Roberto Giugliani

Population Genetics, Cambridge, Massachusetts, United States

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Publications (395)928.61 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: In this article, the genotype-MR phenotype correlation of the most common or clinically important inherited metabolic diseases (IMD) in the pediatric population is reviewed. A nonsystematic search of the PubMed/Medline database of relevant studies about "genotype-phenotype correlation" in IMD was performed. Some MR phenotypes related to specific gene mutations were found, such as bilateral hypertrophy of inferior olives in patients harboring POLG and SURF1 mutations, and central lesions in the cervical spinal cord in patients with nonketotic hyperglycinemia harboring GLRX5 gene mutation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuroimaging Clinics of North America 02/2015; 25(1):31-51. · 1.20 Impact Factor
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    ABSTRACT: Mucolipidosis II alpha/beta is an autosomal recessive disorder caused by deficient activity of GlcNAc-1-phosphotransferase. We report the prenatal diagnosis of a fetus who was found to exhibit normal levels of lysosomal enzymes in the amniotic fluid but low levels in amniocytes, and who was found to be heterozygous for the most common GNPTAB mutation. As in some carriers of Mucolipidosis II biochemical abnormalities may hinder prenatal diagnosis, we suggest DNA analysis should be performed whenever possible.
    Meta Gene. 12/2014; 2:403–406.
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    ABSTRACT: Background Morquio A (MPS IVA) is a rare disease characterised by a deficiency of N-acetylgalactosamine-6 sulfatase (GALNS) and presenting with short stature, abnormal gait, cervical spine instability and shortened lifespan.PurposeTo prepare a systematic review of the prevalence of Morquio A in multiple countries and suggest recommendations for reporting rare diseases.Methods Medline, Medline In-Process, Medline Daily Update, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database and PROSPERO were searched from inception to October 2013 to identify relevant information on the epidemiology of Morquio A. Forty Patient Organisation Representatives (POR) and Key Opinion Leaders (KOL) across 24 countries were contacted for data. Observational studies were included and case reports were excluded. Searches were performed without date or language restriction. Two researchers independently screened and extracted data. Quality of study reporting was assessed using a checklist adapted from STROBE (STrengthening the Reporting of OBservational studies in Epidemiology). Point or birth prevalence was stratified according to diagnostic method and discussed narratively.ResultsIn total 9,074 records were retrieved from searching and 25 studies were included for data extraction. Twenty out of 40 KOL and POR responded (50%) and 9 provided data (23%). Point prevalence of Morquio A was 1 per 926,000 in Australia, 1 per 1,872,000 in Malaysia and 1 per 599,000 in UK and Morquio (unclassified) was 1 per 323, 000 in Denmark. Birth prevalence of Morquio A (using recommended diagnostic methods) ranged from 1 per 71,000 in UAE to 1 per 500,000 in Japan. All results were compromised by poor study reporting and internal validity.Conclusions The review highlighted that there is a misunderstanding of the definitions for prevalence and incidence in the field; that studies were poorly reported (diagnostic methods and patient characteristics) and that no suitable quality assessment tool exists. Overestimation and underestimation of prevalence data can occur. Bespoke reporting guidelines and a quality assessment tool specifically for prevalence of rare diseases are recommended.
    Orphanet Journal of Rare Diseases 11/2014; 9(1):173. · 4.32 Impact Factor
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    ABSTRACT: Morquio A syndrome is characterized by progressive impairment of endurance•Longitudinal trends in FVC and MVV are likely influenced by growth•6MWT is a clinically meaningful measure of disease progression in Morquio A
    Molecular Genetics and Metabolism 11/2014; · 2.83 Impact Factor
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    ABSTRACT: Morquio A syndrome (mucopolysaccharidosis IVA) is a lysosomal storage disorder associated with skeletal and joint abnormalities and significant non-skeletal manifestations including respiratory disease, spinal cord compression, cardiac disease, impaired vision, hearing loss, and dental problems. The clinical presentation, onset, severity and progression rate of clinical manifestations of Morquio A syndrome vary widely between patients. Because of the heterogeneous and progressive nature of the disease, the management of patients with Morquio A syndrome is challenging and requires a multidisciplinary approach, involving an array of specialists. The current paper presents international guidelines for the evaluation, treatment and symptom- based management of Morquio A syndrome. These guidelines were developed during two expert meetings by an international panel of specialists in pediatrics, genetics, orthopedics, pulmonology, cardiology, and anesthesia with extensive experience in managing Morquio A syndrome.
    American Journal of Medical Genetics 10/2014; Part A(9999A):1-15.
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    ABSTRACT: Human α-l-iduronidase (IDUA) is a member of glycoside hydrolase family and is involved in the catabolism of glycosaminoglycans (GAGs), heparan sulfate (HS) and dermatan sulfate (DS). Mutations in this enzyme are responsible for mucopolysaccharidosis I (MPS I), an inherited lysosomal storage disorder. Despite great interest in determining and studying this enzyme structure, the lack of a high identity to templates and other technical issues have challenged both bioinformaticians and crystallographers, until the recent publication of an IDUA crystal structure (PDB: 4JXP). In the present work, four alternative IDUA models, generated and evaluated prior to crystallographic determination, were compared to the 4JXP structure. A combined analysis using several viability assessment tools and molecular dynamics simulations highlights the strengths and limitations of different comparative modeling protocols, all of which are based on the same low identity template (only 22%). Incorrect alignment between the target and template was confirmed to be a major bottleneck in homology modeling, regardless of the modeling software used. Moreover, secondary structure analysis during a 50ns simulation seems to be useful for indicating alignment errors and structural instabilities. The best model was achieved through the combined use of Phyre 2 and Modeller, suggesting the use of this protocol for the modeling of other proteins that still lack high identity templates. Copyright © 2014 Elsevier Inc. All rights reserved.
    Journal of Molecular Graphics and Modelling. 10/2014;
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    ABSTRACT: Mucopolysaccharidosis I is a genetic disorder caused by alpha-L-iduronidase deficiency. Its primary treatment is enzyme replacement therapy (ERT), which has limitations such as a high cost and a need for repeated infusions over the patient's lifetime. Considering that nanotechnological approaches may enhance enzyme delivery to organs and can reduce the dosage thereby enhancing ERT efficiency and/or reducing its cost, we synthesized laronidase surface-functionalized lipid-core nanocapsules (L-MLNC).
    Pharmaceutical Research 09/2014; · 4.74 Impact Factor
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    ABSTRACT: Krabbe disease (KD) is an inherited lysosomal storage disease (LSD) caused by the deficiency of galactocerebrosidase (GALC) and is characterized by a severe and progressive leukodystrophy with death frequently before one year of life in the classical early-onset form. As a consequence of the enzyme defect, globoid cells containing undigested galactosylceramide are observed and are characteristic of the disease. Hematopoietic stem cell transplantation is the current treatment for this disease, with some success in the classical cases if performed very early in life. Definitive diagnosis of KD is generally accessed by determination of GALC in leukocytes or fibroblasts. For the last few years, dried-blood filter paper (DBFP) samples have been increasingly used for lysosomal enzyme assays. Originally, some lysosomal enzymes could not be tested in DBFP samples using fluorometric assays, including GALC, heparan-sulfamidase and a few others. Recently, however, we reported successful results using dried-leukocytes filter paper (DLFP) samples for heparan sulfamidase and β-galactosidase.
    Clinica Chimica Acta 09/2014; 438. · 2.85 Impact Factor
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    ABSTRACT: Mucopolysaccharidosis type I is a rare autosomal recessive disorder caused by deficiency ofα-L-iduronidase (IDUA) which leads to a wide spectrum of clinical severity. Here we describe the case of four male patients who present the previously undescribed p.L18P mutation.Patient 1 (p.L18P/p.L18P) presents, despite multiple joint contractures, an attenuated phenotype. Patient 2 (p.L18P/p.W402X) was diagnosed at 4 years of age with bone dysplasia, coarse facies, limited mobility, claw hands and underwent bilateral carpal tunnel surgery at 6 years of age. Patients 3 and 4 (both p.L18P/p.L18P) are brothers. Patient 3 was diagnosed at 4 years of age, when presented claw hands, lower limb and shoulder pain, restricted articular movement and bilateral carpal tunnel syndrome. Patient 4 was diagnosed at 17 months of age when presented lower limb pain at night, respiratory allergy and repeated upper airways infections. Bioinformatics analysis indicates that p.L18P mutation reduces the signal peptide to 25 amino acids and alters its secondary structure. In conclusion, we report a new IDUA variant that alters the structure of the signal peptide, which likely impairs transport to lysosomes. Moreover, it leads to a distinct attenuated phenotype with mainly bone and cartilage symptoms, without visceromegalies, heart disease or cognitive impairment.
    Clinical Genetics 09/2014; · 4.25 Impact Factor
  • Olaf A. Bodamer, Roberto Giugliani, Tim Wood
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    ABSTRACT: Mucopolysaccharidosis type III (MPS III) is characterized by progressive neurological deterioration, behavioral abnormalities, a relatively mild somatic phenotype, and early mortality. Because of the paucity of somatic manifestations and the rarity of the disease, early diagnosis is often difficult. Therapy targeting the underlying disease pathophysiology may offer the greatest clinical benefit when started prior to the onset of significant neurologic sequale. Here we review current practices in the laboratory diagnosis of MPS III in order to facilitate earlier patient identification and diagnosis. When clinical suspicion of MPS III arises, the first step is to order a quantitative assay that screens urine for the presence of glycosaminoglycan biomarkers using a spectrophotometric compound (e.g., dimethylmethylene blue). We recommend testing all patients with developmental delay and/or behavioral abnormalities as part of the diagnostic work-up because quantitative urine screening is inexpensive and non-invasive. Semi-quantitative urine screening assays using cationic dyes on filter paper (e.g., spot tests) have relatively high rates of false-positives and false-negatives and are obsolete. Of note, a negative urinary glycosaminoglycan assay does not necessarily rule out MPS because, in some patients, an overlap in excretion levels with healthy controls may occur. All urine samples that test positive for glycosaminoglycans with a quantitative assay should be confirmed by electrophoresis, thin layer chromatography, or tandem mass spectrometry, which further improves the sensitivity and specificity. The gold standard for diagnosis remains the enzyme activity assay in cultured skin fibroblasts, leukocytes, plasma, or serum, which can be used as a first-line diagnostic test in some regions. Molecular genetic analysis should be offered to all families of patients to allow genetic counseling for informed family planning. For a small number of variants, genotype-phenotype correlations are available and can offer prognostic value. Prenatal testing via enzyme activity assay in chorionic villi or amniotic fluid cells is available at a limited number of centers worldwide, but whenever possible, a molecular genetic analysis is preferred for prenatal diagnosis. To conclude, we discuss the development of newborn screening assays in dried blood spots and high-throughput methods for sequencing the protein-coding regions of the genome (whole exome sequencing) and their relevance to future changes in the MPS III diagnostic landscape.
    Molecular Genetics and Metabolism 09/2014; · 2.83 Impact Factor
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    ABSTRACT: Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disorder caused by deficient activity of Arylsulphatase B (ARSB). The disease is progressive and multisystemic, usually leading to death in the first decades of life. In addition to supportive management, specific treatments for MPS VI are the hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). Both are effective for some aspects of the disease, but fail in correcting important clinical features, such as bone deformities and heart valve thickening. Based on that, new treatments are currently being tested to be used alone or in combination with the current therapies. Here we summarize some of these new approaches and the preliminary results obtained, reporting their limitations and indicating possible future trends in MPS VI treatment. We discuss intrathecal ERT, gene therapy and therapies based on anti-inflammatory molecules, among other approaches. Finally, we highlight the importance of early treatment and diagnosis for a better outcome in these patients.
    Pediatric endocrinology reviews: PER 09/2014; 12 Suppl 1:152-8.
  • Journal of Inherited Metabolic Disease 08/2014; · 4.07 Impact Factor
  • Cell Biology and Toxicology 07/2014; · 2.34 Impact Factor
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    ABSTRACT: This review aims to provide clinicians in Latin America with the most current information on the clinical aspects, diagnosis, and management of Hunter syndrome, a serious and progressive disease for which specific treatment is available. Hunter syndrome is a genetic disorder where iduronate-2-sulfatase (I2S), an enzyme that degrades glycosaminoglycans, is absent or deficient. Clinical manifestations vary widely in severity and involve multiple organs and tissues. An attenuated and a severe phenotype are recognized depending on the degree of cognitive impairment. Early diagnosis is vital for disease management. Clinical signs common to children with Hunter syndrome include inguinal hernia, frequent ear and respiratory infections, facial dysmorphisms, macrocephaly, bone dysplasia, short stature, sleep apnea, and behavior problems. Diagnosis is based on screening urinary glycosaminoglycans and confirmation by measuring I2S activity and analyzing I2S gene mutations. Idursulfase (recombinant I2S) (Elaprase(®), Shire) enzyme replacement therapy (ERT), designed to address the underlying enzyme deficiency, is approved treatment and improves walking capacity and respiratory function, and reduces spleen and liver size and urinary glycosaminoglycan levels. Additional measures, responding to the multi-organ manifestations, such as abdominal/inguinal hernia repair, carpal tunnel surgery, and cardiac valve replacement, should also be considered. Investigational treatment options such as intrathecal ERT are active areas of research, and bone marrow transplantation is in clinical practice. Communication among care providers, social workers, patients and families is essential to inform and guide their decisions, establish realistic expectations, and assess patients' responses.
    Genetics and molecular biology. 06/2014; 37(2):315-29.
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    ABSTRACT: Chondroitin 6-sulfate (C6S), a glycosaminoglycan (GAG), is distributed mainly in the growth plates, aorta, and cornea; however, the physiological function of C6S is not fully understood. One of the limitations is that no rapid, accurate quantitative method to measure C6S has been established. Mucopolysaccharidosis IVA and VII (MPS IVA and VII) are caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase and β-D-glucuronidase, respectively, resulting in accumulation of C6S and other GAG(s). While levels of keratan sulfate (KS), heparan sulfate, and dermatan sulfate in samples from MPS patients are well described, this is the first report of quantitative analysis of C6S levels in samples from MPS IVA and VII patients.We developed a method to digest polymeric C6S and measure resultant disaccharides using liquid chromatography- tandem mass spectrometry (LC-MS/MS). C6S levels were measured in the blood from control subjects and patients with MPS IVA and VII aged from 0 to 58 years of age. We also assayed KS levels in the same samples for comparison with C6S.Levels of C6S in the blood decreased with age and were significantly elevated in patients with MPS IVA and VII, compared with age-matched controls. Levels of KS in patients with MPS IVA were also higher than those in age-matched controls, although differences were less pronounced than with C6S. Combining KS and C6S data, discriminated patients with MPS IVA from age-matched control subjects were better than either C6S or KS levels alone.In conclusion, this first report showing that blood levels of C6S are quantitatively evaluated in patients with MPS IVA and VII indicates that C6S could be a useful biomarker for these metabolic disorders.
    JIMD reports. 05/2014;
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    ABSTRACT: To assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA). Patients with Morquio A aged ≥5 years (N = 176) were randomised (1:1:1) to receive elosulfase alfa 2.0 mg/kg/every other week (qow), elosulfase alfa 2.0 mg/kg/week (weekly) or placebo for 24 weeks in this phase 3, double-blind, randomised study. The primary efficacy measure was 6-min walk test (6MWT) distance. Secondary efficacy measures were 3-min stair climb test (3MSCT) followed by change in urine keratan sulfate (KS). Various exploratory measures included respiratory function tests. Patient safety was also evaluated. At week 24, the estimated mean effect on the 6MWT versus placebo was 22.5 m (95 % CI 4.0, 40.9; P = 0.017) for weekly and 0.5 m (95 % CI -17.8, 18.9; P = 0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95 % CI -2.1, 4.4; P = 0.494) for weekly and -0.5 stairs/min (95 % CI -3.7, 2.8; P = 0.778) for qow. Normalised urine KS was reduced at 24 weeks in both regimens. In the weekly dose group, 22.4 % of patients had adverse events leading to an infusion interruption/discontinuation requiring medical intervention (only 1.3 % of all infusions in this group) over 6 months. No adverse events led to permanent treatment discontinuation. Elosulfase alfa improved endurance as measured by the 6MWT in the weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced urine KS, and had an acceptable safety profile.
    Journal of Inherited Metabolic Disease 05/2014; · 4.07 Impact Factor
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    ABSTRACT: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder of bile acid (BA) synthesis that can cause progressive neurological damage and premature death. Blood (normally serum or plasma) testing for CTX is performed by a small number of specialized laboratories, routinely by gas chromatography-mass spectrometry (GC-MS) measurement of elevated 5α- cholestanol. We report here on a more sensitive biochemical approach to test for CTX particularly useful for confirmation of CTX in the case of a challenging diagnostic sample with 5α-cholestanol that, although elevated, was below the cut-off used for diagnosis of CTX (10μg/ml or 1.0mg/dL). We have previously described liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) methodology utilizing keto derivatization to enable the sensitive quantification of plasma ketosterol BA precursors that accumulate in CTX. We have expanded this methodology to perform isotope dilution LC-ESI-MS/MS quantification of a panel of plasma ketosterol BA precursors, with internal standards readily generated using isotopically-enriched derivatization reagent. Quantification of plasma ketosterol BA precursors (7α-hydroxy-4-cholesten-3-one, 7α,12α-dihydroxy-4-cholesten-3-one and 7α,12α-dihydroxy-5β-cholestan-3-one) in a single LC- ESI/MS/MS test provided better discrimination between a CTX-positive and negative samples analyzed (n=20) than measurement of 5α-cholestanol alone. Quantification of plasma ketosterol BA precursors provides a more sensitive biochemical approach to discriminate between CTX negative and positive samples. A multiplexed LC-ESI-MS/MS test quantifying a panel of plasma ketosterols, with simple sample preparation, rapid analysis time and readily available internal standards, can be performed by most clinical laboratories. Wider availability of testing will benefit those affected with CTX.
    Clinical biochemistry 04/2014; · 2.02 Impact Factor
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    ABSTRACT: Mucopolysaccharidosis VI (MPS VI) is a clinically heterogeneous and progressive disorder with multiorgan manifestations caused by deficient N-acetylylgalactosamine-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. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 04/2014; · 2.30 Impact Factor
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    ABSTRACT: Purpose:In this study, we aimed to describe the natural history of mucopolysaccharidosis I.Methods:Data from 1,046 patients who enrolled in the MPS I Registry as of August 2013 were available for descriptive analysis. Only data from untreated patients and data prior to treatment for patients who received treatment were considered. Age at symptom onset, diagnosis, and treatment initiation were examined by geographic region and phenotype (from most to least severe: Hurler, Hurler-Scheie, and Scheie). For each symptom, frequency and age at onset were examined.Results:Natural history data were available for 987 patients. Most patients were from Europe (45.5%), followed by North America (34.8%), Latin America (17.3%), and Asia Pacific (2.4%). Phenotype distribution was 60.9% for Hurler, 23.0% for Hurler-Scheie, and 12.9% for Scheie (3.2% undetermined) syndromes. Median age at symptom onset for Hurler, Hurler-Scheie, and Scheie syndromes was 6 months, 1.5 years, and 5.3 years, respectively; median age at treatment initiation was 1.5 years, 8.0 years, and 16.9 years, respectively. Coarse facial features and corneal clouding were among the most common symptoms in all three phenotypes.Conclusion:A delay between symptom onset and treatment exists, especially in patients with attenuated mucopolysaccharidosis I. A better understanding of disease manifestations may help facilitate prompt diagnosis and treatment and improve patient outcomes.Genet Med advance online publication 27 March 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.25.
    Genetics in medicine: official journal of the American College of Medical Genetics 03/2014; · 3.92 Impact Factor
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    ABSTRACT: 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. 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. 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. 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.
    Journal of Inherited Metabolic Disease 03/2014; · 4.07 Impact Factor

Publication Stats

4k Citations
928.61 Total Impact Points

Institutions

  • 2014
    • Population Genetics
      Cambridge, Massachusetts, United States
  • 1986–2014
    • Hospital De Clínicas De Porto Alegre
      Pôrto de São Francisco dos Casaes, Rio Grande do Sul, Brazil
  • 1985–2014
    • Universidade Federal do Rio Grande do Sul
      • Departamento de Bioquímica
      Pôrto de São Francisco dos Casaes, Rio Grande do Sul, Brazil
    • Federal University of Santa Catarina
      Nossa Senhora do Destêrro, Santa Catarina, Brazil
  • 2013
    • Washington University in St. Louis
      San Luis, Missouri, United States
    • The University of Manchester
      • Centre for Genetic Medicine
      Manchester, England, United Kingdom
    • Los Andes University (Colombia)
      • Departamento de Ciencias Biológicas
      Bogotá, Bogota D.C., Colombia
  • 2005–2013
    • Children's Hospital & Research Center Oakland
      Oakland, California, United States
  • 2012
    • University of North Carolina at Chapel Hill
      • Department of Pediatrics
      Chapel Hill, NC, United States
    • Birmingham Children's Hospital NHS Foundation Trust
      Birmingham, England, United Kingdom
    • Children's Memorial Hospital
      Chicago, Illinois, United States
    • Greenwood Genetic Center
      Greenwood, South Carolina, United States
    • University of Washington Seattle
      • Division of General Internal Medicine
      Seattle, WA, United States
    • University of Pennsylvania
      • Department of Orthopaedic Surgery
      Philadelphia, PA, United States
  • 2011–2012
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
    • SickKids
      • Division of Clinical and Metabolic Genetics
      Toronto, Ontario, Canada
    • Santa Casa de Porto Alegre
      Pôrto de São Francisco dos Casaes, Rio Grande do Sul, Brazil
  • 2010
    • Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany
  • 2009
    • Fundação Oswaldo Cruz
      • Departamento de Genética (IOC)
      Rio de Janeiro, Rio de Janeiro, Brazil
  • 2008
    • Saint Louis University
      • Department of Pediatrics
      Saint Louis, MI, United States
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
  • 2006
    • Hospital Mãe De Deus
      Pôrto de São Francisco dos Casaes, Rio Grande do Sul, Brazil
  • 2000
    • Faculdade Novo Hamburgo
      Potiguara, Rio Grande do Sul, Brazil
  • 1993–1999
    • Vanderbilt University
      • Department of Pediatrics
      Nashville, MI, United States
  • 1997
    • Universidade Federal da Bahia
      Bahia, Estado de Bahía, Brazil