The goal of this project is to validate brain biochemical, white matter and neuropsychological biomarkers that correlate with the effect of hyperammonemia on the brain in subjects with partial ornithine transcarbamylase deficiency (OTCD). We will use neuroimaging (1H MRS [magnetic resonance spectroscopy], DTI [diffusion tensor imaging], and fMRI [functional magnetic resonance imaging]) and neuropsychological testing to realize this goal. This proposed research represents a continuation and expansion of a cross sectional imaging study (RDCRN 5104) performed by this consortium that has identified elevations in brain glutamine (gin) and reductions of myoinositol (ml) as specific biomarkers in patients with OTCD. We will further study the relationship of these biomarkers under three conditions of nitrogen load: 1) during and following a hyperammonemic episode;2) at clinical and metabolic stability;3) following an infusion of a nitrogen scavenging agent (Ammonul). Our working hypothesis is that gin and ml are related to one another in the pathophysiology of hyperammonemia (HA) in OTCD. We propose that acute brain gin elevations herald acute HA. We further hypothesize that this biochemical alteration is followed by osmotic changes in the white matter detected by depletion in ml and changes of DTI. Lastly, we propose that chronic gin elevations will be seen in subjects with partial OTCD and that the severity of biomarker deviation will correlate with clinical severity. By studying the effects of the magnitude of change in gin and ml independently and in relationship to one another, we will strengthen the hypothesis that they are dependent variables and as such can be used as reliable biomarkers to follow clinical course, and be useful in development of novel therapies.

Public Health Relevance

This study will help to define the contribution, of age, stage of myelination, and early metabolic changes in predicting resolution and subsequent neurocognitive outcome in OTCD. Once these biomarkers are validated, they can be used to assess the stringency of treatment required to optimize outcome and to address the question as to whether patients with even

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD061221-10
Application #
8535252
Study Section
Special Emphasis Panel (ZRG1-HOP-Y)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$77,312
Indirect Cost
$26,537
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
Lee, Brendan; Diaz, George A; Rhead, William et al. (2015) Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder. Genet Med 17:561-8
Gallagher, Renata C; Lam, Christina; Wong, Derek et al. (2014) Significant hepatic involvement in patients with ornithine transcarbamylase deficiency. J Pediatr 164:720-725.e6
Burrage, Lindsay C; Jain, Mahim; Gandolfo, Laura et al. (2014) Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders. Mol Genet Metab 113:131-5
Berry, Susan A; Lichter-Konecki, Uta; Diaz, George A et al. (2014) Glycerol phenylbutyrate treatment in children with urea cycle disorders: pooled analysis of short and long-term ammonia control and outcomes. Mol Genet Metab 112:17-24
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Sprouse, Courtney; King, Jessica; Helman, Guy et al. (2014) Investigating neurological deficits in carriers and affected patients with ornithine transcarbamylase deficiency. Mol Genet Metab 113:136-41
Helman, Guy; Pacheco-Colón, Ileana; Gropman, Andrea L (2014) The urea cycle disorders. Semin Neurol 34:341-9
Pacheco-Colón, Ileana; Fricke, Stanley; VanMeter, John et al. (2014) Advances in urea cycle neuroimaging: Proceedings from the 4th International Symposium on urea cycle disorders, Barcelona, Spain, September 2013. Mol Genet Metab 113:118-26
Landau, Yuval E; Lichter-Konecki, Uta; Levy, Harvey L (2014) Genomics in newborn screening. J Pediatr 164:14-9
Smith, Wendy; Diaz, George A; Lichter-Konecki, Uta et al. (2013) Ammonia control in children ages 2 months through 5 years with urea cycle disorders: comparison of sodium phenylbutyrate and glycerol phenylbutyrate. J Pediatr 162:1228-34, 1234.e1

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