Fifteen years of urea cycle disorders brain research: Looking back, looking forward

Kuntal Sen, Matthew Whitehead, Carlos Castillo Pinto, Ljubica Caldovic, Andrea Gropman, Kuntal Sen, Matthew Whitehead, Carlos Castillo Pinto, Ljubica Caldovic, Andrea Gropman

Abstract

Urea cycle disorders (UCD) are inherited diseases resulting from deficiency in one of six enzymes or two carriers that are required to remove ammonia from the body. UCD may be associated with neurological damage encompassing a spectrum from asymptomatic/mild to severe encephalopathy, which results in most cases from Hyperammonemia (HA) and elevation of other neurotoxic intermediates of metabolism. Electroencephalography (EEG), Magnetic resonance imaging (MRI) and Proton Magnetic resonance spectroscopy (MRS) are noninvasive measures of brain function and structure that can be used during HA to guide management and provide prognostic information, in addition to being research tools to understand the pathophysiology of UCD associated brain injury. The Urea Cycle Rare disorders Consortium (UCDC) has been invested in research to understand the immediate and downstream effects of hyperammonemia (HA) on brain using electroencephalogram (EEG) and multimodal brain MRI to establish early patterns of brain injury and to track recovery and prognosis. This review highlights the evolving knowledge about the impact of UCD and HA in particular on neurological injury and recovery and use of EEG and MRI to study and evaluate prognostic factors for risk and recovery. It recognizes the work of others and discusses the UCDC's prior work and future research priorities.

Keywords: Ammonia; Brain injury; Hyperammonemia; Magnetic resonance spectroscopy; Multimodal neuroimaging; Urea cycle disorder.

Copyright © 2021 Elsevier Inc. All rights reserved.

Figures

Figure 1.
Figure 1.
The urea cycle. Abbreviations: CPS1: Carbamoyl phosphate synthetase 1; OTC: ornithine transcarbamylase deficiency; ASS: arginosuccinate synthase; ASL: arginosuccinate lyase; ARG: arginase.
Figure 2.
Figure 2.
Diffusion tensor imaging was used to evaluate the white matter tracts in a patient with arginase deficiency. Colors denote the dominant direction of the/fibers. Reduction in the volume of fibers in the patient with arginase deficiency has been observed.
Figure 3:
Figure 3:
The Glutamate-glutamine cycle. The glutamate-glutamine cycle refers to the compartmentation of glutamate and glutamine between neurons and glia such that during glutamatergic neurotransmission neurons release glutamate into the extracellular space. This results in the rapid removal of released glutamate by the glial glutamate transporters. Astrocytes are the major cells affected by hyperammonemia in the central nervous system (CNS), partially due to their proximity to the blood vessels Changes that occur in astrocytes following acute ammonia exposure, include extensive swelling, leading to cerebral edema. This cycle is the key mechanism for control of glutamatergic neurotransmission in the human brain
Figure 4:
Figure 4:
This 1H MRS spectrum shows the key differences in patients who are symptomatic and asymptomatic OTCD patients versus age matched control. Key metabolic differences include the elevated glutamine in symptomatic and to a lesser degree, in asymptomatic OTCD carriers; the low myoinositol in symptomatic and asymptomatic patients, and low choline which may be observed in both symptomatic and asymptomatic patients with OTCD.
Figure 5.
Figure 5.
NAGSko mice have seizures while on NCG and as they become hyperammonemic. Video EEG recording was reviewed for behavioral signs of seizures that were graded on a modified Racine scale, and the corresponding electrical activity. Each graph corresponds to recording of one animal and shows when did a mouse experienced a seizure and its grade/severity. X-axis in these graphs is time and the height of bars represents seizure grade (2 through 6).
Figure 6.
Figure 6.
ROI analysis results, fMRI. A) Z-scores reflecting degree of functional connectivity between pairs of ROIs in the Control group. B) Z-scores reflecting degree of functional connectivity between pairs of ROIs in OTCD patient group. C) Controls have significantly greater DMN functional connectivity than OTCD patients between ACC/mPFC node and bilateral IPL. (From: Pacheco-Colón I, Washington SD, Sprouse C, Helman G, Gropman AL, VanMeter JW. Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency. PLoS One. 2015;10(6):e0129595)
Figure 7.
Figure 7.
This figure illustrates our studies in UCD using multimodal imaging approach to interrogate various aspects of the pathophysiology as discussed in this manuscript.

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Source: PubMed

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