Review of Multi-Modal Imaging in Urea Cycle Disorders: The Old, the New, the Borrowed, and the Blue

Abstract

The urea cycle disorders (UCD) are rare genetic disorder due to a deficiency of one of six enzymes or two transport proteins that act to remove waste nitrogen in form of ammonia from the body. In this review, we focus on neuroimaging studies in OTCD and Arginase deficiency, two of the UCD we have extensively studied. Ornithine transcarbamylase deficiency (OTCD) is the most common of these, and X-linked. Hyperammonemia (HA) in OTCD is due to deficient protein handling. Cognitive impairments and neurobehavioral disorders have emerged as the major sequelae in Arginase deficiency and OTCD, especially in relation to executive function and working memory, impacting pre-frontal cortex (PFC). Clinical management focuses on neuroprotection from HA, as well as neurotoxicity from other known and yet unclassified metabolites. Prevention and mitigation of neurological injury is a major challenge and research focus. Given the impact of HA on neurocognitive function of UCD, neuroimaging modalities, especially multi-modality imaging platforms, can bring a wealth of information to understand the neurocognitive function and biomarkers. Such information can further improve clinical decision making, and result in better therapeutic interventions. In vivo investigations of the affected brain using multimodal neuroimaging combined with clinical and behavioral phenotyping hold promise. MR Spectroscopy has already proven as a tool to study biochemical aberrations such as elevated glutamine surrounding HA as well as to diagnose partial UCD. Functional Near Infrared Spectroscopy (fNIRS), which assesses local changes in cerebral hemodynamic levels of cortical regions, is emerging as a non-invasive technique and will serve as a surrogate to fMRI with better portability. Here we review two decades of our research using non-invasive imaging and how it has contributed to an understanding of the cognitive effects of this group of genetic conditions.

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.…”

Are asymptomatic carriers of OTC deficiency always asymptomatic? A multicentric retrospective study of risk using the UCDC longitudinal study database

“…Multimodal neuroimaging in OTCD has shown value in identifying brain biomarkers of disease in female heterozygotes that correlated with measures of cognitive dysfunction in the domains of executive dysfunction. Neuroimaging studies have shown that the white matter tractography in frontal lobe is impacted by severe or mild HA, thereby providing a hypothesis for executive dysfunction in OTCD with partial enzyme activity (Sen et al, 2021(Sen et al, , 2022. Studies using DTI have shown that individuals with OTCD have reduced white matter integrity in specific regions of the brain, which may be related to the cognitive and behavioral problems observed in these individuals (Gropman et al, 2010).…”

Review of Applications of Near-Infrared Spectroscopy in Two Rare Disorders with Executive and Neurological Dysfunction: UCD and PKU

“…The urea cycle disorders (UCD) are a group of genetic disorders associated with an enzyme or a carrier protein insufficiency [ 20 , 21 ]. Table 1 shows the specific UCD and prevalence.…”

“…As referenced above, neurological impairment is of primary significance to the UCD [ 13 , 26 ]. For decades, EEG and MRI have been the main modalities for studying neurological dysfunction in the UCD [ 20 ]. fNIRS has emerged as a non-invasive technique and could serve as a surrogate to fMRI with better portability in assessing hemodynamic change in the brain and further assist the development of new imaging biomarkers [ 31 ].…”

“…This work was the first to show the efficacy of fNIRS in monitoring patients with UCD and indicated the possibility of inefficient neurocognitive function. Sen et al in their review paper on UCD research, reviewed these works and mentioned that they believed fNIRS could provide a novel and non-invasive tool to monitor OTCD progression and to examine neurocognitive changes [ 20 ]…”