Research Studies

Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders

Principal Investigator: Andrea Gropman, MD

Chief, Division of Neurodevelopmental Disabilities & Neurogenetics
Principal Investigator, NIH Rare Diseases Clinical Research Network Urea Cycle Disorders Consortium
Children's National Medical Center, Washington DC

Keyword Definitions: Proximal urea cycle disorders include CPS1 and OTC deficiency (OTCD). Distal urea cycle disorders include citrullinemia (ASSD) and argininosuccinic aciduria/argininosuccinate lyase deficiency (ASA/ASLD).

Status: Completed

This research studied the series of events that occur in the brain during acute hyperammonemia, as well as those that result from having a chronic UCD. The study utilized different types of magnetic resonance imaging (MRI) to evaluate how UCD-related neurologic injuries affect metabolism, cognition, sensation, and movement in patients with UCDs. The research sought to determine whether the proximal and distal UCDs (CPS1 and OTC vs ASL, citrullinemia and AG) differ with regard to the mechanisms that cause neurological injury.

In proximal urea cycle disorders, particularly OTC deficiency, hyperammonemia causes increased brain glutamine (Gln). The dysfunction in the brain triggered by increased glutamine is thought to be the cause of the neurological injury in the proximal UCDs. In contrast, in distal UCDs, cognitive impairment and neuropsychiatric disease are common even if the patient has not experienced acute hyperammonemia. In the distal UCDs, both citrulline and argininosuccinate (ASA) or their metabolic byproducts have been implicated as neurotoxic. This is theorized to be the cause of behavioral and neurocognitive issues in citrullinemia and ASL deficiency.

The investigators used state-of- the-art neuroimaging and neuropsychological testing methods to investigate:

1. Do patients with OTCD have chronically elevated brain Gln and reduced myo inositol (mI) levels that correlate with regional brain structural abnormalities and neurocognitive dysfunction?
2. Do elevated brain Gln and decreased mI levels during an acute episode of hyperammonemia correlate with the magnitude of cytotoxic edema (brain swelling), and can a biomarker be identified to determine the relationship between cytotoxic edema and cell loss?
3. Are regions of brain damage in citrullinemia (ASSD) and/or argininosuccinate lyase deficiency (ASLD) different from those in found in OTCD? Investigators will compare brain Gln levels in ASSD and ASLD without hyperammonemia to those in OTCD.
4. Can brain citrulline and ASA can be identified in the brains of patients with distal UCDs, and do the levels correlate with brain abnormalities seen in MRI and neuropsychological testing?

This study was conducted with three groups. Participants were followed over time at multiple time points. The study was conducted at two sites: Children's National Medical Center and Boston Children's Hospital.

Group 1: OTCD participants
Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD who can undergo MRI and cognitive/behavioral testing (see Inclusion and Exclusion Criteria below)

Group 2: Recovery from Hyperammonemia
Individuals with CPS1, OTCD, ASSD or ASLD, who have had a recent hyperammonemic episode who can undergo MRI and cognitive/behavioral testing. (see Inclusion and Exclusion Criteria below)

Group 3:  Distal UCDs
Males and females with ASSD or ASLD who can undergo MRI and cognitive/behavioral testing. (see Inclusion and Exclusion Criteria below)

In all cases, participants in this study attended an initial study visit that included a review of medical history, current symptoms, impairments, and diet history; a physical exam; a full neurological exam; and cognitive and motor testing. During this visit, participants underwent imaging studies and additional cognitive and motor testing over a 1-2-day period. This included standard MRI studies and four sessions consisting of functional MRI (fMRI) (CNMC only), diffusion tensor imaging, and 1H magnetic resonance spectroscopy. For the fMRI study, participants performed various motor and behavioral tasks while in the imaging scanner. Magnetic resonance spectroscopy (MRS) was used to study and evaluate the chemical makeup of specific brain areas. Diffusion tensor imaging was used to assess myelination of major brain pathways and their alteration in disease states.

Inclusion Criteria:
Inclusion criteria for Group 1:

1. Confirmed diagnosis of ornithine transcarbamylase deficiency (OTCD) by genetic analysis (genotype) and/or enzyme analysis with at least a single episode of HA hyperammonemic (HA) encephalopathy.
2. Ability to undergo MRI without sedation.
3. Ages 7 - 30 years.
4. Ability to provide informed consent or assent to the procedures.
5. Healthy controls (age and gender matched).

Inclusion criteria for Group 2:

1. Males and females with CPS1, OTCD, ASSD or ASLD who are having an acute metabolic crisis, with ammonia levels between 100-300 µM
2. Subjects must be awake, and not comatose and able to maintain patent airway on their own and in the opinion of the examining physician, medically stable without risk for acute decompensation and must continue to be stable based on visual contact, vital sign measurement and voice contact with subjects while in the scanner.
3. Age range 7-30 years.
4. Able to undergo neuroimaging safely (i.e., do not have ferromagnetic devices in the body).
5. Sexually active females of childbearing potential must agree to urine pregnancy test.
6. Admittance to the hospital for treatment of hyperammonemia at one of the sites for this study.
7. Can be subjects who were originally enrolled in Group 1 who experience a subsequent hyperammonemic event (they will cross over into Group 2).

Inclusion criteria for Group 3

1. Confirmed diagnosis of argininosuccinate ASSD, or ASLD by genotype and/or enzyme analysis, or healthy age and gender-matched controls.
2. Ability to undergo MRI without sedation.
3. Age 7 - 30 years.
4. Able to provide informed consent or assent to the procedures.

Exclusion Criteria:
Exclusion Criteria for Group 1:

1. Inability to undergo MRI without sedation.
2. Metal implants, including orthodontic braces.
3. Other health conditions contraindicated in MRI.
4. Medically unstable at time of scheduled research visit.
5. Unable to provide informed consent or assent to the procedures.

Exclusion criteria for Group 2:

1. Ammonia level greater than 300 µM, or less than 100 µM.
2. Presence of coma and/or inability to maintain a patent airway.
3. Age less than 7 years or more than 30 years.
4. Participant has a ferromagnetic device that precludes safe MRI imaging.
5. Pregnant female.
6. Unstable medically, at risk for decompensations.
7. Combative, or severely neurologically compromised irrespective. of ammonia level and showing declining medical status in the scanner based on visual, voice contact and electronic HR monitoring.
8. Participant must be awake, not comatose, and able to maintain patent airway on their own.

Exclusion criteria for Group 3:

1. Inability to undergo MRI without sedation.
2. Metal implants, including orthodontic braces.
3. Other health conditions contraindicated for MRI.
4. Medically unstable at time of scheduled research visit.
5. Unable to provide informed consent or assent.

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 hyperammonemia 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 myo inositol levels may be important biomarkers as predictors of future hyperammonemic events and recovery.
4. 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.

“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