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Abstract Background To inform the development of a core outcome set (COS) for children and youth with mucopolysaccharidoses (MPS), we aimed to identify all outcomes and associated outcome measurement instruments that are reported in recent clinical trials and recommended as measurements in clinical management guidelines. Methods To identify English-language clinical trials and guidelines pertaining to MPS published between 2011 and mid-2021, we applied a comprehensive peer-reviewed search strategy to relevant databases and registers on May 16, 2021. Two reviewers independently screened retrieved citations and then full-text articles to determine eligibility for inclusion. From articles meeting inclusion criteria, we extracted details of the study design, population, intervention, and comparator, along with verbatim outcomes and associated outcome measurement instruments. Outcomes were organized into domains within five a priori core areas: life impact, pathophysiological manifestations, growth and development, resource use, and death. We conducted descriptive analyses at the study level, grouping articles arising from the same study. Results From 2593 unique citations, 73 articles from 61 unique studies were included in the review, pertaining to all MPS subtypes except for exceptionally rare subtypes. Eighty-four unique outcomes were reported across the studies, 33 (39%) of which were reported by three or fewer studies. Most outcomes (55; 65%) were in the pathophysiological manifestations core area, followed by life impact (17; 20%) and growth and development (10; 12%); one outcome each pertained to resource use and death. The most frequently reported outcomes were general adverse events (45; 74%), immune-related adverse events (39; 64%), and urinary glycosaminoglycans (38; 62%). Substantial variability existed in the reporting of outcome measurement instruments. Some differences in outcome reporting were observed by MPS subtype and publication year. Discussion Outcomes reported in clinical trials and guidelines for MPS in children and youth vary considerably and largely focus on pathophysiological manifestations. A COS is needed to standardize the selection and measurement of meaningful outcomes across future studies. We will present the outcomes identified in this review to knowledge users as part of a consensus process to select the most critical outcomes for inclusion in the COS. Trial Registration The protocol for this study was registered in PROSPERO (CRD42021267531) and in the COMET Database.

Abstract Background Patients with mucopolysaccharidosis (MPS) often face delayed diagnoses, limited treatment options and high healthcare costs, that may significantly affect patients' quality of life. The objective of this study was to understand medical service utilization related to diagnosis and treatment, economic burden during diagnosis period, and health-related quality of life among MPS patients in China. Methods A series of patients diagnosed with MPS registered in the national patient organization were recruited for a cross-sectional survey from May to July 2019. Information were collected from patients or their parents via phone interview, including demographic data, utilization of services related to diagnosis and treatment, total cost during the period of MPS diagnosis and health-related quality of life (HRQoL). HRQoL was assessed by PedsQL 4.0 Generic Core Scale (PedsQL) and 36-item short-form health survey (SF-36) depending on the age of patients with MPS and compared with the general Chinese population. Results A total of 180 MPS patients (50, 67, 15, 46, 1 and 1 for type I, II, III, IV, VI and VII), with a mean age of 9.54 years and 137 (76.11%) males, were included in analysis. The mean age at first visit to a medical doctor for MPS related symptoms was 3.65 ± 2.58 years old, while only 12 patients (6.67%) were diagnosed on their first visit. The mean diagnostic delay, which is defined as the time between the first visit to a medical doctor for MPS related symptoms and the final diagnosis, was 9.42 months, with no significant difference between types. The average number of misdiagnosis was 4.56. Before the confirmed diagnosis, the patients made an average of 6.31 visits and visited 4.3 hospitals. During diagnosis period, the mean of ¥81,086.72 direct medical costs accounted for 63.75% of the total cost. Only 32.78% of the patients had ever received specific treatments. The mean scores of PedsQL and SF-36 of patients were significantly lower than the Chinese norms. Household annual income per person, specific treatment use and MPS subtype were significantly associated HRQoL of patients. Conclusion The results highlight challenges faced by MPS patients in terms of diagnosis, access to specific treatments, economic burden and low HRQoL. There is an urgent need to improve early detection and diagnosis, create fair and consistent mechanisms to increase access to specialized treatment and reduce the economic burden of MPS patients in China.

Degradation of heparan sulfate (HS), a glycosaminoglycan (GAG) comprised of repeating units of N-acetylglucosamine and glucuronic acid, begins in the cytosol and is completed in the lysosomes. Acetylation of the terminal non-reducing amino group of α-D-glucosamine of HS is essential for its complete breakdown into monosaccharides and free sulfate. Heparan-α-glucosaminide N-acetyltransferase (HGSNAT), a resident of the lysosomal membrane, catalyzes this essential acetylation reaction by accepting and transferring the acetyl group from cytosolic acetyl-CoA to terminal α-D-glucosamine of HS in the lysosomal lumen. Mutation-induced dysfunction in HGSNAT causes abnormal accumulation of HS within the lysosomes and leads to an autosomal recessive neurodegenerative lysosomal storage disorder called mucopolysaccharidosis IIIC (MPS IIIC). There are no approved drugs or treatment strategies to cure or manage the symptoms of, MPS IIIC. Here, we use cryo-electron microscopy (cryo-EM) to determine a high-resolution structure of the HGSNAT-acetyl-CoA complex, the first step in the HGSNAT-catalyzed acetyltransferase reaction. In addition, we map the known MPS IIIC mutations onto the structure and elucidate the molecular basis for mutation-induced HGSNAT dysfunction.

Key Clinical Message In Hurler syndrome, corneal opacification is a common finding but rarely manifests as hypertrophic scars. A 6‐year‐old boy with Hurler syndrome had a hypertrophic scar on his left eye, which was successfully treated with superficial keratectomy.

Abstract Background The Italian Medicines Agency (AIFA) demands precise information on benefit/risk profile of home-based enzyme replacement therapy (ERT) for the treatment of patients with Pompe disease and Mucopolysaccharidosis type I (MPS I). This passage is necessary to obtain the authorization for ERT home therapy, even after the coronavirus disease-19 (COVID-19) pandemic period. This research intends to evaluate the safety, treatment satisfaction, and compliance of MPS I patients treated with laronidase (Aldurazyme®) and Pompe Disease patients treated with alglucosidase alfa (Myozyme®) in a homecare setting. Results We report herein an early interim analysis of the HomERT (Home infusions of ERT) study, a multicenter, non-interventional, double-cohort study that retrospectively analyzed 38 patients from 14 sites in Italy: cohort A (Pompe disease − 32 patients) and cohort B (MPS I − 6 patients). Among the selected patients who started home therapy before enrollment, the average number of missed home-based infusions was 0.7 (1.3) in cohort A and 3.8 (6.4) in cohort B with no return to the hospital setting. Irrespective of the treatment location, 3 prior ADRs per cohort were reported. The majority of patients preferred home-based infusions (cohort A: 96.9%; cohort B: 100%): the main reason was attributed to treatment convenience (cohort A: 81.3%; cohort B: 83.3%). Despite the underlying conditions, most patients self-evaluated their health as “good” (cohort A: 50%; cohort B: 83.3%). Conclusions Evidence of favorable safety profile, improved treatment compliance and personal satisfaction validates the use of ERT with laronidase and alglucosidase alfa as a strong candidate for home therapy.

Mucopolysaccharidosis is a series of rare diseases where a lack of an enzyme affecting mucopolysaccharides metabolism in the patients′ lysosome induces the intracellular deposition of the mucopolysaccharides, and causes ocular and organ-related complications. Ocular complications included corneal opacity, glaucoma, ametropia, strabismus, and chorioretinopathy. This review summarizes the mechanisms, clinical manifestations, specific ophthalmological examinations, and treatments for offering the ophthalmological knowledge to diagnose and begin treatment earlier.

Abstract Background Mucopolysaccharidosis IIIC (MPSIIIC) is one of four Sanfilippo diseases sharing clinical symptoms of severe cognitive decline and shortened lifespan. The missing enzyme, heparan sulfate acetyl-CoA: α-glucosaminide-N-acetyltransferase (HGSNAT), is bound to the lysosomal membrane, therefore cannot cross the blood-brain barrier or diffuse between cells. We previously demonstrated disease correction in MPSIIIC mice using an Adeno-Associated Vector (AAV) delivering HGSNAT via intraparenchymal brain injections using an AAV2 derived AAV-truetype (AAV-TT) serotype with improved distribution over AAV9. Methods Here, intraparenchymal AAV was delivered in sheep using catheters or Hamilton syringes, placed using Brainlab cranial navigation for convection enhanced delivery, to reduce proximal vector expression and improve spread. Results Hamilton syringes gave improved AAV-GFP distribution, despite lower vector doses and titres. AAV-TT-GFP displayed moderately better transduction compared to AAV9-GFP but both serotypes almost exclusively transduced neurons. Functional HGSNAT enzyme was detected in 24-37% of a 140g gyrencephalic sheep brain using AAV9-HGSNAT with three injections in one hemisphere. Conclusions Despite variabilities in volume and titre, catheter design may be critical for efficient brain delivery. These data help inform a clinical trial for MPSIIIC.

Abstract Background In patients with mucopolysaccharidosis (MPS), systematic assessment and management of cervical instability, cervicomedullary and thoracolumbar junction spinal stenosis and spinal cord compression averts or arrests irreversible neurological damage, improving outcomes. However, few studies have assessed thoracic spinal involvement in MPS IVa patients. We aimed to evaluate thoracic spinal abnormalities in MPS IVa patients and identify associated image manifestations by CT and MRI study. Results Data of patients diagnosed and/or treated for MPS IVa at MacKay Memorial Hospital from January 2010 to December 2020 were extracted from medical records and evaluated retrospectively. Computed tomography (CT), plain radiography and magnetic resonance imaging (MRI) findings of MPS IVa-related spinal abnormalities were reviewed. Spine CT and plain radiography findings of 12 patients (6 males and 6 females with median age 7.5 years, range 1–28 years) revealed two subtypes of spinal abnormalities: thoracic kyphosis apex around T2 (subtype 1, n = 8) and thoracic kyphosis apex around T5 (subtype 2, n = 4). Spine CT and plain radiography clearly identified various degrees of thoracic kyphosis with apex around T2 or T5 in MPS IVa patients. Square-shaped to mild central beaking in middle thoracic vertebral bodies was observed in subtype 1 patients, while greater degrees of central beaking in middle thoracic vertebral bodies was observed in subtype 2 patients. Conclusions Spine CT findings clearly identify new radiological findings of thoracic kyphosis apex around T2 or T5 in MPS IVa patients. The degrees of central beaking at middle thoracic vertebral bodies may be a critical factor associated with different image presentations of thoracic kyphosis.

Abstract Background Patients are the most important stakeholders in the care of any disease and have an educational need to learn about their condition and the treatment they should receive. Considering this need for patient-focused materials, we present a directed approach for mucopolysaccharidosis (MPS) VI and MPS IVA, a pair of rare, inherited diseases that affects multiple organs and parts of the body. Independent guidelines on the treatment of these diseases were recently published, providing evidence- and expertise-driven recommendations to optimize patient management. However, while healthcare providers may have the training and knowledge to understand these guidelines, patients and their caregivers can find the technical content challenging. Hence, we aimed to develop plain language summaries (PLS) of the MPS VI and MPS IVA guidelines with patients as the primary audience. Results A review of the guidelines by an expert team identified six domains of information relevant to patients: The multidisciplinary team, regular tests and check-ups, disease-modifying and supportive treatments, general anesthetics, ear-nose-throat/respiratory care, and surgeries. This information was adapted into a series of infographics specific to either MPS VI or MPS IVA, designed to appeal to patients and clearly present information in a concise manner. Conclusions The use of patient-friendly materials, like the infographics we have developed, has the potential to better inform patients and engage them in their care. We issue a “call to arms” to the medical community for the development of similar PLS materials in rare diseases intended to inform and empower patients.

Abstract Background Lysosomal storage diseases (LSDs) are inherited metabolic disorders that may lead to severe multi-organ disease. Current ERTs are limited by anti-drug antibodies, the blood–brain barrier, and early disease onset and progression before ERT is started. We have opened a phase I clinical trial of enzyme replacement therapy (ERT) for fetuses with LSDs (NCT04532047). We evaluated the attitudes of parents and patients with LSDs towards fetal clinical trials and therapies. Methods A multidisciplinary team designed a survey which was distributed by five international patient advocacy groups. We collected patients’ demographic, diagnostic, and treatment information. Associations between respondent characteristics and attitudes towards fetal therapies/trials were analyzed using multivariate ordinal logistic regression. Results The survey was completed by 181 adults from 19 countries. The majority of respondents were mothers from the United States. The most common diseases were MPS1 (26%), MPS3 (19%), and infantile-onset Pompe (14%). Most patients (88%) were diagnosed after birth, at a median of 21 months. Altogether, 65% of participating patients and children of participants had received ERT, 27% a stem cell transplant, and 4% gene therapy. We found that half (49%) of respondents were unlikely to terminate a future affected pregnancy, 55% would enroll in a phase I clinical trial for fetal ERT, and 46% would enroll in a fetal gene therapy trial. Respondents who received postnatal ERT were significantly more likely enroll in a trial for fetal ERT or gene therapy (ERT OR 4.48, 95% CI 2.13–9.44, p

Abstract Background Mucopolysaccharidosis VI, or Maroteaux–Lamy disease, is an autosomal recessive disease characterized by deficiency of the enzyme arylsulfatase B in the lysosomal catabolism of glycosaminoglycans. Due to reduced (or even null) enzyme activity, glycosaminoglycans (mainly dermatan sulfate) accumulates, leading to a multisystemic disease. Mucopolysaccharidosis VI induces reduced growth, coarse face, audiovisual deficits, osteoarticular deformities, and cardiorespiratory issues, hampering the quality of life of the patient. Enzyme replacement therapy with galsulfase (Naglazyme, BioMarin Pharmaceuticals Inc., USA) is the specific treatment for this condition. Although studies have shown that enzyme replacement therapy slows the progression of the disease, the effects of long-term enzyme replacement therapy remain poorly understood. Case presentation A 29-year-old, Caucasian, male patient diagnosed with mucopolysaccharidosis VI was treated with enzyme replacement therapy for over 15 years. Enzyme replacement therapy was initiated when patient was 13 years old. The patient evolved multiplex dysostosis, carpal tunnel syndrome, thickened mitral valve, and hearing and visual loss. Conclusions Although enzyme replacement therapy did not prevent the main signs of mucopolysaccharidosis VI, it slowed their progression. Additionally, enzyme replacement therapy was associated with a longer survival compared with the untreated affected sibling. Taken together, the results indicate that enzyme replacement therapy positively modified the course of the disease.

Summary. The article is devoted to a topical issue in pediatrics - hepatomegaly syndrome in a rare metabolic pathology - mucopolysaccharidosis type I. Goal. To study the possibilities of early diagnosis of hepatomegaly syndrome as one of the most important clinical manifestations of type I MPS and to determine early diagnostic criteria for the course of the disease. Materials and methods. Retrospective clinical study of 24 children with type I mucopolysaccharidosis who were diagnosed in Ukraine for 17 years (from 2004 to 2021). Patients underwent a complete comprehensive examination of the manifestations of the disease and determined the activity of the enzyme a-L-iduronidase in the lysosomes of leukocytes using a biochemical method, the study of the level of excretion of glycosaminoglycans in the urine. Results. Clinical symptoms and examination results in 24 children diagnosed with type I mucopolysaccharidosis in Ukraine were analyzed. The conducted comprehensive examination revealed a significant frequency of hepatomegaly syndrome among patients of this study. Its combination with other clinical symptoms. Hepatomegaly syndrome in children was found in 79 %, which was combined with other clinical symptoms of mucopolysaccharidosis, but never was the cause of the initial examination of the patient and the key symptom. Hepatomegaly was most often observed in the symptom complex with contractures and stiffness of the joints, curvature of the spine, lesions of the valvular apparatus of the heart and umbilical hernias. In contrast to the previously described studies, only 20% of hepatomegaly syndrome was combined with splenomegaly. Biochemical studies did not reveal liver dysfunction. There was also a direct relationship between the degree of hepatomegaly and the severity of glycosaminoglycan secretion. Conclusions. Liver enlargement syndrome in many childhood diseases, including orphan metabolic diseases, remains an underestimated diagnostic criterion. Detection of hepatomegaly syndrome can direct the diagnostic search of the practitioner to exclude hereditary metabolic disorders, including mucopolysaccharidosis. Early detection of such a complex and severe disease in children as mucopolysaccharidosis type I will allow to start treatment in time and prevent disability and early death.

Abstract Background Mucopolysaccharidosis type VII (Sly syndrome) is an ultra-rare neurometabolic disorder caused by inherited deficiency of the lysosomal enzyme β-glucuronidase. Precise data regarding its epidemiology are scarce, but birth prevalence is estimated to vary from 0.02 to 0.24 per 100,000 live births. The clinical course and disease progression are widely heterogeneous, but most patients have been reported to show signs such as skeletal deformities or cognitive delay. Additionally, detection criteria are not standardized, resulting in delayed diagnosis and treatment. Methods We present a cohort of 9 patients with mucopolysaccharidosis VII diagnosed in the Iberian Peninsula, either in Spain or Portugal. The diagnostic approach, genetic studies, clinical features, evolution and treatment interventions were reviewed. Results We found that skeletal deformities, hip dysplasia, hydrops fetalis, hepatosplenomegaly, hernias, coarse features, respiratory issues, and cognitive and growth delay were the most common features identified in the cohort. In general, patients with early diagnostic confirmation who received the appropriate treatment in a timely manner presented a more favorable clinical evolution. Conclusions This case series report helps to improve understanding of this ultra-rare disease and allows to establish criteria for clinical suspicion or diagnosis, recommendations, and future directions for better management of patients with Sly syndrome.

Abstract Background Mucopolysaccharidosis consists of a group of diseases caused by the deficiency of lysosomal enzymes, which may lead to the compression of the median nerve in the carpal tunnel due to the accumulation of glycosaminoglycan, resulting in the hand disability. The study purpose is to present functional results of carpal tunnel release in mucopolysaccharidosis patients. Patients were selected from an enzyme replacement group in the Department of Pediatric Neurology. The legal guardians of the patients were informed about the likely functional change of the hands induced by compression of the median nerve. Clinical evaluation was performed in those patients who received their legal guardians’ consent to participate and was included inspection, assessment of functional level, wrinkle test and the digital pinch function to manipulate small and large objects. Ultrasound and electromyography were performed to confirm the clinical median nerve compression. Bilateral extended opening technique was performed to access the carpal tunnel and analyze the anatomic findings of the median nerve and the flexed tendons of the fingers. After the surgical release of the carpal tunnel, the clinical evaluation was repeated. Subjective observations of the legal guardians were also considered. Results Seven patients underwent bilateral surgical opening of the carpal tunnel; six boys, mean age of 9.5 (5 to 13), five of them presenting Type II mucopolysaccharidosis, 1 Type I and 1 Type VI. The average follow-up was 12 months (10–13 months). The functional results observed included the improvement in the handling of small and large objects in all children who underwent decompression of the median nerve. The comparison between the pre-operative and post-operative functional levels revealed that 2 patients evolved from Level II to IV, 3 from Level III to IV, 1 from Level IV to V and 1 patient remained in Level III. Tenosynovitis around the flexor tendons and severe compression of the median nerve in the fourteen carpal tunnels were observed during the surgical procedure. In 6 wrists, partial tenosynovitis was performed. Conclusions Despite the improvement in the overall function of the children' hands, we cannot conclude that only surgery was responsible for the benefit. Better designed studies are required

Abstract Mucopolysaccharidoses are a group of lysosomal storage disorders that are caused by deficiency of enzymes involved in glycosaminoglycans degradation. Due to low prevalence and high childhood mortality, researches on mucopolysaccharidoses were mainly focused on the fatal manifestations. With the development of treatments, more and more mucopolysaccharidoses patients were treated by approved therapies, thereby getting prolonged life span and improved quality of life. Abnormal accumulation of glycosaminoglycans in the eye may block trabecular meshwork, thicken sclera and change mechanical behavior of lamina cribrosa, which, by increasing intraocular pressure and damaging optic nerve, could cause glaucoma. Glaucoma was the leading cause of irreversible blindness worldwide, but it was rarely reported in mucopolysaccharidoses patients. Although non-fatal, it seriously affected quality of life. Prevalence of glaucoma in mucopolysaccharidoses patients (ranged from 2.1 to 12.5%) indicated that glaucoma in patients with mucopolysaccharidoses was worthy of attention and further study, thereby improving the quality of life for MPSs patients.

Background: The need for systematization, generalization and analysis of structural changes in various organs and systems that occur in patients with mucopolysaccharidosis (MPS). MPS is a rare disease, therefore, there is a lack of structured information in Russian publications in the field of radiology. Aims: The purpose of the study is to summarize our own experience, identifying the incidence of changes in various organs and describing the most significant changes and their causes. Identification of more informative and safe diagnostic methods of various organs, taking into account the specificity of changes in MPS. Methods: Retrospectively, 303 children with MPS of different types were examined (the sample included 70 cases verified by the laboratory studies and molecular genetics), the revision of tomograms and radiographs was carried out for the studies from 2015 to 2021. All the patients underwent MRI of the brain and cervical spine, X-ray of the skeletal bones. Results: The analysis of the obtained images revealed the most common changes, such as dysostosis (in 100%; 70 patients), stenosis of the spinal canal at the craniovertebral level (73%; 51 patients), atrophy (47%; 33 patients) and focal lesions of the brain substance (67%; 47 patients), hydrocephalus (28%; 20 patients), expansion of the perivascular spaces (70%; 58 patients). The pathophysiological mechanisms of the occurrence of structural changes have been analyzed and described. Conclusions: The assessment and comparison of various diagnostic methods for different organs and systems has demonstrated that MRI is the most informative imaging method for the assessment of the craniovertebral junction. Given the lower radiation exposure compared to computed tomography, it is preferable to use digital radiography for examining the bones of the extremities.

Abstract In traditional clinical trial design, efficacy is typically assessed using a single primary endpoint in a randomized controlled trial to detect an expected treatment effect of a therapy in a narrowly selected patient population. This accepted paradigm is based on clinical evaluations that may not actually capture the breadth of the impact of a disease, which is especially true in the setting of complex, multisystem, rare diseases with small, extremely heterogeneous patient populations. The multi-domain responder index (MDRI) is a novel approach that accommodates complex and heterogeneous disease manifestations and evaluates a broad array of clinical disease without impairing the power or rigor of a study to fully understand a treatment. The MDRI sums the scores corresponding to clinically significant thresholds of change for each component domain in each individual patient, capturing the mean clinically meaningful change across multiple domains within individuals. This novel approach combines and then sums the results of independent domain endpoint responder analyses into one responder score to provide a broad basis for the assessment of efficacy. The impact of a treatment across multiple, physiologically independent domains, can be assessed clinically, reducing the adverse impact of heterogeneity on trial outcomes and allowing eligibility criteria to enroll a wider range of patients, ultimately resulting in efficacy and safety assessments of a therapy across a broad group of heterogeneous patients in rare disease programs. Trial registration The following studies are referenced within this manuscript (CLINICALTRIALS.GOV registration numbers): NCT00912925; NCT00146770; NCT00067470; NCT00104234; NCT00069641; NCT02230566; NCT02377921; NCT02432144.

Mucopolysaccharidoses (MPS) are a group of rare, heterogeneous, lysosomal storage disorders. Patients show a broad spectrum of clinical features with a substantial unmet medical need. Individual treatment trials (ITTs) might be a valid, time- and cost-efficient way to facilitate personalized medicine in the sense of drug repurposing in MPS. However, this treatment option has so far hardly been used—at least hardly been reported or published. Therefore, we aimed to investigate the awareness and utilization of ITTs among MPS clinicians, as well as the potential challenges and innovative approaches to overcome key hurdles, by using an international expert survey on ITTs, namely, ESITT. Although 74% (20/27) were familiar with the concept of ITTs, only 37% (10/27) ever used it, and subsequently only 15% (2/16) published their results. The indicated hurdles of ITTs in MPS were mainly the lack of time and know-how. An evidence-based tool, which provides resources and expertise needed for high-quality ITTs, was highly appreciated by the vast majority (89%; 23/26). The ESITT highlights a serious deficiency of ITT implementation in MPS—a promising option to improve its treatability. Furthermore, we discuss the challenges and innovative approaches to overcome key barriers to ITTs in MPS.

Mucopolysaccharidosis type-II (MPS-II) is an X-linked lysosomal storage disorder. Here, we report an 8-year-old boy with pebbling sign in the scapular region, coarse facies, claw hand, diastolic murmur, and hepatomegaly. With decreased iduronate-2-sulfatase activity and hemizygous mutation in the IDS gene, the diagnosis was MPS-II. Pebbling sign is a rare but pathognomonic sign of MPS-II.

Abstract Background Mucopolysaccharidoses (MPSs) are a group of inherited metabolic diseases, which are characterized by the accumulation of glycosaminoglycans, and eventually lead to the progressive damage of various tissues and organs. Methods An epidemiological study of MPS in Taiwan was performed using multiple sources. The survival and diagnostic age for different types of MPS between 1985 and 2019 were evaluated. Results Between 1985 and 2019, there were 175 patients diagnosed with MPS disorders in the Taiwanese population, with a median diagnostic age of 3.9 years. There were 21 (12%), 78 (45%), 33 (19%), 32 (18%) and 11 (6%) patients diagnosed with MPS I, II, III, IV and VI, respectively, with median diagnostic ages of 1.5, 3.8, 4.7, 4.5 and 3.7 years, respectively. Diagnosis of MPS patients was significantly earlier in recent decades (p

Abstract Background Mucopolysaccharidoses (MPS) are rare, inherited disorders associated with enzyme deficiencies that result in glycosaminoglycan (GAG) accumulation in multiple organ systems. Management of MPS is evolving as patients increasingly survive to adulthood and undergo multiple surgeries throughout their lives. As surgeries in these patients are considered to be high risk, this can result in a range of critical clinical situations in adult patients. Results We discuss strategies to prepare for and manage critical clinical situations in adult patients with MPS, including supporting the multidisciplinary team, preoperative and airway assessments, surgical preparations, and postoperative care. We also present eight critical clinical cases (age range: 21–38 years) from four leading inherited metabolic disease centres in Europe to highlight challenges and practical solutions to optimise the care of adult patients with MPS. Critical clinical situations included surgical procedures, pregnancy and a thrombus in a port-a-cath. Conclusions Individualised strategies to manage critical clinical situations need to be developed for each patient to compensate for the heterogeneous symptoms that may be present and the potential complications that may occur. These strategies should include input from the wider MDT, and be coordinated by metabolic specialists with expertise in the management of MPS disorders and surgery in adult patients with MPS.

Abstract Background The mucopolysaccharidoses (MPSs) are lysosomal storage disorders associated with progressive multi-organ and skeletal abnormalities. Clinical manifestations can affect each of the five senses: hearing, vision, smell, taste, and touch. Main body of the abstract On 24–26 May 2018, 46 specialists with expertise in managing symptoms of MPS and experts specialized in evaluating and managing impairments in each one of the five senses gathered in Lisbon, Portugal at the “MPS & the five senses” meeting to discuss how loss of one or multiple senses can affect activities of daily living (ADL) and quality of life (QoL) in MPS patients and best practices in evaluating and managing the loss of senses in these individuals. The meeting confirmed that MPS can affect the senses considerably, but how these impairments affect ADL and overall QoL from a patient’s perspective remains unclear. A better insight may be achieved by prospectively collecting patient-reported outcome (PRO) data internationally in a standardized way, using a standard battery of tools. To identify relevant PRO tools, a systematic literature review and a selection of existing published questionnaires, focused on adults with no intellectual delay, were performed after the meeting. The search strategy identified 33 PRO tools for hearing, 30 for speech, 125 for vision, 49 for touch (including pain and upper limb function), and 15 for smell/taste. A further selection was made based on several criteria, including applicability/relevance for MPS, applicability in different countries (languages)/cultures, availability in English, ease of use, validation, and normative data, resulting in a final set of 11 tools. In addition to these sense-specific PRO tools, a general QoL tool, the EuroQol (EQ)-5D-5 L, was selected to assess overall QoL and reveal coping behaviors. Short conclusion MPS can affect each of the five senses, but current knowledge on the impact of sense impairments on QoL/ADL in MPS patients remains limited. Collection of data in a standardized fashion using sense-specific patient-reported outcome tools and a general QoL tool may fill the current knowledge gap.

Abstract Background The necessity of early treatment for lysosomal storage diseases (LSDs) has triggered the development of newborn screening for LSDs in recent years. Here we report the first 70,000 newborns screened for Mucopolysaccharidosis (MPS) type 4A (Morquio syndrome) and other LSDs by an 8-plex assay including the original 4-plex LSD screening tandem mass spectrometry (MS/MS) assay for Pompe disease, Fabry disease, Gaucher disease, and MPS I disease. Methods The additional reaction for MPS II, MPS 3B, MPS 4A, and MPS 6 enzymes was performed separately from the 4-plex reaction. The two reactions were quenched and extracted, then combined before carrying out a single 2-min UPLC-MS/MS analysis. Results From Mar. 2018 to Apr. 2019, 73,743 newborns were screened with the 8-plex LSD screening assay. The 8-plex assay revealed a better analytical precision than the previous 4-plex assay possibly because the 8-plex was carried out using UPLC-MS/MS. Six newborns were found to have low MPS-4A enzyme (N-acetylgalactosamine-6-sulfatase) activity and biallelic GALNS pathogenic mutations in trans; these patients are presumably affected with MPS4A, making an incidence of one in 12,291 (95% confident interval (CI): 5633-26,817). One mutation, c.857C > T (p.T286 M) of the GALNS gene, accounted 5 of the 12 mutated alleles. These newborns had immature vertebral bodies at 1 month of age, and one case was treated with elosulfase alfa 2 mg/kg/week starting from 4 months of age. Among other MPSs screened, one case of MPS I, 3 cases of MPS II, and 3 cases of MPS 3B were detected. One case of mucolipidosis type III was also diagnosed. In conjunction with another 9 patients of Pompe disease, Gaucher disease, and classical Fabry disease, making an incidence of LSDs as one in 3206 newborns (95% CI: 2137 - 4811). The one with infantile-onset Pompe disease and the one with Gaucher disease were treated since the age of 8 days and 41 days respectively. Conclusions Routine newborn screening of MPS 4A and other LSDs were made possible by the 8-plex LSD screening assay. However, detailed phenotype prediction and the time to start treatment will need further elucidation.

Abstract Mucopolysaccharidoses (MPSs) are a class of lysosomal storage disorders resulting in progressive disease manifestations and are caused by pathogenic variants in genes coding for enzymes needed to degrade glycosaminoglycans. While most of the seven MPSs are autosomal recessive disorders, MPS II, also known as Hunter syndrome, is inherited in an X‐linked recessive manner and is the most common MPS. Here, we report a 1‐year and 4‐month‐old boy who presented with delayed developmental milestones, back deformity, and left scrotal swelling noticed by parents at one year of age. He has coarse facial appearance with macrocephaly, widened wrists, congenital dermal melanocytosis on his back, kyphotic deformity in the thoracolumbar area and left‐sided inguinal hernia all consistent with a suspected MPS II diagnosis. The MPS II diagnosis was subsequently confirmed with genetic testing of the IDS gene. To our knowledge, this is the first case of MPS II reported from Ethiopia. This case shows the importance of early clinical recognition of genetic conditions and the utility of genetic testing for confirmation. The diagnosis provided important surveillance and natural history information for the patient's providers and family.

Introduction Mucopolysaccharidosis (MPS) is a set of rare diseases caused by deficiency of lysosomal enzymes that lead to the accumulation of glycosaminoglycans (GAG) in tissues and organs, which, in turn, is responsible for the multisystemic clinical, chronic, and progressive symptoms. Objective To describe the profile of the otorhinolaryngological clinical examination and audiology tests of patients with MPS disease. Methods The present study is a case series. The evaluation was performed, initially, in 24 patients with MPS types I, II, IIIA, IV and VI. Results The most common hearing complaint was hearing loss, which was confirmed by audiology tests in almost 100% of the patients, most of whom presented conductive hearing loss. Conclusions It is important to evaluate the complaints, physical examination, and audiology tests in patients with MPS. The otorhinolaryngologistshould be part of the group of professionals that follows these patients to better monitor their hearing and provide early hearing rehabilitation.

Mucopolysaccharidosis type II (MPS II) is a rare, X-linked recessive disease characterized by deficiency of lysosomal iduronate-2-sulfatase. Progressive upper airway obstruction is common in patients with MPS II. Tracheostomy is an effective way of managing airway obstruction when less invasive interventions are no longer adequate. Here, we report a patient with MPS II who developed sudden respiratory distress in the emergency department and required tracheostomy as endotracheal intubation and laryngeal mask airway (LMA) failed to secure the airway.

Abstract Introduction Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, which impairs lysosomal degradation of keratan sulphate and chondroitin-6-sulphate. The multiple clinical manifestations of MPS IVA present numerous challenges for management and necessitate the need for individualised treatment. Although treatment guidelines are available, the methodology used to develop this guidance has come under increased scrutiny. This programme was conducted to provide evidence-based, expert-agreed recommendations to optimise management of MPS IVA. Methods Twenty six international healthcare professionals across multiple disciplines, with expertise in managing MPS IVA, and three patient advocates formed the Steering Committee (SC) and contributed to the development of this guidance. Representatives from six Patient Advocacy Groups (PAGs) were interviewed to gain insights on patient perspectives. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with experience managing patients with MPS IVA and the manuscript was evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers. Results A total of 87 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) disease-modifying interventions (enzyme replacement therapy [ERT] and haematopoietic stem cell transplantation [HSCT]); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions (including spinal, limb, ophthalmic, cardio-thoracic and ear-nose-throat [ENT] surgeries). Consensus was reached on all statements after two rounds of voting. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance). Conclusion This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS IVA and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.

Abstract Introduction Mucopolysaccharidosis (MPS) VI or Maroteaux-Lamy syndrome (253200) is an autosomal recessive lysosomal storage disorder caused by deficiency in N-acetylgalactosamine-4-sulfatase (arylsulfatase B). The heterogeneity and progressive nature of MPS VI necessitates a multidisciplinary team approach and there is a need for robust guidance to achieve optimal management. This programme was convened to develop evidence-based, expert-agreed recommendations for the general principles of management, routine monitoring requirements and the use of medical and surgical interventions in patients with MPS VI. Methods 26 international healthcare professionals from various disciplines, all with expertise in managing MPS VI, and three patient advocates formed the Steering Committee group (SC) and contributed to the development of this guidance. Members from six Patient Advocacy Groups (PAGs) acted as advisors and attended interviews to ensure representation of the patient perspective. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with expertise and experience managing patients with MPS VI and the manuscript has been evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers. Results A total of 93 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions. Consensus was reached on all statements after two rounds of voting. The greatest challenges faced by patients as relayed by consultation with PAGs were deficits in endurance, dexterity, hearing, vision and respiratory function. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance). Conclusion This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS VI and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.

Hunter's Syndrome or mucopolysaccharidosis Type II is a rare metabolic disorder caused by the deficiency of lysosomal enzyme iduronate-2-sulfatase. It results in progressive accumulation of deramatan and heparan sulfates in tissues leading to a wide clinical spectrum of systemic manifestations. This is a case report of a 6-year-old boy with classical features of Hunter's Syndrome who presented with a chief complaint of multiple decayed teeth. The purpose of this case report is to highlight the role of a pediatric dentist in the management of such special children with advanced dental care.

A 1½-year-old female child presented with swelling in thoracolumbar region and delayed developmental milestones. The routine hemogram analysis on Sysmex XN 1000 showed flags of white blood cell (WBC) abnormal scattergram and lymphocytosis. The peripheral smear examination showed Alder–Reilly (AR) granules leading to a suspicion of underlying Mucopolysaccharidosis (MPS). Further clinical workup, radiographic studies, chemical test lead to the confirmatory diagnosis of MPS. A flag of abnormal WBC scattergram and AR anomaly are the hematological findings that can be seen in a case of MPS.

Abstract Background Sanfilippo syndrome (mucopolysaccharidosis type III; MPS III) is an inherited monogenic lysosomal storage disorder divided into subtypes A, B, C and D. Each subtype is characterized by deficiency of a different enzyme participating in metabolism of heparan sulphate. The resultant accumulation of this substrate in bodily tissues causes various malfunctions of organs, ultimately leading to premature death. Eighty-four, 24 and 5 death certificates of patients with Sanfilippo syndrome types A, B and C, respectively, were obtained from the Society of Mucopolysaccharide Diseases (UK) to better understand the natural course of these conditions, covering the years 1977–2007. Results In Sanfilippo syndrome type A mean age at death (± standard deviation) was 15.22 ± 4.22 years, 18.91 ± 7.33 years for patients with Sanfilippo syndrome type B and 23.43 ± 9.47 years in Sanfilippo syndrome type C. Patients with Sanfilippo syndrome type A showed significant increase in longevity over the period of observation (p = 0.012). Survival rates of patients with Sanfilippo syndrome type B did not show a statistically significant improvement (p = 0.134). In Sanfilippo syndrome types A and B, pneumonia was identified as the leading cause of death. Conclusions The analysis of 113 death certificates of patients with Sanfilippo syndrome in the UK has demonstrated that the longevity has improved significantly in patients with Sanfilippo syndrome type A over a last few decades. The numbers of patients with Sanfilippo syndrome types B and C were too small to identify any significant trend changes for these groups. Respiratory tract infections, notably pneumonia, remain the leading cause of mortality in Sanfilippo syndrome types A and B. The extended lifespans of patients with Sanfilippo syndrome type A were achieved despite the lack of therapies to target the primary insult or pathophysiology of the disease. However, the mean age at death of these patients remains low when compared with the general population. Therefore, there is an urgent need for effective disease-specific therapies to be developed so that the quality of life and survival of patients with Sanfilippo syndrome can be improved.

Abstract Background Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease due to deficiency of α-L-iduronidase (IDUA), a lysosomal enzyme that degrades glycosaminoglycans (GAG) heparan and dermatan sulfate. To achieve optimal clinical outcomes, early and proper treatment is essential, which requires early diagnosis and phenotype severity prediction. Results To establish a genotype/phenotype correlation of MPS I disease, a combination of bioinformatics tools including SIFT, PolyPhen, I-Mutant, PROVEAN, PANTHER, SNPs&GO and PHD-SNP are utilized. Through analyzing single nucleotide polymorphisms (SNPs) by these in silico approaches, 28 out of 285 missense SNPs were predicted to be damaging. By integrating outcomes from these in silico approaches, a prediction algorithm (sensitivity 94%, specificity 80%) was thereby developed. Three dimensional structural analysis of 5 candidate SNPs (P533R, P496R, L346R, D349G, T374P) were performed by SWISS PDB viewer, which revealed specific structural changes responsible for the functional impacts of these SNPs. Additionally, SNPs in the untranslated region were analyzed by UTRscan and PolymiRTS. Moreover, by investigating known pathogenic mutations and relevant patient phenotypes in previous publications, phenotype severity (severe, intermediate or mild) of each mutation was deduced. Conclusions Collectively, these results identified potential candidate SNPs with functional significance for studying MPS I disease. This study also demonstrates the effectiveness, reliability and simplicity of these in silico approaches in addressing complexity of underlying genetic basis of MPS I disease. Further, a step-by-step guideline for phenotype prediction of MPS I disease is established, which can be broadly applied in other lysosomal diseases or genetic disorders.

Aim: Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders caused by the deficiency of spesific lysosomal enzymes required to break down glycosaminoglycans. MPSs should be suspected in a child with coarse facial features, organomegaly, and bone disease (dysostosis multiplex), with central nervous system abnormalities. Early diagnosis and treatment can improve outcomes in MPS. The aim of this study was to evaluate the demographic characteristics and clinical findings of our MPS patients. Materials and Methods: This is a retrospective study which included 27 MPS patients who were diagnosed and treated in our center. Results: The mean age of the group was 112.3±52.5 months (36-196 months); the mean onset age of symptoms was 40.8±30.6 months (4-112 months), and the mean time from symptom onset to diagnosis was 16.3±21.4 months (0-80 months). MPS subgroups were Type III in 13 (48%) patients, Type II in seven (26%), Type VI in four (15%), Type I in two (7%) patients and Type IV in one patient. Nine (33.3%) patients received enzyme replacement therapy (ERT). The mean duration of ERT was 31.3±21.5 months (9-67 months). Conclusion: MPS Type III was found to be the most common subgroup in our center. We can speculate that the mean time from symptom onset to diagnosis was found too long for MPS in which early diagnosis improves the prognosis. Increasing awareness of the disease in physicians encountering these patients in different clinics will be an important factor in the early diagnosis of the disease.

Mucopolysaccharidosis VII (MPS VII) is a recessively inherited lysosomal storage disorder caused by β-glucuronidase enzyme deficiency. The disease is characterized by widespread accumulation of non-degraded or partially degraded glycosaminoglycans, leading to cellular and multiple tissue dysfunctions. The patients exhibit diverse clinical symptoms, and eventually succumb to premature death. The only possible remedy is the recently approved enzyme replacement therapy, which is an expensive, invasive and lifelong treatment procedure. Small-molecule therapeutics for MPS VII have so far remained elusive primarily due to lack of molecular insights into the disease pathogenesis and unavailability of a suitable animal model that can be used for rapid drug screening. To address these issues, we developed a Drosophila model of MPS VII by knocking out the CG2135 gene, the fly β-glucuronidase orthologue. The CG2135−/− fly recapitulated cardinal features of MPS VII, such as reduced lifespan, progressive motor impairment and neuropathological abnormalities. Loss of dopaminergic neurons and muscle degeneration due to extensive apoptosis was implicated as the basis of locomotor deficit in this fly. Such hitherto unknown mechanistic links have considerably advanced our understanding of the MPS VII pathophysiology and warrant leveraging this genetically tractable model for deeper enquiry about the disease progression. We were also prompted to test whether phenotypic abnormalities in the CG2135−/− fly can be attenuated by resveratrol, a natural polyphenol with potential health benefits. Indeed, resveratrol treatment significantly ameliorated neuromuscular pathology and restored normal motor function in the CG2135−/− fly. This intriguing finding merits further preclinical studies for developing an alternative therapy for MPS VII. This article has an associated First Person interview with the first author of the paper.