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Longitudinal Studies of Brain Structure and Function in MPS Disorders

This study is currently recruiting participants.
Verified August 2017 by University of Minnesota - Clinical and Translational Science Institute
Sponsor:
ClinicalTrials.gov Identifier:
NCT01870375
First Posted: June 6, 2013
Last Update Posted: August 31, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Rare Diseases Clinical Research Network
National Center for Advancing Translational Science (NCATS)
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Lysosomal Disease Network
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
  Purpose
Neurobehavioral function and quality of life are compromised in many patients with mucopolysaccharidosis (MPS) disorders. The long-term goals of this research are to: 1) more accurately inform patients/parents regarding potential neurobehavioral outcomes; 2) develop sensitive measures of disease progression and central nervous system (CNS) treatment outcome; and 3) help clinical researchers develop direct treatments for specific brain structures/functions. The investigators hypothesize that specific and localized neuroimaging and neuropsychological findings and their relationship will be distinct for each MPS disorder. It is further hypothesized that without treatment, functions will decline and structure will change over time in a predictable fashion, and will be related to locus of abnormality and stage of disease.

Condition
Mucopolysaccharidosis Type I Mucopolysaccharidosis Type II Mucopolysaccharidosis Type VI Mucopolysaccharidosis Type IV Mucopolysaccharidosis Type VII

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Longitudinal Studies of Brain Structure and Function in MPS Disorders

Resource links provided by NLM:


Further study details as provided by University of Minnesota - Clinical and Translational Science Institute:

Primary Outcome Measures:
  • Change in Cognitive Ability (IQ) [ Time Frame: Baseline, Year 1, Year 2, Year 3 ]
    Age-appropriate IQ tests will be administered at baseline and during subject's annual visit.


Secondary Outcome Measures:
  • Change in Quality of Life [ Time Frame: Baseline, Year 1, Year 2, Year 3 ]
    Age-appropriate Quality of Life measures will be administered at baseline and during subject's annual visit.

  • Change in Neuropsychological Status [ Time Frame: Baseline, Year 1, Year 2, Year 3 ]
    Memory, Attention, Visual Spatial, and Visual Motor functions will be assessed with age-appropriate measures administered at baseline and during subject's annual visit.

  • Change in Emotional and Behavioral Health [ Time Frame: Baseline, Year 1, Year 2, Year 3 ]
    Age-appropriate measures of emotional and behavioral health will be administered at baseline and during subject's annual visit.

  • Change Shown in Magnetic Resonance Imaging of the Brain [ Time Frame: Baseline, Year 1, Year 2, Year 3 ]
    Magnetic resonance imaging of each subject's brain will be performed at baseline and during subject's annual visit to acquire volumetric, diffusion tensor imaging (DTI), and resting state data. These data will be analyzed to identify any changes occurring over time.

  • Change in Adaptive Functions [ Time Frame: Baseline, Year 1, Year 2, Year 3 ]
    Vineland Adaptive Behavior Scales, a measure of communication, daily living skills, socialization and motor function, will be administered at baseline and during subject's annual visit.


Estimated Enrollment: 100
Study Start Date: September 2009
Estimated Study Completion Date: August 2019
Estimated Primary Completion Date: August 2019 (Final data collection date for primary outcome measure)
Groups/Cohorts
MPS IH, MPS IHS, MPS IS
MPS IH (Hurler syndrome) patients; MPS IHS (Hurler-Scheie syndrome) patients; and MPS IS (Scheie syndrome) patients
MPS II
Hunter syndrome patients
MPS IV
Morquio syndrome patients who will be considered for enrollment in the study on an individual basis
MPS VI
Maroteaux-Lamy syndrome patients
MPS VII
Sly syndrome patients who will be considered for enrollment in the study on an individual basis

Detailed Description:

The mucopolysaccharidoses (MPS diseases) are lysosomal disorders (inborn errors of metabolism) that progressively affect most organ systems in the body, usually beginning in childhood. Recent treatment advances have produced amelioration of some of these malfunctions, but notably brain and bone have been difficult to effectively treat. This research addresses the brain abnormalities in the MPS disorders, about which little is known.

The objectives of this research are:

  1. to identify abnormalities of central nervous system (CNS) structure and function as well as to measure quality-of-life (QOL) in both treated and untreated MPS patients over time. The investigators will accomplish this through longitudinal studies of enrolled patients in designated centers in North America.
  2. to develop quantitative measurements of change, including direct measurement of neuropsychological function; surrogate MRI markers; and biomarkers to measure stage of disease and treatment outcomes.
  3. to examine the degree to which independent variables have an impact on both functional and structural outcome. Independent variables may include, but are not limited to: age at first treatment, severity of disease, types of medical abnormalities, nature of genetic mutation, medical events, and sensory abnormalities.
  4. to examine how treatments such as Enzyme Replacement Therapy (ERT), Hematopoietic Cell Transplant (HCT), substrate reduction, and other palliative and rehabilitative therapies differentially affect CNS structure and function, as well as the subject's quality of life.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   6 Years to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients who have a verified diagnosis of MPS I, II, IV, VI or VII, aged 6-25 years.
Criteria

Inclusion Criteria:

  • Any MPS I, II, IV, VI or VII child or adult aged 6-25 years

Exclusion Criteria:

  • Exclusion Criteria for Neuroimaging:

    • Participants with:

      • Pacemakers
      • Any indwelling electronic device including programmable shunts
      • Orthodontic braces unless they are not made of metal
      • Other implanted metal in the body other than titanium
      • Unable to stay still during MRI because of low cognitive function, behavioral dysregulation, or young age, if the patient is not a clinical patient having sedation/anesthesia
      • Pregnancy
  • Exclusion Criteria for Neuropsychological and Neurobehavioral Testing

    • Participants who:

      • Are too functionally impaired for testing
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01870375


Contacts
Contact: Ashley Schneider 612-301-1371 amwiesen@umn.edu

Locations
United States, California
Oakland Children's Hospital Recruiting
Oakland, California, United States, 94609
Contact: Jo Ann Johnson    510-428-3885 ext 5421    JAJohnson@mail.cho.org   
Principal Investigator: Paul Harmatz, M.D.         
United States, Georgia
Emory University Recruiting
Atlanta, Georgia, United States, 30033
Contact: Stephanie Cagle, M.S.    404-778-8421    scagle@emory.edu   
Principal Investigator: Nadia Ali, Ph.D.         
United States, Minnesota
University of Minnesota Enrolling by invitation
Minneapolis, Minnesota, United States, 55455
United States, New York
New York University Recruiting
New York, New York, United States, 10016
Contact: Michele Ford    212-263-6981    michele.ford@nyumc.org   
Principal Investigator: Heather Lau, M.D.         
Canada, Ontario
Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, M5G1X8
Contact: Mohammed Hussain    416-813-7654 ext 2646    mohammed.hussain@sickkids.ca   
Principal Investigator: Michal Inbar-Feigenberg, M.D.         
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
Rare Diseases Clinical Research Network
National Center for Advancing Translational Science (NCATS)
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Lysosomal Disease Network
Investigators
Principal Investigator: Chester B. Whitley, M.D., Ph.D. University of Minnesota - Clinical and Translational Science Institute
Study Director: Ashley Schneider University of Minnesota - Clinical and Translational Science Institute
Study Chair: Paul Harmatz, M.D. Oakland Children's Hospital
Study Chair: Michal Inbar-Feigenberg, M.D. Hospital for Sick Children, Toronto, Ontario, CA
Study Chair: Nadia Ali, Ph.D. Emory University
Study Chair: Heather Lau, M.D. New York University
  More Information

Additional Information:
Publications:
Shapiro E, Guler OE, Rudser K, Delaney K, Bjoraker K, Whitley C, Tolar J, Orchard P, Provenzale J, Thomas KM. An exploratory study of brain function and structure in mucopolysaccharidosis type I: long term observations following hematopoietic cell transplantation (HCT). Mol Genet Metab. 2012 Sep;107(1-2):116-21. doi: 10.1016/j.ymgme.2012.07.016. Epub 2012 Jul 20.
Eisengart JB, Rudser KD, Tolar J, Orchard PJ, Kivisto T, Ziegler RS, Whitley CB, Shapiro EG. Enzyme replacement is associated with better cognitive outcomes after transplant in Hurler syndrome. J Pediatr. 2013 Feb;162(2):375-80.e1. doi: 10.1016/j.jpeds.2012.07.052. Epub 2012 Sep 10.
Shapiro EG, Nestrasil I, Rudser K, Delaney K, Kovac V, Ahmed A, Yund B, Orchard PJ, Eisengart J, Niklason GR, Raiman J, Mamak E, Cowan MJ, Bailey-Olson M, Harmatz P, Shankar SP, Cagle S, Ali N, Steiner RD, Wozniak J, Lim KO, Whitley CB. Neurocognition across the spectrum of mucopolysaccharidosis type I: Age, severity, and treatment. Mol Genet Metab. 2015 Sep-Oct;116(1-2):61-8. doi: 10.1016/j.ymgme.2015.06.002. Epub 2015 Jun 17.
Yund B, Rudser K, Ahmed A, Kovac V, Nestrasil I, Raiman J, Mamak E, Harmatz P, Steiner R, Lau H, Vekaria P, Wozniak JR, Lim KO, Delaney K, Whitley C, Shapiro EG. Cognitive, medical, and neuroimaging characteristics of attenuated mucopolysaccharidosis type II. Mol Genet Metab. 2015 Feb;114(2):170-7. doi: 10.1016/j.ymgme.2014.12.299. Epub 2014 Dec 9.
Ahmed A, Whitley CB, Cooksley R, Rudser K, Cagle S, Ali N, Delaney K, Yund B, Shapiro E. Neurocognitive and neuropsychiatric phenotypes associated with the mutation L238Q of the α-L-iduronidase gene in Hurler-Scheie syndrome. Mol Genet Metab. 2014 Feb;111(2):123-7. doi: 10.1016/j.ymgme.2013.11.014. Epub 2013 Dec 12.
Shapiro EG, Rudser K, Ahmed A, Steiner RD, Delaney KA, Yund B, King K, Kunin-Batson A, Eisengart J, Whitley CB. A longitudinal study of emotional adjustment, quality of life and adaptive function in attenuated MPS II. Mol Genet Metab Rep. 2016 Apr 1;7:32-9. doi: 10.1016/j.ymgmr.2016.03.005. eCollection 2016 Jun.
Ahmed A, Shapiro E, Rudser K, Kunin-Batson A, King K, Whitley CB. Association of somatic burden of disease with age and neuropsychological measures in attenuated mucopolysaccharidosis types I, II and VI. Mol Genet Metab Rep. 2016 Apr 1;7:27-31. doi: 10.1016/j.ymgmr.2016.03.006. eCollection 2016 Jun.
Ahmed A, Rudser K, Kunin-Batson A, Delaney K, Whitley C, Shapiro E. Mucopolysaccharidosis (MPS) Physical Symptom Score: Development, Reliability, and Validity. JIMD Rep. 2016;26:61-8. doi: 10.1007/8904_2015_485. Epub 2015 Aug 25.
Aldenhoven M, Wynn RF, Orchard PJ, O'Meara A, Veys P, Fischer A, Valayannopoulos V, Neven B, Rovelli A, Prasad VK, Tolar J, Allewelt H, Jones SA, Parini R, Renard M, Bordon V, Wulffraat NM, de Koning TJ, Shapiro EG, Kurtzberg J, Boelens JJ. Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study. Blood. 2015 Mar 26;125(13):2164-72. doi: 10.1182/blood-2014-11-608075. Epub 2015 Jan 26.
Braunlin E, Orchard PJ, Whitley CB, Schroeder L, Reed RC, Manivel JC. Unexpected coronary artery findings in mucopolysaccharidosis. Report of four cases and literature review. Cardiovasc Pathol. 2014 May-Jun;23(3):145-51. doi: 10.1016/j.carpath.2014.01.001. Epub 2014 Jan 10. Review.
Stevenson DA, Rudser K, Kunin-Batson A, Fung EB, Viskochil D, Shapiro E, Orchard PJ, Whitley CB, Polgreen LE. Biomarkers of bone remodeling in children with mucopolysaccharidosis types I, II, and VI. J Pediatr Rehabil Med. 2014;7(2):159-65. doi: 10.3233/PRM-140285.
Polgreen LE, Thomas W, Orchard PJ, Whitley CB, Miller BS. Effect of recombinant human growth hormone on changes in height, bone mineral density, and body composition over 1-2 years in children with Hurler or Hunter syndrome. Mol Genet Metab. 2014 Feb;111(2):101-6. doi: 10.1016/j.ymgme.2013.11.013. Epub 2013 Dec 11.
Taylor NE, Dengel DR, Lund TC, Rudser KD, Orchard PJ, Steinberger J, Whitley CB, Polgreen LE. Isokinetic muscle strength differences in patients with mucopolysaccharidosis I, II, and VI. J Pediatr Rehabil Med. 2014;7(4):353-60. doi: 10.3233/PRM-140305.
Wolf DA, Banerjee S, Hackett PB, Whitley CB, McIvor RS, Low WC. Gene therapy for neurologic manifestations of mucopolysaccharidoses. Expert Opin Drug Deliv. 2015 Feb;12(2):283-96. doi: 10.1517/17425247.2015.966682. Epub 2014 Dec 16. Review.
Ou L, Herzog TL, Wilmot CM, Whitley CB. Standardization of α-L-iduronidase enzyme assay with Michaelis-Menten kinetics. Mol Genet Metab. 2014 Feb;111(2):113-5. doi: 10.1016/j.ymgme.2013.11.009. Epub 2013 Nov 26.
Kunin-Batson AS, Shapiro EG, Rudser KD, Lavery CA, Bjoraker KJ, Jones SA, Wynn RF, Vellodi A, Tolar J, Orchard PJ, Wraith JE. Long-Term Cognitive and Functional Outcomes in Children with Mucopolysaccharidosis (MPS)-IH (Hurler Syndrome) Treated with Hematopoietic Cell Transplantation. JIMD Rep. 2016;29:95-102. Epub 2016 Jan 30.
Polgreen LE, Kunin-Batson A, Rudser K, Vehe RK, Utz JJ, Whitley CB, Dickson P. Pilot study of the safety and effect of adalimumab on pain, physical function, and musculoskeletal disease in mucopolysaccharidosis types I and II. Mol Genet Metab Rep. 2017 Jan 15;10:75-80. doi: 10.1016/j.ymgmr.2017.01.002. eCollection 2017 Mar.

Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT01870375     History of Changes
Other Study ID Numbers: 0905M65804
U54NS065768 ( U.S. NIH Grant/Contract )
0905M65804 ( Other Identifier: Univ. of Minnesota IRB Identifier Number )
First Submitted: August 2, 2011
First Posted: June 6, 2013
Last Update Posted: August 31, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The study's data will be input to the Data Management and Coordinating Center ("DMCC"), which is a part of the NIH-funded Rare Diseases Clinical Research Network. Eventually the data will be available to researchers on the database of Genotypes and Phenotypes ("dbGaP"), a part of National Center for Biotechnology Information, U.S. National Library of Medicine.

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:
Mucopolysaccharidosis
Longitudinal
Brain
Cognition
Quality-of-Life
Hurler syndrome
Hunter syndrome
Hurler-Scheie syndrome
Scheie syndrome
Maroteaux-Lamy syndrome
MPS I
MPS II
MPS VI
Mucopolysaccharidosis type I
Mucopolysaccharidosis type II
Mucopolysaccharidosis type VI
MPS IV
MPS VII
Mucopolysaccharidosis type IV
Mucopolysaccharidosis type VII
Morquio syndrome
Sly syndrome

Additional relevant MeSH terms:
Mucopolysaccharidoses
Mucopolysaccharidosis I
Mucopolysaccharidosis II
Mucopolysaccharidosis VI
Mucopolysaccharidosis IV
Osteochondrodysplasias
Mucopolysaccharidosis VII
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Mucinoses
Connective Tissue Diseases
Metabolic Diseases
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Genetic Diseases, X-Linked
Heredodegenerative Disorders, Nervous System
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases


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