OTHER CLINICAL TRIALS FOR UCD
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It's All About the Brain - New studies unlock the mysteries of the effects of UCD on the brain
How does the brain respond to elevated ammonia? Are the effects of UCD on the brain preventable or reversible? New UCD research using specialized neuroimaging techniques may provide the answers and lead the way to developing new interventions to protect the brain.
Up to now, how hyperammonemia disrupts brain function has not been well understood. What exactly causes the brain to be injured? How much injury occurs and precisely what areas of the brain are involved? Why is there often variation in the recovery of patients after a hyperammonemic event?
Dr. Andrea Gropman is a rare breed. Dr. Gropman is a neurologist and a geneticist (how smart can one person be?). She is leading critical UCD brain research that uses specialized brain imaging techniques to study how UCDs affect the brain. This special neuroimaging can be used to obtain information about the timing, extent, and reversibility of these effects, as well as the mechanism of brain injury.
Finding brain biomarkers for UCD
Can we then use these technologies to track or prevent injury? Gaining an understanding of how and why the brain is being affected in UCD adults and children is critical to improving outcomes. A crucial step is the identification of “biomarkers” in the brain. Biomarkers are biochemical features or characteristics that can be used to measure the progress of disease or the effects of treatment. Brain biomarkers for UCD could help predict the severity of a hyperammonemic event, and be useful for clinical monitoring (effects and timing of treatment) and interventional studies. These biomarkers are critical to advancing the development of new interventions and treatments to protect the brain in UCD.
Is the brain compensating?
Neuropsychological testing is also being used to measure the secondary effects of UCD on the brain. Dr. Gropman’s cutting-edge research combines special neuroimaging techniques that characterize alterations in the brain chemistry and neural structure, with special neuropsychological tests. For example, while the patient is in the scanner, they perform tasks, like pressing a button when they see certain letters on a video screen. This allows Dr. Gropman to simultaneously “see” and monitor changes as the brain activates in reaction to performing tasks. The more complex the task, the more the brain activates; Dr. Gropman can then identify abnormalities or deficits in the activation patterns. She is finding that in OTC patients, the brain may be compensating for damage in one area by activating other parts of the brain. Their brains are actually working harder compared to an unaffected person to accomplish the same tasks.
Previous neuropsychological studies in OTC carriers reported by Gyato, et al, indicated that despite average IQ scores, OTC carriers displayed specific neurocognitive deficits in nonverbal intelligence, fine motor/dexterity/speed, visual memory, attention and executive function skills, and math. These findings are typically associated with white matter or subcortical dysfunction. By using special imaging techniques (1H MRS, DTI and fMRI) Dr. Gropman has been able to confirm white matter injury in OTC patients and carriers affecting the frontal lobe that involves working memory and executive function.
Glutamine - a biomarker?
Over the last few years, Dr. Gropman’s work has revealed that even in the absence of hyperammonemia, there are subtle or even significant alterations in the biochemistry of patients with OTC deficiency and OTC carriers . This raises an important question about the role of glutamine in OTC and CPS1 deficiencies. In animal and human studies, accumulations of ammonia, glutamine and glutamate have been shown to exert toxic effects on the brain. Clinical signs of hyperammonemia can begin at 60 micromol/L, including anorexia, irritability, lethargy, disorientation, vomiting and somnolence, eventually progressing to brain swelling and coma. A rise in glutamine levels in the blood has long been theorized to be a predictor of impending hyperammonemia. For the first time, Dr. Gropman’s studies using 1H MRS revealed elevated brain glutamine in OTC patients with hyperammonemic encephalopathy (HE - an alteration of brain function or structure caused by high levels of ammonia). The results provide evidence that HE is related to elevated concentration of glutamine in the brain and a disruption of cerebral metabolism.
Dr. Gropman used the same 1H MRS technique to investigate cerebral metabolism in stable patients with partial OTC deficiency. The results showed that both symptomatic and asymptomatic patients had significant increases in glutamine and decreased concentrations of myoinositol compared to normal controls. This observation in women with OTC who were asymptomatic suggests the possibility of unrecognized biochemical disturbances and may explain some of the neurocognitive deficits observed in these patients.
It’s all about the brain
The studies provide details about the pattern and type of injury in UCD and characterize several important brain biomarkers. Biomarkers in OTC deficiency include increased brain glutamine levels and possibly depletion of myoinositol – indicators of disturbed osmatic balance in brain chemistry. Markers of white matter injury reveal alterations that may impair learning and memory.
The National Urea Cycle Disorders Foundation is driving and funding the expansion of these studies to better understand when these alterations may be occurring, their relationship to age, early metabolic changes and progression. Most importantly, can there be recovery? The studies will help address whether even “asymptomatic” OTC patients or carriers should receive treatment to avoid long term effects on cognition.
New studies have been proposed using these techniques to identify brain biomarkers in citrullinemia and ASA – which may be different than those found in OTC deficiency. These biomarkers can then be used to access and monitor effectiveness of treatment and help evaluate current and novel therapies to improve neurological outcome.
For more information and to participate in the study: Investigation of Brain Nitrogen Metabolism in OTC Deficiency
Questions and Information
If you have questions about current studies or trials, or would like more information on how you can participate, please contact:
Cynthia Le Mons, Executive Director, National Urea Cycle Disorders Foundation
Validation of Newborn Screen to identify OTC/CPS1/NAGS deficiencies at birth: Requires parental consent to release stored NBS screen of children diagnosed with these disorders. Contact NUCDF at OTC/CPS/NAGS NBS Study
Urea Cycle Nutrition and Immunity Study at National Institutes of Health to investigate the effects of the UCD diet on immune response. Peter McGuire, MD, Principal Investigator.
Contact Janet Shiffer, Study Coordinator
Watch Video here
UCD Consortium Research Studies
Longitudinal Study for UCDs with list of all UCD Consortium Research Centers
Investigation of Brain Nitrogen Metabolism in Partial Ornithine Transcarbamylase Deficiency (OTCD) using 1H Magnetic Resonance Spectroscopy, Diffusion Tensor Imaging, and functional MRI.
The Effect of Sodium Phenylbutyrate (Buphenyl) and Low-Dose Arginine Compared to High-Dose Arginine Alone on Liver Function, Ureagenesis and Subsequent Nitric Oxide Production in Patients with Argininosuccinic Aciduria (ASA).
N-carbamylglutamate (NCLG) treatment in N-acetylglutamate synthetase deficiency (NAGS), partial carbamyl phosphate synthetase deficiency (CPS1) or partial ornithine transcarbamylase deficiency (OTC)
Industry-Sponsored Clinical Trials
Investigational Drug HPN-100
(Sponsor: Hyperion Therapeutics)
Safety and Effectivness of Hepatocyte Transfer
“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