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.
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 asymptomatic OTCD should receive medical management
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