Publications by authors named "Joseph Muenzer"

60 Publications

A charitable access program for patients with lysosomal storage disorders in underserved communities worldwide.

Orphanet J Rare Dis 2021 Jan 6;16(1). Epub 2021 Jan 6.

Ann & Robert H. Lurie Children's Hospital and Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Background: Lysosomal storage disorders (LSDs) are rare genetic disorders, with heterogeneous clinical manifestations and severity. Treatment options, such as enzyme replacement therapy (ERT), substrate replacement therapy, and pharmacological chaperone therapy, are available for several LSDs, including Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (mucopolysaccharidosis type II [MPS II]). However, patients in some countries face challenges accessing treatments owing to limited availability of locally licensed, approved drugs.

Methods: The Takeda LSD Charitable access program aims to meet the needs of individuals with GD, FD or MPS II with the greatest overall likelihood of benefit, in selected countries, through donation of ERT to nonprofit organizations, and support for medical capacity-building as well as family support via independent grants. Long-term aims of the program are to establish sustainable healthcare services delivered by local healthcare providers for patients with rare metabolic diseases. Patients receiving treatment through the program are monitored regularly, and their clinical data and progress are reviewed annually by an independent medical expert committee (MEC). The MEC also selects patients for enrollment completely independent from the sponsoring company.

Results: As of 31 August, 2019, 199 patients from 13 countries were enrolled in the program; 142 with GD, 41 with MPS II, and 16 with FD. Physicians reported improvements in clinical condition for 147 (95%) of 155 patients with follow-up data at 1 year.

Conclusions: The response rate for follow-up data at 1 year was high, with data collected for > 90% of patients who received ERT through the program showing clinical improvements in the majority of patients. These findings suggest that the program can benefit selected patients previously unable to access disease-specific treatments. Further innovative solutions and efforts are needed to address the challenges and unmet needs of patients with LSDs and other rare diseases around the world.
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http://dx.doi.org/10.1186/s13023-020-01645-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788852PMC
January 2021

Improvement in time to treatment, but not time to diagnosis, in patients with mucopolysaccharidosis type I.

Arch Dis Child 2020 Nov 2. Epub 2020 Nov 2.

Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Objective: Early diagnosis and treatment initiation are important factors for successful treatment of mucopolysaccharidosis type I (MPS I). The purpose of this observational study was to assess whether age at diagnosis and time to first treatment for individuals with MPS I have improved over the last 15 years.

Study Design: Data from the MPS I Registry (NCT00144794) for individuals with attenuated or severe disease who initiated therapy with laronidase enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT) between 1 January 2003 and 31 December 2017 were included.

Results: Data were available for 740 individuals with attenuated (n=291) or severe (n=424) MPS I (unknown n=25). Median age at diagnosis for attenuated disease did not change over time and ranged between 4.5 and 6 years of age while the median duration from diagnosis to first ERT decreased from 5.6 years before/during 2004 to 2.4 months in 2014-2017. For severe MPS I treated with HSCT, median age at diagnosis was less than 1 year and median time to first treatment was less than 3 months throughout the 15-year observation period.

Conclusions: Times to diagnosis and HSCT initiation for individuals with severe MPS I were consistent over time. For individuals with attenuated MPS I, the time to ERT initiation after diagnosis has improved substantially in the last 15 years, but median age at diagnosis has not improved. Efforts to improve early diagnosis in attenuated MPS I are needed to ensure that patients receive appropriate treatment at the optimal time.
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http://dx.doi.org/10.1136/archdischild-2020-319040DOI Listing
November 2020

Therapy development for the mucopolysaccharidoses: Updated consensus recommendations for neuropsychological endpoints.

Mol Genet Metab 2020 Sep - Oct;131(1-2):181-196. Epub 2020 Aug 31.

Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Shapiro Neuropsychology Consulting LLC, Portland, OR, USA. Electronic address:

Neurological dysfunction represents a significant clinical component of many of the mucopolysaccharidoses (also known as MPS disorders). The accurate and consistent assessment of neuropsychological function is essential to gain a greater understanding of the precise natural history of these conditions and to design effective clinical trials to evaluate the impact of therapies on the brain. In 2017, an International MPS Consensus Panel published recommendations for best practice in the design and conduct of clinical studies investigating the effects of therapies on cognitive function and adaptive behavior in patients with neuronopathic mucopolysaccharidoses. Based on an International MPS Consensus Conference held in February 2020, this article provides updated consensus recommendations and expands the objectives to include approaches for assessing behavioral and social-emotional state, caregiver burden and quality of life in patients with all mucopolysaccharidoses.
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http://dx.doi.org/10.1016/j.ymgme.2020.08.007DOI Listing
August 2020

Growth patterns for untreated individuals with MPS I: Report from the international MPS I registry.

Am J Med Genet A 2019 12 22;179(12):2425-2432. Epub 2019 Oct 22.

Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Femme Mère Enfant, Lyon, France.

Mucopolysaccharidosis Type I (MPS I), caused by deficiency of α-L-iduronidase results in progressive, multisystemic disease with a broad phenotypic spectrum including patients with severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) disease. Disordered growth is common with either phenotype. The study objectives were to construct sex- and age-specific estimated length/height and head circumference growth curves for untreated individuals with severe and attenuated disease and compare them with clinical reference standards. Untreated individuals in the MPS I Registry with at least one observation for length/height and/or head circumference and assigned phenotype as of May 2017 were included. Median growth for 463 untreated individuals with severe disease deviated from reference growth curves by ~6 months of age and fell below the third percentile by 4 years of age. Median head circumference was above reference curves from 3 to 4 months through 3 years of age. Among 207 individuals with untreated attenuated disease, median height fell below the third percentile by 9 years of age with divergence from reference curves by 2 years of age. MPS I-specific growth curves will be useful in evaluation of long-term outcomes of therapeutics interventions and will provide a foundation for understanding the pathogenesis of skeletal disease in MPS I.
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http://dx.doi.org/10.1002/ajmg.a.61378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899772PMC
December 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

Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry.

Clin Genet 2019 10 2;96(4):281-289. Epub 2019 Jul 2.

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resulting from pathogenic variants in the α-L-iduronidase (IDUA) gene. Clinical phenotypes range from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) and vary in age of onset, severity, and rate of progression. Defining the phenotype at diagnosis is essential for disease management. To date, no systematic analysis of genotype-phenotype correlation in large MPS I cohorts have been performed. Understanding genotype-phenotype is critical now that newborn screening for MPS I is being implemented. Data from 538 patients from the MPS I Registry (380 severe, 158 attenuated) who had 2 IDUA alleles identified were examined. In the 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 were unique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenuated and 22% of patients with severe MPS I had unique genotypes. About 67.6% of severe patients had genotypes where both variants identified are predicted to severely disrupt protein/gene function and 96.1% of attenuated patients had at least one missense or intronic variant. This dataset illustrates a close genotype/phenotype correlation in MPS I but the presence of unique IDUA missense variants remains a challenge for disease prediction.
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http://dx.doi.org/10.1111/cge.13583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852151PMC
October 2019

Metabonomics reveals altered metabolites related to inflammation and energy utilization at recovery of cystic fibrosis lung exacerbation.

Metabol Open 2019 Sep 8;3:100010. Epub 2019 Jun 8.

Dept. Pediatrics, Division Metabolism and Genetics, University of North Carolina at Chapel Hill, USA.

Background: Cystic fibrosis lung disease is characterized by chronic bacterial infections in the setting of mucus abnormalities. Patients experience periodic exacerbations that manifest with increased respiratory symptoms that require intensification of therapy with enhanced airway clearance and intravenous (IV) antibiotics.

Objectives: In an observational study we tested if the profile of metabolites in serum distinguished the pre-from post-exacerbation state and which systemically measurable pathways were affected during the process to recovery.

Methods: Serum collected within 48 h of start and completion, respectively of IV antibiotics was collected from people with CF ages 6-30 years. Three day food records were collected prior to each sample. To reduce variation between subjects only subjects who had pancreatic insufficiency, had similar CF mutations, and did not have CF liver disease or diabetes were included. Metabolomic profiling was conducted by Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy with metabolites being identified based on retention time/index, mass to charge ratio and comparison to known compounds. Biostatistical analyses used paired -test with correction for multiple comparisons and orthogonal partial least square discriminant analysis.

Results: Thirty subjects (20 male) with a mean ± SEM age of 15.3 ± 1.2 years participated, 17 of whom had matched food-records. Lung function was significantly improved post-therapy compared to pre-therapy, (mean ± SEM) 75 ± 4% vs. 68 ± 4% predicted (n = 26). Serum metabonomics showed distinction of the pre-vs. post-therapy groups with 123 compounds contributing to the differentiation pre-versus post-antibiotics by multiple biostatistical analyses. Compounds and pathways affected included bile acids and microbial derived amino acid metabolites, increases in lipid classes of the glycerophospholipid, glycerolipids, cholesterol, phopsholipids, and most pronounced, the class of sphingolipids. Changes in n6/n3 fatty acids, decreased polyamines but increased metabolites in the nitric oxide pathway, and changes in the tryptophan-kynurenine pathway indicated decreased inflammation at resolution of exacerbation.

Conclusions: Changes in serum metabolites that distinguished CF pulmonary exacerbation vs. resolution of symptoms showed evidence of decreased inflammation and improvement from a catabolic state.
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http://dx.doi.org/10.1016/j.metop.2019.100010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424819PMC
September 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

The North Carolina Experience with Mucopolysaccharidosis Type I Newborn Screening.

J Pediatr 2019 08 24;211:193-200.e2. Epub 2019 May 24.

University of North Carolina at Chapel Hill, Chapel Hill,NC.

Objective: To evaluate the performance of a 2-tiered newborn screening method for mucopolysaccharidosis type I (MPS I) in North Carolina.

Study Design: The screening algorithm included a flow injection analysis-tandem mass spectrometry assay as a first-tier screening method to measure α-L-iduronidase (IDUA) enzyme activity and Sanger sequencing of the IDUA gene on dried blood spots as a second-tier assay. The screening algorithm was revised to incorporate the Collaborative Laboratory Integrated Reports, an analytical interpretive tool, to reduce the false-positive rate. A medical history, physical examination, IDUA activity, and urinary glycosaminoglycan (GAG) analysis were obtained on all screen-positive infants.

Results: A total of 62 734 specimens were screened with 54 screen-positive samples using a cut-off of 15% of daily mean IDUA activity. The implementation of Collaborative Laboratory Integrated Reports reduced the number of specimens that screened positive to 19 infants. Of the infants identified as screen-positive, 1 had elevated urinary GAGs and a homozygous pathogenic variant associated with the severe form of MPS I. All other screen-positive infants had normal urinary GAG analysis; 13 newborns had pseudodeficiency alleles, 3 newborns had variants of unknown significance, and 2 had heterozygous pathogenic variants.

Conclusions: An infant with severe MPS I was identified and referred for a hematopoietic stem cell transplant. Newborn IDUA enzyme deficiency is common in North Carolina, but most are due to pseudodeficiency alleles in infants with normal urinary GAG analysis and no evidence of disease. The pilot study confirmed the need for second-tier testing to reduce the follow-up burden.
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http://dx.doi.org/10.1016/j.jpeds.2019.04.027DOI Listing
August 2019

Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial.

Mol Genet Metab 2019 02 24;126(2):121-130. Epub 2018 Oct 24.

Shire, Lexington, MA, USA. Electronic address:

Background: Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA) is a lysosomal disorder wherein deficient heparan-N-sulfatase (HNS) activity results in the accumulation of heparan sulfate in the central nervous system and is associated with progressive neurodegeneration in early childhood. We report on the efficacy, pharmacokinetics, safety, and tolerability of intrathecal (IT) administration of recombinant human HNS (rhHNS) from a phase IIb randomized open-label trial.

Methods: Twenty-one patients, randomized 1:1:1 to rhHNS IT 45 mg administered every 2 weeks (Q2W), every 4 weeks (Q4W), or no treatment, were assessed for amelioration in neurocognitive decline as determined by the Bayley Scales of Infant and Toddler Development®, Third Edition. The primary efficacy goal was defined as ≤10-point decline (responder) in at least three patients in a dosing cohort after 48 weeks. Other efficacy assessments included adaptive behavioral function, assessments of cortical gray matter volume, and glycosaminoglycan (GAG) levels in urine.

Results: A clinical response to rhHNS IT was observed in three treated patients (two in the Q2W group, one in the Q4W group). Cerebrospinal fluid heparan sulfate and urine GAG levels were reduced in all treated patients. However, most secondary efficacy assessments were similar between treated patients (n = 14; age, 17.8-47.8 months) and untreated controls (n = 7; age, 12.6-45.0 months). Treatment-emergent adverse events that occurred with rhHNS IT were mostly mild, none led to study discontinuation, and there were no deaths.

Conclusion: rhHNS IT treatment reduced heparan sulfate and GAG levels in treated patients. Though the primary neurocognitive endpoint was not met, important lessons in the design and endpoints for evaluation of cognitive and behavioral diseases resulted.

Trial Registration: ClinicalTrials.govNCT02060526; EudraCT 2013-003450-24.
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http://dx.doi.org/10.1016/j.ymgme.2018.10.006DOI Listing
February 2019

Targeting Root Cause by Systemic scAAV9-h Gene Delivery: Functional Correction and Reversal of Severe MPS II in Mice.

Mol Ther Methods Clin Dev 2018 Sep 4;10:327-340. Epub 2018 Sep 4.

Division of Genetics and Metabolism, Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.

No treatment is available to address the neurological need and reversibility of MPS II. We developed a scAAV9-h vector to deliver the human iduronate-2-sulfatase gene and test it in mouse model. We treated MPS II mice at different disease stages with an intravenous injection of scAAV9-mCMV-h at different doses. The treatments led to rapid and persistent restoration of IDS activity and the reduction of glycosaminoglycans (GAG) throughout the CNS and somatic tissues in all cohorts. Importantly, the vector treatment at up to age 6 months improved behavior performance in the Morris water maze and normalized the survival. Notably, vector treatment at age 9 months also resulted in persistent rIDS expression and GAG clearance in MPS II mice, and the majority of these animals survived within the normal range of lifespan. Notably, the vector delivery did not result in any observable adverse events or detectable systemic toxicity in any treated animal groups. We believe that we have developed a safe and effective gene therapy for treating MPS II, which led to recent IND approval for a phase 1/2 clinical trial in MPS II patients, further supporting the extended potential of the demonstrated systemic rAAV9 gene delivery platform for broad disease targets.
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http://dx.doi.org/10.1016/j.omtm.2018.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125796PMC
September 2018

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

Carpal tunnel syndrome in mucopolysaccharidosis I: a registry-based cohort study.

Dev Med Child Neurol 2017 12 11;59(12):1269-1275. Epub 2017 Sep 11.

Department of Orthopedics, University of Utah, Salt Lake City, UT, USA.

Aim: To characterize carpal tunnel syndrome (CTS) in patients with mucopolysaccharidosis I (MPS I).

Method: Data were included for patients with MPS I who had either nerve conduction examination that included a diagnosis of CTS or who had CTS release surgery. Although this represented a subset of patients with CTS in the MPS I Registry, the criteria were considered the most objective for data analysis.

Results: As of March 2016, 994 patients were categorized with either severe (Hurler syndrome) or attenuated (Hurler-Scheie or Scheie syndromes) MPS I. Among these, 291 had a CTS diagnosis based on abnormal nerve conduction (n=54) or release surgery (n=237). Median ages (minimum, maximum) at first CTS diagnosis were 5 years 2 months (10mo, 16y 2mo) and 9y 11mo (1y 8mo, 44y 1mo) for patients with severe and attenuated MPS I respectively. Most patients had their first CTS diagnosis after MPS I diagnosis (94%) and treatment (hematopoietic stem cell transplant and/or enzyme replacement therapy) (74%). For 11% of patients with attenuated disease, CTS diagnosis preceded MPS I diagnosis by a mean of 7 years 6 months.

Interpretation: CTS is a rare complication in pediatric patients and should alert medical care providers to the potential diagnosis of MPS I. Significant delays exist between diagnosis of CTS and MPS I for patients with attenuated disease.

What This Paper Adds: There are significant delays in diagnosing carpal tunnel syndrome (CTS) in patients with mucopolysaccharidosis I (MPS I). Enzyme replacement therapy or hematopoietic stem cell transplant do not prevent the development of CTS. Testing for CTS in patients with MPS I is recommended to prevent irreparable damage. CTS in pediatric patients should alert physicians to potential diagnosis of MPS I.
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http://dx.doi.org/10.1111/dmcn.13545DOI Listing
December 2017

Co-occurring Down syndrome and SUCLA2-related mitochondrial depletion syndrome.

Am J Med Genet A 2017 Oct 27;173(10):2720-2724. Epub 2017 Jul 27.

Department of Pediatrics, Division of Genetics and Metabolism, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Mitochondrial DNA depletion syndrome 5 (MIM 612073) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the beta subunit of the succinate-CoA ligase gene located within the 13q14 band. We describe two siblings of Hispanic descent with SUCLA2-related mitochondrial depletion syndrome (encephalomyopathic form with methylmalonic aciduria); the older sibling is additionally affected with trisomy 21. SUCLA2 sequencing identified homozygous p.Arg284Cys pathogenic variants in both patients. This mutation has previously been identified in four individuals of Italian and Caucasian descent. The older sibling with concomitant disease has a more severe phenotype than what is typically described in patients with either SUCLA2-related mitochondrial depletion syndrome or Down syndrome alone. The younger sibling, who has a normal female chromosome complement, is significantly less affected compared to her brother. While the clinical and molecular findings have been reported in about 50 patients affected with a deficiency of succinate-CoA ligase caused by pathogenic variants in SUCLA2, this report describes the first known individual affected with both a mitochondrial depletion syndrome and trisomy 21.
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http://dx.doi.org/10.1002/ajmg.a.38351DOI Listing
October 2017

Cognitive endpoints for therapy development for neuronopathic mucopolysaccharidoses: Results of a consensus procedure.

Mol Genet Metab 2017 06 6;121(2):70-79. Epub 2017 May 6.

Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Shapiro Neuropsychology Consulting, LLC, Portland, OR, USA. Electronic address:

The design and conduct of clinical studies to evaluate the effects of novel therapies on central nervous system manifestations in children with neuronopathic mucopolysaccharidoses is challenging. Owing to the rarity of these disorders, multinational studies are often needed to recruit enough patients to provide meaningful data and statistical power. This can make the consistent collection of reliable data across study sites difficult. To address these challenges, an International MPS Consensus Conference for Cognitive Endpoints was convened to discuss approaches for evaluating cognitive and adaptive function in patients with mucopolysaccharidoses. The goal was to develop a consensus on best practice for the design and conduct of clinical studies investigating novel therapies for these conditions, with particular focus on the most appropriate outcome measures for cognitive function and adaptive behavior. The outcomes from the consensus panel discussion are reported here.
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http://dx.doi.org/10.1016/j.ymgme.2017.05.004DOI Listing
June 2017

Ten years of the Hunter Outcome Survey (HOS): insights, achievements, and lessons learned from a global patient registry.

Orphanet J Rare Dis 2017 05 2;12(1):82. Epub 2017 May 2.

Shire Human Genetic Therapies, Inc., 300 Shire Way HA100-310, Lexington, MA, 02421, USA.

Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) is a rare lysosomal storage disease with progressive multisystem manifestations caused by deficient activity of the enzyme iduronate-2-sulfatase. Disease-specific treatment is available in the form of enzyme replacement therapy with intravenous idursulfase (Elaprase®, Shire). Since 2005, the Hunter Outcome Survey (HOS) has collected real-world, long-term data on the safety and effectiveness of this therapy, as well as the natural history of MPS II. Individuals with a confirmed diagnosis of MPS II who are untreated or who are receiving/have received treatment with idursulfase or bone marrow transplant can be enrolled in HOS. A broad range of disease- and treatment-related information is captured in the registry and, over the past decade, data from more than 1000 patients from 124 clinics in 29 countries have been collected. Evidence generated from HOS has helped to improve our understanding of disease progression in both treated and untreated patients and has extended findings from the formal clinical trials of idursulfase. As a long-term, global, observational registry, various challenges relating to data collection, entry, and analysis have been encountered. These have resulted in changes to the HOS database platform, and novel approaches to maximize the value of the information collected will also be needed in the future. The continued evolution of the registry should help to ensure that HOS provides further insights into the burden of the disease and patient care and management in the coming years.
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http://dx.doi.org/10.1186/s13023-017-0635-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414331PMC
May 2017

Mucopolysaccharidosis Type I Newborn Screening: Best Practices for Diagnosis and Management.

J Pediatr 2017 03 7;182:363-370. Epub 2016 Dec 7.

University of North Carolina at Chapel Hill, Chapel Hill, NC.

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http://dx.doi.org/10.1016/j.jpeds.2016.11.036DOI Listing
March 2017

Progression of Polysomnographic Abnormalities in Mucolipidosis II (I-Cell Disease).

J Clin Sleep Med 2016 12 15;12(12):1695-1696. Epub 2016 Dec 15.

Department of Neurology, Division of Sleep Medicine, University of North Carolina at Chapel Hill.

Abstract: Mucolipidosis II (Inclusion cell or I-cell disease) is an autosomal recessive lysosomal storage disorder clinically comparable to the mucopolysaccharidoses (MPS), characterized by progressive respiratory and neurologic deterioration. Sleep problems, especially obstructive sleep apnea (OSA) and disrupted sleep architecture, are observed in other lysosomal storage diseases but have not been described in mucolipidosis II. We report the progression of polysomnographic abnormalities in a child with mucolipidosis II, demonstrated by worsening sleep-related hypoventilation, OSA, and sleep state fragmentation despite advancing PAP therapy. Background slowing and reduction in spindle activity on limited EEG may reflect progressive CNS disease affecting thalamic neurons.
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http://dx.doi.org/10.5664/jcsm.6362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155191PMC
December 2016

Inborn Error of Cobalamin Metabolism Associated with the Intracellular Accumulation of Transcobalamin-Bound Cobalamin and Mutations in ZNF143, Which Codes for a Transcriptional Activator.

Hum Mutat 2016 09 12;37(9):976-82. Epub 2016 Jul 12.

Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

Vitamin B12 (cobalamin, Cbl) cofactors adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) are required for the activity of the enzymes methylmalonyl-CoA mutase (MCM) and methionine synthase (MS). Inborn errors of Cbl metabolism are rare Mendelian disorders associated with hematological and neurological manifestations, and elevations of methylmalonic acid and/or homocysteine in the blood and urine. We describe a patient whose fibroblasts had decreased functional activity of MCM and MS and decreased synthesis of AdoCbl and MeCbl (3.4% and 1.0% of cellular Cbl, respectively). The defect in cultured patient fibroblasts complemented those from all known complementation groups. Patient cells accumulated transcobalamin-bound-Cbl, a complex which usually dissociates in the lysosome to release free Cbl. Whole-exome sequencing identified putative disease-causing variants c.851T>G (p.L284*) and c.1019C>T (p.T340I) in transcription factor ZNF143. Proximity biotinylation analysis confirmed the interaction between ZNF143 and HCFC1, a protein that regulates expression of the Cbl trafficking enzyme MMACHC. qRT-PCR analysis revealed low MMACHC expression levels both in patient fibroblasts, and in control fibroblasts incubated with ZNF143 siRNA.
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http://dx.doi.org/10.1002/humu.23037DOI Listing
September 2016

Homocysteinemia due to MTHFR deficiency in a young adult presenting with bilateral lens subluxations.

Ophthalmic Genet 2017 Jan-Feb;38(1):91-94. Epub 2016 Apr 4.

b Department of Pediatrics, Division of Genetics and Metabolism , University of North Carolina School of Medicine , Chapel Hill , NC , USA.

The most common cause of isolated inherited homocysteinemia is a deficiency of the enzyme cystathionine β-synthase (CBS). Clinical manifestations of CBS deficiency can include ectopia lentis, thromboembolism, marfanoid habits, and intellectual disability. CBS deficiency, which affects the transsulfuration pathway, is marked biochemically by elevated serum homocysteine and plasma methionine. We report a patient with homocysteinemia, low plasma methionine, and no significant neurological abnormalities who presented with bilateral subluxated crystalline lenses due to a 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency. MTHFR deficiency, a disorder in the remethylation pathway, can cause mild to severe disease, although most presentations include neurological involvement. MTHFR deficiency has not been previously associated with lens subluxation or complete dislocation. Prolonged exposure to elevated serum homocysteine levels is most likely the explanation for her ectopia lentis. This case expands the differential diagnosis of homocysteinemia and highlights the need for a correct diagnosis to optimize the clinical outcome of patients with this condition.
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http://dx.doi.org/10.3109/13816810.2016.1143017DOI Listing
November 2017

Levels of glycosaminoglycans in the cerebrospinal fluid of healthy young adults, surrogate-normal children, and Hunter syndrome patients with and without cognitive impairment.

Mol Genet Metab Rep 2015 Dec 9;5:103-106. Epub 2015 Nov 9.

Shire, 300 Shire Way, Lexington, MA 02421, USA.

In mucopolysaccharidoses (MPS), glycosaminoglycans (GAG) accumulate in tissues. In MPS II, approximately two-thirds of patients are cognitively impaired. We investigated levels of GAG in cerebrospinal fluid (CSF) in different populations from four clinical studies (including NCT00920647 and NCT01449240). Data indicate that MPS II patients with cognitive impairment have elevated levels of CSF GAG, whereas those with the attenuated phenotype typically have levels falling between those of the cognitively affected patients and healthy controls.
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http://dx.doi.org/10.1016/j.ymgmr.2015.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471392PMC
December 2015

High-Pressure Transvenous Perfusion of the Upper Extremity in Human Muscular Dystrophy: A Safety Study with 0.9% Saline.

Hum Gene Ther 2015 Sep 30;26(9):614-21. Epub 2015 Jul 30.

1 Department of Neurology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina.

We evaluated safety and feasibility of high-pressure transvenous limb perfusion in an upper extremity of adult patients with muscular dystrophy, after completing a similar study in a lower extremity. A dose escalation study of single-limb perfusion with 0.9% saline was carried out in nine adults with muscular dystrophies under intravenous analgesia. Our study demonstrates that it is feasible and definitely safe to perform high-pressure transvenous perfusion with 0.9% saline up to 35% of limb volume in the upper extremities of young adults with muscular dystrophy. Perfusion at 40% limb volume is associated with short-lived physiological changes in peripheral nerves without clinical correlates in one subject. This study provides the basis for a phase 1/2 clinical trial using pressurized transvenous delivery into upper limbs of nonambulatory patients with Duchenne muscular dystrophy. Furthermore, our results are applicable to other conditions such as limb girdle muscular dystrophy as a method for delivering regional macromolecular therapeutics in high dose to skeletal muscles of the upper extremity.
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http://dx.doi.org/10.1089/hum.2015.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575535PMC
September 2015

A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II.

Genet Med 2016 Jan 2;18(1):73-81. Epub 2015 Apr 2.

Shire, Lexington, Massachusetts, USA.

Purpose: Approximately two-thirds of patients with the lysosomal storage disease mucopolysaccharidosis II have progressive cognitive impairment. Intravenous (i.v.) enzyme replacement therapy does not affect cognitive impairment because recombinant iduronate-2-sulfatase (idursulfase) does not penetrate the blood-brain barrier at therapeutic concentrations. We examined the safety of idursulfase formulated for intrathecal administration (idursulfase-IT) via intrathecal drug delivery device (IDDD). A secondary endpoint was change in concentration of glycosaminoglycans in cerebrospinal fluid.

Methods: Sixteen cognitively impaired males with mucopolysaccharidosis II who were previously treated with weekly i.v. idursulfase 0.5 mg/kg for ≥6 months were enrolled. Patients were randomized to no treatment or 10-mg, 30-mg, or 1-mg idursulfase-IT monthly for 6 months (four patients per group) while continuing i.v. idursulfase weekly.

Results: No serious adverse events related to idursulfase-IT were observed. Surgical revision/removal of the IDDD was required in 6 of 12 patients. Twelve total doses were administrated by lumbar puncture. Mean cerebrospinal fluid glycosaminoglycan concentration was reduced by approximately 90% in the 10-mg and 30-mg groups and approximately 80% in the 1-mg group after 6 months.

Conclusions: These preliminary data support further development of investigational idursulfase-IT in MPS II patients with the severe phenotype who have progressed only to a mild-to-moderate level of cognitive impairment.Genet Med 18 1, 73-81.
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http://dx.doi.org/10.1038/gim.2015.36DOI Listing
January 2016

The Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) Questionnaire: item reduction and further validation.

Qual Life Res 2014 Nov 8;23(9):2457-62. Epub 2014 May 8.

Evidera, London, UK,

Purpose: The Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) Questionnaire is a patient and parent-completed disease-specific instrument used in Hunter syndrome (mucopolysaccharidosis II), a rare paediatric progressive multi-systemic lysosomal storage disease. The objective of this study was to shorten the number of items of the Questionnaire to reduce response burden while maintaining its content validity.

Methods: Data collected in a clinical trial were used. An iterative process helped identifying redundant or low performing items based on content validity and psychometric properties. Validation on the retained items was assessed using patients and parent's responses in terms of reliability, validity and responsiveness.

Results: The HS-FOCUS was completed by 49 patients and 84 parents. Items were mainly removed owing to high floor effects, high inter-item correlations (>0.80) or inadequate content. The shortened patient and parent versions (18 and 21 items) each contained five function domains. Internal consistency and test-retest reliability were >0.70 for most domains, except Breathing and School/work. Concurrent validity was demonstrated by significant correlations (>0.30) with similar concepts of previously validated measures. Significant differences were found in all domain scores across levels of disability.

Conclusions: The shortened HS-FOCUS is a reliable, valid and responsive measure, where burden in answering the Questionnaire was reduced without compromising its validity.
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http://dx.doi.org/10.1007/s11136-014-0703-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186975PMC
November 2014

The natural history of MPS I: global perspectives from the MPS I Registry.

Genet Med 2014 Oct 27;16(10):759-65. Epub 2014 Mar 27.

Genzyme, a Sanofi company, Cambridge, Massachusetts, USA.

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.
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http://dx.doi.org/10.1038/gim.2014.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4189384PMC
October 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

Patient-specific biomechanical modeling of ventricular enlargement in hydrocephalus from longitudinal magnetic resonance imaging.

Med Image Comput Comput Assist Interv 2013 ;16(Pt 3):291-8

Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, NC, 27599, USA.

Ogden type of hyperelastic constitutive law has recently emerged in modeling ventricular enlargement in hydrocephalic brain with finite element method, but this material property for brain tissue has not been investigated in a patient-specific setting in hydrocephalus. Consequently, the accuracy of the simulated ventricular enlargement using this hyperelastic tissue property remains unknown. In this study, we evaluated this brain material model in four patients with communicating hydrocephalus under a small trans-mantle pressure difference (TPMD) between brain ventricle and subarachnoid space (< 1 mmHg). Based upon changes in ventricular geometries obtained with sequential MRI, we found that this hyper-elastic model has a great flexibility and accuracy in modeling ventricular enlargement (with errors less than 1 mm). Our study supports the utility of this hyperelastic constitutive law for future hydrocephalus modeling and suggests that the observed ventricular enlargement in these patients may be caused by a slight increase in TMPD.
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http://dx.doi.org/10.1007/978-3-642-40760-4_37DOI Listing
February 2014

Early initiation of enzyme replacement therapy for the mucopolysaccharidoses.

Authors:
Joseph Muenzer

Mol Genet Metab 2014 Feb 11;111(2):63-72. Epub 2013 Dec 11.

Division of Genetics and Metabolism, Department of Pediatrics, CB 7487, Medical School Wing E Room 117, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7487, USA. Electronic address:

The mucopolysaccharidoses (MPS), a group of rare genetic disorders caused by defects in glycosaminoglycan (GAG) catabolism, are progressive, multi-systemic diseases with a high burden of morbidity. Enzyme replacement therapy (ERT) is available for MPS I, II, and VI, and may improve walking ability, endurance, and pulmonary function as evidenced by data from pivotal trials and extension studies. Despite these demonstrable benefits, cardiac valve disease, joint disease, and skeletal disease, all of which cause significant morbidity, do not generally improve with ERT if pathological changes are already established. Airway disease improves, but usually does not normalize. These limitations can be well understood by considering the varied functions of GAG in the body. Disruption of GAG catabolism has far-reaching effects due to the triggering of secondary pathogenic cascades. It appears that many of the consequences of these secondary pathogenic events, while they may improve on treatment, cannot be fully corrected even with long-term exposure to enzyme, thereby supporting the treatment of patients with MPS before the onset of clinical disease. This review examines the data from clinical trials and other studies in human patients to explore the limits of ERT as currently used, then discusses the pathophysiology, fetal tissue studies, animal studies, and sibling reports to explore the question of how early to treat an MPS patient with a firm diagnosis. The review is followed by an expert opinion on the rationale for and the benefits of early treatment.
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http://dx.doi.org/10.1016/j.ymgme.2013.11.015DOI Listing
February 2014

Relationship of sleep to pulmonary function in mucopolysaccharidosis II.

J Pediatr 2013 Jun 8;162(6):1210-5. Epub 2013 Jan 8.

Division of Pulmonology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7217, USA.

Objective: To study the sleep characteristics, pulmonary function, and their relationships in an enzyme naive population of patients with mucopolysaccharidoses (MPS) II (Hunter syndrome).

Study Design: The analyzed subjects (30 patients with MPS II with a median age of 9 years) had been enrolled in an MPS II natural history study and a phase I/II enzyme replacement clinical study in which they underwent standard polysomnography including spirometry and plethysmography, if cooperative. Descriptive statistics and nonparametric correlation were performed for demographic, sleep, and pulmonary function variables.

Results: Median apnea-hypopnea index was 6.4, with obstructive sleep apnea observed in 27/30 subjects. Sleep architecture was characterized by diminished rapid-eye movement sleep duration (median 13%), and decline in sleep efficiency and slow-wave sleep duration in older individuals. Oxygen desaturation below 90% occurred in 26/30 subjects, and hypoventilation above 50 Torr occurred in 11/23 subjects with accurate end-tidal carbon dioxide recordings. Of 15 subjects with reliable spirometry, median forced expiratory volume in 1 second was below 80% predicted in 12/15 subjects. Forced expiratory volume in 1 second in percent-predicted was inversely related to apnea-hypopnea index and increase from baseline end-tidal carbon dioxide (P=.023, rs=-0.58), (P<.001, rs=-0.82).

Conclusion: Sleep in MPS II is characterized by obstructive sleep apnea, altered sleep architecture, and impaired gas exchange. Sleep disruption is related to daytime pulmonary function, thus both systems should be evaluated when sleep abnormalities are suspected.
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http://dx.doi.org/10.1016/j.jpeds.2012.11.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665636PMC
June 2013

Bronchoscopy and airway management in patients with mucopolysaccharidoses (MPS).

Pediatr Pulmonol 2013 Jun 4;48(6):601-7. Epub 2012 Sep 4.

Division of Pulmonology, Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina 27599-7217, USA.

Introduction: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders characterized by tissue deposition of glycosaminoglycans (GAG). Their musculoskeletal abnormalities and the GAG storage in the airway result in increased risk for patients undergoing anesthesia. This study evaluates a multi-disciplinary airway management approach and reports upper and lower airway findings of flexible bronchoscopy performed during these procedures.

Methods: This is a retrospective study over 10 years evaluating approaches to and outcomes of airway management and bronchoscopic findings in this patient group.

Results: Thirty-one patients underwent a total of 105 anesthetic events of which 74 involved multiple surgical services. The majority of patients were either MPS I (n = 9) or MPS II (n = 19). The median age was 8.6 years (range 1.1-24 years). Airway management by anesthesiologists alone occurred in 31 cases including natural airway (n = 7), perilaryngeal airway (n = 7), oral or nasal intubation (n = 7) or tracheostomy (n = 6) and emergent fiberoptic intubation in four cases. In 74 of the procedures, flexible bronchoscopy was performed which included fiberoptic intubation in 22 cases. Post-operative complications occurred in eight cases mostly when prolonged airway instrumentation had occurred. The most frequent findings on bronchoscopy were GAG deposits/adenoid hypertrophy in 72%, laryngomalacia in 31% and lower airway deposits and/or tracheobronchomalacia in 46% of procedures. Deposits of GAG were seen in patients as young as 4 years of age.

Conclusion: Our experience demonstrates that a multidisciplinary approach and combined surgeries in MPS provides for safe airway management and allows diagnostic assessments for further patient care without added risks. Significant, multi-factorial airway compromise may occur already in early childhood including upper and lower airway GAG deposits.
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http://dx.doi.org/10.1002/ppul.22629DOI Listing
June 2013