PCORI Urea Cycle Disorder Study
PCORI Urea Cycle Disorder Study
Urea cycle disorders (UCD) are genetic disorders caused by the liver's inability to break
 down ammonia from proteins; ammonia then accumulates and is toxic to the brain. UCD cause
 brain damage and intellectual and developmental disabilities and even death.

 Treatment for UCD is either conservative management which involves a low-in-protein diet,
 drugs, and amino acid supplements or liver transplantation; each carries their own risks.

 This study aims to help patients to make the decision about different management alternatives
 by providing them with scientific information that is currently lacking.

 Aim 1 of this study will compare survival, neurocognitive function, and patient-reported
 quality of life.
Urea cycle disorders (UCD) are genetic disorders caused by the liver's inability to break
 down ammonia from proteins; ammonia then accumulates and is toxic to the brain. UCD cause
 brain damage and intellectual and developmental disabilities and even death.

 Treatment involves a special diet low in protein, drugs that help metabolize ammonia and
 amino acid supplements (conservative management). Many patients and families choose liver
 transplantation rather than conservative treatment; both alternatives are effective in
 reducing or normalizing blood ammonia. While liver transplantation eliminates the ammonia
 problem, conservative management does so only temporarily and in many patients, blood ammonia
 can rise during an infection.

 The long-term objective of this study is to help patients make decisions about management
 alternatives (conservative vs. liver transplantation) by providing them with scientific
 information that is currently lacking. The questions the investigators will address are:

 1. What is the disease's risk of mortality and illness in the two treatment approaches?

 2. What can parents expect in terms of the development of their child and his/her school
 performance?

 3. What are the expected effects of each treatment on short-term and long-term quality of
 life?

 The investigators will use statistical methods to compare numbers or percentages of survival,
 illness, psychological testing for IQ, executive function, memory, behaviors, and quality of
 life among patients that choose conservative management and those who have chosen liver
 transplantation. Some of this information is already being collected by the Urea Cycle
 Disorders Consortium (UCDC) in 14 metabolic clinics (11 of them in the US) as part of its
 long-term follow-up study. To ensure that the information the investigators analyze is
 representative of the UCD patient population in the US, the investigators will also obtain
 data from the Studies of Pediatric Liver Transplantation (SPLIT) registry, which collects
 information about children who undergo liver transplantation for many different diseases
 (including UCD).

 The National Urea Cycle Disorders Foundation (NUCDF) and the Patients' Research Working Group
 collaborated with the clinical investigators to design this research and to ensure that it
 that it covers the questions that are most important to patients and their families. The
 results of this study will be disseminated to patients, their doctors, and clinical staff so
 they receive current, validated information before making a decision about the best treatment
 for them.
Inclusion Criteria:

 Aim 1 (UCD patients):

 -  Age 18 and under

 -  Diagnosed with the following Neonatal-type urea cycle disorders:

 -  CPSD, OTCD, ASD or ALD, as defined as follows:

 -  Diagnosis of CPS I deficiency, defined as decreased (less than 20 % of control)
 CPS I enzyme activity in liver, and/or an identified pathogenic mutation, and/or
 hyperammonemia and first-degree relative meets at least one of the criteria for
 CPS I deficiency

 -  Diagnosis of OTC deficiency, defined as the identification of a pathogenic
 mutation, and/or less than 20% of control of OTC activity in the liver, and/or
 elevated urinary orotate (greater than 20 uM/mM) in a random urine sample or
 after allopurinol challenge test, and/or hyperammonemia and first degree relative
 meets at least one of the criteria for OTC deficiency

 -  Diagnosis of AS deficiency (Citrullinemia), defined as a greater than or equal to
 10-fold elevation of citrulline in plasma, and/or decreased (less than 20% of
 control) AS enzyme activity in cultured skin fibroblasts or other appropriate
 tissue, and/or identification of a pathogenic mutation in the AS gene, and/or
 hyperammonemia and first degree relative meets at least one of the criteria for
 AS Deficiency

 -  Diagnosis of AL deficiency (Argininosuccinic Aciduria, ASA), defined as the
 presence of argininosuccinic acid in the blood or urine, and/or decreased (less
 than 20% of control) AL enzyme activity in cultured skin fibroblasts or other
 appropriate tissue, and/or identification of a pathogenic mutation in the AL
 gene, and/or hyperammonemia and first degree relative meets at least one of the
 criteria for AL Deficiency

 -  Willing to participate in at least 1 neurocognitive assessment and 1 quality of life
 assessment

 -  Permit access to medical records and medical providers

 Exclusion Criteria:

 Aim 1:

 -  Rare and unrelated comorbidities (e.g., Down's syndrome, intraventricular hemorrhage
 in the newborn period, and extreme prematurity)