Advances in urea cycle neuroimaging: Proceedings from the 4th International Symposium on urea cycle disorders, Barcelona, Spain, September 2013

Abstract

Our previous imaging research performed as part of a Urea Cycle Rare Disorders Consortium (UCRDC) grant, has identified specific biomarkers of neurologic injury in ornithine transcarbamylase deficiency, OTCD. While characterization of mutations can be achieved in most cases, this information does not necessarily predict the severity of the underlying neurological syndrome. The biochemical consequences of any mutation may be modified additionally by a large number of factors, including contributions of other enzymes and transport systems that mediate flux through the urea cycle, diet and other environmental factors. These factors likely vary from one patient to another, and they give rise to heterogeneity of clinical severity. Affected cognitive domains include non-verbal learning, fine motor processing, reaction time, visual memory, attention, and executive function. Deficits in these capacities may be seen in symptomatic patients, as well as asymptomatic carriers with normal IQ and correlate with variances in brain structure and function in these patients. Using neuroimaging we can identify biomarkers that reflect the downstream impact of UCDs on cognition. This manuscript is a summary of the presentation from the 4th International Consortium on Urea cycle disorders held in, Barcelona, Spain, September 2, 2014.

Glycerol phenylbutyrate for the maintenance treatment of patients with deficiencies in enzymes of the urea cycle

“…Neuroimaging suggests that UCDs are associated with white matter abnormalities of the brain even in OTC females [21,23,24]. Neuropsychological testing and new neuroimaging capabilities may assist in diagnosis and assessment of UCD patients by allowing the identification of microstructural abnormalities in the white matter of the brain [25][26][27].…”

New Insight in Hyperinsulinism/Hyperammonemia Syndrome by Magnetic Resonance Imaging and Spectroscopy

“…Ammonia toxicity in the brain is tightly connected to glutamine metabolism [21][22][23]. This observation is supported by MRS that has shown high glutamine concentrations during HA in rat models [24,25] but also in human with UCD or hepatic encephalopathy (Table 1) [13,14,[26][27][28][29][30][31][32][33][34][35][36][37]. Reduction in myoinositol and choline [34] Valproateinduced encephalopathy Metabolic-toxic lesion pattern with bilateral T2-hyperintense lesion in the cerebellar white matter and in the globus pallidus Elevated glutamine and glutamate.…”

“…In addition, MRSI showed decreased choline and myoinositol compared to controls (Figure 2). Myoinositol functions as a marker of astrocyte activity while choline relates to membrane turnover [14,36]. Both metabolites have been shown to decrease in HA disorders such as UCD or hepatic encephalopathy and might be surrogate markers of neuronal suffering [37].…”

“…Magnetic resonance imaging (MRI) and spectroscopy (MRS) are used to capture information on possible mechanism of neural injury and brain metabolites [11,12]. The application of MRS in patients with chronic hepatic encephalopathy and UCD has shown abnormalities in cerebral glutamate-glutamine (Glx), myoinositol and choline metabolites, suspected to contribute to neurotoxicity [13,14].…”

Bilateral symmetrical basal ganglia and thalamic lesions in children: an update (2015)

“…Additional imaging, including MRS diffusion tensor imaging (DTI), and functional magnetic resonance imaging (fMRI) are being utilized in urea cycle defects [116][117][118]. Increased glutamine and decreased myoinositol may be observed [119].…”