Clinical trial NCT01873911: Neurobehavioral Phenotypes in MPS III
Official title: Characterizing the Neurobehavioral Phenotype(s) in MPS III
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Sanfilippo Syndrome Type A
Sanfilippo Syndrome Type B
Hurler Syndrome
Keywords: MPS IIIA
MPS IIIB
Sanfilippo syndrome type A
Sanfilippo syndrome type B
Hurler syndrome
cognitive decline
MPS IH
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: Rare Diseases Clinical Research Network
name: National Center for Advancing Translational Sciences (NCATS)
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: National MPS Society
name: Shire Human Genetic Therapies, Inc.
First posted: 2013-06-10
Enrollment: 30
Sex: ALL
Minimum age (years): 2
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Assessment of Temperament
timeFrame: Within One Year of Enrollment
Secondary outcomes:
measure: Quality of Life Measures
timeFrame: Within One Year of Enrollment
measure: Event-Related Potentials Measurement
timeFrame: Within One Year of Enrollment
measure: Magnetic Resonance Imaging Examination
timeFrame: Within One Year of Enrollment
measure: Assessment of Cognitive Development
timeFrame: Within One Year of Enrollment
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
Study officials:
affiliation: University of Minnesota
name: Elsa G Shapiro, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Minnesota
name: Michael Potegal, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis Child. 1993 Sep;69(3):403-6. doi: 10.1136/adc.69.3.403. No abstract available.
citation: Meyer A, Kossow K, Gal A, Muhlhausen C, Ullrich K, Braulke T, Muschol N. Scoring evaluation of the natural course of mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics. 2007 Nov;120(5):e1255-61. doi: 10.1542/peds.2007-0282. Epub 2007 Oct 15.
citation: Jha S, Patel R. Kluver-Bucy syndrome -- an experience with six cases. Neurol India. 2004 Sep;52(3):369-71.
citation: Angrilli A, Mauri A, Palomba D, Flor H, Birbaumer N, Sartori G, di Paola F. Startle reflex and emotion modulation impairment after a right amygdala lesion. Brain. 1996 Dec;119 ( Pt 6):1991-2000. doi: 10.1093/brain/119.6.1991.