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Clinical Case Reports Feb 2021Clinical exome sequencing is a powerful approach to overcome the wide clinical and genetic heterogeneity of mucopolysaccharidosis. These data could be useful for...
Clinical exome sequencing is a powerful approach to overcome the wide clinical and genetic heterogeneity of mucopolysaccharidosis. These data could be useful for prenatal diagnosis of MPS VII, genetic counseling, and preimplantation genetic testing.
PubMed: 33598246
DOI: 10.1002/ccr3.3644 -
Molecular Genetics and Metabolism... Jun 2021Two unique gene mutations in the enzyme beta-glucuronidase (GUSB) that result in the lysosomal storage disease Mucopolysaccharidosis (MPS) type VII had previously been...
The beta-glucuronidase intracisternal A particle insertion model results in similar overall MPSVII phenotype as the single base deletion model when on the same C57BL/6J mouse background.
Two unique gene mutations in the enzyme beta-glucuronidase (GUSB) that result in the lysosomal storage disease Mucopolysaccharidosis (MPS) type VII had previously been reported to have differing disease phenotype severities when compared on differing mouse strains. The MPSVII mouse has proven to be a highly efficacious model to study mucopolysaccharidoses and for evaluating potential gene or stem cell therapies for lysosomal storage diseases. We examined the single base pair deletion (MPSVII) and the intracisternal A particle element insertion (MPSVII2J) in GUSB compared with control animals by skeletal measures, electroretinography, auditory-evoked brainstem response and life span on a C57BL/6J background strain. In all measures, both mutations result in either a trend toward or significant changes from the background strain control. In all measures, there is no significant phenotypic difference between the two mutations. The 2J variant is a more easily genotyped and equally affected phenotype, which holds promise for further studies of chimerism and stem cell therapy approaches.
PubMed: 33604242
DOI: 10.1016/j.ymgmr.2021.100727 -
Diagnostics (Basel, Switzerland) Feb 2020The effectiveness of hematopoietic stem cell transplantation (HSCT) for type-VII mucopolysaccharidosis (MPS VII, Sly syndrome) remains controversial, although recent...
The effectiveness of hematopoietic stem cell transplantation (HSCT) for type-VII mucopolysaccharidosis (MPS VII, Sly syndrome) remains controversial, although recent studies have shown that it has a clinical impact. In 1998, Yamada et al. reported the first patient with MPS VII, who underwent HSCT at 12 years of age. Here, we report the results of a 22-year follow-up of that patient post-HSCT, who harbored the p.Ala619Val mutation associated with an attenuated phenotype. The purpose of this study was to evaluate changes in physical symptoms, the activity of daily living (ADL), and the intellectual status in the 34-year-old female MPS VII patient post-HSCT, and to prove the long-term effects of HSCT in MPS VII. Twenty-two years after HSCT, the β-glucuronidase activity in leukocytes remained at normal levels, and urinary glycosaminoglycan excretion was reduced and kept within normal levels. At present, she is capable of sustaining simple conversation, and her intellectual level is equivalent to that of a 6-year-old. She can walk alone and climb upstairs by holding onto a handrail, although she feels mild pain in the hip joint. The cervical vertebrae are fused with the occipital bone, causing dizziness and light-headedness when the neck is bent back. Overall, her clinical condition has been stabilized and kept well for long-term post-HSCT, indicating that HSCT is a therapeutic option for MPS VII.
PubMed: 32079065
DOI: 10.3390/diagnostics10020105 -
Pharmaceutical Biology Dec 2022Chondroitin 6 sulphate (C6S) is a glycosaminoglycan (GAG) whose accumulation is notable in mucopolysaccharidosis type IVA and VII. Flaxseed, L. (Linaceae) (FS), is...
Flaxseed extract reduces tissue accumulation and enhances urinary excretion of chondroitin sulphate in the rat: a possible new path in substrate reduction therapy for mucopolysaccharidosis.
CONTEXT
Chondroitin 6 sulphate (C6S) is a glycosaminoglycan (GAG) whose accumulation is notable in mucopolysaccharidosis type IVA and VII. Flaxseed, L. (Linaceae) (FS), is reported to have comparable properties to those of soybean, a source of genistein, a potential new treatment for MPSs.
OBJECTIVE
We assess the effect of total ethanol flaxseed extract (EFSE) in an animal model of C6S accumulation.
MATERIALS AND METHODS
The study was performed in adult male Wistar rats ( = 24) for 15 successive days. The animals were divided into four groups: (1) control injected with physiological saline buffer, (2) intoxicated rats injected intraperitoneally with C6S, (3) intoxicated with C6S and treated with EFSE, and (4) treated with EFSE. All groups were subjected to histopathological and biochemical studies. The antioxidant and phytochemical properties of EFSE were examined.
RESULTS
Dry EFSE contains total phenols (6.28 mg EAG/g), condensed tannins (2.98 mg ECAT/g) and flavonoids (0.44 mg ECAT/g) with high antioxidant potential [RPE (IC = 8.37 ± 0.176), DPPH (IC = 12.79 ± 0.273)]. The LD is higher than 5000 mg/kg. The histopathological examination showed an accumulation of C6S in the C6S intoxicated group, which disappeared in the C6S-EFSE treated group. GAGs assays showed an increased excretion in the C6S intoxicated group and increased excretion of 14% in the C6S-EFSE group compared to the C6S group.
DISCUSSION AND CONCLUSIONS
EFSE showed significant potential for chelation. Its use for the treatment of GAG accumulation could be suggested and generalized to a larger study population.
Topics: Animals; Antioxidants; Chondroitin Sulfates; Flax; Glycosaminoglycans; Humans; Male; Mucopolysaccharidoses; Plant Extracts; Rats; Rats, Wistar
PubMed: 35634909
DOI: 10.1080/13880209.2022.2068618 -
JIMD Reports Sep 2019Mucopolysaccharidosis (MPS) VII is an ultra-rare, progressively debilitating, life-threatening lysosomal disease caused by deficiency of the enzyme, β-glucuronidase....
Mucopolysaccharidosis (MPS) VII is an ultra-rare, progressively debilitating, life-threatening lysosomal disease caused by deficiency of the enzyme, β-glucuronidase. Vestronidase alfa is an approved enzyme replacement therapy for MPS VII. UX003-CL301 was a phase 3, randomized, placebo-controlled, blind-start study examining the efficacy and safety of vestronidase alfa 4 mg/kg intravenously administered every 2 weeks to 12 patients with MPS VII. Due to the rarity of disease, broad eligibility criteria resulted in a highly heterogeneous population with variable symptoms. For an integrated view of the diverse data, the changes from baseline (or randomization for the placebo period) in clinical endpoints were grouped into three functional domains (mobility, fatigue, and fine motor + self-care) and analyzed post-hoc as subject-level heat maps. Mobility assessments included the 6-minute walk test, 3-minute stair climb test, Bruininks-Oseretsky test (BOT-2) gross motor function subtests, and patient-reported outcome assessments (PROs) related to movement, pain, and ambulation. Fatigue assessments included the Pediatric Quality of Life Multidimensional Fatigue Scale and other fatigue-related PROs. Fine motor + self-care assessments included BOT-2 fine motor function subtests and PROs for eating, dressing, hygiene, and caregiver assistance. Most subjects showed improvement in at least one domain. Two subjects improved in two or more domains and two subjects did not show clear improvement in any domain. Both severely and mildly affected subjects improved with vestronidase alfa in clinical assessments, PRO results, or both. Heat map analysis demonstrates how subjects responded to treatment across multiple domains, providing a useful visual tool for studying rare diseases with variable symptoms.
PubMed: 31497482
DOI: 10.1002/jmd2.12043 -
Orphanet Journal of Rare Diseases Sep 2021Although the clinical efficacy of laminoplasty in adult cervical spondylotic myelopathy or ossification of posterior longitudinal ligament has been frequently reported,...
BACKGROUND
Although the clinical efficacy of laminoplasty in adult cervical spondylotic myelopathy or ossification of posterior longitudinal ligament has been frequently reported, there are only few reports of laminoplasty for patients with lysosome storage diseases (LSDs). Therefore, this study aimed to report the midterm clinical and radiological outcomes of patients with LSDs after cervical laminoplasty.
METHODS
Six patients with LSD who underwent laminoplasty with/without C1 laminectomy for cervical myelopathy were enrolled. Clinical evaluations, including the cervical Japanese Orthopedic Association (cJOA) score and visual analog scale (VAS) scores for upper extremity numbness, and radiographic parameters, including C2-C7 lordotic angle, atlanto-dens interval (ADI), and ⊿ADI, were evaluated preoperatively, at 2 years postoperatively, and at the final follow-up.
RESULTS
Five patients had mucopolysaccharidoses (type I: n = 1, II: n = 3, VII: n = 1) and one patient had mucolipidoses type III. The mean age of patients at surgery was 27.5 years, and the mean postoperative follow-up period was 61 months. All mucopolysaccharidoses cases required C1 posterior arch resection with C2-C7 laminoplasty. No critical complications were observed postoperatively. There were no significant differences in C2-C7 angle (p = 0.724) and ⊿ADI (p = 0.592) between the preoperative and final follow-ups. The cJOA score and VAS for numbness significantly improved at the final follow-up (p = 0.004 and p = 0.007, respectively).
CONCLUSIONS
The cervical myelopathy in patients with LSD could be safely and effectively treated with laminoplasty with/without C1 posterior arch resection after excluding patients with atlantoaxial instability. Atlantoaxial stability and symptom improvement could be maintained at an average of 5 years postoperatively.
Topics: Adult; Cervical Vertebrae; Humans; Laminoplasty; Lysosomal Storage Diseases; Mucolipidoses; Mucopolysaccharidoses; Retrospective Studies; Spinal Cord Diseases; Treatment Outcome
PubMed: 34583711
DOI: 10.1186/s13023-021-02031-9 -
BMC Medical Genetics Feb 2020The Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome (OMIM 253200) is an autosomal recessive lysosomal disorder, caused by the deficiency of...
BACKGROUND
The Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome (OMIM 253200) is an autosomal recessive lysosomal disorder, caused by the deficiency of the enzyme N-acetylgalactosamine 4-sulfatase (also known as arylsulfatase B) due to mutations of the ARSB gene. Cardiologic features are well recognized, and are always present in MPS VI patients. Generally, the onset and the progression of the cardiologic symptoms are insidious, and just a few patients have developed a rapidly progressive disease. Cardiac involvement in MPS VI is a common and progressive feature. For MPS patients, cardiac evaluations are recommended every 1 to 2 years, including blood pressure measurement, electrocardiography and echocardiography. However, congestive heart failure and valvular surgical repair are not frequently seen, and if so, they are performed in adults. Here we report on an atypical MPS VI case with ascites fetalis and a rapidly progressive cardiac disease.
CASE PRESENTATION
A 6-month-old Brazilian male, only child of a Brazilian healthy non-consanguineous couple. During pregnancy, second trimester ultrasonography observed fetal ascites and bilateral hydrocele. Physical exam at 6 months-old revealed a typical gibbus deformity and MPS was suspected. Biochemical investigation revealed a diagnosis of MPS type VI, confirmed by molecular test. Baseline echocardiogram revealed discrete tricuspid regurgitation and a thickened mitral valve with posterior leaflet prolapse, causing moderate to severe regurgitation. The patient evolved with mitral insufficiency and congestive heart failure, eventually requiring surgical repair by the first year of age.
CONCLUSIONS
We report the first case of MPS VI whose manifestations started in the prenatal period with fetal ascites, with severe cardiac valvular disease that eventually required early surgical repair. Moreover, in MPS with neonatal presentation, including fetal hydrops, besides MPS I, IVA and VII, clinicians should include MPS VI in the differential diagnosis.
Topics: Ascites; Brazil; Disease Progression; Heart; Heart Failure; Humans; Infant; Male; Mucopolysaccharidosis VI; Mutation; N-Acetylgalactosamine-4-Sulfatase; Phenotype
PubMed: 32075597
DOI: 10.1186/s12881-020-0972-y -
International Journal of Molecular... Feb 2020Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases caused by mutations leading to defective degradation of glycosaminoglycans (GAGs) and their...
Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases caused by mutations leading to defective degradation of glycosaminoglycans (GAGs) and their accumulation in cells. Among 11 known types and subtypes of MPS, neuronopathy occurs in seven (MPS I, II, IIIA, IIIB, IIIC, IIID, VII). Brain dysfunctions, occurring in these seven types/subtypes include various behavioral disorders. Intriguingly, behavioral symptoms are significantly different between patients suffering from various MPS types. Molecular base of such differences remains unknown. Here, we asked if expression of genes considered as connected to behavior (based on Gene Ontology, GO terms) is changed in MPS. Using cell lines of all MPS types, we have performed transcriptomic (RNA-seq) studies and assessed expression of genes involved in behavior. We found significant differences between MPS types in this regard, with the most severe changes in MPS IIIA (the type considered as the behaviorally most severely affected), while the lowest changes in MPS IVA and MPS VI (types in which little or no behavioral disorders are known). Intriguingly, relatively severe changes were found also in MPS IVB (in which, despite no behavioral disorder noted, the same gene is mutated as in GM1 gangliosidosis, a severe neurodegenerative disease) and MPS IX (in which only a few patients were described to date, thus, behavioral problems are not well recognized). More detailed analyses of expression of certain genes allowed us to propose an association of specific changes in the levels of transcripts in specific MPS types to certain behavioral disorders observed in patients. Therefore, this work provides a principle for further studies on the molecular mechanism of behavioral changes occurring in MPS patients.
Topics: Brain; Cell Line; Cells, Cultured; Child; Child, Preschool; Female; G(M1) Ganglioside; Humans; Infant; Male; Mental Disorders; Mucopolysaccharidoses; Transcriptome
PubMed: 32050523
DOI: 10.3390/ijms21031156 -
Medical Science Monitor : International... Oct 2019BACKGROUND Lysosomal storage diseases (LSDs), a group of rare inherited metabolic disorders, result from specific lysosomal proteins deficiencies in the degradation of...
BACKGROUND Lysosomal storage diseases (LSDs), a group of rare inherited metabolic disorders, result from specific lysosomal proteins deficiencies in the degradation of biomacromolecule, including over 70 different diseases, most of which are autosomal recessive. LSDs are multisystem disorders, and the clinical manifestations are usually broad and severe, involving the skeletal system, central nervous system (CNS), cardiovascular system, etc. Besides, patients with some subtypes of LSD have distinctive facial features. MATERIAL AND METHODS We performed next generation sequencing on 4 suspected mucopolysaccharidosis (MPS) cases to determine the genetic causes of the disease. By in vitro molecular cell assay, such as real-time polymerase chain reaction (RT-PCR) and western blot, we tested the pathogenicity of candidate variants. RESULTS We detected 5 novel mutations in 4 patients. The mutations were: c.211_214del and c.1270C>T in GUSB; c.1284+1C>A and c.2404C>T in GNPTAB; and c.717C>A in FUCA1). We identified a rare mucopolysaccharidosis VII patient, a rare fucosidosis patient, and 2 rare mucolipidosis II patients, one of which was an atypical patient. We also present a new pathogenic conjecture about a small deletion in GUSB. CONCLUSIONS Our study described rare diseases in Chinese patients and our results enrich the phenotype spectrum of related diseases, as well as mutation spectrum of related genes, which might be significant for clinical disease diagnosis and prenatal diagnosis.
Topics: Base Sequence; Child; Child, Preschool; Fatal Outcome; Female; Genetic Predisposition to Disease; Heterozygote; Homozygote; Humans; Infant; Lysosomal Storage Diseases; Male; Mutation; Phenotype; Rare Diseases; Transferases (Other Substituted Phosphate Groups)
PubMed: 31603145
DOI: 10.12659/MSM.915876 -
The Journal of Pediatrics Jan 2020To test, in a newborn screening (NBS) laboratory, the performance of liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assay 5 enzymatic activities in dried...
OBJECTIVE
To test, in a newborn screening (NBS) laboratory, the performance of liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assay 5 enzymatic activities in dried blood spots (DBS) for NBS of 5 lysosomal storage diseases (mucopolysaccharidosis [MPS]-II, MPS-IIIB, MPS-IVA, MPS-VI, and MPS-VII).
STUDY DESIGN
Three mm punches from de-identified DBS were obtained from the Washington NBS laboratory and submitted to the 5-plex LC-MS/MS assay. Screen cut-offs were established by analyzing the enzymatic activity in patients confirmed to have the MPS disorder. DNA sequencing of the relevant gene was performed on a second DBS punch for all samples with enzyme activity below 10% of the mean daily activity.
RESULTS
(1) For MPS-II, 18 below cut-off samples, 1 pathogenic genotype, and 2 "high risk" genotypes; (2) For MPS-IIIB, no below cut-off samples; (3) For MPS-IVA, 8 below cut-off samples, 4 non-pathogenic genotypes, 4 genotypes unobtainable; (4) For MPS-VI, 4 below cut-off samples and no high-risk genotypes; (5) For MPS-VII, 1 below cut-off sample confirmed by genotype and clinical report to be affected.
CONCLUSIONS
These results establish that the number of initial screen positive samples is low and manageable. Thus, population newborn screening for these conditions is feasible in a state newborn screening laboratory.
Topics: Chromatography, Liquid; Dried Blood Spot Testing; Humans; Infant, Newborn; Mucopolysaccharidoses; Neonatal Screening; Pilot Projects; Tandem Mass Spectrometry
PubMed: 31732130
DOI: 10.1016/j.jpeds.2019.09.036