Clinical trial NCT01569568: Investigation of Brain Nitrogen in Partial Ornithine Transcarbamylase Deficiency (OTCD) Using 1 H MRS, DTI, and fMRI
Official title: Investigation of Brain Nitrogen in Partial Ornithine Transcarbamylase Deficiency (OTCD) Using 1 H MRS, DTI, and fMRI
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Ornithine Transcarbamylase Deficiency
Keywords: Neuroimaging
MRI
Urea cycle
hyperammonemia
cognitive function
ornithine transcarbamylase deficiency
Lead sponsor: Children's National Research Institute
Sponsor class: OTHER
Collaborators: name: Children's National Research Institute
First posted: 2012-04-03
Enrollment: 49
Sex: ALL
Minimum age (years): 7
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Males and females, ages 7-60 years with ornithine transcarbamylase deficiency Males and females, ages 7-60 years who are healthy controls without ornithine transcarbamylase deficiency

Brief summary: The purpose of this study is to use various types of MRI and cognitive testing to evaluate changes in the brain and cognitive function that occur in subjects with ornithine transcarbamylase deficiency (OTCD) relative to healthy individuals

Detailed description: The overall goal of this project is to characterize metabolic, structural and cognitive changes in OTCD using 1H MRS, DTI, volumetric averaging and fMRI with cognitive testing of executive function measures to validate biomarkers for the effect of HA and its treatment on the brain.

The investigators will measure gln and mI in blood and brain (using 1H MRS) in affected participants, and mI in brain in controls, fractional anisotropy as a measure of white matter microstructural damage (by DTI) and brain activation pathways alterations with tasks probing working memory (fMRI). As a secondary outcome measure, the investigators will correlate the findings from neuroimaging with cognitive functioning. This protocol is based on the previous 5104 protocol, now includes children to evaluate the age and stage of disease on these indices in a cohort that is undergoing important developmental events against an age matched typically developing cohort.

Eligibility criteria: Inclusion Criteria:

Subject inclusion criteria:

1. Patients with OTCD;
2. Age range: 7-60 years
3. Able to undergo neuroimaging safely (i.e. without presence of ferromagnetic devices)
4. Subject has a documented full scale IQ \> 70

Control participant inclusion criteria:

1. Healthy males and females without metabolic disease aged 7-60 years
2. Subject has a documented full scale IQ \> 70

Exclusion Criteria:

Subject exclusion criteria:

1. Mental retardation (i.e., Full Scale IQ\< 70)
2. Age range \<7 or \>60 years
3. Presence of ferromagnetic device(s) that preclude safe imaging
4. Pregnant female

Control exclusion criteria:

1. Subjects with a documented history of an intellectual deficit (i.e., Full Scale IQ\< 70)
2. Age range \<7 or \>60 years
3. Presence of ferromagnetic device(s) that preclude safe imaging
4. Pregnant female

Primary outcomes:
measure: Concentration of Glutamine and Myoinositol
timeFrame: Baseline
measure: Functional Connectivity of Assessed by Resting-state fMRI
timeFrame: Baseline
measure: Fractional Anisotropy Assessed Using DTI
timeFrame: Baseline
Secondary outcomes:
measure: Neuropsychological Assessment
timeFrame: Baseline
Other outcomes:
Locations:
Study officials:
affiliation: Children's National Research Institute
name: Andrea L Gropman, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gropman AL, Shattuck K, Prust MJ, Seltzer RR, Breeden AL, Hailu A, Rigas A, Hussain R, VanMeter J. Altered neural activation in ornithine transcarbamylase deficiency during executive cognition: an fMRI study. Hum Brain Mapp. 2013 Apr;34(4):753-61. doi: 10.1002/hbm.21470. Epub 2011 Nov 23.
citation: Prust MJ, Gropman AL, Hauser N. New frontiers in neuroimaging applications to inborn errors of metabolism. Mol Genet Metab. 2011 Nov;104(3):195-205. doi: 10.1016/j.ymgme.2011.06.020. Epub 2011 Jun 30.
citation: Gropman AL, Gertz B, Shattuck K, Kahn IL, Seltzer R, Krivitsky L, Van Meter J. Diffusion tensor imaging detects areas of abnormal white matter microstructure in patients with partial ornithine transcarbamylase deficiency. AJNR Am J Neuroradiol. 2010 Oct;31(9):1719-23. doi: 10.3174/ajnr.A2122. Epub 2010 May 20.
citation: Gropman A. Brain imaging in urea cycle disorders. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S20-30. doi: 10.1016/j.ymgme.2010.01.017. Epub 2010 Feb 13.
citation: Oldham MS, VanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL. Diffusion tensor imaging in arginase deficiency reveals damage to corticospinal tracts. Pediatr Neurol. 2010 Jan;42(1):49-52. doi: 10.1016/j.pediatrneurol.2009.07.017.
citation: Gropman AL, Sailasuta N, Harris KC, Abulseoud O, Ross BD. Ornithine transcarbamylase deficiency with persistent abnormality in cerebral glutamate metabolism in adults. Radiology. 2009 Sep;252(3):833-41. doi: 10.1148/radiol.2523081878. Epub 2009 Jun 30.
citation: Gropman AL, Fricke ST, Seltzer RR, Hailu A, Adeyemo A, Sawyer A, van Meter J, Gaillard WD, McCarter R, Tuchman M, Batshaw M; Urea Cycle Disorders Consortium. 1H MRS identifies symptomatic and asymptomatic subjects with partial ornithine transcarbamylase deficiency. Mol Genet Metab. 2008 Sep-Oct;95(1-2):21-30. doi: 10.1016/j.ymgme.2008.06.003. Epub 2008 Jul 26.