Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders

Status: Recruiting
Location: See location...
Intervention Type: Behavioral, Procedure
Study Type: Observational
SUMMARY

In proximal urea cycle disorders (UCD), particularly ornithine transcarbamylase deficiency (OTCD), hyperammonemia (HA) causes increased brain glutamine (Gln) which perturbation is thought to be at the core of the neurological injury. In contrast, in distal UCD such as citrullinemia (argininosuccinate synthetase deficiency; (ASSD) and argininosuccinic aciduria (argininosuccinate lyase deficiency); (ASLD) cognitive impairment and neuropsychiatric disease are common even in the absence of acute HA. As a consequence, both citrulline and argininosuccinate (ASA) or their metabolic products have been implicated as neurotoxic. In this project the investigators will use state-of- the-art neuroimaging and neuropsychological methods to investigate whether patients with OTCD have chronically elevated brain Gln and reduced myo-inositol (mI) levels that correlate with regional brain structural abnormalities and neurocognitive dysfunction. The researchers will further investigate whether during an acute episode of HA elevated brain Gln and decreased mI levels correlate with the magnitude of cytotoxic edema and whether a Gln/mI ratio threshold can be identified at which the cytotoxic edema is followed by cell loss. Finally, the researchers will investigate whether regions of brain damage in ASSD and/or ASLD are distinct from those in OTCD and compare brain Gln levels in ASSD and ASLD in the absence of HA to those in OTCD. The investigators will also seek to determine if brain citrulline and ASA can be identified in the brains of patients with distal UCD and whether they correlate with brain abnormalities seen in MRI and neuropsychological testing. This project will elucidate the chronology of brain pathology both in acute hyperammonemia and chronic UCD and whether, proximal and distal UCD differ in their pathophysiology of brain damage.

Eligibility
Participation Requirements
Sex: All
Minimum Age: 7
Maximum Age: 50
Healthy Volunteers: t
View:

• 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

• Ability to undergo MRI without sedation

• Ages 7 - 50 years

• Ability to provide informed consent or assent to the procedures

• Healthy controls (age and gender matched)

• Males and females with a UCD who are having an acute metabolic crisis, with ammonia levels between 100-300 µM

• 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

• Age range 7-30 years

• Able to undergo neuroimaging safely (i.e. without ferromagnetic devices)

• Sexually active female of childbearing potential must agree to urine pregnancy test

• Admitted to the hospital for treatment of HA at one of the 4 sites for this study

• Can be subjects who were originally enrolled in aim 1 who then have HA (they will cross over to aim 2)

• Confirmed diagnosis of arginosuccinate ASSD, and ASLD by genotype and/or enzyme analysis or healthy age and gender matched control

• Ability to undergo MRI without sedation

• Age 7 - 30 years

• Able to provide informed consent or assent to the procedures

Locations
United States
Washington, D.c.
Children's Research Institute
RECRUITING
Washington D.c.
Contact Information
Primary
Andrea L Gropman, M.D.
agropman@childrensnational.org
202-476-3511
Backup
Andrea L. Gropman, M.D.
202-476-3511
Time Frame
Start Date: 2016-08
Estimated Completion Date: 2025-12
Participants
Target number of participants: 56
Treatments
OTCD participants
Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD who can undergo MRI and behavioral testing
Normal controls
Healthy males or females without known medical or metabolic disorder (control group) who can undergo MRI and behavioral testing
HA recovery group
Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD or participants with CPS-1 who have had a recent hyperammonemic episode who can undergo MRI and behavioral testing
Distal UCD
Males and females with ASSD and ASLD who can undergo MRI and behavioral testing
Authors
Susan Waisbren, Gerard Berry
Sponsors
Leads: Children's National Research Institute
Collaborators: Boston Children's Hospital

This content was sourced from clinicaltrials.gov

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