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Molecular Genetics and Metabolism... Sep 2023This study assessed growth patterns in patients with mucopolysaccharidosis (MPS) VII before enzyme replacement therapy.
OBJECTIVE
This study assessed growth patterns in patients with mucopolysaccharidosis (MPS) VII before enzyme replacement therapy.
METHODS
Height, weight, and body mass index (BMI) measurements and -scores from patients from three clinical studies were compared with those from CDC healthy population growth charts. Relationships with age/sex and history of non-immune hydrops fetalis (NIHF) were assessed by linear regression and ANOVA, respectively.
RESULTS
Among 20 enrolled patients with MPS VII, height -scores were near normal until 1 year of age but declined thereafter, particularly among males. There was no consistent pattern in weight -score. BMI -scores were above normal and increased slightly with age among males and were slightly below normal among females. Male patients with a history of NIHF had greater declines in height and weight -scores over time versus males without history of NIHF. There was no clear effect of NIHF history on height and weight -scores in female patients.
CONCLUSIONS
In patients with MPS VII, declines in height -score began early in life, particularly among males, while changes in BMI varied by sex. Patients with MPS VII and a history of NIHF had greater declines in height -score with age than did patients without a history of NIHF. This retrospective analysis included patients enrolled in an open-label phase 2 study (UX003-CL203; ClinicalTrials.gov, NCT02418455), a randomized, placebo-controlled, blind-start phase 3 study (UX003-CL301; ClinicalTrials.gov, NCT02230566), or its open-label, long-term extension (UX003-CL202; ClinicalTrials.gov, NCT02432144). Requests for individual de-identified participant data and the clinical study report from this study are available to researchers providing a methodologically sound proposal that is in accordance with the Ultragenyx data sharing commitment. To gain access, data requestors will need to sign a data access and use agreement. Data will be shared via secured portal. The study protocol and statistical analysis plan for this study are available on the relevant clinical trial registry websites with the tabulated results.
PubMed: 37415957
DOI: 10.1016/j.ymgmr.2023.100987 -
Nature Communications Nov 2023Matrix Gla protein (MGP) is a vitamin K-dependent post-translationally modified protein, highly expressed in vascular and cartilaginous tissues. It is a potent inhibitor...
Matrix Gla protein (MGP) is a vitamin K-dependent post-translationally modified protein, highly expressed in vascular and cartilaginous tissues. It is a potent inhibitor of extracellular matrix mineralization. Biallelic loss-of-function variants in the MGP gene cause Keutel syndrome, an autosomal recessive disorder characterized by widespread calcification of various cartilaginous tissues and skeletal and vascular anomalies. In this study, we report four individuals from two unrelated families with two heterozygous variants in MGP, both altering the cysteine 19 residue to phenylalanine or tyrosine. These individuals present with a spondyloepiphyseal skeletal dysplasia characterized by short stature with a short trunk, diffuse platyspondyly, midface retrusion, progressive epiphyseal anomalies and brachytelephalangism. We investigated the cellular and molecular effects of one of the heterozygous deleterious variants (C19F) using both cell and genetically modified mouse models. Heterozygous 'knock-in' mice expressing C19F MGP recapitulate most of the skeletal anomalies observed in the affected individuals. Our results suggest that the main underlying mechanism leading to the observed skeletal dysplasia is endoplasmic reticulum stress-induced apoptosis of the growth plate chondrocytes. Overall, our findings support that heterozygous variants in MGP altering the Cys19 residue cause autosomal dominant spondyloepiphyseal dysplasia, a condition distinct from Keutel syndrome both clinically and molecularly.
Topics: Animals; Humans; Mice; Calcium-Binding Proteins; Extracellular Matrix Proteins; Mucopolysaccharidosis IV; Osteochondrodysplasias; Matrix Gla Protein
PubMed: 37923733
DOI: 10.1038/s41467-023-41651-6 -
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 -
The International Journal of... Jan 2024Mucopolysaccharidoses (MPS) are a group of rare genetic diseases and heart involvement is one of the important conflicts in most types, which may cause serious...
PURPOSE
Mucopolysaccharidoses (MPS) are a group of rare genetic diseases and heart involvement is one of the important conflicts in most types, which may cause serious complications. We used M-Mode and two-dimensional speckle tracking echocardiography (2D-STE) to explore cardiovascular involvements in MPS patients.
METHOD
The present cross-sectional study investigated the frequency of cardiac involvements in MPS patients. Included participants were MPS types I, II, III, IV, and VI who underwent specialized echocardiography exams to assess valvular function, systolic and diastolic function, left ventricular ejection fraction (LVEF), and global longitudinal strain (GLS).
RESULTS
35 patients were enrolled in this study. The total mean age of patients was 9.58 ± 5.11 years and 71.4% were male. Type IV (40%) and type III (31.4%) were the most frequent MPS. Although LVEF did not differ notably among MPS types, GLS was significantly different (p = 0.029). Mitral regurgitation was observed remarkably more in MPS type III (p = 0.001) while mitral stenosis was more common in type III (p = 0.007). There was a significant association between LVEF and GLS (β= -0.662; p = 0.025) and between LVEF and MPS type (β = 1.82; p = 0.025) when adjusted for GLS.
CONCLUSION
Cardiac complications are very common and are one of the most important causes of death in MPS patients. 2D-STE seems to be superior to M-Mode for detection of early and subclinical cardiac dysfunction in MPS patients.
Topics: Humans; Male; Child, Preschool; Child; Adolescent; Female; Stroke Volume; Ventricular Function, Left; Cross-Sectional Studies; Predictive Value of Tests; Mucopolysaccharidoses; Mitral Valve Insufficiency; Ventricular Dysfunction, Left
PubMed: 37845409
DOI: 10.1007/s10554-023-02983-y -
Molecular Genetics and Metabolism 2023We describe our experience with population-based newborn screening for mucopolysaccharidosis type II (MPS II) in 586,323 infants by measurement of iduronate-2-sulfatase...
We describe our experience with population-based newborn screening for mucopolysaccharidosis type II (MPS II) in 586,323 infants by measurement of iduronate-2-sulfatase activity in dried blood spots between December 12, 2017 and April 30, 2022. A total of 76 infants were referred for diagnostic testing, 0.01% of the screened population. Of these, eight cases of MPS II were diagnosed for an incidence of 1 in 73,290. At least four of the eight cases detected had an attenuated phenotype. In addition, cascade testing revealed a diagnosis in four extended family members. Fifty-three cases of pseudodeficiency were also identified, for an incidence of 1 in 11,062. Our data suggest that MPS II may be more common than previously recognized with a higher prevalence of attenuated cases.
Topics: Infant; Infant, Newborn; Humans; Mucopolysaccharidosis II; Neonatal Screening; Incidence; Family; Iduronate Sulfatase
PubMed: 36907694
DOI: 10.1016/j.ymgme.2023.107557 -
Genes Aug 2023Mucopolysaccharidosis-plus syndrome (MPSPS) is an autosomal-recessive disorder caused by c.1492C>T (p.R498W) in the gene. MPSPS is a severe disorder that causes a short...
Mucopolysaccharidosis-plus syndrome (MPSPS) is an autosomal-recessive disorder caused by c.1492C>T (p.R498W) in the gene. MPSPS is a severe disorder that causes a short lifespan in patients. Currently, there is no specific treatment for patients. The Yakut population is more prone to this disease than others. Diagnosing MPSPS relies on clinical manifestations, and genetic testing (GT) is used to confirm the diagnosis. In this research, we examined two pregnancy cases, one of which involved a prenatal diagnosis for MPSPS. Notably, neither pregnant woman had a known family history of the disorder. During their pregnancies, both women underwent prenatal ultrasonography, which revealed increased prenasal thickness during the second trimester. In the first case, ultrasonography indicated increased prenasal thickness in the second trimester, but a definitive diagnosis was not made at that time. The patient was eventually diagnosed with MPSPS at 11 months of age. On the contrary, in the second case, GT uncovered that the parents were carriers of MPSPS. Consequently, a placental biopsy was performed, leading to an early diagnosis of MPSPS. This study emphasizes the importance of ultrasonography findings in prenatal MPSPS diagnosis. Combining ultrasonography with GT can be a valuable approach to confirming MPSPS at an early stage, allowing for the appropriate planning of delivery methods and medical care. Ultimately, this comprehensive approach can significantly enhance the quality of life of both affected patients and their parents.
Topics: Pregnancy; Humans; Female; Quality of Life; Placenta; Prenatal Diagnosis; Genetic Testing; Mucopolysaccharidoses
PubMed: 37628632
DOI: 10.3390/genes14081581 -
Molecular Genetics and Metabolism Nov 2023Newborn screening (NBS) for the full set of mucopolysaccharidoses (MPSs) is now possible by either measuring all of the relevant enzymatic activities in dried blood... (Review)
Review
Newborn screening for the full set of mucopolysaccharidoses in dried blood spots based on first-tier enzymatic assay followed by second-tier analysis of glycosaminoglycans.
Newborn screening (NBS) for the full set of mucopolysaccharidoses (MPSs) is now possible by either measuring all of the relevant enzymatic activities in dried blood spots (DBS) using tandem mass spectrometry followed by measurement of accumulated glycosaminoglycans (GAGs) or the vice-versa approach. In this study we considered multiple factors in detail including reagent costs, time per analysis, false positive rates, instrumentation requirements, and multiplexing capability. Both NBS approaches are found to provide acceptable solutions for comprehensive MPS NBS, but the enzyme-first approach allows for better multiplexing to include numerous additional diseases that are appropriate for NBS expansion. By using a two-tier NBS approach, the false positive and false negatives rates are expected to acceptably low and close to zero.
Topics: Infant, Newborn; Humans; Glycosaminoglycans; Neonatal Screening; Mucopolysaccharidoses; Tandem Mass Spectrometry; Enzyme Assays
PubMed: 37820575
DOI: 10.1016/j.ymgme.2023.107698 -
Molecular Genetics and Metabolism 2023Measurement of enzymatic activity in newborn dried blood spots (DBS) is the preferred first-tier method in newborn screening (NBS) for mucopolysaccharidoses (MPSs). Our...
Endogenous, non-reducing end glycosaminoglycan biomarkers are superior to internal disaccharide glycosaminoglycan biomarkers for newborn screening of mucopolysaccharidoses and GM1 gangliosidosis.
Measurement of enzymatic activity in newborn dried blood spots (DBS) is the preferred first-tier method in newborn screening (NBS) for mucopolysaccharidoses (MPSs). Our previous publications on glycosaminoglycan (GAG) biomarker levels in DBS for mucopolysaccharidosis type 1 (MPS-I) and MPS-II demonstrated that second-tier GAG biomarker analysis can dramatically reduce the false positive rate in NBS. In the present study, we evaluate two methods for measuring GAG biomarkers in seven MPS types and GM1 gangliosidosis. We obtained newborn DBS from patients with MPS-IIIA-D, -IVA, -VI, -VII, and GM1 gangliosidosis. These samples were analyzed via two GAG mass spectrometry methods: (1) The internal disaccharide biomarker method; (2) The endogenous non-reducing end (NRE) biomarker method. This study supports the use of second-tier GAG analysis of newborn DBS by the endogenous NRE biomarker method, as part of NBS to reduce the false positive rate.
Topics: Infant, Newborn; Humans; Glycosaminoglycans; Neonatal Screening; Gangliosidosis, GM1; Disaccharides; Tandem Mass Spectrometry; Mucopolysaccharidoses; Biomarkers
PubMed: 37407323
DOI: 10.1016/j.ymgme.2023.107632 -
American Journal of Medical Genetics.... Apr 2024Mucopolysaccharidosis type 10 is caused by biallelic variants in ARSK, which encodes for a lysosomal sulfatase. To date, seven patients with a mild phenotype resembling...
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.
PubMed: 38634625
DOI: 10.1002/ajmg.a.63635 -
Journal of Inherited Metabolic Disease Jul 2023The mucopolysaccharidosis (MPS) disorders have many potential new therapies on the horizon. Thus, historic control data on disease progression and variability are... (Observational Study)
Observational Study
The mucopolysaccharidosis (MPS) disorders have many potential new therapies on the horizon. Thus, historic control data on disease progression and variability are urgently needed. We conducted a 10-year prospective observational study of 55 children with MPS IH (N = 23), MPS IA (N = 10), non-neuronopathic MPS II (N = 13), and MPS VI (N = 9) to systematically evaluate bone and joint disease. Annual measurements included height, weight, and goniometry. Mixed effects modeling was used to evaluate changes over time. All participants had been treated with hematopoietic cell transplantation and/or enzyme replacement therapy. Height z-score decreased over time in MPS IH, MPS II, and MPS VI, but not MPS IA. Adult heights were 136 ± 10 cm in MPS IH, 161 ± 11 cm in MPS IA, 161 ± 14 cm in MPS II, and 128 ± 15 cm in MPS VI. Adult average BMI percentiles were high: 75 ± 30%ile in MPS IH, 71 ± 37%ile in MPS IA, 71 ± 25%ile in MPS II, and 60 ± 42%ile in MPS VI. Every participant had joint contractures of the shoulders, elbows, hips, and/or knees. Joint contractures remained stable over time. In conclusion, despite current treatments for MPS I, II, and VI, short stature and joint contractures persist. The elevation in average BMI may be related, in part, to physical inactivity due to the ongoing bone and joint disease. Data from this longitudinal historical control study may be used to expedite testing of experimental bone and joint directed therapies and to highlight the need for weight management as part of routine clinical care for patients with MPS.
Topics: Child; Adult; Humans; Prospective Studies; Mucopolysaccharidosis I; Mucopolysaccharidoses; Mucopolysaccharidosis VI; Mucopolysaccharidosis II; Joint Diseases; Contracture
PubMed: 36840680
DOI: 10.1002/jimd.12598