Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders

Conditions

• Urea Cycle Disorders

Eligibility Criteria

Sex

ALL

Age

7 Years - 50 Years

Healthy Volunteers

Accepted

Interventions

• MRI — PROCEDURE
  MRI, fMRI, 1H MRS, DTI
• Behavioral — BEHAVIORAL
  Battery of executive function tasks

Study Details

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.

Key Dates

Start date

Aug 31, 2016

Status verified

Jun 2024

Primary completion

Jul 31, 2025

Completion

Dec 31, 2025

Study Design

Enrollment

56 participants (estimated)

Arms

• Arm: OTCD participants
  Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD who can undergo MRI and behavioral testing
• Arm: Normal controls
  Healthy males or females without known medical or metabolic disorder (control group) who can undergo MRI and behavioral testing
• Arm: 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
• Arm: Distal UCD
  Males and females with ASSD and ASLD who can undergo MRI and behavioral testing

Primary Outcome Measure

Change in Concentration of Glutamine and Myoinositol by MRS [ Time Frame: baseline and 2year follow up ]

Central Contacts

• Andrea L Gropman, M.D.
  202-476-3511
  [email protected]
• Andrea L. Gropman, M.D.
  202-476-3511

Locations (1)

Find similar trials in Washington D.C., DC

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