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Neurobehavioral Phenotypes in MPS III

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ClinicalTrials.gov Identifier: NCT01873911
Recruitment Status : Completed
First Posted : June 10, 2013
Last Update Posted : November 20, 2014
Information provided by (Responsible Party):

Study Description
Brief Summary:

Hypothesis #1: Factor analysis of the revised Sanfilippo Behavior Rating Scale (SBRS) will identify a group of externalizing behaviors and a group of Klüver-Bucy syndrome-like behaviors as two different factors that are at least partially independent.

Hypothesis #2a: Children with MPS III will show more hyperlocomotion, fearlessness, asociality and noncompliance than children of similar cognitive ability with MPS I.

Hypothesis #2b: These behaviors will become more frequent and/or intensify over time, consistent with the Cleary and Wraith (1993) model. Quantifying them will provide a more empirical framework for staging disease progression.

Hypothesis #3: Brain volumetric analysis and diffusion-tensor imaging will reveal abnormalities of frontal and temporal lobe structures that will correlate with externalizing and Klüver-Bucy syndrome-like behaviors, respectively.

Hypothesis #4. Loss of cognitive and language function as measures of neurologic decline will directly precede or co-vary with behavioral decline.

The primary objective of this study is to identify the behavioral phenotype and its neural basis in MPS III (Sanfilippo syndrome). Is the behavioral phenotype similar to that of Klüver-Bucy syndrome, and is there evidence for amygdala abnormality? The secondary objective of this research study is to develop easily administered, sensitive and specific neurobehavioral and neuroimaging markers to characterize the behavioral phenotype(s) of MPS III; to track their progression; and to delineate their neural substrates. Such markers are critical for identifying the stage of disease for each patient, and to measure treatment outcome. Although we know that severe cognitive decline is one essential characteristic of MPS III, the other highly salient characteristic is a range of abnormal and disruptive behaviors that can include, but go well beyond, childhood noncompliance and oppositionality. These behaviors set Sanfilippo syndrome apart from the other MPS disorders. They cause major disruption in the child's familial, school, and community environments. Delineating these behavioral abnormalities will help in better understanding the neurological disease.

Condition or disease
Sanfilippo Syndrome Type A Sanfilippo Syndrome Type B Hurler Syndrome

Detailed Description:
Like some other mucopolysaccharidosis (MPS) syndromes, MPS III (Sanfilippo syndrome) is characterized by a severe cognitive decline ending in dementia and death. Unlike other MPS syndromes, earlier-stage MPS III is also associated with a range of abnormal and disruptive behaviors that can include, but go well beyond, childhood noncompliance and oppositionality. These behaviors, which cause major disruption in the child's familial, school, and community environments, set MPS III apart from the other MPS disorders. These behaviors may also indicate the identity of the neural pathways affected in this disease; their sequence of onsets may indicate the order in which these pathways are affected. We propose to define and categorize the behavioral profile(s) or phenotype(s) of MPS III and correlate them with clinical quantitative neuroimaging in order to understand the neural bases of the disease. In addition, we will use these results to develop a set of sensitive and specific measures that can be easily administered by health care professionals to help monitor the disease and the efficacy of future treatments.

Study Design

Study Type : Observational
Actual Enrollment : 30 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Characterizing the Neurobehavioral Phenotype(s) in MPS III
Study Start Date : December 2010
Primary Completion Date : July 2014
Study Completion Date : August 2014

Groups and Cohorts

Outcome Measures

Primary Outcome Measures :
  1. Assessment of Temperament [ Time Frame: Within One Year of Enrollment ]
    Using Risk Room procedures of the established "Laboratory Temperament Assessment Battery" (Lab-TAB), the investigators will measure and record each subject's startle, exploration (fear), compliance, and attachment.

Secondary Outcome Measures :
  1. Quality of Life Measures [ Time Frame: Within One Year of Enrollment ]
    Assessments of research subjects' quality of life will be made using age-appropriate standardized assessment tools.

  2. Event-Related Potentials Measurement [ Time Frame: Within One Year of Enrollment ]
    High-density Event-Related Potentials (ERPs) will be elicited and recorded. ERPs provide information about the timing and location of neurocognitive processes associated with the individual's processing of discrete stimuli. Two sets of stimuli will be used: 1. auditory stimuli consisting of non-language sounds and phonemes; and 2. visual stimuli consisting of images of emotional faces. All stimuli will be presented in an oddball paradigm format (repetition of stimuli with a random insertion of a novel stimulus).

  3. Magnetic Resonance Imaging Examination [ Time Frame: Within One Year of Enrollment ]
    To examine the neural substrate of MPS III behavioral phenotypes of participating research subjects, the investigators will perform high-resolution brain volumetric magnetic resonance imaging (MRI) during clinical scans.

  4. Assessment of Cognitive Development [ Time Frame: Within One Year of Enrollment ]
    Research subjects' cognitive development will be assessed using age-appropriate standardized assessment tools.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Twenty children who have been diagnosed with MPS III type A or type B. Ten age-matched children (as controls) who have been diagnosed with MPS I (Hurler syndrome), who in the past have undergone hematopoietic cell transplantation, and who have been clinically-determined to have low cognitive function.

Inclusion Criteria:

Research Subjects: Verified diagnosis of MPS IIIA or MPS IIIB (having proof of either genetic mutation or enzymatic analysis prior to enrollment in this study); must be between the ages of 2 and 12 years; must be able to walk.

Control group: Verified diagnosis of MPS IH; must have already undergone hematopoietic cell transplantation in the past; must be aged between 2 and 5 years; and must be able to walk without support.

Exclusion Criteria:

Participants will be excluded who are unable to cooperate or comply with this study's procedures; in the opinion of the principal investigator, participants who have other severely-limiting co-existing conditions such as severe hearing or visual impairment, will be excluded from this study.

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): NCT01873911

United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
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)
National MPS Society
Shire Human Genetic Therapies, Inc.
Principal Investigator: Elsa G Shapiro, PhD University of Minnesota - Clinical and Translational Science Institute
Principal Investigator: Michael Potegal, PhD University of Minnesota - Clinical and Translational Science Institute
More Information

Additional Information:
Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT01873911     History of Changes
Other Study ID Numbers: RDCRNLDN6707
U54NS065768 ( U.S. NIH Grant/Contract )
First Posted: June 10, 2013    Key Record Dates
Last Update Posted: November 20, 2014
Last Verified: November 2014

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:
Sanfilippo syndrome type A
Sanfilippo syndrome type B
Hurler syndrome
cognitive decline

Additional relevant MeSH terms:
Mucopolysaccharidosis I
Mucopolysaccharidosis III
Pathologic Processes
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Connective Tissue Diseases
Metabolic Diseases