs as biomarkers for MPS diagnosis and treatment monitoring.
Topics: Humans; Aged; Glycosaminoglycans; Chromatography, Liquid; Tandem Mass Spectrometry; Glycomics; Workflow; Mucopolysaccharidoses; Biomarkers
PubMed: 37462780
DOI: 10.1007/s10719-023-10128-5 -
Orphanet Journal of Rare Diseases May 2024Mucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by reduced activity of...
Disease characteristics, effectiveness, and safety of vestronidase alfa for the treatment of patients with mucopolysaccharidosis VII in a novel, longitudinal, multicenter disease monitoring program.
BACKGROUND
Mucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by reduced activity of β-glucuronidase (GUS) enzyme. Vestronidase alfa (recombinant human GUS) intravenous enzyme replacement therapy is an approved treatment for patients with MPS VII.
METHODS
This disease monitoring program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N ≈ 50 planned) treated with vestronidase alfa or any other management approach. Data are monitored and recorded in compliance with Good Clinical Practice guidelines and planned interim analyses of captured data are performed annually. Here we summarize the safety and efficacy outcomes as of 17 November 2022.
RESULTS
As of the data cutoff date, 35 patients were enrolled: 28 in the Treated Group and seven in the Untreated Group. Mean (SD) age at MPS VII diagnosis was 4.5 (4.0) years (range, 0.0 to 12.4 years), and mean (SD) age at DMP enrollment was 13.9 (11.1) years (range, 1.5 to 50.2 years). Ten patients (29%) had a history of nonimmune hydrops fetalis. In the 23 patients who initiated treatment prior to DMP enrollment, substantial changes in mean excretion from initial baseline to DMP enrollment were observed for the three urinary glycosaminoglycans (uGAGs): dermatan sulfate (DS), -84%; chondroitin sulfate (CS), -55%; heparan sulfate (HS), -42%. Also in this group, mean reduction from initial baseline to months 6, 12, and 24 were maintained for uGAG DS (-84%, -87%, -89%, respectively), CS (-70%, -71%, -76%, respectively), and HS (+ 3%, -32%, and - 41%, respectively). All adverse events (AEs) were consistent with the known vestronidase alfa safety profile. No patients discontinued vestronidase alfa. One patient died.
CONCLUSIONS
To date, the DMP has collected invaluable MPS VII disease characteristic data. The benefit-risk profile of vestronidase alfa remains unchanged and favorable for its use in the treatment of pediatric and adult patients with MPS VII. Reductions in DS and CS uGAG demonstrate effectiveness of vestronidase alfa to Month 24. Enrollment is ongoing.
Topics: Humans; Mucopolysaccharidosis VII; Glucuronidase; Male; Child, Preschool; Female; Child; Enzyme Replacement Therapy; Recombinant Proteins; Infant; Longitudinal Studies; Adolescent
PubMed: 38715031
DOI: 10.1186/s13023-024-03176-z -
Scientific Reports Aug 2023Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal disorder that causes syndromes characterized by physiological dysfunction in many organs and tissues....
Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal disorder that causes syndromes characterized by physiological dysfunction in many organs and tissues. Despite the recognizable morphological and behavioral deficits associated with MPS I, neither the underlying alterations in functional neural connectivity nor its restoration following gene therapy have been shown. By employing high-resolution resting-state fMRI (rs-fMRI), we found significant reductions in functional neural connectivity in the limbic areas of the brain that play key roles in learning and memory in MPS I mice, and that adeno-associated virus (AAV)-mediated gene therapy can reestablish most brain connectivity. Using logistic regression in MPS I and treated animals, we identified functional networks with the most alterations. The rs-fMRI and statistical methods should be translatable into clinical evaluation of humans with neurological disorders.
Topics: Humans; Animals; Mice; Mucopolysaccharidosis I; Brain; Genetic Therapy; Brain Mapping; Magnetic Resonance Imaging
PubMed: 37543633
DOI: 10.1038/s41598-023-39939-0