Objective To evaluate brain metabolism in subjects with partial ornithine transcarbamylase deficiency (OTCD) utilizing 1H MRS. Methods Single voxel 1H MRS was performed on 25 medically-stable adults with partial OTCD, and 22 similarly aged controls. Metabolite concentrations from frontal and parietal white matter (FWM, PWM), frontal gray matter (FGM), posterior cingulate gray matter (PCGM), and thalamus (tha) were compared with controls and IQ, plasma ammonia, glutamine, and disease severity. Results Cases ranged from 19–59 years; average 34 years; controls ranged from 18–59 years; average 33 years. IQ scores were lower in cases (full scale 111 vs. 126; performance IQ 106 vs. 117). Decreased myoinositol (mI) in FWM (p=0.005), PWM (p <0.001), PCGM (p=0.003), and tha (p=0.004), identified subjects with OTCD, including asymptomatic heterozygotes. Glutamine (gln) was increased in FWM (p<0.001), PWM (p<0.001), FGM (p=0.002), and PCGM (p=0.001). Disease severity was inversely correlated with [mI] in PWM (r= −0.403; p= 0.046) and [gln] in PCGM (r= 0.548; p=0.005). N-acetylaspartate (NAA) was elevated in PWM (p=0.002); choline was decreased in FWM (p=0.001) and tha (p =0.002). There was an inverse relationship between [mI] and [gln] in cases only. Total buffering capacity (measured by [mI/mI + gln] ratio, a measure of total osmolar capacity) was inversely correlated with disease severity in FWM (r= −0.479; p=0.018), PWM (r= −0.458; p=0.021), PCGM (r= −0.567; p= 0.003), and tha (r= −0.345; p=0.037). Conclusion Brain metabolism is impaired in partial OTCD. Depletion of mI and total buffering capacity are inversely correlated with disease severity, and serve as biomarkers.

BACKGROUND AND PURPOSE OTCD, an X-linked disorder, is the most common of the UCDs. Neonatal onset is associated with uniformly poor outcome. Males with late-onset OTCD show deficits in executive function, motor planning, and working memory. A broad phenotype is observed in heterozygous females. A specific neurobehavioral phenotype with white matter dysfunction and impaired attention and working memory has been described. The extent to which the deficits involve specific pathways in the brain is unknown. We hypothesized that DTI would disclose white matter microstructure in OTCD correlating with cognitive deficits. MATERIALS AND METHODS Nineteen adults with partial OTCD and 18 adult control subjects ages 19–59 years participated. MR imaging was performed by using a 3T whole-body scanner. Anisotropy was calculated from the eigenvalues of the diffusion tensor by using the FA metric and was compared between the study and control groups. RESULTS FA of the frontal white matter was significantly decreased in subjects, indicating changes in white matter microstructure. There was an inverse relationship between FA and disease severity, but not with age. CONCLUSIONS Findings of MR imaging in OTCD are often normal in patients with late-onset disease, heterozygotes, or in those not in hyperammonemic crisis. DTI was more sensitive than FSE T2- weighted imaging for detecting abnormalities in normal-appearing white matter. The extent of abnormality correlated with cognitive deficits. The location of the deficits in the frontal white matter is important because this area connects fibers that are vital to executive function, attention, and working memory.

Background Urea cycle disorders are caused by dysfunction in any of the six enzymes and two transport proteins involved in urea biosynthesis. Our study focuses on Ornithine Transcarbamylase deficiency (OTCD), an X-linked disorder that results in a dysfunctional mitochondrial enzyme, which prevents the synthesis of citrulline from carbamoyl phosphate and ornithine. This enzyme deficiency can lead to hyperammonemic episodes and severe cerebral edema. The objective of this study was to use a cognitive battery to expose the cognitive deficits in asymptomatic carriers of OTCD. Materials and Methods In total, 81 participants were recruited as part of a larger urea cycle disorder imaging consortium study. There were 25 symptomatic participants (18 female, 7 male, 25.6 years ± 12.72 years), 20 asymptomatic participants (20 female, 0 male, 37.6 years ± 15.19 years), and 36 healthy control participants (21 female, 15 male, 29.8 years ± 13.39 years). All participants gave informed consent to participate and were then given neurocognitive batteries with standard scores and T scores recorded. Results When stratified by symptomatic participant, asymptomatic carrier, and control, the results showed significant differences in measures of executive function (e.g. CTMT and Stroop) and motor ability (Purdue Assembly) between all groups tested. Simple attention, academic measures, language and non-verbal motor abilities showed no significant differences between asymptomatic carriers and control participants, however, there were significant differences between symptomatic and control participant performance in these measures. Conclusions In our study, asymptomatic carriers of OTCD showed no significant differences in cognitive function compared to control participants until they were cognitively challenged with fine motor tasks, measures of executive function, and measures of cognitive flexibility. This suggests that cognitive dysfunction is best measurable in asymptomatic carriers after they are cognitively challenged.

Background Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder characterized by hyperammonemia resulting in white matter injury and impairments in working memory and executive cognition. Objective To test for differences in BOLD signal activation between subjects with OTCD and healthy controls during a working memory task. Design, Setting and Patients Nineteen subjects with OTCD and 21 healthy controls participated in a case-control, IRB-approved study at Georgetown University Medical Center. Intervention An N-back working memory task was performed in a block design using 3T functional magnetic resonance imaging. Results In subjects with OTCD we observed increased BOLD signal in the right dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) relative to healthy age matched controls. Conclusions Increased neuronal activation in OTCD subjects despite equivalent task performance points to sub-optimal activation of the working memory network in these subjects, most likely reflecting damage caused by hyperammonemic events. These increases directly relate to our previous finding of reduced frontal white matter integrity in the superior extents of the corpus callosum; key hemispheric connections for these areas. Future studies using higher cognitive load are required to further characterize these effects.

Despite an expanding pediatric population with CCI, we lack an intentional care model to minimize their hospitalizations. In this study, we generate several hypotheses for exploring the potential impact of expanded access to home nursing, robust care coordination, and family and clinician support to reduce hospital days for this population of high health care utilizers.