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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 -
IScience Mar 2024Mucopolysaccharidoses (MPSs) are lysosomal disorders with neurological involvement for which no cure exists. Here, we show that recombinant NK1 fragment of hepatocyte...
Mucopolysaccharidoses (MPSs) are lysosomal disorders with neurological involvement for which no cure exists. Here, we show that recombinant NK1 fragment of hepatocyte growth factor rescues substrate accumulation and lysosomal defects in MPS I, IIIA and IIIB patient fibroblasts. We investigated PI3K/Akt pathway, which is of crucial importance for neuronal function and survival, and demonstrate that PI3K inhibition abolishes NK1 therapeutic effects. We identified that autophagy inhibition, by Beclin1 silencing, reduces MPS IIIB phenotype and that NK1 downregulates autophagic-lysosome (ALP) gene expression, suggesting a possible contribution of autophagosome biogenesis in MPS. Indeed, metabolomic analyses revealed defects of mitochondrial activity accompanied by anaerobic metabolism and inhibition of AMP-activated protein kinase (AMPK), which acts on metabolism and autophagy, rescues lysosomal defects. These results provide insights into the molecular mechanisms of MPS IIIB physiopathology, supporting the development of new promising approaches based on autophagy inhibition and metabolic rewiring to correct lysosomal pathology in MPSs.
PubMed: 38361619
DOI: 10.1016/j.isci.2024.108959 -
Frontiers in Public Health 2024Mucopolysaccharidoses (MPS) constitute a group of progressive and multisystemic inherited metabolic diseases that profoundly affect both the mental health of patients...
INTRODUCTION
Mucopolysaccharidoses (MPS) constitute a group of progressive and multisystemic inherited metabolic diseases that profoundly affect both the mental health of patients and the wellbeing of their families. This study aims to evaluate the impact of MPS on family functioning and related factors.
METHODS AND RESULTS
Twenty-five patients with MPS, including types I ( = 4), II ( = 11), IIIB ( = 2), IVA ( = 3), and VI ( = 5), and their families participated in this study. The mean patient age was 13 years [standard deviation (SD): 7.7 years]. Behavioral and emotional problems were noted in 9.1% of all patients. While the type of MPS did not directly influence mental problems, the presence of neuronal involvement did ( = 0.006). Patients with MPS III exhibited difficulties primarily in emotional areas, conduct, hyperactivity, and peer problems. Importantly, both patients with MPS II and those with MPS III experienced a significant impact on communication [mean scores for communication domain: MPS II, 35.6 (SD: 24.3); MPS III, 35.0 (SD: 22.6)]; poorer communication was directly linked to worse adaptive behavior ( = 0.012), and worse adaptive behavior was associated with lower quality of life ( = 0.001). Quality of life and caregiver burden among family members did not significantly differ across MPS types; however, higher caregiver burden was negatively associated with quality of life ( = 0.002). Concerning family functioning, the most impacted domains included independence, intellectual/cultural orientation, activity/recreation, and expressiveness. Domain scores did not vary based on MPS type, treatment, or neurological involvement. Quality-of-life scores were positively associated with the cultural/intellectual domain score.
CONCLUSION
The impacts of quality of life and family extend beyond clinical characteristics and MPS type, strongly influenced by patient cognition and communication, as well as type of family functioning, especially those with greater cultural/intellectual skills of their family members. A multidisciplinary approach addressing the broader needs of individuals with MPS becomes essential. Techniques aimed at improving communication, including prompt interventions such as speech therapy and augmentative and alternative communication strategies, can contribute to overall family functioning improvement.
Topics: Humans; Adolescent; Quality of Life; Mucopolysaccharidoses; Family; Mental Disorders; Mental Health
PubMed: 38327584
DOI: 10.3389/fpubh.2024.1305878 -
Frontiers in Medicine 2023A 12-year-old girl with mucopolysaccharidosis (MPS) type I (Gurler-Scheie syndrome, Q70X/del C683 of the IDUA gene in the compound heterozygous state) regularly received...
Evaluation of etanercept (a tumor necrosis factor alpha inhibitor) as an effective treatment for joint disease in mucopolysaccharidosis type I. A case report with whole-body magnetic resonance imaging.
SUMMARY
A 12-year-old girl with mucopolysaccharidosis (MPS) type I (Gurler-Scheie syndrome, Q70X/del C683 of the IDUA gene in the compound heterozygous state) regularly received enzyme replacement therapy (laronidase) since the preclinical stage (6 months old) due to positive family history, and started etanercept treatment due to progression of joint pain and decreasing capability to walk. The patient had a significant reduction of pain in the joints and an expansion of daily physical activity without adverse events. A decrease in bone marrow edema without foci progression compared to baseline assessment was observed in the whole-body MRI.During the treatment (baseline/6 months/12 months) the following was observed: childhood health assessment questionnaire (CHAQ) index of 1.88/2.13/1.63 points; patient's pediatric quality of life inventory (PedsQL) of 37/30/31 points; parental PedsQL of 26/27/34 points; and patient's pain visual-analog scale (VAS) of 75/45/40, with no VAS recorded for the mother. Juvenile arthritis functional assessment report (JAFAR) scores of 35/34/8 points were observed. A significant reduction in the taking of NSAIDs was observed. In the second half of the year, the nasal breathing became normal, and remission in chronic rhinitis and adenoiditis was achieved (no infection episodes) without otitis episodes.
CONCLUSION
Etanercept in mucopolysaccharidosis type 1 is safe and well tolerated. The reduction of joint pain and increased walking capacity were observed. A decreased number of respiratory infection episodes and nasal breathing improvement were noted during the treatment. The observation shows the role of inflammation in the different aspects of MPS. Further investigations on immune system dysregulation in patients with MPS I are needed. Additional studies on the efficacy and safety of anti-rheumatic biological drugs in patients with MPSI are required.
PubMed: 38314027
DOI: 10.3389/fmed.2023.1252704 -
Saudi Journal of Anaesthesia 2024"Mucopolysaccharidosis" (MPS) is a rare, autosomal recessive lysosomal storage disease characterized by deficiencies in 11 different lysosomal enzymes involved in the...
"Mucopolysaccharidosis" (MPS) is a rare, autosomal recessive lysosomal storage disease characterized by deficiencies in 11 different lysosomal enzymes involved in the metabolism of glycosaminoglycans (GAGs) leading to its accumulation, the condition which results in anatomic abnormalities and multi-organ dysfunction that increases the risk of anesthesia complications. The patterns of accumulation form the basis of MPS classification into seven types of progressive diseases. Most of the MPS types have facial and oral characteristics that increase the risk of airway management. We are reporting a case of MPS with a challenging airway, an 11-years-old boy diagnosed with MPS type VI with a prominent facial character planned for cervical spine fixation versus decompression, successfully managed with fiberoptic bronchoscopy (FOB) guided by video laryngoscopy (VL).
PubMed: 38313740
DOI: 10.4103/sja.sja_515_23 -
Molecular Genetics and Metabolism Mar 2024Mucopolysaccharidosis type VII (MPS VII) is an ultra-rare, life-threatening, progressive disease caused by genetic mutations that affect lysosomal storage/function. MPS... (Review)
Review
Mucopolysaccharidosis type VII (MPS VII) is an ultra-rare, life-threatening, progressive disease caused by genetic mutations that affect lysosomal storage/function. MPS VII has an estimated prevalence of <1:1,000,000 and accounts for <3% of all MPS diagnoses. Given the rarity of MPS VII, comprehensive information on the disease is limited and we present a review of the current understanding. In MPS VII, intracellular glycosaminoglycans accumulate due to a deficiency in the lysosomal enzyme that is responsible for their degradation, β-glucuronidase, which is encoded by the GUSB gene. MPS VII has a heterogeneous presentation. Features can manifest across multiple systems and can vary in severity, age of onset and progression. The single most distinguishing clinical feature of MPS VII is non-immune hydrops fetalis (NIHF), which presents during pregnancy. MPS VII usually presents within one month of life and become more prominent at 3 to 4 years of age; key features are skeletal deformities, hepatosplenomegaly, coarse facies, and cognitive impairment, although phenotypic variation is a hallmark. Current treatments include hematopoietic stem cell transplantation and enzyme replacement therapy with vestronidase alfa. Care should be individualized for each patient. Development of consensus guidelines for MPS VII management and treatment is needed, as consolidation of expert knowledge and experience (for example, through the MPS VII Disease Monitoring Program) may provide a significant positive impact to patients.
Topics: Pregnancy; Female; Humans; Mucopolysaccharidosis VII; Glucuronidase; Hepatomegaly; Splenomegaly; Glycosaminoglycans; Hematopoietic Stem Cell Transplantation; Rare Diseases
PubMed: 38301529
DOI: 10.1016/j.ymgme.2024.108145 -
Genes & Diseases May 2024
PubMed: 38292179
DOI: 10.1016/j.gendis.2023.06.003 -
Rheumatology Advances in Practice 2024Musculoskeletal (MSK) problems in children are common, and health-care professionals must identify those requiring onward referral. Paediatric gait, arms, legs and spine... (Review)
Review
Musculoskeletal (MSK) problems in children are common, and health-care professionals must identify those requiring onward referral. Paediatric gait, arms, legs and spine (pGALS) is an MSK assessment to discern abnormal joints. We aimed to identify MSK assessments to add to pGALS (pGALSplus) to facilitate decision-making in the context of exemplar conditions representing a spectrum of MSK presentations, namely JIA, mucopolysaccharidoses, muscular dystrophy and developmental co-ordination disorder. A literature review identified 35 relevant articles that focused on clinical assessments [including questionnaire(s), physical examination and functional tests] used by health-care professionals in the context of the exemplar conditions. We provide a description of these assessments and the rationale regarding how they, or components of such tools, might be useful within pGALSplus. This process provides a foundation for further work to develop and validate pGALSplus.
PubMed: 38283055
DOI: 10.1093/rap/rkae004 -
International Journal of Molecular... Jan 2024Mucopolysaccharidoses (MPSs) are a group of inborn errors of the metabolism caused by a deficiency in the lysosomal enzymes required to break down molecules called... (Review)
Review
Mucopolysaccharidoses (MPSs) are a group of inborn errors of the metabolism caused by a deficiency in the lysosomal enzymes required to break down molecules called glycosaminoglycans (GAGs). These GAGs accumulate over time in various tissues and disrupt multiple biological systems, including catabolism of other substances, autophagy, and mitochondrial function. These pathological changes ultimately increase oxidative stress and activate innate immunity and inflammation. We have described the pathophysiology of MPS and activated inflammation in this paper, starting with accumulating the primary storage materials, GAGs. At the initial stage of GAG accumulation, affected tissues/cells are reversibly affected but progress irreversibly to: (1) disruption of substrate degradation with pathogenic changes in lysosomal function, (2) cellular dysfunction, secondary/tertiary accumulation (toxins such as GM2 or GM3 ganglioside, etc.), and inflammatory process, and (3) progressive tissue/organ damage and cell death (e.g., skeletal dysplasia, CNS impairment, etc.). For current and future treatment, several potential treatments for MPS that can penetrate the blood-brain barrier and bone have been proposed and/or are in clinical trials, including targeting peptides and molecular Trojan horses such as monoclonal antibodies attached to enzymes via receptor-mediated transport. Gene therapy trials with AAV, ex vivo LV, and Sleeping Beauty transposon system for MPS are proposed and/or underway as innovative therapeutic options. In addition, possible immunomodulatory reagents that can suppress MPS symptoms have been summarized in this review.
Topics: Humans; Therapies, Investigational; Mucopolysaccharidoses; Osteochondrodysplasias; Antibodies, Monoclonal; Glycosaminoglycans; Inflammation
PubMed: 38256186
DOI: 10.3390/ijms25021113 -
Bioinformation 2023Human alpha-L-iduronidase (IDUA) is a 653 amino acid protein involved in the sequential degradation of glycos-amino-glycans (GAG), heparan sulfate (HS), and dermatan...
Human alpha-L-iduronidase (IDUA) is a 653 amino acid protein involved in the sequential degradation of glycos-amino-glycans (GAG), heparan sulfate (HS), and dermatan sulfate (DS). Some variants in the IDUA gene produce a deficient enzyme that causes un-degraded DS and HS to accumulate in multiple tissues, leading to an organ dysfunction known as muco-poly-saccharidosis type I (MPS I). Molecular and catalytic activity assays of new or rare variants of IDUA do not predict the phenotype that a patient will develop. Therefore, it is of interest to describe the molecular docking analysis, to locate binding regions of DS to IDUA to better understand the effect of a variant on MPS I development. The results presented herein demonstrate the presence of a polar/acidic catalytic site and a basic region in the putative binding site of DS to IDUA. Further, synthetic substrate docking with the enzyme could help in the predictions of the MPS I phenotype.
PubMed: 38250526
DOI: 10.6026/973206300191116