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

Kuntal Sen,Andrea L Gropman,Matthew T Whitehead,Afrouz A Anderson

doi:10.3389/fneur.2021.632307

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.

Highlights

The urea cycle disorders (UCD) are rare disorders due to a deficiency of the enzymes or transport proteins that remove ammonia from the body (Figure 1)
An example of how this may work may involve the collection of diffusion tensor imaging (DTI), functional magnetic resonance imaging, magnetic resonance spectroscopy (MRS), and functional near infrared spectroscopy in ornithine transcarbamlyase deficiency (OTCD), one of the UCDs
In subjects with Ornithine transcarbamylase deficiency (OTCD), we further demonstrated a significant correlation between cortical activation in left and right pre-frontal cortex (PFC), where patients with OTCD showed bilateral increase in PFC activation (r = 0.62, p = 0.01) but such trend was not observed in control subjects (r = 0.23, p = 0.42) [57] (Figure 6)

Summary

Introduction

The urea cycle disorders (UCD) are rare disorders due to a deficiency of the enzymes or transport proteins that remove ammonia from the body (Figure 1). Combination of methods such as electroencephalogram (EEG) that measures the neural electrical activity with that of fMRI and fNIRS that measure the hemodynamic response can provide complementary information about neurocognitive function and has shown to be effective in increasing the accuracy in seizure detection and classification [51, 52].

Results

Conclusion