OTC DEFICIENCY

Neuroimaging in Urea Cycle Disorders

Principal Investigator: Andrea Gropman, MD

Chief, Division of Neurogenetics and Developmental Pediatrics
Associate Professor in Neurology and Pediatrics
Children's National Medical Center, Washington DC

Neuroimaging studies led by Dr. Gropman’s team are investigating how people with a urea cycle disorder think and what their brain biochemistry looks like. Her studies focusing on OTC deficiency (OTCD) suggest that hyperammonemia and high brain glutamine are causing changes in brain biochemistry, cognitive function and neural networks and fiber tracks.


With advanced MRI technology, one can look at biochemicals in the brain, pathways involved in thinking and movement, and tracks connecting various important functions in the brain. Dr. Gropman uses these sophisticated neuroimaging techniques to understand the effects of UCD on brain function.

Patterns of Brain Injury in Inborn Errors of Metabolism

Dr. Gropman has found there is change in the fiber tracks in the brain which are comprised of myelin, a substance that coats the nerve cells and speeds conduction of impulses. By using a technique known as diffusion tensor imaging or DTI, small disruptions in myelin can be measured and correlated with changes in cognitive and motor function.

Findings of routine MR imaging in OTCD are often normal in patients with late-onset OTCD, in heterozygotes (female carriers who have the OTCD mutation on one chromosome with another non-affected chromosome), or in those not in hyperammonemic crisis. DTI is more sensitive for detecting abnormalities in normal-appearing white matter (fiber tracks). The extent of abnormality correlated with cognitive deficits. The location of the white matter track abnormalities was in the frontal white matter.  This is important because this area connects fibers that are vital to executive function, attention, and working memory—all areas of weakness in patients with OTCD. 

An fMRI Study of Altered Neural Activation During Executive Cognition

Functional MRI is a technique in which a subject performs a thinking or motor task in the scanner, and imaging can show what parts of the brain are active during the function. This research has shown that brains of people with OTCD have to work harder and activate more areas to assist in these tasks than subjects without OTCD. The OTCD subjects take longer to respond, although accuracy may still be good. There is a time-to-accuracy tradeoff and the brain is less efficient in performing these tasks.

OTCD participants show increased brain activity (neuronal activation) compared to control (those without OTCD) participants when performing the same tasks. This points to sub-optimal activation of the working memory network in the brains of OTCD patients, most likely reflecting damage caused by elevated glutamine or hyperammonemic events.

1H MRS Identifies Symptomatic and Asymptomatic Subjects with Partial Ornithine Transcarbamylase Deficiency

Brain glutamine can be elevated even when the glutamine levels in the blood are normal or on the high side of normal. This is measured by a technique known as Magnetic Resonance Spectroscopy (MRS). Some subjects were on the verge of a hyperammonemic event during their studies, but did not have noticeable symptoms. When glutamine increases in the brain it causes swelling. A counter regulatory, or buffering molecule, called myoinositol, decreases to try to decrease swelling. This is an adaptive, protective function. One question is whether the amount of brain myoinosital that remains after hyperammonemia can predict the severity of a future hyper-ammonemic episode. If it can, MRS can be a useful way to monitor patients who might have elevated brain glutamine levels despite normal blood labs. This monitoring could help physicians intervene before glutamine rises to damaging levels and may help to prevent future hyperammonemia.

This study showed that brain metabolism is impaired in partial OTCD. Depletion of myoinositol and total buffering capacity are inversely correlated with disease severity, and serve as biomarkers. Biomarkers are important to developing interventions and treatments to prevent the effects of UCD on the brain.

References:

Patterns of Brain Injury in Inborn Errors of Metabolism

Gropman AL. Seminars in Pediatric Neurology. 2012 Dec;19(4):203-10. doi: 10.1016/j.spen.2012.09.007. PMID:23245554

Diffusion Tensor Imaging Detects Areas of Abnormal White Matter Microstructure in Patients with Partial Ornithine Transcarbamylase Deficiency.  Gropman AL, Gertz B, Shattuck K, Kahn IL, Seltzer R, Krivitsky L, Van Meter J. American Journal of Neuroradiology. 2010 Oct;31(9):1719-23. doi: 10.3174/ajnr.A2122. PMID:20488904

Altered Neural Activation in Ornithine Transcarbamylase Deficiency During Executive Cognition: An fMRI Study. Gropman AL, Shattuck K, Prust MJ, Seltzer RR, Breeden AL, Hailu A, Rigas A, Hussain R, Vanmeter Human Brain Mapping. 2013 Apr;34(4):753-61. doi: 10.1002/hbm.21470. Epub 2011 Nov 23. PMID: 22110002

1H MRS Identifies Symptomatic and Asymptomatic Subjects with Partial Ornithine Transcarbamylase Deficiency. Gropman AL, Fricke ST, Seltzer RR, Hailu A, Adeyemo A, Sawyer A, van Meter J, Gaillard WD, McCarter R, Tuchman M, Batshaw M; Urea Cycle Disorders Consortium. Journal of Molecular Genetics and Metabolism. 2008 Sep-Oct;95(1-2):21-30. doi: 10.1016/j.ymgme.2008.06.003. Epub 2008 Jul 26. PMID: 18662894

Questions and Information

If you have questions about current studies or trials, or would like more information on how you can participate, please contact:

National Urea Cycle Disorders Foundation

 

 

 


Key Points - Neuroimaging

1. For the first time, it has been shown that OTCD carriers who may not be exhibiting symptoms or signs of hyperammonemia may still have changes in their brain chemistry, neural networks and fibers, although this may be milder than in those who have had hyperammonemia.

2. Certain areas of the brain appear to be more sensitive to the effects of hyper-ammonemia than others.

3. Glutamine in the brain can be many times higher than in the blood. This may cause changes in brain biochemistry, cognitive function, attention and working memory.  Brain glutamine and myoinisotol levels may be important biomarkers as predictors of future hyper-ammonemic events and recovery.

3. The studies suggest that MRS and fMRI are valuable tools for monitoring patients after hyperammonemic episodes, especially if they have not returned to their normal (baseline) functioning.

 

Article: New studies unlock the mysteries of UCD on brain function

Associated Research Project:

Investigation of Brain Nitrogen Metabolism in Partial Ornithine Transcarbamylase Deficiency (OTCD) using 1H Magnetic Resonance Spectroscopy, Diffusion Tensor Imaging, and functional MRI.


 

“I have been a participant or observer in many efforts to bring together families and researchers in regard to a specific disorder or group of disorders, and I have never seen one in which there was such a superb collaboration and focus on the common goal.” 

Hugo Moser, M.D., Adrenoleukodystrophy Researcher (“Lorenzo’s Oil”), Kennedy-Krieger Institute, NIH Monitor to UCDC