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Molecular Genetics and Metabolism May 2022Mucopolysaccharidosis (MPS) VII is an ultra-rare, autosomal-recessive, metabolic disease caused by a deficiency of β-glucuronidase, a lysosomal enzyme that hydrolyzes...
Mucopolysaccharidosis (MPS) VII is an ultra-rare, autosomal-recessive, metabolic disease caused by a deficiency of β-glucuronidase, a lysosomal enzyme that hydrolyzes glycosaminoglycans (GAGs), including dermatan sulfate (DS), chondroitin sulfate, and heparan sulfate (HS). β-glucuronidase deficiency leads to progressive accumulation of undegraded GAGs in lysosomes of affected tissues, which may cause hydrops fetalis, short stature, hepatosplenomegaly, and cognitive impairment. An open-label, multicenter, phase II study was conducted in 8 pediatric subjects <5 years of age with MPS VII. Subjects received the recombinant human β-glucuronidase vestronidase alfa 4 mg/kg by intravenous infusion every other week for 48 weeks (treatment period). Those who completed the 48-week treatment were offered to continue treatment with vestronidase alfa 4 mg/kg for up to 240 weeks or until withdrawal of consent, discontinuation, or study termination (continuation period). The level of GAG excreted in urine (uGAG) above normal has been shown to correlate with disease severity and clinical outcomes in MPS diseases. Therefore, the primary efficacy endpoint of this study was to determine the mean percentage change in uGAG DS excretion from baseline to week 48. Statistically significant reductions in uGAG DS from baseline were observed at each visit (p < 0.0001), with a least square mean (standard error) percentage change of -60% (6.6) at week 4 (first post-baseline assessment) and -61% (6.41) at week 48 (final assessment during treatment period). Secondary efficacy endpoints included change from baseline to week 48 in growth and hepatosplenomegaly. Positive trends were observed toward increased standing height Z-score (mean [standard deviation] at baseline, -2.630 [1.17], n = 8; at week 48, -2.045 [0.27], n = 7) and growth velocity (mean [SD] Z-score at baseline, -2.59 [1.49], n = 4; at week 48, -0.39 [2.10], n = 4; p = 0.27). Hepatomegaly was resolved in 3 of 3 subjects assessed by ultrasound and in 5 of 6 subjects assessed by physical examination; splenomegaly was resolved in 1 of 3 subjects assessed by ultrasound and in 2 of 2 subjects assessed by physical examination. There were no new safety signals identified during this study. Mild-to-moderate infusion-associated reactions occurred in 4 (50%) subjects. In conclusion, long-term vestronidase alfa treatment demonstrated a rapid and sustained reduction in uGAGs, maintained growth, and improved hepatosplenomegaly in pediatric subjects with MPS VII <5 years of age. Trial registration: NCT02418455.
Topics: Child; Enzyme Replacement Therapy; Glucuronidase; Glycosaminoglycans; Hepatomegaly; Humans; Hydrolases; Mucopolysaccharidosis VII; Splenomegaly
PubMed: 35331634
DOI: 10.1016/j.ymgme.2022.03.002 -
Intractable & Rare Diseases Research Feb 2020Mucopolysaccharidoses (MPS) are a group of rare lysosomal storage diseases (LSD) with multi-organic and severe symptoms. MPS occur worldwide in various forms though have... (Review)
Review
Mucopolysaccharidoses (MPS) are a group of rare lysosomal storage diseases (LSD) with multi-organic and severe symptoms. MPS occur worldwide in various forms though have relative a low incidence. The prevalent type of MPS varies among different continents, indicating that it may be associated with region and ethnic background. Undegraded glycosaminoglycans (GAGs) induced by deficiency of enzymes are the primary cause of MPS. Clinical features differ depending on the specific enzyme deficiency including coarse facial features, cognitive retardation, hepatosplenomegaly, hernias, kyphoscoliosis, corneal clouding, Symptoms of different types are usually similar especially MPS I and II, but may have distinguishable features such as severe neurological problems in MPS III and hydrops fetails in MPS VII. These clinical features contribute to diagnosis, but early and precisely diagnosis in the asymptomatic stage is imperative for better outcomes. Novel approaches including urinary and blood GAG test, enzyme assay and gene test help to diagnose MPS and to determine its subtype. Hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) are conventional treatment for MPS, but are not effective at treating all MPS. Newer threatments, such as advanced ERT, gene therapy and substrate reduction therapy (SRT), improve therpeutic efficacy. In this review, we update information on the clinical manifestations, diagnosis, and treatment of the different forms of this disease in the hopes of stimulating further interest in MPS.
PubMed: 32201668
DOI: 10.5582/irdr.2020.01011 -
Bone Nov 2019Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder characterized by deficient activity of β-glucuronidase, leading to progressive accumulation of...
Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder characterized by deficient activity of β-glucuronidase, leading to progressive accumulation of incompletely degraded heparan, dermatan, and chondroitin sulfate glycosaminoglycans (GAGs). Patients with MPS VII exhibit progressive skeletal deformity including kyphoscoliosis and joint dysplasia, which decrease quality of life and increase mortality. Previously, using the naturally-occurring canine model, we demonstrated that one of the earliest skeletal abnormalities to manifest in MPS VII is failed initiation of secondary ossification in vertebrae and long bones at the requisite postnatal developmental stage. The objective of this study was to obtain global insights into the molecular mechanisms underlying this failed initiation of secondary ossification. Epiphyseal tissue was isolated postmortem from the vertebrae of control and MPS VII-affected dogs at 9 and 14 days-of-age (n = 5 for each group). Differences in global gene expression across this developmental window for both cohorts were measured using whole-transcriptome sequencing (RNA-Seq). Principal Component Analysis revealed clustering of samples within each group, indicating clear effects of both age and disease state. At 9 days-of-age, 1375 genes were significantly differentially expressed between MPS VII and control, and by 14 days-of-age, this increased to 4719 genes. A targeted analysis focused on signaling pathways important in the regulation of endochondral ossification was performed, and a subset of gene expression differences were validated using qPCR. Osteoactivin (GPNMB) was the top upregulated gene in MPS VII at both ages. In control samples, temporal changes in gene expression from 9 to 14 days-of-age were consistent with chondrocyte maturation, cartilage resorption, and osteogenesis. In MPS VII samples, however, elements of key osteogenic pathways such as Wnt/β-catenin and BMP signaling were not upregulated during this same developmental window suggesting that important bone formation pathways are not activated. In conclusion, this study represents an important step towards identifying therapeutic targets and biomarkers for bone disease in MPS VII patients during postnatal growth.
Topics: Animals; Bone Diseases; Cell Differentiation; Chondrocytes; Dogs; Matrix Metalloproteinases; Mucopolysaccharidosis VII; Mutation, Missense; Osteogenesis; Principal Component Analysis; Exome Sequencing
PubMed: 31442675
DOI: 10.1016/j.bone.2019.115042 -
Lysosomal storage disease spectrum in nonimmune hydrops fetalis: a retrospective case control study.Prenatal Diagnosis May 2020Nonimmune hydrops fetalis (NIHF) accounts for 90% of hydrops fetalis cases. About 15% to 29% of unexplained NIHF cases are caused by lysosomal storage diseases (LSD). We...
OBJECTIVES
Nonimmune hydrops fetalis (NIHF) accounts for 90% of hydrops fetalis cases. About 15% to 29% of unexplained NIHF cases are caused by lysosomal storage diseases (LSD). We review the spectrum of LSD and associated clinical findings in NIHF in a cohort of patients referred to our institution.
METHODS
We present a retrospective case-control study of cases with NIHF referred for LSD biochemical testing at a single center. Cases diagnosed with LSD were matched to controls with NIHF and negative LSD testing and analyzed according to the STROBE criteria to the extent the retrospective nature of this study allowed.
RESULTS
Between January 2006 and December 2018, 28 patients with NIHF were diagnosed with a LSD. Eight types of LSD were diagnosed: galactosialidosis 8/28 (28.6%), sialic acid storage disease (SASD) 5/28 (17.9%), mucopolysaccharidosis VII 5/28 (17.9%), Gaucher 4/28 (14.3%), sialidosis 2/28 (7.1%), GM1 gangliosidosis 2/28 (7.1%), Niemann-Pick disease type C 1/28 (3.6%), and mucolipidosis II/III 1/28 (3.6%). Associated clinical features were hepatomegaly 16/21 (76.2%) vs 22/65 (33.8%), P < .05, splenomegaly 12/20 (60.0%) vs 14/58 (24.1%), P < .05, and hepatosplenomegaly 10/20 (50.0%) vs 13/58 (22.4%) P < .05.
CONCLUSION
The most common LSD in NIHF were galactosialidosis, SASD, mucopolysaccharidosis VII, and Gaucher disease. LSD should be considered in unexplained NIHF cases, particularly if hepatomegaly, splenomegaly, or hepatosplenomegaly is visualized on prenatal ultrasound.
Topics: Adult; Ascites; Case-Control Studies; Edema; Female; Gaucher Disease; Gestational Age; Hepatomegaly; Humans; Hydrops Fetalis; Infant, Newborn; Lysosomal Storage Diseases; Male; Mucolipidoses; Mucopolysaccharidosis VII; Niemann-Pick Disease, Type C; Pericardial Effusion; Pleural Effusion; Polyhydramnios; Pregnancy; Prenatal Diagnosis; Retrospective Studies; Sialic Acid Storage Disease; Skin; Splenomegaly; Young Adult
PubMed: 32134517
DOI: 10.1002/pd.5678 -
European Journal of Medical Genetics Apr 2024This study aimed to explore the clinical and genetic features of Chinese patients with mucopolysaccharidosis type VII (MPS VII), thereby improving early detection,...
OBJECTIVE
This study aimed to explore the clinical and genetic features of Chinese patients with mucopolysaccharidosis type VII (MPS VII), thereby improving early detection, disease management, and patient outcomes.
METHODS
A retrospective review of medical records for five patients presenting with coarse facial features, rib protrusion, chest deformities, and scoliosis was conducted. Exome sequencing was employed to identify causative genetic mutations.
RESULTS
The study comprised five patients (four males, one female) with disease onset at six months of age (range: 0-1.5 years). Common symptoms included coarse facial features, skeletal abnormalities, delayed motor and language development, and intellectual disability. Approximately 80% of the patients exhibited multiple skeletal dysplasias, enlarged adenoids or tonsils, and snoring; 60% had hernias; 40% reported hearing loss and hepatosplenomegaly. Less frequent manifestations were short stature, valvular heart disease, non-immune hydrops fetalis, and corneal opacity. All patients demonstrated elevated urine glycosaminoglycans levels and absent β-glucuronidase activity in leukocytes. Exome sequencing identified compound heterozygous mutations in the GUSB gene in all four tested patients, uncovering seven mutations in total, three of which were novel (c.189G > A, c.869C > T, and c.1745 T > C). Furthermore, prenatal diagnosis through chorionic villus sampling in subsequent pregnancies of one patient's mother revealed both fetuses had normal β-glucuronidase activity and no disease-causing mutations in the GUSB gene.
CONCLUSION
The study's patients all presented with classic symptoms of MPS VII due to β-glucuronidase deficiency, with three new pathogenic mutations identified in the GUSB gene. Genetic counseling and prenatal testing were highlighted as crucial for disease prevention.
Topics: Male; Pregnancy; Humans; Female; Infant, Newborn; Infant; Mucopolysaccharidosis VII; Glucuronidase; Facies; Mutation
PubMed: 38442846
DOI: 10.1016/j.ejmg.2024.104933 -
Molecular Genetics and Metabolism May 2021MPS disorders are associated with a wide spectrum of neurocognitive effects, from mild problems with attention and executive functions to progressive and degenerative... (Review)
Review
MPS disorders are associated with a wide spectrum of neurocognitive effects, from mild problems with attention and executive functions to progressive and degenerative neuronopathic disease. Studies of the natural history of neurocognition are necessary to determine the profile of abnormality and the rates of change, which are crucial to select endpoints for clinical trials of brain treatments and to make clinical recommendations for interventions to improve patients' quality of life. The goal of this paper is to review neurocognitive natural history studies to determine the current state of knowledge and assist in directing future research in all MPS disorders. There are seven different types of MPS diseases, each resulting from a specific enzyme deficiency and each having a separate natural history. MPS IX, will not be discussed as there are only 4 cases reported in the literature without cognitive abnormality. For MPS IH, hematopoietic cell transplant (HCT) is standard of care and many studies have documented the relationship between age at treatment and neurocognitive outcome, and to a lesser extent, neurocognitive status at baseline. However, the mortality and morbidity associated with the transplant process and residual long-term problems after transplant, have led to renewed efforts to find better treatments. Rather than natural history, new trials will likely need to use the developmental trajectories of the patients with HCT as a comparators. The literature has extensive data regarding developmental trajectories post-HCT. For attenuated MPS I, significant neurocognitive deficits have been documented, but more longitudinal data are needed in order to support a treatment directed at their attention and executive function abnormalities. The neuronopathic form of MPS II has been a challenge due to the variability of the trajectory of the disease with differences in timing of slowing of development and decline. Finding predictors of the course of the disease has only been partially successful, using mutation type and family history. Because of lack of systematic data and clinical trials that precede a thorough understanding of the disease, there is need for a major effort to gather natural history data on the entire spectrum of MPS II. Even in the attenuated disease, attention and executive function abnormalities need documentation. Lengthy detailed longitudinal studies are needed to encompass the wide variability in MPS II. In MPS IIIA, the existence of three good natural history studies allowed a quasi-meta-analysis. In patients with a rapid form of the disease, neurocognitive development slowed up until 42 to 47 months, halted up to about 54 months, then declined rapidly thereafter, with a leveling off at an extremely low age equivalent score below 22 months starting at about chronological age of 6. Those with slower or attenuated forms have been more variable and difficult to characterize. Because of the plethora of studies in IIIA, it has been recommended that data be combined from natural history studies to minimize the burden on parents and patients. Sufficient data exists to understand the natural history of cognition in MPS IIIA. MPS IIIB is quite similar to IIIA, but more attenuated patients in that phenotype have been reported. MPS IIIC and D, because they are so rare, have little documentation of natural history despite the prospects of treatments. MPS IV and VI are the least well documented of the MPS disorders with respect to their neurocognitive natural history. Because, like attenuated MPS I and II, they do not show progression of neurocognitive abnormality and most patients function in the range of normality, their behavioral, attentional, and executive function abnormalities have been ignored to the detriment of their quality of life. A peripheral treatment for MPS VII, extremely rare even among MPS types, has recently been approved with a post-approval monitoring system to provide neurocognitive natural history data in the future. More natural history studies in the MPS forms with milder cognitive deficits (MPS I, II, IV, and VI) are recommended with the goal of improving these patients' quality of life with and without new brain treatments, beyond the benefits of available peripheral enzyme replacement therapy. Recommendations are offered at-a-glance with respect to what areas most urgently need attention to clarify neurocognitive function in all MPS types.
Topics: Brain; Cognition; Enzyme Replacement Therapy; Hematopoietic Stem Cell Transplantation; Humans; Mucopolysaccharidosis I; Mucopolysaccharidosis II; Mucopolysaccharidosis III; Neurocognitive Disorders; Quality of Life
PubMed: 33741271
DOI: 10.1016/j.ymgme.2021.03.002 -
Molecular Genetics and Metabolism Mar 2020Vestronidase alfa (recombinant human beta-glucuronidase) is an enzyme replacement therapy (ERT) for Mucopolysaccharidosis (MPS) VII, a highly heterogeneous, ultra-rare... (Randomized Controlled Trial)
Randomized Controlled Trial
Vestronidase alfa (recombinant human beta-glucuronidase) is an enzyme replacement therapy (ERT) for Mucopolysaccharidosis (MPS) VII, a highly heterogeneous, ultra-rare disease. Twelve subjects, ages 8-25 years, completed a Phase 3, randomized, placebo-controlled, blind-start, single crossover study (UX003-CL301; NCT02377921), receiving 24-48 weeks of vestronidase alfa 4 mg/kg IV. All 12 subjects completed the blind-start study, which showed significantly reduced urinary glycosaminoglycans (GAG) and clinical improvement in a multi-domain responder index, and enrolled in a long-term, open-label, extension study (UX003-CL202; NCT02432144). Here, we report the final results of the extension study, up to an additional 144 weeks after completion of the blind-start study. Three subjects (25%) completed all 144 weeks of study, eight subjects (67%) ended study participation before Week 144 to switch to commercially available vestronidase alfa, and one subject discontinued due to non-compliance after receiving one infusion of vestronidase alfa in the extension study. The safety profile of vestronidase alfa in the extension study was consistent with observations in the preceding blind-start study, with most adverse events mild to moderate in severity. There were no treatment or study discontinuations due to AEs and no noteworthy changes in a standard safety chemistry panel. Out of the eleven subjects who tested positive for anti-drug antibodies at any time during the blind-start or extension study, including the baseline assessment in the blind-start study, seven subjects tested positive for neutralizing antibodies and all seven continued to demonstrate a reduction in urinary GAG levels. There was no association between antibody formation and infusion associated reactions. Subjects receiving continuous vestronidase alfa treatment showed a sustained urinary GAG reduction and clinical response evaluated using a multi-domain responder index that includes assessments in pulmonary function, motor function, range of motion, mobility, and visual acuity. Reduction in fatigue was also maintained in the overall population. As ERT is not expected to cross the blood brain barrier, limiting the impact on neurological signs of disease, and not all subjects presented with neurological symptoms, outcomes related to central nervous system pathology are not focused on in this report. Results from this study show the long-term safety and durability of clinical efficacy in subjects with MPS VII with long-term vestronidase alfa treatment.
Topics: Adolescent; Adult; Antibodies, Neutralizing; Blood-Brain Barrier; Child; Cross-Over Studies; Enzyme Replacement Therapy; Female; Glucuronidase; Glycosaminoglycans; Humans; Male; Mucopolysaccharidosis VII; Rare Diseases; Treatment Outcome
PubMed: 32063397
DOI: 10.1016/j.ymgme.2020.01.003 -
Molecular Genetics and Metabolism... Sep 2021Vestronidase alfa is an enzyme replacement therapy for mucopolysaccharidosis VII (MPS VII). In this open-label, phase 1/2 study, three subjects with MPS VII received...
Vestronidase alfa is an enzyme replacement therapy for mucopolysaccharidosis VII (MPS VII). In this open-label, phase 1/2 study, three subjects with MPS VII received intravenous vestronidase alfa administered every other week (QOW) for 14 weeks (2 mg/kg), followed by 24-week forced-dose titration (1, 4, and 2 mg/kg QOW; 8 weeks each), 36-week continuation (2 mg/kg), and long-term extension (4 mg/kg). Vestronidase alfa was well tolerated and led to dose-responsive, sustained reductions in urinary glycosaminoglycan excretion.
PubMed: 34136357
DOI: 10.1016/j.ymgmr.2021.100774 -
Genetics in Medicine : Official Journal... Feb 2023
Topics: Humans; Genetics, Medical; Rare Diseases; Genetics, Population; Genetic Variation
PubMed: 36476402
DOI: 10.1016/j.gim.2022.11.007 -
Molecular Therapy. Methods & Clinical... Mar 2023Mucopolysaccharidosis (MPS) VII is an inherited lysosomal storage disorder characterized by deficient activity of the enzyme β-glucuronidase. Skeletal abnormalities are...
Mucopolysaccharidosis (MPS) VII is an inherited lysosomal storage disorder characterized by deficient activity of the enzyme β-glucuronidase. Skeletal abnormalities are common in patients and result in diminished quality of life. Enzyme replacement therapy (ERT) for MPS VII using recombinant human β-glucuronidase (vestronidase alfa) was recently approved for use in patients; however, to date there have been no studies evaluating therapeutic efficacy in a large animal model of MPS VII. The objective of this study was to establish the effects of intravenous ERT, administered at either the standard clinical dose (4 mg/kg) or a high dose (20 mg/kg), on skeletal disease progression in MPS VII using the naturally occurring canine model. Untreated MPS VII animals exhibited progressive synovial joint and vertebral bone disease and were no longer ambulatory by age 6 months. Standard-dose ERT-treated animals exhibited modest attenuation of joint disease, but by age 6 months were no longer ambulatory. High-dose ERT-treated animals exhibited marked attenuation of joint disease, and all were still ambulatory by age 6 months. Vertebral bone disease was recalcitrant to ERT irrespective of dose. Overall, our findings indicate that ERT administered at higher doses results in significantly improved skeletal disease outcomes in MPS VII dogs.
PubMed: 36570425
DOI: 10.1016/j.omtm.2022.11.006