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Pediatric Endocrinology, Diabetes, and... 2021Mucopolysaccharidoses (MPSs) are known as rare genetic diseases which are caused by mutation in the enzyme heparin sulfate, which normally leads to degradation and... (Review)
Review
Mucopolysaccharidoses (MPSs) are known as rare genetic diseases which are caused by mutation in the enzyme heparin sulfate, which normally leads to degradation and accumulation of glycosaminoglycans in the cells. There are 11 types of MPSs, whereby neuropathy may occur in seven of them (MPS I, II, IIIA, IIIB, IIIC, IIID and VII). Accumulation of degraded heparin sulfate in lysosomes causes cellular dysfunction and malfunction of several organs. However, the exact molecular mechanism how protein degradation and storage leads to cellular dysfunction is not understood, yet. Nonetheless, several genetic and biochemical methods for diagnosis of MPSs are available nowadays. Here we provide an overview on known molecular basis of MPS in general, including enzyme defects and symptoms of MPS; however, the main focus is on MPS type III together with potential and perspective therapy-options.
Topics: Glycosaminoglycans; Humans; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis III; Mutation
PubMed: 34743503
DOI: 10.5114/pedm.2021.109270 -
JHEP Reports : Innovation in Hepatology Aug 2021Gene therapy is becoming an increasingly valuable tool to treat many genetic diseases with no or limited treatment options. This is the case for hundreds of monogenic... (Review)
Review
Gene therapy is becoming an increasingly valuable tool to treat many genetic diseases with no or limited treatment options. This is the case for hundreds of monogenic metabolic disorders of hepatic origin, for which liver transplantation remains the only cure. Furthermore, the liver contains 10-15% of the body's total blood volume, making it ideal for use as a factory to secrete proteins into the circulation. In recent decades, an expanding toolbox has become available for liver-directed gene delivery. Although viral vectors have long been the preferred approach to target hepatocytes, an increasing number of non-viral vectors are emerging as highly efficient vehicles for the delivery of genetic material. Herein, we review advances in gene delivery vectors targeting the liver and more specifically hepatocytes, covering strategies based on gene addition and gene editing, as well as the exciting results obtained with the use of RNA as a therapeutic molecule. Moreover, we will briefly summarise some of the limitations of current liver-directed gene therapy approaches and potential ways of overcoming them.
PubMed: 34159305
DOI: 10.1016/j.jhepr.2021.100300 -
Therapeutics and Clinical Risk... 2022Mucopolysaccharidosis VII (MPS VII, Sly syndrome) is an ultra-rare lysosomal disease caused by a deficiency of the enzyme β-glucuronidase (GUS). The diagnosis is... (Review)
Review
Mucopolysaccharidosis VII (MPS VII, Sly syndrome) is an ultra-rare lysosomal disease caused by a deficiency of the enzyme β-glucuronidase (GUS). The diagnosis is suspected based on a range of symptoms that are common to many other MPS types, and it is confirmed through biochemical and molecular studies. Besides supportive treatment, current and emerging treatments include enzyme replacement therapy, hematopoietic stem cell transplantation, and gene therapy. This review summarizes the clinical manifestations, diagnosis, and emerging treatments for MPS VII.
PubMed: 36578769
DOI: 10.2147/TCRM.S351300 -
Orphanet Journal of Rare Diseases May 2021Mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome, caused by deficiency of the lysosomal enzyme β-glucuronidase, is an ultra-rare disorder with... (Review)
Review
BACKGROUND
Mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome, caused by deficiency of the lysosomal enzyme β-glucuronidase, is an ultra-rare disorder with scarce epidemiological data and few publications about natural history and clinical spectrum.
METHODS
We conducted a case series report which included retrospective data from all MPS VII patients diagnosed through the "MPS Brazil Network" who were known to be alive in 2020 in Brazil (N = 13). Clinical data were obtained from a review of the medical records and descriptive statistics and variables were summarized using counts and percentages of the total population.
RESULTS
The majority of the patients were from the Northeast region of Brazil. Among the signs and symptoms that raised the clinical suspicion of MPS, coarse face was the most frequent; 58% of the patients had a history of non-immune hydrops fetalis. All the subjects presented short neck and trunk. The majority presented typical phenotypical signs of MPS disorders. They all presented neurodevelopmental delay and cognitive impairment. About half of this cohort had knees deformities. Dysostosis multiplex was identified in almost all patients and cardiomyopathy was less frequent than observed in other types of MPSs. The mean age at diagnosis was 5 years, ranging from 1 to 14 years. Almost all patients (12/13) were homozygous for the c.526C>T (p.Leu176Phe) mutation. A novel variant of the GUSB gene was found, the c.875T>C (p.Leu292Pro), in a compound heterozygous with the c.526C>T (p.Leu176Phe) variant.
CONCLUSIONS
This case series is the biggest data collection of MPS VII patients alive in Latin America. The overall clinical picture of the MPS VII patients is very similar to other MPS disorders, including a spectrum of severity and delayed diagnosis.
Topics: Brazil; Humans; Mucopolysaccharidosis VII; Mutation; Retrospective Studies
PubMed: 34022924
DOI: 10.1186/s13023-021-01870-w -
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 -
Ultrasound in Obstetrics & Gynecology :... Mar 2020
Review
Topics: Female; Humans; Hydrops Fetalis; Lysosomal Storage Diseases; Mucopolysaccharidosis VII; Pregnancy
PubMed: 31180609
DOI: 10.1002/uog.20371 -
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 -
Journal of Clinical Medicine Jul 2021(1) Background: Mucopolysaccharidoses (MPS) are a heterogeneous group of lysosomal storage disorders caused by the absence of enzymes required for degradation of... (Review)
Review
(1) Background: Mucopolysaccharidoses (MPS) are a heterogeneous group of lysosomal storage disorders caused by the absence of enzymes required for degradation of glycosaminoglycans (GAGs). GAGs deposition in tissues leads to progressive airway narrowing and/or tortuosity. Increased longevity of patients has posed newer problems, especially the airway. This study aims to characterise various airway abnormalities in adult MPS from a regional centre and proposes a method to quantify the severity of the airway disease. (2) Methods: Retrospective analysis by case notes review, clinical examination, endoscopy, cross-sectional imaging, 3-dimensional reconstruction, and physiological investigations were used to assess the airway abnormalities. Quantitative assessment of the airway severity was performed a validated questionnaire of 15 parameters to derive Salford Mucopolysaccharidosis Airway Score (SMAS). (3) Results: Thirty-one adult MPS patients (21M/ 9F; median 26.7 years; range 19-42 years) were reviewed. There were 9 MPS I, 12 MPS II, 2 MPS III, 5 MPS IV, 2 MPS VI, and 1 MPS VII. Airway abnormalities in each MPS type are described. Patients scoring more than 35 on SMAS had some form of airway intervention. The area under curve of 0.9 was noted at a score of 25, so SMAS more than 25 may predict a difficult airway and potential to have complications. Pearson's correlation between SMAS and height, weight, BMI were poor ( < 0.05). (4) Conclusions: Airway abnormalities in adult MPS are varied and complex. Assessment of the airway should be holistic and include multiple parameters. An objective multidimensional score such as SMAS may help to predict and manage difficult airways warranting further investigation and validation.
PubMed: 34362059
DOI: 10.3390/jcm10153275 -
PloS One 2022Skeletal alterations in the head and neck region, such as midfacial hypoplasia, foramen magnum stenosis and spinal canal stenosis, are commonly observed in patients with...
Skeletal alterations in the head and neck region, such as midfacial hypoplasia, foramen magnum stenosis and spinal canal stenosis, are commonly observed in patients with mucopolysaccharidosis (MPS). However, enzyme replacement therapy (ERT), one of the major treatment approaches for MPS, shows limited efficacy for skeletal conditions. In this study, we analysed the craniofacial morphology of mice with MPS type VII, and investigated the underlying mechanisms promoting jaw deformities in these animals. Furthermore, we investigated the effects of C-type natriuretic peptide (CNP), a potent endochondral ossification promoter, on growth impairment of the craniofacial region in MPS VII mice when administered alone or in combination with ERT. MPS VII mice exhibited midfacial hypoplasia caused by impaired endochondral ossification, and histological analysis revealed increased number of swelling cells in the resting zone of the spheno-occipital synchondrosis (SOS), an important growth centre for craniomaxillofacial skeletogenesis. We crossed MPS VII mice with transgenic mice in which CNP was expressed in the liver under the control of the human serum amyloid-P component promoter, resulting in elevated levels of circulatory CNP. The maxillofacial morphological abnormalities associated with MPS VII were ameliorated by CNP expression, and further prevented by a combination of CNP and ERT. Histological analysis showed that ERT decreased the swelling cell number, and CNP treatment increased the width of the proliferative and hypertrophic zones of the SOS. Furthermore, the foramen magnum and spinal stenoses observed in MPS VII mice were significantly alleviated by CNP and ERT combination. These results demonstrate the therapeutic potential of CNP, which can be used to enhance ERT outcome for MPS VII-associated head and neck abnormalities.
Topics: Humans; Mice; Animals; Natriuretic Peptide, C-Type; Constriction, Pathologic; Mucopolysaccharidosis VII; Osteogenesis; Mice, Transgenic
PubMed: 36355797
DOI: 10.1371/journal.pone.0277140