Publications by authors named "Christina Lampe"

44 Publications

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

[Home infusion therapy for Pompe disease: Recommendations for German-speaking countries].

Fortschr Neurol Psychiatr 2021 Feb 9. Epub 2021 Feb 9.

Friedrich-Baur- Institut der Neurologischen Klinik , Klinikum der Universität München, Deutschland.

Background: Pompe disease is a lysosomal multisystem disorder with predominant proximal myopathy. Treatment with enzyme replacement therapy (ERT) is available requiring life-long biweekly infusions of recombinant α-glucosidase. To minimize the burden of ERT patients ask for home infusion therapy.

Aims And Methods: Pompe disease experts from Germany, Austria, and Switzerland discussed in two consensus meetings in 2019 and 2020 requirements for home infusion therapy, adequate execution of treatment, and the legal situation for delegating physicians.

Results And Discussion: Home infusion therapy is principally feasible for patients with Pompe disease if certain preconditions are fulfilled, but the decision to implement has to be made on an individual basis. The treating physician delegates the execution of ERT to nursing staff but retains full legal responsibility. Home infusion therapy has to be carried out by specially trained and qualified staff. Infusion-related risks comprise mainly allergic reactions, and adequate medical treatment must be warranted. In German-speaking countries, clear rules for conducting home infusion therapy are needed to reduce psychosocial stress for patients with Pompe disease, and providing legal certainty for delegating physicians.
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http://dx.doi.org/10.1055/a-1365-8977DOI Listing
February 2021

ASAH1 pathogenic variants associated with acid ceramidase deficiency: Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy.

Hum Mutat 2020 Sep 24;41(9):1469-1487. Epub 2020 Jun 24.

National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of rare lysosomal storage disorders characterized by acid ceramidase deficiency (ACD), resulting from pathogenic variants in N-acylsphingosine amidohydrolase 1 (ASAH1). Other than simple listings provided in literature reviews, a curated, comprehensive list of ASAH1 mutations associated with ACD clinical phenotypes has not yet been published. This publication includes mutations in ASAH1 collected through the Observational and Cross-Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NHS), ClinicalTrials.gov identifier NCT03233841, in combination with an up-to-date curated list of published mutations. The NHS is the first to collect retrospective and prospective data on living and deceased patients with ACD presenting as Farber disease, who had or had not undergone hematopoietic stem cell transplantation. Forty-five patients representing the known clinical spectrum of Farber disease (living patients aged 1-28 years) were enrolled. The curation of known ASAH1 pathogenic variants using a single reference transcript includes 10 previously unpublished from the NHS and 63 that were previously reported. The publication of ASAH1 variants will be greatly beneficial to patients undergoing genetic testing in the future by providing a significantly expanded reference list of disease-causing variants.
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http://dx.doi.org/10.1002/humu.24056DOI Listing
September 2020

Critical clinical situations in adult patients with Mucopolysaccharidoses (MPS).

Orphanet J Rare Dis 2020 05 14;15(1):114. Epub 2020 May 14.

HELIOS Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.

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.
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http://dx.doi.org/10.1186/s13023-020-01382-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227065PMC
May 2020

Enzyme replacement therapy initiated in adulthood: Findings from the mucopolysaccharidosis VI Clinical Surveillance Program.

Mol Genet Metab 2019 08 2;127(4):355-360. Epub 2019 Jul 2.

BioMarin Pharmaceutical Inc., Novato, CA, USA. Electronic address:

Objective: To evaluate the impact of galsulfase enzyme replacement therapy (ERT) when initiated in adulthood for patients with mucopolysaccharidosis (MPS) VI.

Methods: In 2005, the multi-national, MPS VI Clinical Surveillance Program (CSP) was established to collect long-term observational data from routine clinical and laboratory assessments. A sub-analysis was performed in patients who started ERT at ≥16 years of age and had received galsulfase for ≥6 months. Urinary glycosaminoglycans (uGAG), 6-min walk test (6MWT), 3-min stair climb test (3MSCT), pulmonary function measures, cardiac function, ophthalmology measures, liver and spleen sizes, and safety were evaluated.

Results: Of 223 patients enrolled in the CSP, 51 were included in the sub-analysis. Patients were between 16 and 63 years of age at first infusion. From pre-treatment baseline, uGAG level decreased by a mean (±standard deviation [SD]) of 66 (±45)% (N = 29) after a median follow-up of 7.2 years. 6MWT distance decreased slightly by a mean of 17 (±107) meters (N = 23) after 6.6 years. Stairs/min in the 3MSCT increased by a mean of 26 (±33) (N = 14) after 2.8 years. Pulmonary function measures, forced expiratory volume in 1 second and forced vital capacity, increased by a mean of 0.06 (±0.21) L after 7.3 years and 0.05 (±0.28) L after 7.2 years, respectively (N = 19 for both measures). Overall, galsulfase was well tolerated, with most adverse events reported being MPS-related clinical manifestations and not related to galsulfase.

Conclusions: Results of this sub-analysis of the CSP suggest that initiation of galsulfase in adulthood is well tolerated and can possibly stabilize MPS VI in the long term.
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http://dx.doi.org/10.1016/j.ymgme.2019.06.008DOI Listing
August 2019

Targeting specificity of nuclear-encoded organelle proteins with a self-assembling split-fluorescent protein toolkit.

J Cell Sci 2019 06 3;132(11). Epub 2019 Jun 3.

Institute of Biology-Plant Physiology, Martin Luther University Halle-Wittenberg, Weinbergweg 10, 06120 Halle (Saale), Germany.

A large number of nuclear-encoded proteins are targeted to the organelles of endosymbiotic origin, namely mitochondria and plastids. To determine the targeting specificity of these proteins, fluorescent protein tagging is a popular approach. However, ectopic expression of fluorescent protein fusions commonly results in considerable background signals and often suffers from the large size and robust folding of the reporter protein, which may perturb membrane transport. Among the alternative approaches that have been developed in recent years, the self-assembling split-fluorescent protein (split-FP) technology appears particularly promising to analyze protein targeting specificity Here, we improved the sensitivity of this technology and systematically evaluated its utilization to determine protein targeting to plastids and mitochondria. Furthermore, to facilitate high-throughput screening of candidate proteins we developed a Golden Gate-based vector toolkit (PlaMinGo). As a result of these improvements, dual targeting could be detected for a number of proteins that had earlier been characterized as being targeted to a single organelle only. These results were independently confirmed with a plant phenotype complementation approach based on the mutant.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/jcs.230839DOI Listing
June 2019

Enzyme replacement therapy outcomes across the disease spectrum: Findings from the mucopolysaccharidosis VI Clinical Surveillance Program.

J Inherit Metab Dis 2019 05 8;42(3):519-526. Epub 2019 Apr 8.

BioMarin Pharmaceutical Inc., Novato, California, USA.

The impact of galsulfase enzyme replacement therapy in patients with mucopolysaccharidosis (MPS) VI with phenotypes at either end of the disease spectrum was evaluated. The MPS VI Clinical Surveillance Program (CSP) was established to collect long-term observational data from routine clinical and laboratory assessments. A subanalysis of the CSP was performed in patients with pretreatment urinary glycosaminoglycan (uGAG) levels <100 μg/mg and ≥200 μg/mg creatinine (low- and high-uGAG) who had received galsulfase for ≥6 months. uGAG, 6-minute walk test (6MWT), 3-minute stair climb test (3MSCT), pulmonary function measures, height/growth, cardiac function, and safety were evaluated. Patients with a high-uGAG level at pre-treatment baseline (N = 68) showed greater impairments in endurance and pulmonary function than those with low-baseline uGAG levels (N = 39). From pre-treatment baseline, the distance walked on the 6MWT in the low- and high-uGAG groups increased by a mean (±SD) of 49 (±151) meters and 42 (±165) meters (median follow-up 5.5 and 7.7 years), respectively. The number of stairs/min climbed in the 3MSCT in the low- and high-uGAG groups increased by a mean of 18 (±33) and 30 (±45) (median follow-up 2.8 and 3.5 years), respectively. Overall, pulmonary function remained unchanged for both groups. No impact was seen on cardiac function. Galsulfase was generally well tolerated in both groups, with most adverse events being MPS-related complications unrelated to galsulfase. Results of this CSP sub-analysis suggest that galsulfase stabilizes MPS VI in the long-term and has an acceptable safety profile, regardless of baseline disease severity.
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http://dx.doi.org/10.1002/jimd.12079DOI Listing
May 2019

Künstliche Intelligenz zur diagnostischen Unterstützung ausgewählter seltener lysosomaler Speichererkrankungen: Ergebnisse einer Pilotstudie.

Klin Padiatr 2019 Mar 10;231(2):60-66. Epub 2019 Jan 10.

Pädiatrische Hämatologie und Onkologie, Hannover, Medizinische Hochschule Hannover.

Background: Diagnosing a rare metabolic disease challenges physicians and affected individuals and their families. To support the diagnostic pathway, a diagnostic tool was developed using the experiences of the affected individuals gained in interviews.

Methods: 17 interviews with parents or individuals with a selected rare metabolic disease (Mucopolysaccharidosis (MPS), M. Fabry and M. Gaucher) were performed and qualitatively analysed using the standardized methods of Colaizzi. The results are reflected in diagnostic questionnaires. The questionnaires were distributed and answered by parents or individuals with an established diagnosis of MPS, M. Fabry or M. Gaucher and a control group. Four combined data mining classifiers were trained to detect suspicious answer patterns in the questionnaires.

Results: 56 questionnaires were used for training and cross-validation tests of the binary data mining system resulting in a sensitivity value of 91% for the diagnosis 'MPS'. Another 20 questionnaires which have not been used for the training process could be evaluated as a preliminary prospective test. Out of these 20 questionnaires the test delivered 18 correct diagnoses (90%).

Discussion And Conclusions: Questionnaires for diagnostic support based on interviews with parents and affected individuals were developed and answer patterns were analysed with an ensemble of classifiers. Although preliminary, the results illustrate the potential of answer pattern recognition using data mining techniques. This approach might prove useful for diagnostic support in selected metabolic diseases.
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http://dx.doi.org/10.1055/a-0816-5681DOI Listing
March 2019

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

Spinal cord issues in adult patients with MPS: transition of care survey.

Childs Nerv Syst 2018 09 27;34(9):1759-1765. Epub 2018 May 27.

UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.

Purpose: This study aims to raise awareness of the need for research and appropriate guidelines for managing spinal cord issues in adult patients with mucopolysaccharidosis (MPS) and transition of these patients from pediatric to adult care.

Methods: Pediatric/adult neurosurgeons, orthopedic spine surgeons, and treating physicians with expertise in metabolic disorders and spinal cord issues were invited to complete a survey to assess their experience with spinal cord problems in MPS and their opinion on transitioning routes from pediatric to adult care.

Results: Twenty specialists completed the survey; 16 had treated spinal cord issues in patients with MPS. Foramen magnum and cervical stenosis (87%), atlanto-axial instability (67%), and lumbar spine instability (33%) were the main spinal cord issues encountered; 28% had treated adult patients for one or more spinal cord issues. In 40% of cases, this concerned an intervention or procedures performed during childhood. The main specialist responsible for the care of adult patients with MPS differed considerably between institutions and included both pediatric and adult specialists (30% pediatric neurosurgeons, 10% pediatric spine orthopedic surgeons, 30% adult spine neurosurgeons, 20% general adult surgeons). The preferred option (> 50%) for the transition of care was an interdisciplinary team of pediatric and adult specialists.

Conclusions: Further work needs to be done to address problems of managing spinal cord issues in adult patients with MPS. Currently, the responsibility for the care of patients with MPS with spinal cord issues is inconsistent. The best strategy for transitioning these patients from pediatric to adult care is likely an interdisciplinary approach.
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http://dx.doi.org/10.1007/s00381-018-3834-6DOI Listing
September 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

Stand-alone craniocervical decompression is feasible in children with mucopolysaccharidosis type I, IVA, and VI.

Spine J 2018 08 9;18(8):1455-1459. Epub 2018 Apr 9.

Department of Neurosurgery and Paediatric Neurosurgery, HELIOS Dr. Horst-Schmidt Kliniken, Ludwig-Erhard-Straße 100, 65199 Wiesbaden, Germany; Department of Pediatrics, HELIOS Dr. Horst-Schmidt Kliniken, Ludwig-Erhard-Straße 100, 65199 Wiesbaden, Germany.

Background Context: In patients with mucopolysaccharidosis (MPS), glycosaminoglycan deposits in the dura mater and supporting ligaments cause spinal cord compression and consecutive myelopathy, predominantly at the craniocervical junction. Disease characteristics of craniocervical stenosis (CCS) in patients with MPS differ profoundly from other hereditary and degenerative forms. Because of high periprocedural morbidity and mortality, patients with MPS pose a substantial challenge to the inexperienced medical care provider. As literature remains scarce, we present our experience with a large cohort of patients with MPS treated for CCS without atlanto-occipital instrumentation.

Purpose: The present study aimed to describe a safe and least traumatic approach for treating CCS in children with MPS, avoiding primary instrumentation.

Study Design: This is a prospective follow-up (cohort) study.

Patient Samples: We report 15 consecutive patients with CCS related to MPS, who were treated with stand-alone cervical decompression.

Outcome Measures: Myelopathy was assessed using magnetic resonance imaging (MRI), somatosensory evoked potentials, and clinical evaluation. Cervical instability was evaluated using plain x-ray and MRI. The disability status is quantified using either the Karnofsky or Lansky Performance Score.

Methods: We describe 15 consecutive patients treated with craniocervical decompression. Data were collected prospectively. The mean follow-up is 6 years (5 standard deviation). The technique and treatment principles are described.

Results: The overall clinical outcome in this patient cohort is good (mean Karnofsky Performance Score of 80). No patient developed signs of C0-C1-C2 instability or progressive myelopathy. Restenosis occurred in seven patients, requiring a total of eight reoperations.

Conclusions: Surgery in patients with MPS is associated with high morbidity and mortality of up to 4.2%. Because of the unique nature of the disease, recurring stenosis is inevitable. To shorten the procedure time and simplify the anticipated reoperation, we provide data that craniocervical decompression is feasible without the necessity of primary osteosynthesis. In the absence of craniocervical instability, decompression surgery without occipitocervical stabilization yields good postoperative results and challenges the long-standing paradigm of prophylactic craniocervical fixation.
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http://dx.doi.org/10.1016/j.spinee.2018.04.002DOI Listing
August 2018

The Xanthomonas effector XopL uncovers the role of microtubules in stromule extension and dynamics in Nicotiana benthamiana.

Plant J 2018 03 2;93(5):856-870. Epub 2018 Feb 2.

Department of Plant Physiology, Institute for Biology, Martin Luther University Halle-Wittenberg, D-06099, Halle, Germany.

Xanthomonas campestris pv. vesicatoria type III-secreted effectors were screened for candidates influencing plant cell processes relevant to the formation and maintenance of stromules in Nicotiana benthamiana lower leaf epidermis. Transient expression of XopL, a unique type of E3 ubiquitin ligase, led to a nearly complete elimination of stromules and the relocation of plastids to the nucleus. Further characterization of XopL revealed that the E3 ligase activity is essential for the two plastid phenotypes. In contrast to the XopL wild type, a mutant XopL lacking E3 ligase activity specifically localized to microtubules. Interestingly, mutant XopL-labeled filaments frequently aligned with stromules, suggesting an important, yet unexplored, microtubule-stromule relationship. High time-resolution movies confirmed that microtubules provide a scaffold for stromule movement and contribute to stromule shape. Taken together, this study has defined two populations of stromules: microtubule-dependent stromules, which were found to move slower and persist longer, and microtubule-independent stromules, which move faster and are transient. Our results provide the basis for a new model of stromule dynamics including interactions with both actin and microtubules.
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http://dx.doi.org/10.1111/tpj.13813DOI Listing
March 2018

Practical management of behavioral problems in mucopolysaccharidoses disorders.

Mol Genet Metab 2017 12 27;122S:35-40. Epub 2017 Sep 27.

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

The mucopolysaccharidosis (MPS) disorders are caused by deficiencies of specific lysosomal enzymes, resulting in progressive glycosaminoglycan (GAG) accumulation in cells and tissues throughout the body. Excessive GAG storage can lead to a variety of somatic manifestations as well as primary and secondary neurological symptoms. Behavioral problems (like hyperactivity, attention difficulties, and severe frustration) and sleeping problems are typical primary neurological symptoms of MPS caused by GAG accumulation in neurons, and are frequently observed in patients with MPS I, II, III, and VII. As these problems often place a significant burden on the family, proper management is important. This review summarizes current insights into behavioral and sleeping problems in MPS disorders and the most optimal management approaches, as presented and discussed during a meeting of 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.2017.09.010DOI Listing
December 2017

Surgical management of neurological manifestations of mucopolysaccharidosis disorders.

Mol Genet Metab 2017 12 28;122S:41-48. Epub 2017 Sep 28.

Department of Neuroradiology, DASA Group, São Paulo, Brazil.

The mucopolysaccharidosis (MPS) disorders are ultra-rare lysosomal storage disorders associated with progressive accumulation of glycosaminoglycans (GAGs) in cells and tissues throughout the body. Clinical manifestations and progression rates vary widely across and within the different types of MPS. Neurological symptoms occur frequently, and may result directly from brain damage caused by infiltration of GAGs, or develop secondary to somatic manifestations such as spinal cord compression, hydrocephalus, and peripheral nerve entrapment. Management of secondary neurological manifestations often requires surgical correction of the underlying somatic cause. The present review discusses the surgical management of neurological disease in patients with MPS, including diagnostic imaging. Background information is derived from presentations and discussions during a meeting on the brain in MPS, attended by an international group of experts (April 28-30, 2016, Stockholm, Sweden), and additional literature searches.
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http://dx.doi.org/10.1016/j.ymgme.2017.09.011DOI Listing
December 2017

[Lysosomal Storage Diseases: Challenges in Multiprofessional Patient Care with Enzyme Replacement Therapy].

Klin Padiatr 2017 May 2;229(3):168-174. Epub 2017 May 2.

Paediatrics, HELIOS Dr Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.

 Due to their rarity studies in (ultra-) rare diseases are difficult. Only for a minority of these diseases causal therapies are available. Development and production of enzyme replacement therapies (ERT) for example are challenging and expensive. The number of patients is low, costs per patient are high. We will focus on the challenges of providing long-term ERT to patients with lysosomal storage diseases (LSD) in an out- and inpatient setting based on a literature search in Pubmed and own experience. Many ERTs for LSDs have a positive cost-benefit ratio. Possible side-effects are severe allergic reactions. ERT is covered by the insurance companies when prescribed by a physician, however they are liable to recourse by the insurance company as the expenses for drugs of the prescribing physician will be above average. In most cases the recourse can be averted if diagnoses of individual patients are disclosed. Intravenous infusion of ERT is not well-regulated in Germany/Austria. Infusion on a ward is safe however often not covered by the insurance companies as patients do not stay overnight. Another option is infusion in a day-care setting, however the lump sum paid for infusion does not cover costs for ERT. On an individual basis, reimbursement for medication (ERT) has to be negotiated with the insurance companies before infusion takes place. Home infusions are feasible, however careful evaluations of the infusion-team and the risk for side-effects have to be performed on an individual basis, legal issues have to be considered. In- and outpatient ERT of patients with LSDs is challenging but feasible after individual evaluation of patient and infusion team.
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http://dx.doi.org/10.1055/s-0043-103088DOI Listing
May 2017

The ethical framework for performing research with rare inherited neurometabolic disease patients.

Eur J Pediatr 2017 Mar 16;176(3):395-405. Epub 2017 Jan 16.

Fondazione Per la Ricerca Farmacologica Gianni Benzi Onlus, Via Abate Eustasio 30, 70010, Valenzano, BA, Italy.

The need for performing clinical trials to develop well-studied and appropriate medicines for inherited neurometabolic disease patients faces ethical concerns mainly raising from four aspects: the diseases are rare; include young and very young patients; the neurological impairment may compromise the capability to provide 'consent'; and the genetic nature of the disease leads to further ethical implications. This work is intended to identify the ethical provisions applicable to clinical research involving these patients and to evaluate if these cover the ethical issues. Three searches have been performed on the European regulatory/legal framework, the literature and European Union-funded projects. The European legal framework offers a number of ethical provisions ruling the clinical research on paediatric, rare, inherited diseases with neurological symptoms. In the literature, relevant publications deal with informed consent, newborn genetic screenings, gene therapy and rights/interests of research participants. Additional information raised from European projects on sharing patients' data from different countries, the need to fill the gap of the regulatory framework and to improve information to stakeholders and patients/families.

Conclusion: Several recommendations and guidelines on ethical aspects are applicable to the inherited neurometabolic disease research in Europe, even though they suffer from the lack of a common ethical approach. What is Known: • When planning and conducting clinical trials, sponsors and researchers know that clinical trials are to be performed according to well-established ethical rules, and patients should be aware about their rights. • In the cases of paediatric patients, vulnerable patients unable to provide consent, genetic diseases' further rules apply. What is New: • This work discusses which ethical rules apply to ensure protection of patient's rights if all the above-mentioned features coexist. • This work shows available data and information on how these rules have been applied.
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http://dx.doi.org/10.1007/s00431-017-2852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321701PMC
March 2017

Heart and Cardiovascular Involvement in Patients with Mucopolysaccharidosis Type IVA (Morquio-A Syndrome).

PLoS One 2016 9;11(9):e0162612. Epub 2016 Sep 9.

Division of Pediatric Cardiology and Congenital Heart Diseases, Center for Diseases in Childhood and Adolescence, Mainz Medical University, Mainz, Germany.

Background: Mucopolysaccharidosis (MPS) IVA is a rare lysosomal storage disorder with multiple skeletal and non-skeletal abnormalities requiring multiple surgical interventions. It is well known that patients with MPS IVA suffer from tachycardia, but cardiac and hemodynamic alterations have not been reported to date. We investigated the cardiovascular and hemodynamic alterations in patients with MPS IVA and developed a possible patho-mechanism for cardiovascular deterioration during anesthesia.

Material And Methods: In this observational study, serial cardiac examinations were performed in 54 patients with MPS IVA who were followed at the Children's Hospital of the Mainz Medical University (Mainz, Germany) between 1991 and 2014 (follow-up 1-24 years; median 5.8 years). Results were compared with data from a large central European cohort of more than 2000 healthy infants and children.

Results: None of the patients had arterial hypertension, but 4% had evidence of increased pulmonary artery pressure. Patients developed aortic root extension up to 6.9 standard deviations above normal. Left-sided valve leaflet thickening occurred in 26 patients (five with valve disease). Patients had lower left ventricular dimensions (z: -1.02±0.1), lower stroke volumes (z: -2.3±0.17), lower left ventricular mass (z: -1.5±0.21), but higher wall thickness (z: +0.8±0.16), and higher work index (z: +2.5±0.2) compared to healthy control subjects. Cardiac output was preserved by an increase in heart rate of 21%. Sixty % of patients showed impaired diastolic filling; heart rate (99.0±1.8 vs. 92.0±2.1 bpm), age (18.0±1.8 vs. 14.2±1 years), and cardiothoracic ratio (61.6±3.6% vs. 55±4.2%) of these patients were higher compared to those with normal filling.

Conclusions: The results of this study suggest an age-progressive disproportion of the intra-thoracic organs of patients with MPS IVA, which is accompanied by aortic root extension and thickened left ventricles, with reduced stroke volumes, impaired diastolic filling patterns, and increased heart rates.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162612PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017658PMC
August 2017

Health-related quality of life in mucopolysaccharidosis: looking beyond biomedical issues.

Orphanet J Rare Dis 2016 08 26;11(1):119. Epub 2016 Aug 26.

Keck School of Medicine, Departments of Anesthesiology, Pediatrics, and Psychiatry & Behavioral Sciences, Children's Hospital Los Angeles, Anesthesiology Critical Care Medicine, Pediatric Pain Management Clinic, University of Southern California, California, USA.

The mucopolysaccharidoses (MPS) comprise a heterogeneous family of rare, genetic lysosomal storage disorders that result in severe morbidity and reduced life expectancy. Emerging treatments for several of these disorders have triggered the search for clinically relevant biomarkers and clinical markers associated with treatment efficacy in populations and individuals. However, biomedical measures do not tell the whole story when characterizing a complex chronic disorder such as MPS. Health-related quality of life (HRQoL) tools that utilize patient reported outcomes to address patient parameters such as symptoms (pain, fatigue, psychological health), functioning (activity and limitations), or quality of life, have been used to supplement traditional biomedical endpoints. Many of these HRQoL tools have demonstrated that quality of life is negatively impacted in patients with MPS. There is both the opportunity and need to formally standardize and validate HRQoL tools for the different MPS disorders.
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http://dx.doi.org/10.1186/s13023-016-0503-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5000418PMC
August 2016

Cervical cord compression in mucopolysaccharidosis VI (MPS VI): Findings from the MPS VI Clinical Surveillance Program (CSP).

Mol Genet Metab 2016 08 3;118(4):310-8. Epub 2016 Jun 3.

UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.

Objectives: To gain insight into the frequency, age of onset, and management of cervical cord compression in mucopolysaccharidosis VI (MPS VI).

Methods: Cervical spine magnetic resonance imaging (MRI) data and/or cervical decompression surgery data collected between 30 June 2005 and 1 September 2015 were analyzed from subjects enrolled in the MPS VI Clinical Surveillance Program (CSP) (ClinicalTrials.gov: NCT00214773), an ongoing multicenter, observational, retrospective and prospective registry.

Results: Of 213 subjects enrolled in the CSP, 134 (62.9%) had at least one documented cervical spine MRI assessment. An additional four subjects were identified through surgery records alone to yield a study population comprising 138 subjects (mean age at enrollment =15.1years; age range=0.80-65.0years). Cervical cord compression was documented in 101 (75.4%) of the 134 subjects with ≥1 MRI assessment, the majority (95.0%) by the time of the first recorded MRI. In general, subjects with cervical cord compression had significantly lower height Z-scores compared to those without cervical cord compression (p<0.0001); nevertheless, a few subjects of taller stature had documented cervical cord compression at a young age. Most subjects >20years of age (31/33, 93.9%) presented with cervical cord compression. There was an insufficient number of subjects with both pre- and post-enzyme replacement therapy (ERT) MRI data to determine any association between ERT and cervical cord compression. Surgical decompression was performed on 58 subjects (42.0%), with mean age at first surgery of 13.1years. Decompression plus stabilization procedures accounted for 12.1% of surgeries. Eight subjects (13.8%) underwent reoperation. Complications during or following surgery were reported in 3 subjects, with anesthesia-related complications resulting in two deaths.

Conclusions: All individuals with MPS VI are at high risk of developing cervical cord compression at an early age. Routine MRI assessments should be initiated from the time of MPS VI diagnosis. The perioperative management of MPS VI patients can be challenging. This study contributes to the understanding of the natural history of MPS VI.
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http://dx.doi.org/10.1016/j.ymgme.2016.06.001DOI Listing
August 2016

Review and evaluation of the methodological quality of the existing guidelines and recommendations for inherited neurometabolic disorders.

Orphanet J Rare Dis 2015 Dec 30;10:164. Epub 2015 Dec 30.

Neurology, gastroenterology pathology and clinical biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain.

Background: Inherited neurometabolic disorders (iNMDs) represent a group of almost seven hundred rare diseases whose common manifestations are clinical neurologic or cognitive symptoms that can appear at any time, in the first months/years of age or even later in adulthood. Early diagnosis and timely treatments are often pivotal for the favorable course of the disease. Thus, the elaboration of new evidence-based recommendations for iNMD diagnosis and management is increasingly requested by health care professionals and patients, even though the methodological quality of existing guidelines is largely unclear. InNerMeD-I-Network is the first European network on iNMDs that was created with the aim of sharing and increasing validated information about diagnosis and management of neurometabolic disorders. One of the goals of the project was to determine the number and the methodological quality of existing guidelines and recommendations for iNMDs.

Methods: We performed a systematic search on PubMed, the National Guideline Clearinghouse (NGC), the Guidelines International Network (G-I-N), the Scottish Intercollegiate Guideline Network (SIGN) and the National Institute for Health and Care Excellence (NICE) to identify all the published guidelines and recommendations for iNMDs from January 2000 to June 2015. The methodological quality of the selected documents was determined using the AGREE II instrument, an appraisal tool composed of 6 domains covering 23 key items.

Results: A total of 55 records met the inclusion criteria, 11 % were about groups of disorders, whereas the majority encompassed only one disorder. Lysosomal disorders, and in particular Fabry, Gaucher disease and mucopolysaccharidoses where the most studied. The overall methodological quality of the recommendation was acceptable and increased over time, with 25 % of the identified guidelines strongly recommended by the appraisers, 64 % recommended, and 11 % not recommended. However, heterogeneity in the obtained scores for each domain was observed among documents covering different groups of disorders and some domains like 'stakeholder involvement' and 'applicability' were generally scarcely addressed.

Conclusions: Greater efforts should be devoted to improve the methodological quality of guidelines and recommendations for iNMDs and AGREE II instrument seems advisable for new guideline development. The elaboration of new guidelines encompassing still uncovered disorders is badly needed.
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http://dx.doi.org/10.1186/s13023-015-0376-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696316PMC
December 2015

Comparison of Rebound Tonometry, Perkins Applanation Tonometry and Ocular Response Analyser in Mucopolysaccharidosis Patients.

PLoS One 2015 28;10(8):e0133586. Epub 2015 Aug 28.

Department of Ophthalmology, University Medical Center of the Johannes Gutenberg- University Mainz, Mainz, Germany.

Aims: To investigate the feasibility and to compare three devices measuring intraocular pressure (IOP) in mucopolysaccharidosis patients (MPS): iCare rebound tonometer (RT), Perkins applanation tonometer (PAT) and ocular response analyzer (ORA).

Methods: MPS patients who underwent at least two examinations out of: RT, PAT and ORA at the same visit were identified and retrospectively analyzed in this study.

Results: 17 patients fulfilled the inclusion criterion. In all 17 patients IOP measurements were performed with RT (34 eyes) and ORA (33 eyes), while PAT measurement was possible in only 12 (24 eyes) patients. The RT, corneal-compensated intraocular pressure (IOPcc) and Goldmann-correlated intraocular pressure (IOPg) differed relevantly from IOP assessed with PAT. Corneal clouding in MPS patients correlated positively with PAT, RT and IOPg (r = 0.3, 0.5, and 0.5 respectively), but not with IOPcc (r = 0.07). The MPS-related corneal clouding correlated positively with biomechanical corneal parameters assessed with ORA: corneal hysteresis (r = 0.77) and corneal resistance factor (r = 0.77) either.

Conclusions: RT and ORA measurements were tolerated better than applanation tonometry in MPS patients. IOP measurements assessed with RT and ORA differed relevantly from PAT. Corneal-compensated IOP assessed with ORA seems to be less affected by the MPS-related corneal clouding than applanation or rebound tonometry. RT and ORA measurements should be preferred for IOP assessment in patients with MPS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133586PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552832PMC
May 2016

Neuronopathic lysosomal storage disorders: Approaches to treat the central nervous system.

Best Pract Res Clin Endocrinol Metab 2015 Mar 5;29(2):159-71. Epub 2015 Jan 5.

Brains for Brains Foundation, Department of Women and Children Health, Via Giustiniani 3, Padova, Italy; Kings College London, Institute of Pharmaceutical Science, Franklin-Wilkins Building, Stamford Street, London SE1 9NH, UK. Electronic address:

Pharmacological research has always focused on developing new therapeutic strategies capable of modifying a disease's natural history and improving patients' quality of life. Despite recent advances within the fields of medicine and biology, some diseases still represent a major challenge for successful therapy. Neuronopathic lysosomal storage disorders, in particular, have high rates of morbidity and mortality and a devastating socio-economic effect. Many of the available therapies, such as enzyme replacement therapy, can reverse the natural history of the disease in peripheral organs but, unfortunately, are still unable to reach the central nervous system effectively because they cannot cross the blood-brain barrier that surrounds and protects the brain. Moreover, many lysosomal storage disorders are characterized by a number of blood-brain barrier dysfunctions, which may further contribute to disease neuropathology and accelerate neuronal cell death. These issues, and their context in the development of new therapeutic strategies, will be discussed in detail in this chapter.
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http://dx.doi.org/10.1016/j.beem.2014.12.001DOI Listing
March 2015

Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome)--10-year follow-up of patients who previously participated in an MPS VI Survey Study.

Am J Med Genet A 2014 Aug 24;164A(8):1953-64. Epub 2014 Apr 24.

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

Mucopolysaccharidosis VI (MPS VI) is a clinically heterogeneous and progressive disorder with multiorgan manifestations caused by deficient N-acetylgalactosamine-4-sulfatase activity. A cross-sectional Survey Study in individuals (n = 121) affected with MPS VI was conducted between 2001 and 2002 to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of disease. We conducted a Resurvey Study (ClinicalTrials.gov: NCT01387854) to obtain 10-year follow-up data, including medical histories and clinical assessments (n = 59), and survival status over 12 years (n = 117). Patients received a mean (SD) of 6.8 (2.2) years of galsulfase ERT between baseline (Survey Study) and follow-up. ERT patients increased in height by 20.4 cm in the 4-7-year-old baseline age group and by 16.8 cm in the 8-12-year-old baseline age group. ERT patients <13 years-old demonstrated improvement in forced vital capacity (FVC) by 68% and forced expiratory volume in 1 sec (FEV1) by 55%, and those ≥13 years-old increased FVC by 12.8% and maintained FEV1. Patients with >200 µg/mg baseline uGAG levels increased FVC by 48% in the <13-year-old baseline age group and by 15% in the ≥13-year-old baseline age group. ERT patients who completed the 6-min walk test demonstrated a mean (SD) increase of 65.7 (100.6) m. Cardiac outcomes did not significantly improve or worsen. Observed mortality rate among naïve patients was 50% (7/14) and 16.5% (17/103) in the ERT group (unadjusted hazard ratio, 0.24; 95% CI, 0.10-0.59). Long-term galsulfase ERT was associated with improvements in pulmonary function and endurance, stabilized cardiac function and increased survival.
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http://dx.doi.org/10.1002/ajmg.a.36584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107078PMC
August 2014

Burden of disease in patients with Morquio A syndrome: results from an international patient-reported outcomes survey.

Orphanet J Rare Dis 2014 Mar 7;9:32. Epub 2014 Mar 7.

Manchester Academic Health Science Centre, The Mark Holland Metabolic Unit, Salford Royal Foundation NHS Trust, Salford, UK.

Background: Morquio A syndrome (or mucopolysaccharidosis IVa) is an ultra-rare multi-organ disease, resulting in significantly impaired functional capacity, mobility and quality of life (QoL).

Methods: This patient-reported outcomes survey evaluated the global burden of Morquio A among adults (≥18 years, N = 27) and children (7-17 years, N = 36), including the impact on mobility, QoL, pain and fatigue. QoL was assessed using the general Health-Related Quality of Life (HRQoL) questionnaire (the EuroQol [EQ]-5D-5L). Pain and pain interference with daily activities were assessed using the Brief Pain Inventory Short Form (BPI-SF) in adults and the Adolescent Pediatric Pain Tool (APPT) in children. Fatigue was assessed by questioning the patients on the number of evenings in a week they felt extremely tired.

Results: The clinical data showed a wide heterogeneity in clinical manifestations between patients, with the majority of patients showing differing levels of endurance, short stature, bone and joint abnormalities, abnormal gait and eye problems. Mobility was considerably impaired: 44.4% of children and 85.2% of adult patients were using a wheelchair. High wheelchair reliance significantly reduced QoL. This was mainly driven by reduced scores in the Mobility, Self-care, and Usual Activity domains. The HRQoL utility values were 0.846, 0.582 and 0.057 respectively in adults not using a wheelchair, using a wheelchair only when needed and always using a wheelchair; values were 0.534, 0.664 and -0.180 respectively in children. Employed adult patients had a better HRQoL than unemployed patients (HRQoL utility value 0.640 vs. 0.275, respectively).64% of children and 74% of adult patients had joint pain; fatigue was reported by 69% of children and 63% of adults. Overall, increased mobility was associated with more severe and widespread pain and more fatigue.

Conclusions: The HRQoL of Morquio A patients is mainly driven by the ability to remain independently mobile without becoming wheelchair dependent. Their QoL reduces dramatically if they always have to use their wheelchair. Even a slightly better mobility (wheelchair use only when needed) greatly improves QoL. Maintenance of functional capacity and mobility paired with better pain management are likely to improve QoL.
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http://dx.doi.org/10.1186/1750-1172-9-32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016149PMC
March 2014

Long-term experience with enzyme replacement therapy (ERT) in MPS II patients with a severe phenotype: an international case series.

J Inherit Metab Dis 2014 Sep 5;37(5):823-9. Epub 2014 Mar 5.

Department of Pediatric and Adolescent Medicine, Villa Metabolica, University Medical Center of Mainz, Mainz, Germany,

Introduction: No published clinical trial data are available to inform the use of enzyme replacement therapy (ERT) in patients with the severe (neuropathic) phenotype of mucopolysaccharidosis II (MPS II). Current guidelines recommend ERT administered intravenously be used on a trial basis in this population.

Aims/methods: A retrospective chart review was conducted at five international centers for this case series of 22 patients with neuropathic MPS II who received intravenous idursulfase 0.5 mg/kg weekly for at least 2 consecutive years. We collected data about urinary glycosaminoglycan levels, adverse events, and the following somatic signs/symptoms: skeletal disease, joint range of motion, liver/spleen size, respiratory infections, cardiac disease, diarrhea, skin/hair texture, and hospitalizations.

Results: The age at diagnosis was 2 months to 5 years, and the age at idursulfase initiation was between 18 months and 21 years. One of 22 patients experienced improvements in seven somatic signs/symptoms; 17/22 experienced improvements in five to six somatic signs/symptoms; and 4/22 experienced improvements in four somatic signs/symptoms. None experienced fewer than four improvements. No new safety concerns arose. Infusion-related reactions were experienced by 4/22 patients but were successfully managed using accepted strategies.

Conclusions: Long-term treatment with idursulfase was associated with improvements in somatic manifestations in this case series of patients with neuropathic MPS II. The family and medical team should maintain open lines of communication to make treatment decisions that take into consideration the benefits and limitations of ERT in this population.
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http://dx.doi.org/10.1007/s10545-014-9686-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4158409PMC
September 2014

Enzyme Replacement Therapy in Mucopolysaccharidosis II Patients Under 1 Year of Age.

JIMD Rep 2014 11;14:99-113. Epub 2014 Feb 11.

Villa Metabolica, Children's Hospital, University of Mainz, Mainz, Germany,

Mucopolysaccharidosis (MPS) II, or Hunter syndrome, is a lysosomal storage disease characterized by multi-systemic involvement and a progressive clinical course. Enzyme replacement therapy with idursulfase has been approved in more than 50 countries worldwide; however, safety and efficacy data from clinical studies are currently only available for patients 1.4 years of age and older. Sibling case studies of infants with MPS I, II, and VI who initiated ERT in the first weeks or months of life have reported no new safety concerns and a more favorable clinical course for the sibling treated in infancy than for the later-treated sibling. Here we describe our experiences with a case series of eight MPS II patients for whom idursulfase treatment was initiated at under 1 year of age. The majority of the patients were diagnosed because of a family history of disease. All of the infants displayed abnormalities consistent with MPS II at diagnosis. The youngest age at treatment start was 10 days and the oldest was 6.5 months, with duration of treatment varying between 6 weeks and 5.5 years. No new safety concerns were observed, and none of the patients experienced an infusion-related reaction. All of the patients treated for more than 6 weeks showed improvements and/or stabilization of some somatic manifestations while on treatment. In some cases, caregivers made comparisons with other affected family members and reported that the early-treated patients experienced a less severe clinical course, although a lack of medical records for many family members precluded a rigorous comparison.
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http://dx.doi.org/10.1007/8904_2013_289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213327PMC
October 2014

Mucopolysaccharidosis IVA (Morquio A syndrome) and VI (Maroteaux-Lamy syndrome): under-recognized and challenging to diagnose.

Skeletal Radiol 2014 Mar 4;43(3):359-69. Epub 2014 Jan 4.

International Skeletal Dysplasia Registry, Cedars-Sinai Medical Center/University of California, Los Angeles, Los Angeles, CA, USA,

Objective: Mucopolysaccharidosis IVA (MPS IVA, or Morquio A syndrome) and VI (MPS VI, or Maroteaux-Lamy syndrome) are autosomal recessive lysosomal storage disorders. Skeletal abnormalities are common initial presenting symptoms and, when recognized early, may facilitate timely diagnosis and intervention, leading to improved patient outcomes. Patients with slowly progressing disease and nonclassic phenotypes can be particularly challenging to diagnose. The objective was to describe the radiographic features of patients with a delayed diagnosis of MPS IVA or VI.

Materials And Methods: This was a retrospective study. The records of 5 MPS IVA and 3 MPS VI patients with delayed diagnosis were reviewed. Radiographs were evaluated by a radiologist with special expertise in skeletal dysplasias.

Results: An important common theme in these cases was the appearance of multiple epiphyseal dysplasia (MED) with epiphyseal changes seemingly confined to the capital (proximal) femoral epiphyses. Very few patients had the skeletal features of classical dysostosis multiplex.

Conclusions: Radiologists should appreciate the wide phenotypic variability of MPS IVA and VI. The cases presented here illustrate the importance of considering MPS in the differential diagnosis of certain skeletal dysplasias/disorders, including MED, some forms of spondylo-epiphyseal dysplasia (SED), and bilateral Perthes-like disease. It is important to combine radiographic findings with clinical information to facilitate early testing and accurate diagnosis.
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http://dx.doi.org/10.1007/s00256-013-1797-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901942PMC
March 2014

Treatment of hip dysplasia in patients with mucopolysaccharidosis type I after hematopoietic stem cell transplantation: results of an international consensus procedure.

Orphanet J Rare Dis 2013 Oct 3;8:155. Epub 2013 Oct 3.

Department of Pediatrics and Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, H7-270, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Background: Mucopolysaccharidosis type I (MPS-I) is a lysosomal storage disorder characterized by progressive multi-organ disease. The standard of care for patients with the severe phenotype (Hurler syndrome, MPS I-H) is early hematopoietic stem cell transplantation (HSCT). However, skeletal disease, including hip dysplasia, is almost invariably present in MPS I-H, and appears to be particularly unresponsive to HSCT. Hip dysplasia may lead to pain and loss of ambulation, at least in a subset of patients, if left untreated. However, there is a lack of evidence to guide the development of clinical guidelines for the follow-up and treatment of hip dysplasia in patients with MPS I-H. Therefore, an international Delphi consensus procedure was initiated to construct consensus-based clinical practice guidelines in the absence of available evidence.

Methods: A literature review was conducted, and publications were graded according to their level of evidence. For the development of consensus guidelines, eight metabolic pediatricians and nine orthopedic surgeons with experience in the care of MPS I patients were invited to participate. Eleven case histories were assessed in two written rounds. For each case, the experts were asked if they would perform surgery, and they were asked to provide information on the aspects deemed essential or complicating in the decision-making process. In a subsequent face-to-face meeting, the results were presented and discussed. Draft consensus statements were discussed and adjusted until consensus was reached.

Results: Consensus was reached on seven statements. The panel concluded that early corrective surgery for MPS I-H patients with hip dysplasia should be considered. However, there was no full consensus as to whether such a procedure should be offered to all patients with hip dysplasia to prevent complications or whether a more conservative approach with surgical intervention only in those patients who develop clinically relevant symptoms due to the hip dysplasia is warranted.

Conclusions: This international consensus procedure led to the construction of clinical practice guidelines for hip dysplasia in transplanted MPS I-H patients. Early corrective surgery should be considered, but further research is needed to establish its efficacy and role in the treatment of hip dysplasia as seen in MPS I.
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http://dx.doi.org/10.1186/1750-1172-8-155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852175PMC
October 2013