Publications by authors named "Maurizio Scarpa"

98 Publications

A generic emergency protocol for patients with inborn errors of metabolism causing fasting intolerance: a retrospective, single-center study and the generation of www.emergencyprotocol.net.

J Inherit Metab Dis 2021 Apr 12. Epub 2021 Apr 12.

Section of Metabolic Diseases, Beatrix Children's Hospital, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.

Introduction: Patients with inborn errors of metabolism causing fasting intolerance can experience acute metabolic decompensations. Long-term data on outcomes using emergency letters are lacking.

Methods: This is a retrospective, observational, single-center study of the use of emergency letters based on a generic emergency protocol in patients with hepatic glycogen storage diseases (GSD) or fatty acid oxidation disorders (FAOD). Data on hospital admissions, initial laboratory results and serious adverse events were collected. Subsequently, the website www.emergencyprotocol.net was generated in the context of the CONNECT MetabERN eHealth project following multiple meetings, protocol revisions and translations.

Results: Representing 470 emergency protocol years, 127 hospital admissions were documented in 54/128(42%) patients who made use of emergency letters generated based on the generic emergency protocol. Hypoglycemia (here defined as glucose concentration <3.9 mmol/l) was reported in only 15% of hospital admissions and was uncommon in patients with ketotic GSD and patients with FAOD aged > 5 years. Convulsions, coma or death were not documented. By providing basic information, emergency letters for individual patients with hepatic GSD or the main FAOD can be generated at www.emergencyprotocol.net, in 9 different languages.

Discussion: Generic emergency protocols are safe and easy for home management by the caregivers and the first hour in-hospital management to prevent metabolic emergencies in patients with hepatic GSD and medium-chain Acyl CoA dehydrogenase deficiency. The website www.emergencyprotocol.net is designed to support families and healthcare providers to generate personalized emergency letters for patients with hepatic GSD and the main FAOD. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jimd.12386DOI Listing
April 2021

Challenges in Transition From Childhood to Adulthood Care in Rare Metabolic Diseases: Results From the First Multi-Center European Survey.

Front Med (Lausanne) 2021 25;8:652358. Epub 2021 Feb 25.

MetabERN, Regional Coordinating Center for Rare Diseases, Udine University Hospital, Udine, Italy.

Inherited Metabolic Diseases (IMDs) are rare diseases caused by genetic defects in biochemical pathways. Earlier diagnosis and advances in treatment have improved the life expectancy of IMD patients over the last decades, with the majority of patients now surviving beyond the age of 20. This has created a new challenge: as they grow up, the care of IMD patients' needs to be transferred from metabolic pediatricians to metabolic physicians specialized in treating adults, through a process called "transition." The purpose of this study was to assess how this transition is managed in Europe: a survey was sent to all 77 centers of the European Reference Network for Hereditary Metabolic Disorders (MetabERN) to collect information and to identify unmet needs regarding the transition process. Data was collected from 63/77 (81%) healthcare providers (HCPs) from 20 EU countries. Responders were mostly metabolic pediatricians; of these, only ~40% have received appropriate training in health issues of adolescent metabolic patients. In most centers (~67%) there is no designated transition coordinator. About 50% of centers provide a written individualized transition protocol, which is standardized in just ~20% of cases. In 77% of centers, pediatricians share a medical summary, transition letter and emergency plan with the adult team and the patient. According to our responders, 11% of patients remain under pediatric care throughout their life. The main challenges identified by HCPs in managing transition are lack of time and shortage of adult metabolic physician positions, while the implementations that are most required for a successful transition include: medical staff dedicated to transition, a transition coordinator, and specific metabolic training for adult physicians. Our study shows that the transition process of IMD patients in Europe is far from standardized and in most cases is inadequate or non-existent. A transition coordinator to facilitate collaboration between the pediatric and adult healthcare teams should be central to any transition program. Standardized operating procedures, together with adequate financial resources and specific training for adult physicians focused on IMDs are the key aspects that must be improved in the rare metabolic field to establish successful transition processes in Europe.
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http://dx.doi.org/10.3389/fmed.2021.652358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962750PMC
February 2021

European Reference Networks: challenges and opportunities.

J Community Genet 2021 Mar 17. Epub 2021 Mar 17.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

European Reference Networks (ERNs) were founded on the principle that many rare disease (RD) issues are pan-European and any single Member State cannot solve them alone. In 2021, ERNs are already in the deployment stage; however, their day-to-day functioning and realization of their potential are still severely hampered by many challenges, including issues in governance and regulation, lack of legal status, insufficient and unsustainable funding, lack of ERN integration into national systems, endangered collaboration with UK RD experts due to Brexit, insufficient exploitation of ERN potential in RD research, underappreciation of highly qualified human resources, problems with the involvement of patient representatives, and still unclear place of ERNs in the overall European RD and digital ecosystem. Bold and innovative solutions that must be taken to solve these challenges inevitably involve pan-European collaboration across several sectors and among multistakeholder RD communities and in many cases crucially rely on the constructive dialogue and coherent, united decisions of national and European authorities that are based on common EU values. Importantly, unresolved challenges may have a strong impact on the further sustainability of ERNs and their ability to realize full potential in addressing huge unmet needs of RD patients and their families.
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http://dx.doi.org/10.1007/s12687-021-00521-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968406PMC
March 2021

U-IMD: the first Unified European registry for inherited metabolic diseases.

Orphanet J Rare Dis 2021 Feb 18;16(1):95. Epub 2021 Feb 18.

Division of Neuropediatrics and Metabolic Medicine, Department of General Pediatrics, Centre for Child and Adolescent Medicine, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.

Background: Following the broad application of new analytical methods, more and more pathophysiological processes in previously unknown diseases have been elucidated. The spectrum of clinical presentation of rare inherited metabolic diseases (IMDs) is broad and ranges from single organ involvement to multisystemic diseases. With the aim of overcoming the limited knowledge about the natural course, current diagnostic and therapeutic approaches, the project has established the first unified patient registry for IMDs that fully meets the requirements of the European Infrastructure for Rare Diseases (ERDRI).

Results: In collaboration with the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN), the Unified European registry for Inherited Metabolic Diseases (U-IMD) was established to collect patient data as an observational, non-interventional natural history study. Following the recommendations of the ERDRI the U-IMD registry uses common data elements to define the IMDs, report the clinical phenotype, describe the biochemical markers and to capture the drug treatment. Until today, more than 1100 IMD patients have been registered.

Conclusion: The U-IMD registry is the first observational, non-interventional patient registry that encompasses all known IMDs. Full semantic interoperability for other registries has been achieved, as demonstrated by the use of a minimum common core data set for equivalent description of metabolic patients in U-IMD and in the patient registry of the European Rare Kidney Disease Reference Network (ERKNet). In conclusion, the U-IMD registry will contribute to a better understanding of the long-term course of IMDs and improved patients care by understanding the natural disease course and by enabling an optimization of diagnostic and therapeutic strategies.
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http://dx.doi.org/10.1186/s13023-021-01726-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893973PMC
February 2021

Parkinson's disease in Gaucher disease patients: what's changing in the counseling and management of patients and their relatives?

Orphanet J Rare Dis 2020 09 23;15(1):262. Epub 2020 Sep 23.

Professor Emeritus "Federico II" University Hospital, Naples, Italy.

Background: How to address the counseling of lifetime risk of developing Parkinson's disease in patients with Gaucher disease and their family members carrying a single variant of the GBA1 gene is not yet clearly defined. In addition, there is no set way of managing Gaucher disease patients, taking into account the possibility that they may show features of Parkinson's disease.

Methods: Starting from an overview on what has recently changed in our knowledge on this issue and grouping the experiences of healthcare providers of Gaucher disease patients, we outline a path of counseling and management of Parkinson's disease risk in Gaucher disease patients and their relatives.

Conclusion: The approach proposed here will help healthcare providers to communicate Parkinson's disease risk to their patients and will reduce the possibility of patients receiving inaccurate information from inadequate sources. Furthermore, this resource will help to empower healthcare providers to identify early signs and/or symptoms of Parkinson's disease and decide when to refer these patients to the neurologist for appropriate specific therapy and follow-up.
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http://dx.doi.org/10.1186/s13023-020-01529-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510137PMC
September 2020

Impact of COVID-19 related healthcare crisis on treatments for patients with lysosomal storage disorders, the first Italian experience.

Mol Genet Metab 2020 07 29;130(3):170-171. Epub 2020 Apr 29.

Regional Coordinating Center for Rare Diseases, University Hospital of Udine, Udine, Italy.

The direct and indirect effects of Coronavirus Disease-19 (COVID-19) pandemic, on Italian patients with lysosomal storage disorders receiving therapy, were analyzed by a phone questionnaire. No proved COVID-19 emerged among 102 interviewed. No problems were reported by patients receiving oral treatments. Forty-nine% of patients receiving enzyme replacement therapy in hospitals experienced disruptions, versus 6% of those home-treated. The main reasons of missed infusions were fear of infection (62.9%) and re-organization of the infusion centers (37%).
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http://dx.doi.org/10.1016/j.ymgme.2020.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189198PMC
July 2020

Fabry cardiomyopathy: Gb3-induced auto-reactive panmyocarditis requiring heart transplantation.

ESC Heart Fail 2020 06 29;7(3):1331-1337. Epub 2020 Apr 29.

Cardiothoracic Surgery, Udine University Hospital, Rome, Italy.

Resistance to enzyme replacement therapy (ERT) is a major therapeutic challenge in Fabry disease (FD). Recent reports attribute to immune-mediated inflammation a main role in promoting disease progression and resistance to ERT. Aim of the study is to report a Gb3-induced auto-reactive panmyocarditis causing inefficacy of ERT and severe electrical instability, which required cardiac transplantation. Examining the explanted heart from a 57-year-old man with FD cardiomyopathy (CM) on 3-year ERT presenting incoming ventricular fibrillation, we documented a severe virus-negative myocarditis extended to cardiomyocytes, intramural coronary vessels, conduction tissue, and subepicardial ganglia. Serology was positive for anti-Gb3, anti-heart, and anti-myosin antibodies. In vitro Gb3 stimulation of patient's peripheral blood mononuclear cells (PBMC) induced high amount production of inflammatory cytokine IL1-β, IL-6, IL-8, and TNF-α. PBMC were stained using the monoclonal antibodies CD3-V500, CD4-V450, CD8-APCcy7, CD45RO-PerCPcy5.5 and CD27-FITC from BD Biosciences and CD56-PC7 from Bekman Coulter. The phenotypic analysis of PBMC showed a lower frequency of CD8 (9.2%) vs. 19.3% and NKT cells (1.6% vs. 2.4%) in Fabry patient respect to healthy donor, suggesting a possible homing to peripheral tissues. A Gb3-induced auto-reactive myocarditis is suggested as a possible cause of FDCM progression and ERT resistance. Immune-mediated inflammation of systemic Fabry cells may coexist and be controlled by implemental immunosuppressive therapy.
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http://dx.doi.org/10.1002/ehf2.12723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261584PMC
June 2020

Assessing the impact of the five senses on quality of life in mucopolysaccharidoses.

Orphanet J Rare Dis 2020 04 19;15(1):97. Epub 2020 Apr 19.

Regional Center for Rare Diseases, University Hospital of Udine, Udine, Italy.

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. 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.
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http://dx.doi.org/10.1186/s13023-020-01368-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168888PMC
April 2020

Molecular Genetics of Niemann-Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18 Novel Variants.

J Clin Med 2020 Mar 3;9(3). Epub 2020 Mar 3.

Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, 33100 Udine, Italy.

Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disorder caused by mutations in or genes. In 2009, the molecular characterization of 44 NPC Italian patients has been published. Here, we present an update of the genetic findings in 105 Italian NPC patients belonging to 83 unrelated families (77 NPC1 and 6 NPC2). and genes were studied following an algorithm recently published. Eighty-four different and five alleles were identified. Only two alleles remained non detected. Sixty-two percent of alleles were due to missense variants. The most frequent mutation was the p.F284Lfs*26 (5.8% of the alleles). All mutations were found in the homozygous state, and all but one was severe. Among newly diagnosed patients, 18 novel mutations were identified. The pathogenic nature of 7/9 missense alleles and 3/4 intronic variants was confirmed by filipin staining and NPC1 protein analysis or mRNA expression in patient's fibroblasts. Taken together, our previous published data and new results provide an overall picture of the molecular characteristics of NPC patients diagnosed so far in Italy.
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http://dx.doi.org/10.3390/jcm9030679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141276PMC
March 2020

Availability, accessibility and delivery to patients of the 28 orphan medicines approved by the European Medicine Agency for hereditary metabolic diseases in the MetabERN network.

Orphanet J Rare Dis 2020 01 6;15(1). Epub 2020 Jan 6.

MetabERN, Regional Coordinating Center for Rare Diseases, Udine University Hospital, Piazzale Santa Maria della Misericordia, 15, 33100, Udine, Italy.

Background: The European Medicine Agency granted marketing approval to 164 orphan medicinal products for rare diseases, among which 28 products intended for the treatment of hereditary metabolic diseases. Taking advantage of its privileged connection with 69 healthcare centres of excellence in this field, MetabERN, the European Reference Network for hereditary metabolic diseases, performed a survey asking health care providers from 18 European countries whether these products are available on the market, reimbursed and therefore accessible for prescription, and actually delivered in their centre.

Results: Responses received from 52 centres (75%) concerned the design of treatment plans, the access to marketed products, and the barriers to delivery. Treatment options are always discussed with patients, who are often involved in their treatment plan. Most products (26/28) are available in most countries (15/18). Among the 15 broadly accessible products (88.5% of the centres), 9 are delivered to most patients (mean 70.1%), and the others to only few (16.5%). Among the 10 less accessible products (40.2% of the centres), 6 are delivered to many patients (66.7%), and 4 are rarely used (6.3%). Information was missing for 3 products. Delay between prescription and delivery is on average one month. Beside the lack of availability or accessibility, the most frequent reasons for not prescribing a treatment are patients' clinical status, characteristic, and personal choice.

Conclusions: Data collected from health care providers in the MetabERN network indicate that two-third of the orphan medicines approved by EMA for the treatment of hereditary metabolic diseases are accessible to treating patients, although often less than one-half of the patients with the relevant conditions actually received the approved product to treat their disease. Thus, in spite of the remarkable achievement of many products, patients concerned by EMA-approved orphan medicinal products have persistent unmet needs, which deserve consideration. The enormous investments made by the companies to develop products, and the high financial burden for the Member States to purchase these products emphasize the importance of a scrupulous appreciation of treatment value involving all stakeholders at early stage of development, before marketing authorization, and during follow up.
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http://dx.doi.org/10.1186/s13023-019-1280-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945588PMC
January 2020

The Authors' Reply: The tRNA(Ile) Variant m.4309G>A May Not Cause Kearns-Sayre Syndrome.

Transplantation 2019 12;103(12):e396

Cadiothoracic Department, University Hospital of Udine, Udine, Italy.

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http://dx.doi.org/10.1097/TP.0000000000002953DOI Listing
December 2019

Seronegative Arthritis and Whipple Disease: Risk of Misdiagnosis in the Era of Biologic Agents.

Case Rep Rheumatol 2019 13;2019:3410468. Epub 2019 Oct 13.

Rheumatology Clinic, Department of Medical Area, Academic Hospital Santa Maria della Misericordia, University of Udine, Udine, Italy.

We report 2 cases of Whipple disease (WD), previously diagnosed as seronegative polyarthritis and treated for several years with immunosuppressive agents, accordingly. Both cases had been treated over years with cDMARDs and bDMARDs. The first patient was a 48-year-old male, who developed a life-threatening disease characterized by fever, significant weight loss, and bloody diarrhoea, supported with RBC transfusions. The second patient was a 55-year-old man, presenting with arthritis, fever, serositis, lymphadenopathy, thoracic rash, and systemic inflammation; at the beginning he was diagnosed as adult onset Still's disease. He was treated with steroids and antitumour necrosis factor agents, but showed no improvement. Both patients were eventually treated with antimicrobial therapy for WD with dramatic improvement and no clinical relapse in 6 months. This paper reviews the literature on WD mimicking chronic inflammatory arthritis. WD may lead to chronic seronegative arthritis that might often be misrecognized. Importantly, patients treated with bDMARDs and glucocorticoids might develop a life-threatening disease. Therefore, WD should be suspected and excluded in patients showing resistance or frequent recurrence of chronic arthritis, if seronegative, under treatment with bDMARDs, especially in the presence of new, unexpected sign and/or symptoms.
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http://dx.doi.org/10.1155/2019/3410468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815603PMC
October 2019

Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance.

Orphanet J Rare Dis 2019 06 13;14(1):137. Epub 2019 Jun 13.

Center for Rare Diseases at Host Schmidt Kliniken, Wiesbaden, Germany and Department of Paediatrics University of Padova, Padova, Italy.

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.
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http://dx.doi.org/10.1186/s13023-019-1074-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567385PMC
June 2019

Recommendations for the management of MPS VI: systematic evidence- and consensus-based guidance.

Orphanet J Rare Dis 2019 05 29;14(1):118. Epub 2019 May 29.

Center for Rare Diseases at Host Schmidt Kliniken, Wiesbaden, Germany and Department of Paediatrics, University of Padova, Padova, Italy.

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.
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http://dx.doi.org/10.1186/s13023-019-1080-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541999PMC
May 2019

Research activity and capability in the European reference network MetabERN.

Orphanet J Rare Dis 2019 05 29;14(1):119. Epub 2019 May 29.

Maurizio Scarpa, MetabERN, Udine, Italy.

Background: MetabERN is one of the 24 European Reference Networks created according to the European Union directive 2011/24/EU on patient's rights in cross border healthcare. MetabERN associates 69 centres in 18 countries, which provide care for patients with Hereditary Metabolic Diseases, and have the mission to reinforce research and provide training for health professionals in this field. MetabERN performed a survey in December 2017 with the aim to produce an overview documenting research activities and potentials within the network. As the centres are multidisciplinary, separated questionnaires were sent to the clinical, university and laboratory teams. Answers were received from 52 out of the 69 centres of the network, covering 16 countries. A descriptive analysis of the information collected is presented.

Results: The answers indicate a marked interest of the respondents for research, who expressed high motivation and commitment, and estimated that the conditions to do research in their institution were mostly satisfactory. They are active in research, which according to several indicators, is competitive and satisfies standards of excellence, as well as the education programs offered in the respondent's universities. Research in the centres is primarily performed in genetics, pathophysiology, and epidemiology, and focuses on issues related to diagnosis. Few respondents declared having activity in human and social sciences, including research on patient's quality of life, patient's awareness, or methods for social support. Infrastructures offering services for medical research were rarely known and used by respondents, including national and international biobanking platforms. In contrast, respondents often participate to patient registries, even beyond their specific field of interest.

Conclusions: Taken as a whole, these results provide an encouraging picture of the research capacities and activities in the MetabERN network, which, with respect to the number and representativeness of the investigated centres, gives a comprehensive picture of research on Hereditary Metabolic Diseases in Europe, as well as the priorities for future actions. Marginal activity in human and social sciences points out the limited multidisciplinary constitution of the responding teams with possible consequences on their current capability to participate to patient's empowerment programs and efficiently collaborate with patient's advocacy groups.
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http://dx.doi.org/10.1186/s13023-019-1091-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542047PMC
May 2019

Targeting Brain Disease in MPSII: Preclinical Evaluation of IDS-Loaded PLGA Nanoparticles.

Int J Mol Sci 2019 Apr 24;20(8). Epub 2019 Apr 24.

Department of Women's and Children's Health, University of Padova, 35128 Padova, Italy.

Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the enzyme iduronate 2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans in most organ-systems, including the brain, and resulting in neurological involvement in about two-thirds of the patients. The main treatment is represented by a weekly infusion of the functional enzyme, which cannot cross the blood-brain barrier and reach the central nervous system. In this study, a tailored nanomedicine approach based on brain-targeted polymeric nanoparticles (g7-NPs), loaded with the therapeutic enzyme, was exploited. Fibroblasts from MPSII patients were treated for 7 days with NPs loaded with the IDS enzyme; an induced IDS activity like the one detected in healthy cells was measured, together with a reduction of GAG content to non-pathological levels. An in vivo short-term study in MPSII mice was performed by weekly administration of g7-NPs-IDS. Biochemical, histological, and immunohistochemical evaluations of liver and brain were performed. The 6-weeks treatment produced a significant reduction of GAG deposits in liver and brain tissues, as well as a reduction of some neurological and inflammatory markers (i.e., LAMP2, CD68, GFAP), highlighting a general improvement of the brain pathology. The g7-NPs-IDS approach allowed a brain-targeted enzyme replacement therapy. Based on these positive results, the future aim will be to optimize NP formulation further to gain a higher efficacy of the proposed approach.
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http://dx.doi.org/10.3390/ijms20082014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514713PMC
April 2019

Molecular diagnosis of patients affected by mucopolysaccharidosis: a multicenter study.

Eur J Pediatr 2019 May 26;178(5):739-753. Epub 2019 Feb 26.

Laboratorio di Diagnosi e Terapia delle Malattie Lisosomiali, Department of Women's and Children's Health, University of Padova, Padova, Italy.

Mucopolysaccharidoses (MPS) are a subgroup of 11 monogenic lysosomal storage disorders due to the deficit of activity of the lysosomal hydrolases deputed to the degradation of mucopolysaccharides. Although individually rare, all together they account for at least 1:25,000 live births. In this study, we present the genetic analysis of a population of 71 MPS patients enrolled in a multicenter Italian study. We re-annotated all variants, according to the latest recommendations, and re-classified them as suggested by the American College of Medical Genetics and Genomics. Variant distribution per type was mainly represented by missense mutations. Overall, 10 patients had received no molecular diagnosis, although 6 of them had undergone either HSCT or ERT, based on clinical and enzymatic evaluations. Moreover, nine novel variants are reported.Conclusions: Our analysis underlines the need to complete the molecular diagnosis in patients previously diagnosed only on a biochemical basis, suggests a periodical re-annotation of the variants and solicits their deposition in public databases freely available to clinicians and researchers. We strongly recommend a molecular diagnosis based on the analysis of the "trio" instead of the sole proband. These recommendations will help to obtain a complete and correct diagnosis of mucopolysaccharidosis, rendering also possible genetic counseling. What is known • MPS are a group of 11 metabolic genetic disorders due to deficits of enzymes involved in the mucopolysaccharides degradation. • Molecular analysis is commonly performed to confirm enzymatic assays. What is new • Eighty-six percent of the 71 patients we collected received a molecular diagnosis; among them, 9 novel variants were reported. • We stress the importance of molecular diagnosis in biochemically diagnosed patients, encourage a periodical re-annotation of variants according to the recent nomenclature and their publication in open databases.
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http://dx.doi.org/10.1007/s00431-019-03341-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459791PMC
May 2019

Possible strategies to cross the blood-brain barrier.

Ital J Pediatr 2018 Nov 16;44(Suppl 2):131. Epub 2018 Nov 16.

Brains For Brain Foundation, Padova, Italy.

The mucopolysaccharidoses (MPS) are a heterogeneous group of in-born metabolic conditions caused by genetic defects that result in the absence or severe deficiency of one of the lysosomal hydrolases responsible for the degradation of glycosaminoglycans (GAGs). Such enzyme deficiency causes accumulation of GAGs that begins in infancy and progressively worsens, often affecting several organs including the central nervous system (CNS) inducing mental retardation, progressive neurodegeneration, and premature death. Over the last years, enormous progress has been made in the treatment of many MPS types, and available treatments are efficacious for many of them. Nevertheless, treatment of MPS with CNS involvement is limited mostly because of delivery impediments related to the presence of the blood-brain barrier (BBB). This chapter presents an overview of the BBB and of the different strategies that have been developed to overcome the problem of drug transport at the BBB, assuring efficient delivery of therapeutic agents to the brain.
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http://dx.doi.org/10.1186/s13052-018-0563-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238258PMC
November 2018

International working group identifies need for newborn screening for mucopolysaccharidosis type I but states that existing hurdles must be overcome.

Acta Paediatr 2018 12 23;107(12):2059-2065. Epub 2018 Oct 23.

Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General Faculty Hospital, Prague, Czech Republic.

Aim: Mucopolysaccharidosis type I is a lysosomal storage disorder that can result in significant disease burden, disability and premature death, if left untreated. The aim of this review was to elaborate on the diagnosis of mucopolysaccharidosis type I and the pros and cons of newborn screening.

Methods: An international working group was established to discuss ways to improve the early diagnosis of mucopolysaccharidosis type I. It consisted of 13 experts in paediatrics, rare diseases and inherited metabolic diseases from Europe and the Middle East.

Results: It is becoming increasingly clearer that the delay between symptom onset and clinical diagnosis is considerable for mucopolysaccharidosis type I and other rare lysosomal storage disorders, despite numerous awareness campaigns since therapies became available. Diagnosis currently depends on recognising the signs and symptoms of the disease. The practice of newborn screening, which is being explored by pilot programmes around the world, enables early diagnosis and consequently early treatment. However, these studies have highlighted numerous new problems and pitfalls that must be faced before newborn screening becomes generally available.

Conclusion: Newborn screening for mucopolysaccharidosis type I offers the potential for early diagnosis and early pre-symptomatic treatment, but existing hurdles need to be overcome.
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http://dx.doi.org/10.1111/apa.14587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282980PMC
December 2018

Easy-to-use algorithm would provide faster diagnoses for mucopolysaccharidosis type I and enable patients to receive earlier treatment.

Acta Paediatr 2018 08;107(8):1402-1408

Center for Rare Diseases, Clinic for Paediatric and Adolescent Medicine, HELIOS Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.

Aim: The aim of this study was to develop an algorithm to prompt early clinical suspicion of mucopolysaccharidosis type I (MPS I).

Methods: An international working group was established in 2016 that comprised 11 experts in paediatrics, rare diseases and inherited metabolic diseases. They reviewed real-world clinical cases, selected key signs or symptoms based on their prevalence and specificity and reached consensus about the algorithm. The algorithm was retrospectively tested.

Results: An algorithm was developed. In patients under two years of age, kyphosis or gibbus deformity were the key symptoms that raised clinical suspicion of MPS I and in those over two years they were kyphosis or gibbus deformity, or joint stiffness or contractures without inflammation. The algorithm was tested on 35 cases, comprising 16 Hurler, 10 Hurler-Scheie, and nine Scheie patients. Of these 35 cases, 32 (91%) - 16 Hurler, nine Hurler-Scheie and seven Scheie patients - would have been referred earlier if the algorithm had been used.

Conclusion: The expert panel developed and tested an algorithm that helps raise clinical suspicion of MPS I and would lead to a more prompt final diagnosis and allow earlier treatment.
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http://dx.doi.org/10.1111/apa.14417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055821PMC
August 2018

Inborn Errors of Metabolism Involving Complex Molecules: Lysosomal and Peroxisomal Storage Diseases.

Pediatr Clin North Am 2018 04;65(2):353-373

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Peroxisomes and lysosomes are distinct subcellular compartments that underlie several pediatric metabolic disorders. Knowledge of their function and cell biology leads to understanding how the disorders result from genetic defects. Diagnostic and therapeutic approaches for the disorders take advantage of the cell biology mechanisms. Whereas peroxisomal disorders are characterized by enzymatic defects in peroxisomal pathways leading to metabolic and lipid changes, lysosomal storage disorders are marked by accumulation of substrates of lysosomal pathways inside the lysosome. The human diseases related to these two organelles are reviewed, focusing on general disease patterns and underlying diagnosis and treatment principles.
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http://dx.doi.org/10.1016/j.pcl.2017.11.011DOI Listing
April 2018

Epilepsy in mucopolysaccharidosis disorders.

Mol Genet Metab 2017 12 16;122S:55-61. Epub 2017 Oct 16.

Department of Child Neurology, Hospital Universitario Austral, Buenos Aires, Argentina.

The mucopolysaccharidosis (MPS) disorders are caused by deficiencies of specific lysosomal enzymes involved in the catabolism of glycosaminoglycans (GAGs). The resulting GAG accumulation in cells and tissues throughout the body leads to progressive multi-organ dysfunction. MPS patients present with several somatic manifestations, including short stature, musculoskeletal abnormalities, and cardiorespiratory dysfunction, and several primary and secondary neurological signs and symptoms. Epileptic seizures are neurological signs of MPS thought to develop due to accumulation of GAGs in the brain, triggering alterations in neuronal connectivity and signaling, and release of inflammatory mediators. The amount of literature on the prevalence, pathophysiology, clinical features, and management of epileptic seizures in patients with MPS is limited. This review discusses current knowledge on this topic, as well as two case examples, presented and discussed during a closed meeting on MPS and the brain among an international group of experts with extensive experience in managing and treating MPS.
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http://dx.doi.org/10.1016/j.ymgme.2017.10.006DOI Listing
December 2017

Treatment of brain disease in the mucopolysaccharidoses.

Mol Genet Metab 2017 12 16;122S:25-34. Epub 2017 Oct 16.

Department of Genetics, UFRGS & Medical Genetics Service, HCPA, INAGEMP, Porto Alegre, RS, Brazil.

The mucopolysaccharidosis (MPS) disorders are a group of lysosomal storage diseases caused by lysosomal enzyme deficits that lead to glycosaminoglycan accumulation, affecting various tissues throughout the body based on the specific enzyme deficiency. These disorders are characterized by their progressive nature and a variety of somatic manifestations and neurological symptoms. There are established treatments for some MPS disorders, but these mostly alleviate somatic and non-neurological symptoms and do not cure the disease. Patients with MPS I, II, III, and VII can present with neurological manifestations such as neurocognitive decline and behavioral problems. Treatment of these neurological manifestations remains challenging due to the blood-brain barrier (BBB) that limits delivery of therapeutic agents to the central nervous system (CNS). New therapies that circumvent this barrier and target brain disease in MPS are currently under development. They primarily focus on facilitating penetration of drugs through the BBB, delivery of recombinant enzyme to the brain by gene therapy, or direct CNS administration. This review summarizes existing and potential future treatment approaches that target brain disease in MPS. The information in this review is based on current literature and presentations and discussions during a closed meeting by an international group of experts with extensive experience in managing and treating MPS.
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http://dx.doi.org/10.1016/j.ymgme.2017.10.007DOI Listing
December 2017

Clinical outcomes in idursulfase-treated patients with mucopolysaccharidosis type II: 3-year data from the hunter outcome survey (HOS).

Orphanet J Rare Dis 2017 10 3;12(1):161. Epub 2017 Oct 3.

Department of Pediatrics, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.

Background: Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare, X-linked disorder caused by deficient activity of the enzyme iduronate-2-sulfatase (I2S). Treatment is available in the form of enzyme replacement therapy (ERT) with recombinant I2S. Clinical outcomes following ≥3 years of ERT with idursulfase were investigated in a broad population of patients with MPS II enrolled in the Hunter Outcome Survey (HOS).

Methods: As of January 2016, 639 patients (excluding female patients, individuals who had received a bone marrow transplant and those enrolled in the phase 1/2 [TKT018] or phase 2/3 [TKT024] clinical trial) followed prospectively in the registry had received idursulfase for ≥6 months. These individuals all had data available for ≥1 clinical parameter at baseline and ≥1 additional time point following treatment initiation. Changes in clinical parameters were assessed in the subcohorts of patients with a measurement at baseline and at year 1, 2 or 3 of treatment. Safety data from patients who started treatment at or after enrollment in HOS (n = 233) were also assessed.

Results: Median (10th, 90th percentiles) age at first treatment was 6.2 (2.1, 18.2) years and median treatment duration was 56.3 (18.2, 97.6) months. Urinary glycosaminoglycan (uGAG) levels decreased from baseline to year 3 in patients with data available at this time point (median change from baseline: -201.0 [-591.4, -21.9] μg/mg creatinine [n = 121]). Improvements in the following parameters were observed at year 3 in the subcohorts: 6-min walking test (6MWT) distance, 10.6 (-33.6, 50.8)% (n = 26); left ventricular mass index (LVMI), -9.3 (-31.5, 19.7)% (n = 52); absolute forced vital capacity (FVC), 29.7 (-13.4, 66.7)% (n = 23); absolute forced expiratory volume in 1 s (FEV), 22.8 (-15.2, 62.1)% (n = 22); palpable liver size, -54.5 (-85.7, 50.0)% (n = 53); palpable spleen size, -33.3 (-80.0, 33.3)% (n = 17). No new or unexpected safety concerns were identified in this analysis.

Conclusions: These findings suggest that idursulfase has a positive effect on uGAG levels, 6MWT results, LVMI, FVC, FEV and hepatosplenomegaly after 1, 2 and 3 years treatment.
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http://dx.doi.org/10.1186/s13023-017-0712-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627440PMC
October 2017

Open issues in Mucopolysaccharidosis type I-Hurler.

Orphanet J Rare Dis 2017 06 15;12(1):112. Epub 2017 Jun 15.

Department for the Woman and Child Health, University of Padova, Padova, Italy.

Mucopolysaccharidosis I-Hurler (MPS I-H) is the most severe form of a metabolic genetic disease caused by mutations of IDUA gene encoding the lysosomal α-L-iduronidase enzyme. MPS I-H is a rare, life-threatening disease, evolving in multisystem morbidity including progressive neurological disease, upper airway obstruction, skeletal deformity and cardiomyopathy. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the gold standard for the treatment of MPS I-H in patients diagnosed and treated before 2-2.5 years of age, having a high rate of success. Beyond the child's age, other factors influence the probability of treatment success, including the selection of patients, of graft source and the donor type employed. Enzyme replacement therapy (ERT) with human recombinant laronidase has also been demonstrated to be effective in ameliorating the clinical conditions of pre-transplant MPS I-H patients and in improving HSCT outcome, by peri-transplant co-administration. Nevertheless the long-term clinical outcome even after successful HSCT varies considerably, with a persisting residual disease burden. Other strategies must then be considered to improve the outcome of these patients: one is to pursue early pre-symptomatic diagnosis through newborn screening and another one is the identification of novel treatments. In this perspective, even though newborn screening can be envisaged as a future attractive perspective, presently the best path to be pursued embraces an improved awareness of signs and symptoms of the disorder by primary care providers and pediatricians, in order for the patients' timely referral to a qualified reference center. Furthermore, sensitive new biochemical markers must be identified to better define the clinical severity of the disease at birth, to support clinical judgement during the follow-up and to compare the effects of the different therapies. A prolonged neuropsychological follow-up of post-transplant cognitive development of children and residual disease burden is needed. In this perspective, the reference center must guarantee a multidisciplinary follow-up with an expert team. Diagnostic and interventional protocols of reference centers should be standardized whenever possible to allow comparison of clinical data and evaluation of results. This review will focus on all these critical issues related to the management of MPS I-H.
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http://dx.doi.org/10.1186/s13023-017-0662-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472858PMC
June 2017

The treatment of juvenile/adult GM1-gangliosidosis with Miglustat may reverse disease progression.

Metab Brain Dis 2017 10 3;32(5):1529-1536. Epub 2017 Jun 3.

Department of Pediatrics, University Children's Hospital, Padua, Italy.

Juvenile and adult GM1-gangliosidosis are invariably characterized by progressive neurological deterioration. To date only symptomatic therapies are available. We report for the first time the positive results of Miglustat (OGT 918, N-butyl-deoxynojirimycin) treatment on three Italian GM1-gangliosidosis patients. The first two patients had a juvenile form (enzyme activity ≤5%, GLB1 genotype p.R201H/c.1068 + 1G > T; p.R201H/p.I51N), while the third patient had an adult form (enzyme activity about 7%, p.T329A/p.R442Q). Treatment with Miglustat at the dose of 600 mg/day was started at the age of 10, 17 and 28 years; age at last evaluation was 21, 20 and 38 respectively. Response to treatment was evaluated using neurological examinations in all three patients every 4-6 months, the assessment of Movement Disorder-Childhood Rating Scale (MD-CRS) in the second patient, and the 6-Minute Walking Test (6-MWT) in the third patient. The baseline neurological status was severely impaired, with loss of autonomous ambulation and speech in the first two patients, and gait and language difficulties in the third patient. All three patients showed gradual improvement while being treated; both juvenile patients regained the ability to walk without assistance for few meters, and increased alertness and vocalization. The MD-CRS class score in the second patient decreased from 4 to 2. The third patient improved in movement and speech control, the distance covered during the 6-MWT increased from 338 to 475 m. These results suggest that Miglustat may help slow down or reverse the disease progression in juvenile/adult GM1-gangliosidosis.
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http://dx.doi.org/10.1007/s11011-017-0044-yDOI Listing
October 2017

Birth weight in patients with mucopolysaccharidosis type II: Data from the Hunter Outcome Survey (HOS).

Mol Genet Metab Rep 2017 Jun 3;11:62-64. Epub 2017 May 3.

Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Department of Genetics/UFRGS and INAGEMP, Porto Alegre, Brazil.

There is a need to identify early disease markers to facilitate diagnosis of mucopolysaccharidosis type II (MPS II; Hunter syndrome). Mean birth weight and its association with disease severity was investigated in 609 patients enrolled in the Hunter Outcome Survey (HOS). This analysis indicated that birth weight is not an early marker of MPS II and is not associated with disease severity. It remains important to investigate the utility of other factors for early/pre-symptomatic diagnosis.
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http://dx.doi.org/10.1016/j.ymgmr.2017.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426030PMC
June 2017

Brain RNA-Seq Profiling of the Mucopolysaccharidosis Type II Mouse Model.

Int J Mol Sci 2017 May 17;18(5). Epub 2017 May 17.

Women's and Children's Health Department, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.

Lysosomal storage disorders (LSDs) are a group of about 50 genetic metabolic disorders, mainly affecting children, sharing the inability to degrade specific endolysosomal substrates. This results in failure of cellular functions in many organs, including brain that in most patients may go through progressive neurodegeneration. In this study, we analyzed the brain of the mouse model for Hunter syndrome, a LSD mostly presenting with neurological involvement. Whole transcriptome analysis of the cerebral cortex and midbrain/diencephalon/hippocampus areas was performed through RNA-seq. Genes known to be involved in several neurological functions showed a significant differential expression in the animal model for the disease compared to wild type. Among the pathways altered in both areas, axon guidance, calcium homeostasis, synapse and neuroactive ligand-receptor interaction, circadian rhythm, neuroinflammation and Wnt signaling were the most significant. Application of RNA sequencing to dissect pathogenic alterations of complex syndromes allows to photograph perturbations, both determining and determined by these disorders, which could simultaneously occur in several metabolic and biochemical pathways. Results also emphasize the common, altered pathways between neurodegenerative disorders affecting elderly and those associated with pediatric diseases of genetic origin, perhaps pointing out a general common course for neurodegeneration, independent from the primary triggering cause.
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http://dx.doi.org/10.3390/ijms18051072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454982PMC
May 2017

The Complexity of Pain Management in Children Affected by Mucopolysaccharidoses.

Case Rep Pediatr 2017 3;2017:7257230. Epub 2017 Apr 3.

Pediatric Pain and Palliative Care Service, Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.

Mucopolysaccharidoses (MPSs) are a group of rare, genetic lysosomal storage disorders. They are caused by deficiencies of the lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). Pain is a common feature in mucopolysaccharidoses. However, the pathophysiology of pain in this group of diseases is still unclear and genesis of pain is multifactorial. Currently, poor data about pain management in these patients are available. Here, we present our clinical experience in complex pain management in three children with MPS.
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http://dx.doi.org/10.1155/2017/7257230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394408PMC
April 2017