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Mucopolysaccharidoses: Diagnosis, Treatment, and Management
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Mucopolysaccharidoses: Diagnosis, Treatment, and Management

A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 90466

Special Issue Editors

Prof. Dr. Shunji Tomatsu

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Guest Editor
Skeletal Dysplasia Lab Nemours Biomedical Research Nemours/Alfred I. du Pont Hospital for Children, 1600 Rockland Road., Wilmington, DE 19803, USA
Interests: lysosomal storage disease; mucopolysaccharidoses; newborn screening; bone targeting
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Roberto Giugliani

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Guest Editor
1. Department of Genetics UFRGS, Medical Genetics Service, HCPA, DASA and Casa dos Raros, Porto Alegre 91501970, Brazil
2. Medical Genetics Service, HCPA, Porto Alegre 90035-903, Brazil
Interests: inborn errors of metabolism, particularly lysosomal disorders
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Grzegorz Wegrzyn

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Guest Editor
Department of Molecular Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland
Interests: regulation of DNA replication; control of gene expression; oxidative stress in bacterial virulence; molecular mechanisms of mucopolysaccharidoses; development of novel therapeutic options
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Brian Bigger

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Guest Editor
Division of Cell Matrix Biology and Regenerative Medicine, University of Manchester, Manchester M13 9PT, UK
Interests: mucopolysaccharidosis
Special Issues, Collections and Topics in MDPI journals
Dr. Julia B. Hennermann

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Guest Editor
Department of Pediatric and Adolescent Medicine, University Medical Center Mainz, Villa Metabolica, Langenbeckstr. 1, 55131 Mainz, Germany
Interests: mucopolysaccharidoses
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mucopolysaccharidoses (MPS) are relatively frequent as a group among inborn errors of metabolism, with an overall incidence estimated around 1 of 20,000–25,000 births. If the clinical signs and symptoms appear, the excessive excretion of urinary glycosaminoglycans (GAGs) seen in MPS patients will provide a simple screening method with the identification of the specific enzyme deficiency. The development of therapeutic options for MPS, including hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT), has modified the natural history of many MPS types. In spite of the improvement in some tissues and organs, significant challenges remain unsolved, including blood–brain barrier, brain and avascular cartilage, heart valves, and cornea. Newer approaches, such as intrathecal ERT, ERT with fusion proteins to cross the blood–brain barrier, gene therapy, substrate reduction therapy, chaperone therapy, and combined strategies, may provide a better outcome for MPS in the near future.

Therapies should start at a very early stage prior to irreversible bone lesion, and damage due to the severity of CNS involvement and skeletal dysplasia is associated with level of activity during daily life. As early diagnosis and early treatment are imperative to improve therapeutic efficacy, the inclusion of MPS in newborn screening programs should reduce the morbidity associated with MPS diseases. Additionally, we will provide insights into primary storage materials on GAGs (“GAGnomics”), the measurement of GAGs, the pathogenesis pathway with the accumulation of GAGs, and GAGs’ role as a biomarker.

In this Special Issue, we will summarize diagnosis, treatment, and management of MPS and will evaluate available treatments such as ERT; HSCT; and future treatments including gene therapy, substrate reduction therapy, and chaperon therapy, and will describe their advantages and disadvantages. We will also assess the current clinical endpoints and biomarkers used in clinical trials.

Overall, this Special Issue illustrates an up-to-date overview of pathogenesis, diagnosis, biomarker, screening, and updated therapies and their impact in MPS. It comprehensively covers many areas in the MPS field and appeals to a broad range of readers including physicians, scientists, students, pharmaceutical companies, and MPS communities.

You may choose our Joint Special Issue in IJMS.

Welcome submissions to the Second Version of Special Issue "Mucopolysaccharidoses: Diagnosis, Treatment, and Management 2.0".

Prof. Dr. Shunji Tomatsu
Prof. Dr. Roberto Giugliani
Prof. Dr. Grzegorz Wegrzyn
Prof. Dr. Brian Bigger
Dr. Julia B. Hennermann
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Diagnostics is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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18 pages, 5614 KiB  
Article
Growth Plate Pathology in the Mucopolysaccharidosis Type VI Rat Model—An Experimental and Computational Approach
by Johana M. Guevara-Morales, Michael Frohbergh, Hector Castro-Abril, Juan J. Vaca-González, Luis A. Barrera, Diego A. Garzón-Alvarado, Edward Schuchman and Calogera Simonaro
Diagnostics 2020, 10(6), 360; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10060360 - 31 May 2020
Cited by 2 | Viewed by 3133
Abstract
Background: Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases caused by impaired function or absence of lysosomal enzymes involved in degradation of glycosaminoglycans. Clinically, MPS are skeletal dysplasias, characterized by cartilage abnormalities and disturbances in the process of endochondral ossification. Histologic abnormalities [...] Read more.
Background: Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases caused by impaired function or absence of lysosomal enzymes involved in degradation of glycosaminoglycans. Clinically, MPS are skeletal dysplasias, characterized by cartilage abnormalities and disturbances in the process of endochondral ossification. Histologic abnormalities of growth cartilage have been reported at advanced stages of the disease, but information regarding growth plate pathology progression either in humans or in animal models, as well as its pathophysiology, is limited. Methods: Histological analyses of distal femur growth plates of wild type (WT) and mucopolysaccharidosis type VI (MPS VI) rats at different stages of development were performed, including quantitative data. Experimental findings were then analyzed in a theoretical scenario. Results: Histological evaluation showed a progressive loss of histological architecture within the growth plate. Furthermore, in silico simulation suggest the abnormal cell distribution in the tissue may lead to alterations in biochemical gradients, which may be one of the factors contributing to the growth plate abnormalities observed, highlighting aspects that must be the focus of future experimental works. Conclusion: The results presented shed some light on the progression of growth plate alterations observed in MPS VI and evidence the potentiality of combined theoretical and experimental approaches to better understand pathological scenarios, which is a necessary step to improve the search for novel therapeutic approaches. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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13 pages, 6007 KiB  
Article
Pathophysiology of Hip Disorders in Patients with Mucopolysaccharidosis IVA
by Zhigang Wang, Yunlan Xu, Enze Jiang, Jianmin Wang, Shunji Tomatsu and Kaiying Shen
Diagnostics 2020, 10(5), 264; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10050264 - 29 Apr 2020
Cited by 3 | Viewed by 4089
Abstract
Patients with mucopolysaccharidoses IVA (MPS IVA) have a progressive accumulation of the specific glycosaminoglycans (GAGs): chondroitin-6-sulfate (C6S) and keratan sulfate (KS), leading to the degeneration of the cartilage matrix and its connective tissue perturbing the regular microarchitecture of cartilage and successively distorting bone [...] Read more.
Patients with mucopolysaccharidoses IVA (MPS IVA) have a progressive accumulation of the specific glycosaminoglycans (GAGs): chondroitin-6-sulfate (C6S) and keratan sulfate (KS), leading to the degeneration of the cartilage matrix and its connective tissue perturbing the regular microarchitecture of cartilage and successively distorting bone ossification and growth. Impaired cartilage quality and poor bone mineralization lead to serious hip disorders in MPS IVA patients. Although hip dysplasia is seen widely in musculoskeletal abnormality of this disorder, the pathophysiology of the hip bone and cartilage morphology in these patients remains unclear. Until now, no systemic study of the hip joints in MPS IVA has been reported by using the combined images of plain film radiographs (PFR) and Magnetic Resonance Imaging (MRI). This study aimed to assess the bony and cartilaginous features of hip joints and to explore the potentially related factors of femoral head osteonecrosis (FHN) and hip subluxation/dislocation in patients with MPS IVA. Hip joints in MPS IVA patients were retrospectively reviewed, based on the findings of PFR and MRI data from 2014 to 2019. Demographic information was also collected and analyzed with imaging measurements. A total of 19 patients (eight boys and 11 girls) were recruited, and 38 hip joints in these patients were examined. Eleven patients (57.9%) had FHN. FHN patients were statistically compared with those without FHN. Correlations between cartilaginous femoral head coverage (CFHC) and acetabular index (AI), cartilaginous AI (CAI), or neck-shaft angle (NSA) were investigated in patients with hip subluxation or dislocation. The greater cartilaginous coverage of the hips than their osseous inherency was observed. Significant correlation was observed between CFHC and AI (r =−0.351, p = 0.049) or CAI (r =−0.381, p = 0.032). Severe subluxations or dislocations were more likely to be present in those with more dysplastic bony and cartilaginous hips. In conclusion, our study provides the first systemic description of bony and cartilaginous characteristics in the hip morphology of MPS IVA patients. We have demonstrated that plain radiography alone leads to a misunderstanding of hip morphology and that MRI measurements with PFR are an essential tool to evaluate the ‘true’ characterization of hips for MPS IVA patients. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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9 pages, 2183 KiB  
Article
Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses
by Galina Baydakova, Alex Ilyushkina, Lidia Gaffke, Karolina Pierzynowska, Igor Bychkov, Agnieszka Ługowska, Grzegorz Wegrzyn, Anna Tylki-Szymanska and Ekaterina Zakharova
Diagnostics 2020, 10(3), 155; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10030155 - 13 Mar 2020
Cited by 8 | Viewed by 3044
Abstract
Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders associated with impaired glycosaminoglycans (GAGs) catabolism. In MPS I, II, III, and VII, heparan sulfate (HS) cannot be degraded because of the lack of sufficient activity of the respective enzymes, and its accumulation in [...] Read more.
Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders associated with impaired glycosaminoglycans (GAGs) catabolism. In MPS I, II, III, and VII, heparan sulfate (HS) cannot be degraded because of the lack of sufficient activity of the respective enzymes, and its accumulation in the brain causes neurological symptoms. Globotriaosylsphingosine (LysoGb3), the deacylated form of globotriaosylceramide (Gb3), is described as a highly sensitive biomarker for another lysosomal storage disease—Fabry disease. The connection between MPSs and LysoGb3 has not yet been established. This study included 36—MPS I, 15—MPS II, 25—MPS III, 26—MPS IV, and 14—MPS VI patients who were diagnosed by biochemical and molecular methods and a control group of 250 males and 250 females. The concentration of lysosphingolipids (LysoSLs) was measured in dried blood spots by high pressure liquid chromatography—tandem mass spectrometry. We have demonstrated that LysoGb3 concentration was significantly elevated (p < 0.0001) in untreated MPS I (3.07 + 1.55 ng/mL), MPS II (5.24 + 2.13 ng/mL), and MPS III (6.82 + 3.69 ng/mL) patients, compared to the control group (0.87 + 0.55 ng/mL). LysoGb3 level was normal in MPS VI and MPS IVA (1.26 + 0.39 and 0.99 + 0.38 ng/mL, respectively). Activity of α-galactosidase A (α-Gal A), an enzyme deficient in Fabry disease, was not, however, inhibited by heparan sulfate in vitro, indicating that an increase of LysoGb3 level in MPS I, MPS II, and MPS III is an indirect effect of stored MPSs rather than a direct result of impairment of degradation of this compound by HS. Our findings indicate some association of elevated LysoGb3 concentration with the neuronopathic forms of MPSs. The pathological mechanism of which is still to be studied. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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11 pages, 1325 KiB  
Article
Modeling Morquio A Syndrome: An Anthropometric Study of Body Characteristics and Stature
by Agnieszka Różdżyńska-Świątkowska, Krzysztof Szklanny, Jolanta Marucha and Anna Tylki-Szymańska
Diagnostics 2020, 10(2), 116; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10020116 - 20 Feb 2020
Cited by 2 | Viewed by 6395
Abstract
Background: Morquio A syndrome or mucopolysaccharidosis (MPS) IVA is an autosomal recessive, life-limiting lysosomal storage disease caused by deficient activity of the enzyme galactosamine-6-sulfatase. Common early symptoms such as abnormalities of body stature can facilitate timely diagnosis. This study aimed to create a [...] Read more.
Background: Morquio A syndrome or mucopolysaccharidosis (MPS) IVA is an autosomal recessive, life-limiting lysosomal storage disease caused by deficient activity of the enzyme galactosamine-6-sulfatase. Common early symptoms such as abnormalities of body stature can facilitate timely diagnosis. This study aimed to create a pattern of face and body stature based on anthropometric measurements taken from a cohort of Polish patients with MPS IVA. Methods: Analysis of 11 somatometric and 14 craniofacial features was performed on 20 patients with MPS IVA, aged from 3 months to 26 years. The diagnosis of MPS IVA was confirmed by enzymatic and molecular analysis. Two-tailed t-tests were used to compare mean values for body length and weight at birth between the MPS IVA patients and the general population. To show the degree and direction of deviation z-scores were calculated and then used to construct a model of an average MPS IVA patient. Results: Mean values for body height and weight at birth were greater for boys than for the general population. The observed pattern of head and body shape indicated that dwarfism occurred with age as a result of the relatively short trunk and lower limbs. Skeletal abnormalities included a bell-shaped chest with the ratio of chest depth to chest width being significantly above the norm. The head and neck were relatively elongated, in comparison to body height, and tucked between narrow shoulders. The head had dolichocephalic shape, while the nose was short with wide nostrils. Conclusions: Multiple anthropometric measurements, including age ranges, allowed for the creation of a model that showed the most characteristic features of the MPS IVA phenotype. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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8 pages, 211 KiB  
Article
Respiratory Dysfunction in Children and Adolescents with Mucopolysaccharidosis Types I, II, IVA, and VI
by Assel Tulebayeva, Maira Sharipova and Riza Boranbayeva
Diagnostics 2020, 10(2), 63; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10020063 - 24 Jan 2020
Cited by 7 | Viewed by 2598
Abstract
Mucopolysaccharidosis (MPS) is a rare genetic disease involving active storage of glycosaminoglycans (GAGs). Accumulation of GAGs in the connective tissues of airways leads to progressive pulmonary dysfunction. Studies conducted in Taiwan revealed mainly restrictive pulmonary dysfunction, whereas the same studies in Egypt and [...] Read more.
Mucopolysaccharidosis (MPS) is a rare genetic disease involving active storage of glycosaminoglycans (GAGs). Accumulation of GAGs in the connective tissues of airways leads to progressive pulmonary dysfunction. Studies conducted in Taiwan revealed mainly restrictive pulmonary dysfunction, whereas the same studies in Egypt and California revealed obstructive pulmonary dysfunction. The contradictory results and lack of studies of respiratory system in patients with MPS in Asian populations are an indication to study pulmonary impairment in patients with MPS in Kazakhstan. The prospective study of respiratory system in patients with MPS was conducted in the Scientific Centre of Paediatrics and Paediatric Surgery. Patients with MPS (n = 11) were examined for respiratory function. Different types of pulmonary dysfunction were present in MPS patients, they were mainly of a restrictive pathology. One patient with MPS II had obstructive dysfunction. Enzyme replacement therapy was provided for an average duration of four years, leading to improvements in respiratory function in two patients with total normalization in one. All observed patients had respiratory dysfunction, mainly of the restrictive type. Pulmonary impairment in patients with MPS is the main reason for death. Thus, it is necessary to follow up with pulmonary function assessments in children with MPS. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
17 pages, 1353 KiB  
Article
Cardiac Evaluation Using Two-Dimensional Speckle-Tracking Echocardiography and Conventional Echocardiography in Taiwanese Patients with Mucopolysaccharidoses
by Hsiang-Yu Lin, Chih-Kuang Chuang, Chung-Lin Lee, Ming-Ren Chen, Kuo-Tzu Sung, Shan-Miao Lin, Charles Jia-Yin Hou, Dau-Ming Niu, Tung-Ming Chang, Chung-Lieh Hung and Shuan-Pei Lin
Diagnostics 2020, 10(2), 62; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10020062 - 23 Jan 2020
Cited by 9 | Viewed by 3700
Abstract
Background: Mucopolysaccharidoses (MPSs) are a group of rare inherited metabolic disorders that can damage various organs, including the heart. Cardiac abnormalities have been observed in patients with all MPS types, with the most documented abnormalities being cardiac valvular regurgitation and stenosis, valvular thickening, [...] Read more.
Background: Mucopolysaccharidoses (MPSs) are a group of rare inherited metabolic disorders that can damage various organs, including the heart. Cardiac abnormalities have been observed in patients with all MPS types, with the most documented abnormalities being cardiac valvular regurgitation and stenosis, valvular thickening, and hypertrophic cardiomyopathy. Methods: Cardiac features of 53 Taiwanese patients with MPS (31 men and 22 women; age range 1.1–34.9 years; seven with MPS I, 16 with MPS II, nine with MPS III, 14 with MPS IVA, and seven with MPS VI) were evaluated using two-dimensional speckle-tracking echocardiography and conventional echocardiography. Results: The mean z scores of the global longitudinal strain (GLS), left ventricular mass index (LVMI), interventricular septum diameter in diastole (IVSd), left ventricular posterior wall diameter in diastole (LVPWd), and aortic diameter of the 53 patients with MPS were 1.71, 0.35, 1.66, 1.03, and 3.15, respectively. Furthermore, z scores >2 were identified in 45%, 13%, 40%, 13%, and 70% of the GLS, LVMI, IVSd, LVPWd, and aortic diameter, respectively. The most severe GLS was observed in those with MPS VI, followed by in those with MPS II and MPS I. The GLS z score was positively correlated with the LVMI z score (p < 0.01). Moreover, diastolic dysfunction (reversed ratio between early and late (atrial) ventricular filling velocity (E/A ratio < 1)) was identified in 12 patients (23%). Ejection and shortening fractions were abnormal in four (8%) and seven (13%) patients, respectively. Mitral regurgitation (MR) (92%) was the most common valvular heart disease, followed by aortic regurgitation (AR) (57%), mitral stenosis (MS) (21%), and aortic stenosis (AS) (15%). The z scores of the GLS and LVMI and severity scores of the MS, MR, AS, and AR were all positively correlated with increasing age (p < 0.05). Twenty patients (38%) had a left ventricular remodeling pattern. Conclusions: The most significant left ventricular myocardial deformation, hypertrophy and valvular heart disease were observed in the patients with MPS VI, II, and I, followed by those with MPS IV; in contrast, patients with MPS III had the mildest manifestations. Cardiac abnormalities in patients with MPS worsened with increasing age in accordance with the progressive nature of this disease. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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12 pages, 899 KiB  
Article
Assessment of Activity of Daily Life in Mucopolysaccharidosis Type II Patients with Hematopoietic Stem Cell Transplantation
by Yasuyuki Suzuki, Madeleine Taylor, Kenji Orii, Toshiyuki Fukao, Tadao Orii and Shunji Tomatsu
Diagnostics 2020, 10(1), 46; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10010046 - 16 Jan 2020
Cited by 7 | Viewed by 3550
Abstract
The effectiveness of hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis type II (MPS II, Hunter disease) remains controversial although recent studies have shown HSCT provides more clinical impact. This study aims to evaluate the long-term effectiveness of HSCT using the activity of daily [...] Read more.
The effectiveness of hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis type II (MPS II, Hunter disease) remains controversial although recent studies have shown HSCT provides more clinical impact. This study aims to evaluate the long-term effectiveness of HSCT using the activity of daily living (ADL) scores in patients with MPS II. Sixty-nine severely affected MPS II patients (19 patients who received HSCT and 50 untreated patients) and 40 attenuated affected patients (five with HSCT and 35 untreated) were investigated by a simplified ADL questionnaire. The frequency of clinical findings and the scores of ADL (verbal, gross motor, and the level of care) were analyzed statistically. The mean age of onset of 19 severely affected patients who received HSCT was 1.40 years ± 1.06, which is not statistically different from that of 50 untreated patients (p = 0.11). Macroglossia, frequent airway infection, hepatosplenomegaly, joint contracture, and sleep apnea were less frequent in the HSCT-treated group of severe MPS II patients. The severe phenotype HSCT treated group reported a statistically significant higher score of verbal function and gross motor function between the ages of 10 and 15 years and a higher level of care score between 10 and 20 years. Patients with the attenuated phenotype showed high ADL scores, and all of five HSCT treated patients reported a lower frequency of frequent airway infection, coarse skin, umbilical/inguinal hernia, hepatosplenomegaly, heart valve disorders, and carpal tunnel. In conclusion, HSCT is effective, resulting in improvements in clinical features and ADL in patients with MPS II. HSCT should be re-reviewed as a therapeutic option for MPS II patients. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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14 pages, 1125 KiB  
Article
Laryngeal, Tracheal, and Bronchial Disease in the Mucopolysaccharidoses: Endoscopic Study
by Paulo Pires de Mello, Anneliese Lopes Barth, Danielle de Araujo Torres, Mariana Pires de Mello Valente and Dafne Dain Gandelman Horovitz
Diagnostics 2020, 10(1), 37; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10010037 - 10 Jan 2020
Cited by 4 | Viewed by 2797
Abstract
Mucopolysaccharidoses (MPS) are genetically determined diseases, leading to a deficiency of enzymes in the glycosaminoglycan (GAG) degradation pathway. The accumulation of GAG occurs in connective tissue in various organs and systems of the body, including the larynx, trachea, and bronchi. Respiratory symptoms are [...] Read more.
Mucopolysaccharidoses (MPS) are genetically determined diseases, leading to a deficiency of enzymes in the glycosaminoglycan (GAG) degradation pathway. The accumulation of GAG occurs in connective tissue in various organs and systems of the body, including the larynx, trachea, and bronchi. Respiratory symptoms are common and severe in these patients, and respiratory disease is a frequent cause of death. A cross-sectional study with flexible bronchoscopy was conducted in 30 MPS patients (6 MPS I, 8 MPS II, 2 MPS III, 3 MPS IV-A, and 11 MPS VI). Only four patients (13.33%) had a normal airway; nine (30%) had mild to moderate disease, 12 (40%) moderate to severe, and five patients (16.67%) had severe disease. Of particular interest, neuronopathic MPS II had the largest proportion of tracheostomized patients who died due to respiratory complications; in MPS IV-A, all patients had significant tracheobronchial deformity with associated tracheomalacia, despite lacking laryngeal involvement. Laryngotracheobronchial disease (LTBD) was associated to longer disease history and was significantly more severe in older patients. Longer use of enzyme replacement therapy did not prevent the progression of LTBD, although the age of therapy introduction may be a crucial factor in lower airway involvement. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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9 pages, 2193 KiB  
Article
Diagnosis and Management of Carpal Tunnel Syndrome in Children with Mucopolysaccharidosis: A 10 Year Experience
by Ivana Dabaj, Cyril Gitiaux, Daniela Avila-Smirnow, Jacques Ropers, Isabelle Desguerre, Arielle Salon, Stéphanie Pannier, Abdellah Tebani, Vassili Valayannopoulos and Susana Quijano-Roy
Diagnostics 2020, 10(1), 5; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10010005 - 20 Dec 2019
Cited by 9 | Viewed by 3463
Abstract
Introduction: Mucopolysaccharidoses (MPS) are rare and clinically heterogeneous lysosomal storage disorders. Carpal tunnel syndrome (CTS) is a frequent complication in MPS types I, II, VI, and VII. CTS symptoms are difficult to recognize in these children, and often there is a lack of [...] Read more.
Introduction: Mucopolysaccharidoses (MPS) are rare and clinically heterogeneous lysosomal storage disorders. Carpal tunnel syndrome (CTS) is a frequent complication in MPS types I, II, VI, and VII. CTS symptoms are difficult to recognize in these children, and often there is a lack of appropriate investigations. Patients and methods: In this retrospective study, all MPS patients were referred to the electrodiagnostic (EDX) laboratory of a single academic center during a 10-year period. Forty-eight children underwent serial EDX studies for CTS diagnosis and follow-up after surgery. Forty-two patients were diagnosed with CTS. Sensory nerve conduction velocity (SNCV), distal motor latency (DML), and motor nerve conduction velocity through the wrist (MNCV-W) of the median nerve were reviewed and analyzed. Results: One-hundred-three EDX examinations were performed on 48 patients. The median age at disease diagnosis was 2.1 years versus 4.9 years for CTS diagnosis. Analysis of the series revealed that electrophysiological abnormalities of CTS could have started much earlier (before the age of 2 years or at diagnosis of MPS). Diagnosis was based on SNCV and DML results, and MNCV-W was taken into consideration. Bilateral CTS was frequent (88%) in the types of MPS studied in our population and was observed from the first year of life, and may not have be associated with obvious clinical symptoms. EDX studies also helped in the follow-up and detection of CTS relapses, thus leading to an early intervention allowing a better recovery. Conclusion: EDX studies should be performed promptly and regularly in these patients. Prospective studies are required in order to understand the effect of disease-specific therapies in preventing the development of CTS in these patients. Synopsis: EDX studies should be performed in MPS patients soon after diagnosis and during routine follow-up, before and after surgical decompression. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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18 pages, 1440 KiB  
Article
Safety Study of Sodium Pentosan Polysulfate for Adult Patients with Mucopolysaccharidosis Type II
by Kenji Orii, Alaena Lim, Shunji Tomatsu, Molly Stapleton, Yasuyuki Suzuki, Calogera M. Simonaro, Edward H. Schuchman, Toshiyuki Fukao and Tadashi Matsumoto
Diagnostics 2019, 9(4), 226; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics9040226 - 17 Dec 2019
Cited by 10 | Viewed by 4340
Abstract
Current therapies for the mucopolysaccharidoses (MPS) do not effectively address skeletal and neurological manifestations. Pentosan polysulfate (PPS) is an alternative treatment strategy that has been shown to improve bone architecture, mobility, and neuroinflammation in MPS animals. The aims of this study were to [...] Read more.
Current therapies for the mucopolysaccharidoses (MPS) do not effectively address skeletal and neurological manifestations. Pentosan polysulfate (PPS) is an alternative treatment strategy that has been shown to improve bone architecture, mobility, and neuroinflammation in MPS animals. The aims of this study were to a) primarily establish the safety of weekly PPS injections in attenuated MPS II, b) assess the efficacy of treatment on MPS pathology, and c) define appropriate clinical endpoints and biomarkers for future clinical trials. Subcutaneous injections were administered to three male Japanese patients for 12 weeks. Enzyme replacement therapy was continued in two of the patients while they received PPS and halted for two months in one patient before starting PPS. During treatment, one patient experienced an elevation of alanine transaminase, and another patient experienced convulsions; however, these incidences were non-cumulative and unrelated to PPS administration, respectively. Overall, the drug was well-tolerated in all patients, and no serious drug-related adverse events were noted. Generally, PPS treatment led to an increase in several parameters of shoulder range of motion and decrease of the inflammatory cytokines, MIF and TNF-α, which are potential clinical endpoints and biomarkers, respectively. Changes in urine and serum glycosaminoglycans were inconclusive. Overall, this study demonstrates the safety of using PPS in adults with MPS II and suggests the efficacy of PPS on MPS pathology with the identification of potential clinical endpoints and biomarkers. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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10 pages, 637 KiB  
Article
Neonatal Mass Urine Screening Approach for Early Detection of Mucopolysaccharidoses by UPLC-MS/MS
by Iskren Menkovic, Anne-Sophie Marchand, Michel Boutin and Christiane Auray-Blais
Diagnostics 2019, 9(4), 195; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics9040195 - 18 Nov 2019
Cited by 8 | Viewed by 3113
Abstract
Mucopolysaccharidoses (MPSs) are lysosomal storage disorders caused by deficiencies of enzymes involved in the catabolism of glycosaminoglycans (GAGs). Various treatments such as enzyme replacement therapy and/or hematopoietic stem cell transplant are available for MPSs. Early initiation of treatment improves the outcome and delays [...] Read more.
Mucopolysaccharidoses (MPSs) are lysosomal storage disorders caused by deficiencies of enzymes involved in the catabolism of glycosaminoglycans (GAGs). Various treatments such as enzyme replacement therapy and/or hematopoietic stem cell transplant are available for MPSs. Early initiation of treatment improves the outcome and delays the onset of symptoms, highlighting the need for newborn screening for MPSs. The main objective of this project was to devise and validate a multiplex urine filter paper method for GAG analysis using a tandem mass spectrometry (MS/MS) approach to screen newborns for MPSs. Eluted urine samples from 21-day-old newborns were evaporated and a methanolysis reaction was performed. Samples were resuspended and analyzed using a UPLC-MS/MS system. A one-minute chromatographic method allowed the absolute quantification of heparan sulfate (HS), dermatan sulfate (DS), and creatinine. Method validation revealed high precision (< 9% relative standard deviation) and accuracy (< 7% bias) for all analytes. The reference values normalized to creatinine obtained by the analysis of five hundred 21-day-old newborn urine samples were 34.6 +/-6.2 mg/mmol of creatinine and 17.3 +/-3.9 mg/mmol of creatinine for HS and DS, respectively. We present a rapid and efficient method for populational newborn urine screening using MS/MS, which could also be applied to high-risk screening. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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7 pages, 3493 KiB  
Article
Otolaryngologists and the Early Diagnosis of Mucopolysaccharidoses: A Cross-Sectional Study
by Danielle de Araujo Torres, Anneliese Lopes Barth, Mariana Pires de Mello Valente, Paulo Pires de Mello and Dafne Dain Gandelman Horovitz
Diagnostics 2019, 9(4), 187; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics9040187 - 13 Nov 2019
Cited by 2 | Viewed by 2792
Abstract
Mucopolysaccharidoses (MPS) are a group of inborn errors of metabolism with an aggressive and usually fatal course. Therefore, early treatment is essential because the involvement of head and neck structures is almost always present in MPS. Our study aimed to retrospectively assess—via a [...] Read more.
Mucopolysaccharidoses (MPS) are a group of inborn errors of metabolism with an aggressive and usually fatal course. Therefore, early treatment is essential because the involvement of head and neck structures is almost always present in MPS. Our study aimed to retrospectively assess—via a chart review and a survey of caregivers—the history of ear, nose and throat (ENT) symptoms, the number of otolaryngology visits prior to diagnosis, and whether otolaryngologists diagnosed the disease in a cohort of MPS patients followed at an academic medical center. Twenty-three patients were evaluated. Age at diagnosis ranged from 0.2 to 33.0 years (median, 3.2 years). Prior to being diagnosed with MPS, 20/23 (87%) patients presented with at least one episode of otalgia, airway disorder, sleep disturbance, speech delay or suspected hearing loss. One patient had an adenotonsillectomy with paracentesis of tympanic membranes. Ten of the 23 patients (43%) were seen by an otolaryngologist before the diagnosis of MPS, none of which had the disease suspected during these visits. Notwithstanding limitations, our results suggest that increased awareness of MPS among otolaryngologists may allow for earlier diagnosis and better management of these patients. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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11 pages, 1586 KiB  
Article
Relationships among Height, Weight, Body Mass Index, and Age in Taiwanese Children with Different Types of Mucopolysaccharidoses
by Hsiang-Yu Lin, Chung-Lin Lee, Pao Chin Chiu, Dau-Ming Niu, Fuu-Jen Tsai, Wuh-Liang Hwu, Shio Jean Lin, Ju-Li Lin, Tung-Ming Chang, Chih-Kuang Chuang and Shuan-Pei Lin
Diagnostics 2019, 9(4), 148; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics9040148 - 14 Oct 2019
Cited by 13 | Viewed by 3849
Abstract
Background: Children with mucopolysaccharidosis (MPS) generally appear unaffected at birth but may develop multiple clinical manifestations including profound growth impairment as they grow older. Each type of MPS has a variable age at onset and variable rate of progression, however, information regarding growth [...] Read more.
Background: Children with mucopolysaccharidosis (MPS) generally appear unaffected at birth but may develop multiple clinical manifestations including profound growth impairment as they grow older. Each type of MPS has a variable age at onset and variable rate of progression, however, information regarding growth in Asian children is limited. Methods: This retrospective analysis included 129 Taiwanese patients with MPS (age range, 0.7 to 19.5 years, median age, 7.9 years) from eight medical centers in Taiwan from January 1996 through December 2018. Results: The mean z scores for the first recorded values of height, weight, and body mass index in the patients’ medical records were −4.25, −1.04, and 0.41 for MPS I (n = 9), −2.31, 0.19, and 0.84 for MPS II (n = 49), −0.42, 0.08, and −0.12 for MPS III (n = 27), −6.02, −2.04, and 0.12 for MPS IVA (n = 30), and −4.46, −1.52, and 0.19 for MPS VI (n = 14), respectively. MPS IVA had the lowest mean z scores for both height and weight among all types of MPS, followed by MPS VI, MPS I, MPS II, and MPS III, which showed the mildest growth retardation. Both z scores for height and weight were negatively correlated with increasing age for all types of MPS (p < 0.01). Of 32 patients younger than 5 years of age, 16 (50%), and 23 (72%) had positive z scores of height and weight, respectively. A substantial number of younger patients with MPS I, II, III, and IVA had a positive height z score. The median age at diagnosis was 3.9 years (n = 115). Conclusions: The patients with MPS IVA had the most significant growth retardation among all types of MPS, followed by MPS VI, MPS I, MPS II, and MPS III. The height and weight of the MPS patients younger than 2–5 years of age were higher than those of healthy individuals, however, their growth significantly decelerated in subsequent years. Understanding the growth curve and potential involved in each type of MPS may allow for early diagnosis and timely management of the disease, which may improve the quality of life. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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16 pages, 471 KiB  
Article
An At-Risk Population Screening Program for Mucopolysaccharidoses by Measuring Urinary Glycosaminoglycans in Taiwan
by Hsiang-Yu Lin, Chung-Lin Lee, Yun-Ting Lo, Ru-Yi Tu, Ya-Hui Chang, Chia-Ying Chang, Pao Chin Chiu, Tung-Ming Chang, Wen-Hui Tsai, Dau-Ming Niu, Chih-Kuang Chuang and Shuan-Pei Lin
Diagnostics 2019, 9(4), 140; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics9040140 - 05 Oct 2019
Cited by 10 | Viewed by 3614
Abstract
Background: The mucopolysaccharidoses (MPSs) are a group of rare lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs) and which eventually cause progressive damage to various tissues and organs. We developed a feasible MPS screening algorithm and established a cross-specialty collaboration platform [...] Read more.
Background: The mucopolysaccharidoses (MPSs) are a group of rare lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs) and which eventually cause progressive damage to various tissues and organs. We developed a feasible MPS screening algorithm and established a cross-specialty collaboration platform between medical geneticists and other medical specialists based on at-risk criteria to allow for an earlier confirmative diagnosis of MPS. Methods: Children (<19 years of age) with clinical signs and symptoms compatible with MPS were prospectively enrolled from pediatric clinics between July 2013 and June 2018. Urine samples were collected for a non-specific total GAG analysis using the dimethylmethylene blue (DMB) spectrophotometric method, and the quantitation of three urinary GAGs (dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS)) was performed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). The subjects with elevated urinary GAG levels were recalled for leukocyte enzyme activity assay and genetic testing for confirmation. Results: Among 153 subjects enrolled in this study, 13 had a confirmative diagnosis of MPS (age range, 0.6 to 10.9 years—three with MPS I, four with MPS II, five with MPS IIIB, and one with MPS IVA). The major signs and symptoms with regards to different systems recorded by pediatricians at the time of the decision to test for MPS were the musculoskeletal system (55%), followed by the neurological system (45%) and coarse facial features (39%). For these 13 patients, the median age at the diagnosis of MPS was 2.9 years. The false negative rate of urinary DMB ratio using the dye-based method for these 13 patients was 31%, including one MPS I, two MPS IIIB, and one MPS IVA. However, there were no false negative results with urinary DS, HS and KS using the MS/MS-based method. Conclusions: We established an at-risk population screening program for MPS by measuring urinary GAG fractionation biomarkers using the LC-MS/MS method. The program included medical geneticists and other medical specialists to increase awareness and enable an early diagnosis by detecting MPS at the initial onset of clinical symptoms. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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Review

Jump to: Research, Other

21 pages, 2520 KiB  
Review
Emerging Approaches for Fluorescence-Based Newborn Screening of Mucopolysaccharidoses
by Rajendra Singh, Shaileja Chopra, Carrie Graham, Melissa Langer, Rainer Ng, Anirudh J. Ullal and Vamsee K. Pamula
Diagnostics 2020, 10(5), 294; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10050294 - 11 May 2020
Cited by 7 | Viewed by 4428
Abstract
Interest in newborn screening for mucopolysaccharidoses (MPS) is growing, due in part to ongoing efforts to develop new therapies for these disorders and new screening assays to identify increased risk for the individual MPSs on the basis of deficiency in the cognate enzyme. [...] Read more.
Interest in newborn screening for mucopolysaccharidoses (MPS) is growing, due in part to ongoing efforts to develop new therapies for these disorders and new screening assays to identify increased risk for the individual MPSs on the basis of deficiency in the cognate enzyme. Existing tests for MPSs utilize either fluorescence or mass spectrometry detection methods to measure biomarkers of disease (e.g., enzyme function or glycosaminoglycans) using either urine or dried blood spot (DBS) samples. There are currently two approaches to fluorescence-based enzyme function assays from DBS: (1) manual reaction mixing, incubation, and termination followed by detection on a microtiter plate reader; and (2) miniaturized automation of these same assay steps using digital microfluidics technology. This article describes the origins of laboratory assays for enzyme activity measurement, the maturation and clinical application of fluorescent enzyme assays for MPS newborn screening, and considerations for future expansion of the technology. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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21 pages, 2150 KiB  
Review
Diagnosis of Mucopolysaccharidoses
by Francyne Kubaski, Fabiano de Oliveira Poswar, Kristiane Michelin-Tirelli, Maira Graeff Burin, Diana Rojas-Málaga, Ana Carolina Brusius-Facchin, Sandra Leistner-Segal and Roberto Giugliani
Diagnostics 2020, 10(3), 172; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10030172 - 22 Mar 2020
Cited by 47 | Viewed by 7525
Abstract
The mucopolysaccharidoses (MPSs) include 11 different conditions caused by specific enzyme deficiencies in the degradation pathway of glycosaminoglycans (GAGs). Although most MPS types present increased levels of GAGs in tissues, including blood and urine, diagnosis is challenging as specific enzyme assays are needed [...] Read more.
The mucopolysaccharidoses (MPSs) include 11 different conditions caused by specific enzyme deficiencies in the degradation pathway of glycosaminoglycans (GAGs). Although most MPS types present increased levels of GAGs in tissues, including blood and urine, diagnosis is challenging as specific enzyme assays are needed for the correct diagnosis. Enzyme assays are usually performed in blood, with some samples (as leukocytes) providing a final diagnosis, while others (such as dried blood spots) still being considered as screening methods. The identification of variants in the specific genes that encode each MPS-related enzyme is helpful for diagnosis confirmation (when needed), carrier detection, genetic counseling, prenatal diagnosis (preferably in combination with enzyme assays) and phenotype prediction. Although the usual diagnostic flow in high-risk patients starts with the measurement of urinary GAGs, it continues with specific enzyme assays and is completed with mutation identification; there is a growing trend to have genotype-based investigations performed at the beginning of the investigation. In such cases, confirmation of pathogenicity of the variants identified should be confirmed by measurement of enzyme activity and/or identification and/or quantification of GAG species. As there is a growing number of countries performing newborn screening for MPS diseases, the investigation of a low enzyme activity by the measurement of GAG species concentration and identification of gene mutations in the same DBS sample is recommended before the suspicion of MPS is taken to the family. With specific therapies already available for most MPS patients, and with clinical trials in progress for many conditions, the specific diagnosis of MPS as early as possible is becoming increasingly necessary. In this review, we describe traditional and the most up to date diagnostic methods for mucopolysaccharidoses. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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23 pages, 3984 KiB  
Review
Mucopolysaccharidosis Type I
by Francyne Kubaski, Fabiano de Oliveira Poswar, Kristiane Michelin-Tirelli, Ursula da Silveira Matte, Dafne D. Horovitz, Anneliese Lopes Barth, Guilherme Baldo, Filippo Vairo and Roberto Giugliani
Diagnostics 2020, 10(3), 161; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10030161 - 16 Mar 2020
Cited by 39 | Viewed by 16219
Abstract
Mucopolysaccharidosis type I (MPS I) is caused by the deficiency of α-l-iduronidase, leading to the storage of dermatan and heparan sulfate. There is a broad phenotypical spectrum with the presence or absence of neurological impairment. The classical form is known as [...] Read more.
Mucopolysaccharidosis type I (MPS I) is caused by the deficiency of α-l-iduronidase, leading to the storage of dermatan and heparan sulfate. There is a broad phenotypical spectrum with the presence or absence of neurological impairment. The classical form is known as Hurler syndrome, the intermediate form as Hurler–Scheie, and the most attenuated form is known as Scheie syndrome. Phenotype seems to be largely influenced by genotype. Patients usually develop several somatic symptoms such as abdominal hernias, extensive dermal melanocytosis, thoracolumbar kyphosis odontoid dysplasia, arthropathy, coxa valga and genu valgum, coarse facial features, respiratory and cardiac impairment. The diagnosis is based on the quantification of α-l-iduronidase coupled with glycosaminoglycan analysis and gene sequencing. Guidelines for treatment recommend hematopoietic stem cell transplantation for young Hurler patients (usually at less than 30 months of age). Intravenous enzyme replacement is approved and is the standard of care for attenuated—Hurler–Scheie and Scheie—forms (without cognitive impairment) and for the late-diagnosed severe—Hurler—cases. Intrathecal enzyme replacement therapy is under evaluation, but it seems to be safe and effective. Other therapeutic approaches such as gene therapy, gene editing, stop codon read through, and therapy with small molecules are under development. Newborn screening is now allowing the early identification of MPS I patients, who can then be treated within their first days of life, potentially leading to a dramatic change in the disease’s progression. Supportive care is very important to improve quality of life and might include several surgeries throughout the life course. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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Other

Jump to: Research, Review

1 pages, 147 KiB  
Correction
Correction: Barak, S. et al. “Long-Term Outcomes of Early Enzyme Replacement Therapy for Mucopolysaccharidosis IV: Clinical Case Studies of Two Siblings”. Diagnostics 2020, 10, 108
by Sharon Barak, Yair Anikster, Ifat Sarouk, Eve Stern, Etzyona Eisenstein, Tamar Yissar, Nir Sherr-Lurie, Annick Raas-Rothschild and Dafna Guttman
Diagnostics 2020, 10(7), 480; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10070480 - 14 Jul 2020
Viewed by 1873
Abstract
The authors wish to make the following correction to this paper [...] Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
11 pages, 2348 KiB  
Case Report
Long-Term Outcomes of Early Enzyme Replacement Therapy for Mucopolysaccharidosis IV: Clinical Case Studies of Two Siblings
by Sharon Barak, Yair Anikster, Ifat Sarouk, Eve Stern, Etzyona Eisenstein, Tamar Yissar, Nir Sherr-Lurie, Annick Raas-Rothschild and Dafna Guttman
Diagnostics 2020, 10(2), 108; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10020108 - 17 Feb 2020
Cited by 4 | Viewed by 3766 | Correction
Abstract
Enzyme replacement therapy (ERT) is one of the available therapies for mucopolysaccharidosis (MPS). This study presents a follow-up of two siblings with MPS IVA (Morquio A disease) that received ERT. Both siblings received weekly intravenous infusions of elosulfase alfa for 4.5 years. One [...] Read more.
Enzyme replacement therapy (ERT) is one of the available therapies for mucopolysaccharidosis (MPS). This study presents a follow-up of two siblings with MPS IVA (Morquio A disease) that received ERT. Both siblings received weekly intravenous infusions of elosulfase alfa for 4.5 years. One sibling (patient 1, P1; male) started therapy at 54 months of age, and the other sibling (patient 2, P2; female) started at 11 months of age. ERT was well-tolerated. In comparison to P1, P2’s growth curves deviated less from the norm. The orthopedic deformities of P1 were more severe than those of P2 and required several surgical corrections. P1’s sleep test at 48 months revealed obstructive sleep apnea, while by the age of 102 months, parameters were normal. P2 never had sleep apnea. Only P1 demonstrated ear, nose, and throat clinical illnesses. In comparison to P1, P2’s physical function was better maintained. In conclusion, ERT was safe in both patients during a 4.5-year follow-up. Although the typical characteristics of this disease were similar in both patients, P1 had a complex clinical course in comparison to P2, which influenced function and quality of life. Therefore, in order to make the most of ERT, it may be more beneficial when initiated at a relatively young age. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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8 pages, 1742 KiB  
Case Report
Long-Term Follow-up Posthematopoietic Stem Cell Transplantation in a Japanese Patient with Type-VII Mucopolysaccharidosis
by Kenji Orii, Yasuyuki Suzuki, Shunji Tomatsu, Tadao Orii and Toshiyuki Fukao
Diagnostics 2020, 10(2), 105; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10020105 - 16 Feb 2020
Cited by 3 | Viewed by 2325
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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11 pages, 1939 KiB  
Case Report
Molecular Characterization of a Novel Splicing Mutation Underlying Mucopolysaccharidosis (MPS) Type VI—Indirect Proof of Principle on Its Pathogenicity
by Maria Francisca Coutinho, Marisa Encarnação, Liliana Matos, Lisbeth Silva, Diogo Ribeiro, Juliana Inês Santos, Maria João Prata, Laura Vilarinho and Sandra Alves
Diagnostics 2020, 10(2), 58; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics10020058 - 21 Jan 2020
Cited by 4 | Viewed by 2760
Abstract
Here, we present the molecular diagnosis of a patient with a general clinical suspicion of Mucopolysaccharidosis, highlighting the different tools used to perform its molecular characterization. In order to decrease the turnaround time for the final report and contribute to reduce the “diagnostic [...] Read more.
Here, we present the molecular diagnosis of a patient with a general clinical suspicion of Mucopolysaccharidosis, highlighting the different tools used to perform its molecular characterization. In order to decrease the turnaround time for the final report and contribute to reduce the “diagnostic odyssey”, which frequently afflicts affected families, the proband’s sample was simultaneously screened for mutations in a number of lysosomal function-related genes with targeted next-generation sequencing (NGS) protocol. After variant calling, the most probable cause for disease was a novel ARSB intronic variant, c.1213+5G>T [IVS6+5G>T], detected in homozygosity. In general, homozygous or compound heterozygous mutations in the ARSB gene, underlie MPS type VI or Maroteaux-Lamy syndrome. Still, even though the novel c.1213+5G>T variant was easy to detect by both NGS and Sanger sequencing, only through indirect studies and functional analyses could we present proof of principle on its pathogenicity. Globally, this case reminds us that whenever a novel variant is detected, its pathogenicity must be carefully assessed before a definitive diagnosis is established, while highlighting alternative approaches that may be used to assess its effect in the absence RNA/cDNA sample(s) from the proband. This is particularly relevant for intronic variants such as the one here reported. Special attention will be given to the use of reporter minigene systems, which may be constructed/designed to dissect the effect of this sort of alterations, providing an insight into their consequences over the normal pre-mRNA splicing process of the affected gene. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
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